Clinical and Experimental Dermatology 1992; 17: 169-172.
Skin conditions in epileptics E.SWART AND J.DE V.LOCHNER* Department of Dermatology and *Department of Medical Biochemistry, Tygerberg Hospital, University of Stellenbosch, South Africa Accepted for publication 13 August 1991
Summary
Methods
The prevalence of skin and mucous membrane conditions occurring in 173 epileptics between the ages of 6 and 19 years was compared with that of an age-matched group of 211 non-epileptics. The most frequently used anticonvulants, singly or in combination, were carbamazepine in 54 9%, phenytoin in 47-8%, barbiturates in 36-6% and ethosuximide in 11-2% of epileptics. The most frequent combination was phenytoin and carbamazepine in 14% of the males and 18-4% of the females. An increased prevalence of aene was found in epileptic females; 8O-3*!'() compared to 30 2% in non-epilepric females. Hirsutism was found in 43 9% ofthe female epileptics compared to 7-5% of the non-epileptic females. Of interest was the finding of punctate and linear scars on the dorsum of the hands of 27-7% epileptics compared to 3-8% non-epileptics. Both ephilides and naevocellular naevi occurred in 12 7% of the epileptics compared to 29 4% and 52-1% respectively ofthe non-epileptics. Leukonychia was also found more frequently in epileptics than in non-epileptics; 52% and 289% respectively.
One hundred and seventy-three residents of the Jan Kriel School for Epileptics, in Kuilsriver, Republic of South Africa, suffering from grand mal epilepsy and 211 nonepileptics were screened for any skin and mucous membrane lesions as well as for any other conditions known to be associated with epilepsy. Both groups were Caucasians and the epileptics participated in all the usual outdoor activities of non-institutionalized children. The n on-epileptics attended school and lived in the same town as the epileptics. The study included 107 male and 66 female epileptics and 105 male and 106 female non-epileptics. Their ages ranged from 6 to 19 years.
Walshe' did a survey of the skin and mucous membrane lesions of 502 residents of Chalfont Centre for Epilepsy in Buckinghamshire. These included 361 (71 9%) patients over the age of 30 years. A similar survey was carried out among 173 residents ofthe Jan Kriel School for Epileptics in Kuilsriver, Republic of South Africa. Their ages ranged from 6 to 19 years. As a combination of these two age groups may give a better overall picture of the more prevalent skin conditions found in epileptics, we are presenting our data. Walshe' found an incidence of ZS% acne and 32 6% hirsutism in epileptics, which she felt was raised but Greenwood et al} detected clinical evidence of acne in only 4 5% of 240 epileptics compared to 13 3% in a control group of 2176 non-epileptics ranging from 16 to 70 years-of-age. The present study was therefore also undertaken to estimate the prevalence of the above two conditions at the Jan Kriel School for Epileptics.
Results The most frequently prescribed anti-convulsants used singly or in combinations were carbamazepine in 54-9% of cases, phenytoin in 47-8%, barbiturates in 36-6% and ethosuximide in 11-2%. The most common combination was carbamazepine and phenytoin in 15-9% of cases (14% ofthe males and 18 4% ofthe females). Table 1 compares the percentages ofthe most frequent skin conditions found in the epileptics and non-epileptics. Non-dermatologicai conditions found in the 173 epileptics were diabetes mellitus in one boy, gynaecomastia infiveboys and early sexual development in two boys and six girls. Two girls had spina bifida. Discussion A variety of anticonvulsants were used by the epileptics but the ones more commonly used alone or in combination, were carbamazepine (54-9% ofthe patients), phenytoin (47-8% ofthe patients) and barbiturates (36-6% of the patients). The most frequent combination used was carbamazepine plus phenytoin (15 9% ofthe patients). Skin conditions occurring in the normal population were seen but ones which are known to be associated with epilepsy were rare. Only one case of epiloia was seen but none of Sturge-Weber syndrome or Von Recklinghausen's disease. Special note was taken of conditions which could result 169
170
E.SWART AND J.DE V.LOCHNER Table 1. Epileptics
Non-epileptics
Acne Cafe au lait spots Ephilides Hirsutism Hypertrophy of the gums Leukonvchia Linear scars oti the hands Cellular naevi Papular urticaria Tinea pedis Verruca vulgaris and plane
Total
We
Female
Total
Male
Fetnale
29-5
30-2 3-8 321 7-5 027-4 1-9 396 11'3 0' 18-9
299 71 29-4 7-5 0-5 28-9 3'8 52-1 9-0 0-5 18-5
39-2 6'5 149 Not evaluated
80-3'^"^ 12-1 90'^'^ 43-9*'^* 4Q.9*.. 515'^ 36-3'^" 21-2'^ 3-0
54.giiix
21.4XXX
4f{.Q.X>:
3I.7XXX
140
181
15-6
26-7 Not evaluatecI 0-9 30-5 5-7 64-8 67 0-9 18-1
from an androgenic effect. Acne occurred in 54 9% ofthe epileptics (39-2% males and 80-3% females) compared to 29-9% of the non-epileptics (29-5% males and 30-2% females). There is, therefore, an increased prevalence of acne in epileptic females. Data obtained by Cunliffe'' in the period 1950-1975 showed a peak incidence of clinical acne in 30% of females and 20% of males at the age of 18 years. Ebling and Rook"^ state that some papules and pustules are present in 30-50% of all boys between the ages of 16 and 19 years and in girls between 14 and 17 years. Walshe' investigated 502 epileptics between the ages of 11 and 16 years and found acne in 39 3% ofthe males and 264% ofthe females. In the present study, grade I aene was present in 36 (85-7%) ofthe 42 boys with acne and in 41 (78-9%) ofthe 53 girls with acne. Grade II was present in six (14-3%) of the 42 boys with acne and in 11 (21-2%) ofthe 53 girls with acne. Grades III and IV did not occur in any ofthe epileptic groups. Greenwood et al.^ also did not find any difference in severity of acne in epileptics and nonepileptics taking anticonvulsants. In the present study, 83-3% ofthe grade I and 65 5% ofthe grade II acne patients received hydantoin alone or in combination and barbiturates alone or in combination, in 77-7% ofthe grade I and 517% ofthe grade II acne patients. Carbamazepine was used in 44 4% ofthe grade I acne patients and in 62% of the grade II acne patients. Hydantoin, barbiturates and carbamazepine may therefore have eontributed to the development of acne in the female patients. The administration of phenobarbitone, phenytoin and cabamazepine causes a rise in the plasma sex-hormone binding globulin in both sexes but the bound testosterone in men only (Barragry et al.)." These authors state that the regulation of the production of
43.9XXX
52-3'"' 22-4'"^ 0-9
8'6 127'^^ 43-9 42, 7*" 52-0'"' 27.7X.. 12-7''" 17**
testosterone in females differs from that in males and that it is therefore not surprising that anticonvulsive drugs cause different effects in females. Hirsutism occurred in 7 5% of the non-epileptic females and in 43 9% ofthe epileptic females. Hydantoin alone or in combination, was used in 93-1% ofthe hirsute epileptic females, barbiturates, alone or in combination, in 517% and carbamazepine, alone or in combination, in 62%. Hydantoin therefore seems to have played a more important causative role in the hirsutism. Hypertrophy of the gums occurred in 42-7% of the epileptics and in only 0 5% of the non-epileptics. Although the reported incidence varies markedly, Hassel*" agrees that it is about 50%). A hitherto unreported finding was the significantly increased prevalence of punctate and linear scars on the back of the hands (Fig. 1) of the epileptics (27-7%) compared to 3-8% of the non-epileptics. They varied from 1-2 mm punctate to 2 cm x 1 mm linear scars. No excoriations, cuts or wounds were seen and no history of obvious trauma could be elicited. A relationship probably exists between scarring and post-traumatic epilepsy. Hoeppner et al.^ found an increased prevalence of the simultaneous occurrence of keioids and post-traumatic epilepsy in a small group of patients and thought that there may be a genetically determined mechanism controlling the formation of scar tissue. Penfield and Jasper^ showed that meningo-cerebral scarring which often follows cerebral trauma is due to the invasion of fibroblasts of mesodermal origin which contract and distort the neural architecture leading to epileptic seizures. Early'^ found that palmar fibromatosis (Dupuytren's contracture) which is also a genetically determined condition, occurred more frequently in epileptics. It is
SKIN CONDITIONS IN EPTLEPTTCS
Figure 1. Einear scars on the dorsum ofthe hands.
often severe, bilateral and often associated with other fibromatous abnormalities. Another significant finding is the occurrence of leukonychia punctata and striata in 52% of the epileptics (52 3%, males and 515% females) compared to 28-9% of the non-epileptics (30-5% males and 274% females). The prevalence of leukonychia in the normal population is given as 1% for the punctate and 0 4 % for the striata varieties by de Nicola et al.^^ Michell" found that leukonychia was due to the presence of keratohyalin granules in the cytoplasm of parakeratotic cells. Simpson'^ found a lowered serum calcium in several cases of leukonychia and postulated that this led to hyperexcitability and irritability of the central and peripheral nervous systems w irh resultant vascular spasms causing parakeratosis in the nail matrix. Hassell'^ mentions that phenytoin limits calcium flux across cell membranes and its absorption from the bowel and Richens and Rowe''^ found lowered serum calcium levels in 22-5% of epileptics receiving multiple drug therapy. It therefore seems possible that this hypercalcaemia may lead to the development of leukonychia. Laidlaw et al.^'^ also states that
171
massive activation of both the sympathetic and parasympathetic systems occur during generalized tonic seizures and that skin vasoconstriction takes place. One might therefore postulate that if this also occurs in the arterioles of the nail matrix it may lead to parakeratosis and therefore leukonychia. A surprising finding is the significantly decreased prevalence of naevocellular naevi and ephilides in the epileptics, 12 7% in both cases compared to 52-1% and 29-4% in the non-epileptics. Tt was especially the epileptic boys who showed a decreased prevalence of naevocellular naevi, 74"^^ compared to 21 2% for the girls. There is, however, such a great variation in the prevalence of naevocellar naevi and ephilides in normal individuals due to genetic factors, race and age that the decreased prevalence found in epileptics cannot be summarily ascribed to epilepsy or the anticonvulsant drugs. As the epileptics were exposed to the same outdoor activities as the non-epileptics, ultraviolet exposure cannot totally be held responsible for this discrepancy. The increased prevalence of tinea pedis found in the epileptics (31-7% compared to 0-5%) is no surprise as they were all residents in the same institution. From this study it can be concluded that the hirsutism, hypertrophy of the gums, leukonychia and punctate and linear scars occurring more frequently in the epileptics may be related to the epilepsy and/or the anticonvulsants. Although acne was found more frequently in the epileptics the incidence was statistically increased in only the females. The drugs which played a more important role are carbamazepine, phenytoin and barbiturates.
References 1. Walshe MM. Cutaneous drug effects in epilepsy. Transactions of St. John's Hospital Dermatotogicat Society 1972; 5: 269 281, 2. Greenwood R, Fenwick PRC, Cunliffe WJ. Acne and anriconvulsants. Britisb Medieat Journat 1983; 287: 1669-1670, 3. Cunliffe WJ, Acne. Martin Dunitz, 1989: 2-3. 4. Ehling FJG, Rook AJ. Rook k], Wilkinson DS, Ebling FJG. et at. eds. Textbook of Dermatotogy, 4th edn, Oxford: Blackwell Scientific Puhlications. 1986: 1914. 5. Uarragry jU, Makin HLJ, Trafford DJH. Effect of anticonvulsants on plasma testosterone and sex hormone binding globulin levels. Journat of Neurological Neurosurgery and Psyeliiatrv 197841:913-914. , , 6. Hassell TM. Monographs in oral seience. In: Karger S, ed. Epilepsy and lhe Oral Manifestations of Phenyioin Vol 9 Basel 1981: 127. 7. Hoeppner T, Morreli F. Hoeppner JA, Skin scarring and epilepsy. Etectroencephatography and Ctinicat Neurophysiotosy 1973; 34: 728-729, 8. Penfield W, Jasper H, Epitepsy and the Eunetionat Anatomy ofthe Human Brain. London, J, A, Churehill Ltd, 1954: 310-317. 9. Early PF. Population sttidies in Dupuytren's contracture,>Mr«a/ of Bone and Join! Surgery 1962; 44B: 602-613, 10, dc Nicola P, Morsiani G, Zavagli G, \'ail disease m internal medicine. Charles C, Thomas, 1974; 51-52.
172
E.SWART AND J.DE V.LOCHNER
11. Mitchell JC. A clinical study of leukonychia. British Journal of 14. Richens A, Rowe DJF. Disturbance of calcium metabolism by Dermatology 1953; 65: 121-130. anticonvulsant drugs. British Medical Journat 1970; 4:13-lb. 12. Simpson JA. Dermatological cbanges in hypocalcaemia. British 15, Eaidlaw J, Richens A, OxIeyJ. A Textbook of Epilepsy, 3rd edn. Journal of Dermatology 1954; 66: 1-15. Churchill Livingstone, 1988; 222. 13. [lassell TM. Monographs in oral science. In: Kaegel S. ed. Epilepsy and the Oral Manifestations of Phenytoin, Vol 9. Basel, 1981; 74-90.
Skin conditions in epileptics E.SWART AND J.DE V.LOCHNER* Department of Dermatology and *Department of Medical Biochemistry, Tygerberg Hospital, University of Stellenbosch, South Africa Accepted for publication 13 August 1991
Summary
Methods
The prevalence of skin and mucous membrane conditions occurring in 173 epileptics between the ages of 6 and 19 years was compared with that of an age-matched group of 211 non-epileptics. The most frequently used anticonvulants, singly or in combination, were carbamazepine in 54 9%, phenytoin in 47-8%, barbiturates in 36-6% and ethosuximide in 11-2% of epileptics. The most frequent combination was phenytoin and carbamazepine in 14% of the males and 18-4% of the females. An increased prevalence of aene was found in epileptic females; 8O-3*!'() compared to 30 2% in non-epilepric females. Hirsutism was found in 43 9% ofthe female epileptics compared to 7-5% of the non-epileptic females. Of interest was the finding of punctate and linear scars on the dorsum of the hands of 27-7% epileptics compared to 3-8% non-epileptics. Both ephilides and naevocellular naevi occurred in 12 7% of the epileptics compared to 29 4% and 52-1% respectively ofthe non-epileptics. Leukonychia was also found more frequently in epileptics than in non-epileptics; 52% and 289% respectively.
One hundred and seventy-three residents of the Jan Kriel School for Epileptics, in Kuilsriver, Republic of South Africa, suffering from grand mal epilepsy and 211 nonepileptics were screened for any skin and mucous membrane lesions as well as for any other conditions known to be associated with epilepsy. Both groups were Caucasians and the epileptics participated in all the usual outdoor activities of non-institutionalized children. The n on-epileptics attended school and lived in the same town as the epileptics. The study included 107 male and 66 female epileptics and 105 male and 106 female non-epileptics. Their ages ranged from 6 to 19 years.
Walshe' did a survey of the skin and mucous membrane lesions of 502 residents of Chalfont Centre for Epilepsy in Buckinghamshire. These included 361 (71 9%) patients over the age of 30 years. A similar survey was carried out among 173 residents ofthe Jan Kriel School for Epileptics in Kuilsriver, Republic of South Africa. Their ages ranged from 6 to 19 years. As a combination of these two age groups may give a better overall picture of the more prevalent skin conditions found in epileptics, we are presenting our data. Walshe' found an incidence of ZS% acne and 32 6% hirsutism in epileptics, which she felt was raised but Greenwood et al} detected clinical evidence of acne in only 4 5% of 240 epileptics compared to 13 3% in a control group of 2176 non-epileptics ranging from 16 to 70 years-of-age. The present study was therefore also undertaken to estimate the prevalence of the above two conditions at the Jan Kriel School for Epileptics.
Results The most frequently prescribed anti-convulsants used singly or in combinations were carbamazepine in 54-9% of cases, phenytoin in 47-8%, barbiturates in 36-6% and ethosuximide in 11-2%. The most common combination was carbamazepine and phenytoin in 15-9% of cases (14% ofthe males and 18 4% ofthe females). Table 1 compares the percentages ofthe most frequent skin conditions found in the epileptics and non-epileptics. Non-dermatologicai conditions found in the 173 epileptics were diabetes mellitus in one boy, gynaecomastia infiveboys and early sexual development in two boys and six girls. Two girls had spina bifida. Discussion A variety of anticonvulsants were used by the epileptics but the ones more commonly used alone or in combination, were carbamazepine (54-9% ofthe patients), phenytoin (47-8% ofthe patients) and barbiturates (36-6% of the patients). The most frequent combination used was carbamazepine plus phenytoin (15 9% ofthe patients). Skin conditions occurring in the normal population were seen but ones which are known to be associated with epilepsy were rare. Only one case of epiloia was seen but none of Sturge-Weber syndrome or Von Recklinghausen's disease. Special note was taken of conditions which could result 169
170
E.SWART AND J.DE V.LOCHNER Table 1. Epileptics
Non-epileptics
Acne Cafe au lait spots Ephilides Hirsutism Hypertrophy of the gums Leukonvchia Linear scars oti the hands Cellular naevi Papular urticaria Tinea pedis Verruca vulgaris and plane
Total
We
Female
Total
Male
Fetnale
29-5
30-2 3-8 321 7-5 027-4 1-9 396 11'3 0' 18-9
299 71 29-4 7-5 0-5 28-9 3'8 52-1 9-0 0-5 18-5
39-2 6'5 149 Not evaluated
80-3'^"^ 12-1 90'^'^ 43-9*'^* 4Q.9*.. 515'^ 36-3'^" 21-2'^ 3-0
54.giiix
21.4XXX
4f{.Q.X>:
3I.7XXX
140
181
15-6
26-7 Not evaluatecI 0-9 30-5 5-7 64-8 67 0-9 18-1
from an androgenic effect. Acne occurred in 54 9% ofthe epileptics (39-2% males and 80-3% females) compared to 29-9% of the non-epileptics (29-5% males and 30-2% females). There is, therefore, an increased prevalence of acne in epileptic females. Data obtained by Cunliffe'' in the period 1950-1975 showed a peak incidence of clinical acne in 30% of females and 20% of males at the age of 18 years. Ebling and Rook"^ state that some papules and pustules are present in 30-50% of all boys between the ages of 16 and 19 years and in girls between 14 and 17 years. Walshe' investigated 502 epileptics between the ages of 11 and 16 years and found acne in 39 3% ofthe males and 264% ofthe females. In the present study, grade I aene was present in 36 (85-7%) ofthe 42 boys with acne and in 41 (78-9%) ofthe 53 girls with acne. Grade II was present in six (14-3%) of the 42 boys with acne and in 11 (21-2%) ofthe 53 girls with acne. Grades III and IV did not occur in any ofthe epileptic groups. Greenwood et al.^ also did not find any difference in severity of acne in epileptics and nonepileptics taking anticonvulsants. In the present study, 83-3% ofthe grade I and 65 5% ofthe grade II acne patients received hydantoin alone or in combination and barbiturates alone or in combination, in 77-7% ofthe grade I and 517% ofthe grade II acne patients. Carbamazepine was used in 44 4% ofthe grade I acne patients and in 62% of the grade II acne patients. Hydantoin, barbiturates and carbamazepine may therefore have eontributed to the development of acne in the female patients. The administration of phenobarbitone, phenytoin and cabamazepine causes a rise in the plasma sex-hormone binding globulin in both sexes but the bound testosterone in men only (Barragry et al.)." These authors state that the regulation of the production of
43.9XXX
52-3'"' 22-4'"^ 0-9
8'6 127'^^ 43-9 42, 7*" 52-0'"' 27.7X.. 12-7''" 17**
testosterone in females differs from that in males and that it is therefore not surprising that anticonvulsive drugs cause different effects in females. Hirsutism occurred in 7 5% of the non-epileptic females and in 43 9% ofthe epileptic females. Hydantoin alone or in combination, was used in 93-1% ofthe hirsute epileptic females, barbiturates, alone or in combination, in 517% and carbamazepine, alone or in combination, in 62%. Hydantoin therefore seems to have played a more important causative role in the hirsutism. Hypertrophy of the gums occurred in 42-7% of the epileptics and in only 0 5% of the non-epileptics. Although the reported incidence varies markedly, Hassel*" agrees that it is about 50%). A hitherto unreported finding was the significantly increased prevalence of punctate and linear scars on the back of the hands (Fig. 1) of the epileptics (27-7%) compared to 3-8% of the non-epileptics. They varied from 1-2 mm punctate to 2 cm x 1 mm linear scars. No excoriations, cuts or wounds were seen and no history of obvious trauma could be elicited. A relationship probably exists between scarring and post-traumatic epilepsy. Hoeppner et al.^ found an increased prevalence of the simultaneous occurrence of keioids and post-traumatic epilepsy in a small group of patients and thought that there may be a genetically determined mechanism controlling the formation of scar tissue. Penfield and Jasper^ showed that meningo-cerebral scarring which often follows cerebral trauma is due to the invasion of fibroblasts of mesodermal origin which contract and distort the neural architecture leading to epileptic seizures. Early'^ found that palmar fibromatosis (Dupuytren's contracture) which is also a genetically determined condition, occurred more frequently in epileptics. It is
SKIN CONDITIONS IN EPTLEPTTCS
Figure 1. Einear scars on the dorsum ofthe hands.
often severe, bilateral and often associated with other fibromatous abnormalities. Another significant finding is the occurrence of leukonychia punctata and striata in 52% of the epileptics (52 3%, males and 515% females) compared to 28-9% of the non-epileptics (30-5% males and 274% females). The prevalence of leukonychia in the normal population is given as 1% for the punctate and 0 4 % for the striata varieties by de Nicola et al.^^ Michell" found that leukonychia was due to the presence of keratohyalin granules in the cytoplasm of parakeratotic cells. Simpson'^ found a lowered serum calcium in several cases of leukonychia and postulated that this led to hyperexcitability and irritability of the central and peripheral nervous systems w irh resultant vascular spasms causing parakeratosis in the nail matrix. Hassell'^ mentions that phenytoin limits calcium flux across cell membranes and its absorption from the bowel and Richens and Rowe''^ found lowered serum calcium levels in 22-5% of epileptics receiving multiple drug therapy. It therefore seems possible that this hypercalcaemia may lead to the development of leukonychia. Laidlaw et al.^'^ also states that
171
massive activation of both the sympathetic and parasympathetic systems occur during generalized tonic seizures and that skin vasoconstriction takes place. One might therefore postulate that if this also occurs in the arterioles of the nail matrix it may lead to parakeratosis and therefore leukonychia. A surprising finding is the significantly decreased prevalence of naevocellular naevi and ephilides in the epileptics, 12 7% in both cases compared to 52-1% and 29-4% in the non-epileptics. Tt was especially the epileptic boys who showed a decreased prevalence of naevocellular naevi, 74"^^ compared to 21 2% for the girls. There is, however, such a great variation in the prevalence of naevocellar naevi and ephilides in normal individuals due to genetic factors, race and age that the decreased prevalence found in epileptics cannot be summarily ascribed to epilepsy or the anticonvulsant drugs. As the epileptics were exposed to the same outdoor activities as the non-epileptics, ultraviolet exposure cannot totally be held responsible for this discrepancy. The increased prevalence of tinea pedis found in the epileptics (31-7% compared to 0-5%) is no surprise as they were all residents in the same institution. From this study it can be concluded that the hirsutism, hypertrophy of the gums, leukonychia and punctate and linear scars occurring more frequently in the epileptics may be related to the epilepsy and/or the anticonvulsants. Although acne was found more frequently in the epileptics the incidence was statistically increased in only the females. The drugs which played a more important role are carbamazepine, phenytoin and barbiturates.
References 1. Walshe MM. Cutaneous drug effects in epilepsy. Transactions of St. John's Hospital Dermatotogicat Society 1972; 5: 269 281, 2. Greenwood R, Fenwick PRC, Cunliffe WJ. Acne and anriconvulsants. Britisb Medieat Journat 1983; 287: 1669-1670, 3. Cunliffe WJ, Acne. Martin Dunitz, 1989: 2-3. 4. Ehling FJG, Rook AJ. Rook k], Wilkinson DS, Ebling FJG. et at. eds. Textbook of Dermatotogy, 4th edn, Oxford: Blackwell Scientific Puhlications. 1986: 1914. 5. Uarragry jU, Makin HLJ, Trafford DJH. Effect of anticonvulsants on plasma testosterone and sex hormone binding globulin levels. Journat of Neurological Neurosurgery and Psyeliiatrv 197841:913-914. , , 6. Hassell TM. Monographs in oral seience. In: Karger S, ed. Epilepsy and lhe Oral Manifestations of Phenyioin Vol 9 Basel 1981: 127. 7. Hoeppner T, Morreli F. Hoeppner JA, Skin scarring and epilepsy. Etectroencephatography and Ctinicat Neurophysiotosy 1973; 34: 728-729, 8. Penfield W, Jasper H, Epitepsy and the Eunetionat Anatomy ofthe Human Brain. London, J, A, Churehill Ltd, 1954: 310-317. 9. Early PF. Population sttidies in Dupuytren's contracture,>Mr«a/ of Bone and Join! Surgery 1962; 44B: 602-613, 10, dc Nicola P, Morsiani G, Zavagli G, \'ail disease m internal medicine. Charles C, Thomas, 1974; 51-52.
172
E.SWART AND J.DE V.LOCHNER
11. Mitchell JC. A clinical study of leukonychia. British Journal of 14. Richens A, Rowe DJF. Disturbance of calcium metabolism by Dermatology 1953; 65: 121-130. anticonvulsant drugs. British Medical Journat 1970; 4:13-lb. 12. Simpson JA. Dermatological cbanges in hypocalcaemia. British 15, Eaidlaw J, Richens A, OxIeyJ. A Textbook of Epilepsy, 3rd edn. Journal of Dermatology 1954; 66: 1-15. Churchill Livingstone, 1988; 222. 13. [lassell TM. Monographs in oral science. In: Kaegel S. ed. Epilepsy and the Oral Manifestations of Phenytoin, Vol 9. Basel, 1981; 74-90.
