Eur J Pediatr (1992) 151 : 69-72
European Journal of
Pediatrics
9 Springer-Verlag 1992
A case of tubulo-interstitial nephritis with exfoliative dermatitis and hepatitis due to phenobarbital hypersensitivity Y. Sawaishi, K. Komatsu, O.Takeda, Y. Tazawa, I. Takahashi, K. Hayasaka, and G. Takada Department of Paediatrics, Akita University School of Medicine 1-1-1, Hondo, Akita 010, Japan Received December 12, 1990 / Accepted May 2, 1991
Abstract. S e v e r e exfoliative d e r m a t i t i s a n d liver dysfunction d e v e l o p e d in a 5 - y e a r - o l d girl 3 w e e k s after initiation o f p h e n o b a r b i t a l t h e r a p y . L i v e r f u n c t i o n i m p r o v e d g r a d u a l l y a f t e r d i s c o n t i n u a t i o n of p h e n o b a r b i t a l . D u r i n g t h e c o n v a l e s c e n t s t a g e an initially m i l d r e n a l d y s f u n c t i o n was e x a c e r b a t e d b y e p i s o d e s of p o s t - t r a n s f u s i o n h a e m o lysis. L i v e r b i o p s y r e v e a l e d m o d e r a t e p a r e n c h y m a l d a m age with s u b a c u t e cellular infiltration. R e n a l b i o p s y d e m o n s t r a t e d t h e c a r d i n a l findings of i n t e r s t i t i a l n e p h r i t i s , excluding the possibility of acute tubular necrosis caused by h a e m o l y s i s . Serial l y m p h o c y t e t r a n s f o r m a t i o n studies a n d skin p a t c h tests gave p o s i t i v e results for p h e n o b a r b i tal, s u p p o r t i n g t h e view t h a t t h e s e w e r e u n u s u a l c o m p l i cations of phenobarbital hypersensitivity.
Key words: P h e n o b a r b i t a l - I n t e r s t i t i a l n e p h r i t i s - T o x i c hepatitis - Exfoliative dermatitis
Introduction P h e n o b a r b i t a l has b e e n w i d e l y u s e d as an e x c e l l e n t antic o n v u l s a n t b e c a u s e o f its effectiveness a n d safety. H o w ever, s e v e r e e x f o l i a t i v e d e r m a t i t i s a n d l e t h a l h e p a t i c failu r e h a v e b e e n d e s c r i b e d i n f r e q u e n t l y in p a t i e n t s receiving p h e n o b a r b i t a l [ 6 - 8 , 11, 12]. I n t e r s t i t i a l n e p h r i t i s , an e v e n m o r e u n c o m m o n a d v e r s e effect [2], d e v e l o p e d in o u r p a t i e n t following s e v e r e e x f o l i a t i v e d e r m a t i t i s a n d liver d y s f u n c t i o n .
Case report A 5-year-old Japanese girl without allergic diathesis had two episodes of afebrile generalized convulsions and was treated with phenobarbital (4mg/kg per day). Approximately 3 weeks later, she developed intermittent high fever, generalized erythematous rash, and oedematous swelling of the face and limbs. She was admitted to a near by hospital and received intravenous administraOffprint requests to: Y. Sawaishi
tion of piperaciltin (120 mg/kg per day) for 4 days without any effect. On suspicion of a drug-induced toxic dermatitits, phenobarbital was discontinued 9 days after onset. Laboratory tests revealed liver dysfunction (serum aspartate aminotransferase 768 IU/I and serum alanine aminotransferase 682 IU/1). Thirteen days after the onset she was referred to Akita University Hospital. On admission, she was seriously ill with moderate generalized oedema and temperature over 39~ Consciousness was not disturbed. Erythematous maculopapular eruption was generalized and confluent with severe itching (Fig. 1). Perioral and buccal eruption was desquamative. No mucosal inflammation was found and Nikolsky sign was negative. The liver was tender and palpable 12 cm below the costal margin. Splenomegaly and generalized lymphadenopathy were also prominent. Heart sounds were normal and no respiratory rNes were audible. Laboratory investigations gave the following results; C-reactive protein 0.8 mg/dl, haemoglobin 10.4 g/dl, platelet count 153,000/ mm 3, white blood cell count ll,400/mm 3 (32% neutrophils, 48% lymphocytes, 13% monocytes, and 6% eosinophils), serum sodium 138 mmol/1, serum potassium 4.3 mmol/1, serum calcium 1.7 mmol/1 (serum ionized calcium 1.23 mmol/1), blood urea nitrogen 2.1 mmol/l, serum creatinine 35 gmol/1, total protein 4.9 g/dl, albumin 3.1 g/dl, ammonia 47gg/dl, serum aspartate aminotransferase 193IU/1, serum alanine aminotransferase 390IU/1, alkaline phosphatase 729 IU/I, and total serum bilirubin 25 gmol/1. Prothrombin time was 15 s and activated partial thromboplastin time was 48 s. Fibrinogen was decreased (59.8mg/dl: control 200-400) but fibrin degradation products were not increased (3.9 gg/dl: control < 10.0). Immunoglobulins were decreased (IgG 386 mg/dl, IgA 8 mg/dl and IgM 78 mg/dl). Total activity of complement system, CH50, was as low as 12.3 units/ml (control 30.0-40.0). Anti-nuclear antibody titre was not elevated. Mycoplasma titre was normal. Immunological viral studies showed no evidence of acute infection by hepatitis B virus, Ebstein-Barr virus or cytomegalovirus. Serum concentration of phenobarbital was 9.0gg/ml 4 days after withdrawal. Urinalysis showed mild proteinuria with normal sediments. Urinary N-acetyl-~3-D-glucosaminidase was 10.5 units/1 (control < 7.0) and [~2-microglobulin was over 8 000 ~tg/1(control < 250) with slightly elevated serum 132-microglobulin (2.8 gg/l: control < 2.4). Remittent high-grade fever continued over 3 weeks but skin lesions gradually improved resulting in desquamation and subsequent hyperpigmentation. Serum transaminase levels began to decrease gradually after discontinuation of phenobarbital. Haemoglobin level decreased without any sign of haemolysis within a few days after admission. One unit of packed red blood cells was transfused 3 times for 1 week. Thereafter, her course was complicated with episodes of hemolysis due to the development of anti-Rh C
70
Fig. 1. Patient on the 14th day of the disease. Note the severe generalized exfoliative dermatitis
Fig. 2. Microscopic appearance of the liver, showing hydropic hepatocytes and the infiltration of subacute inflammatory cells (H&E, x 200)
and e in I week after the first transfusion. Blood urea nitrogen and serum creatinine began to increase over 2 weeks and reached the maximum values, 82 mg/dl and 4.6 mg/dl, respectively. Urine analysis showed a 3+ reaction for protein (highest level 3.2g/day) and glucose. Significant columnar hyaline bodies were in sediments but no eosinophils. Percutaneous biopsies of the liver and the kindey were performed 40 days after the onset. Liver biopsy (Fig. 2) showed moderate parenchymal damage with diffuse hydropic hepatocytes and evidence of regeneration with slightly disturbed liver cell cords. A moderate infiltration of inflammatory cells, mainly lymphocytes, was seen in the portal areas. There was no intralobular or canalicular choelstasis and no destructive alteration of the reticulum framework. Renal biopsy (Fig. 3) revealed the presence of interstitial oedema and extensive inflammatory infiltration of plasma cells, lymphocytes, and scattered eosinopils. Neutrophils were not observed. Tubular atrophy and degeneration were seen with intratubular cast formation. The
appearance of the glomeruli was relatively normal except for mild diffuse mesangial proliferation. Arterioles appeared normal. Immunofluorescent studies for IgA, IgM, IgE, C3, C4, and fibrin were all negative. Weak staining for IgG was observed in a granular pattern within occasional glomerular mesangial regions. A lymphocyte transformation test for phenobarbital performed on the 9th day of the disease showed a borderline reaction with stimulation index [4], 2.1 (count stimulated with phenobarbital = 513 cpm and blank count = 241cpm), but the subsequent study carried out 4 weeks later indicated a positive reaction with stimulation index, 4.6 (count stimulated with phenobarbital = 2362cpm and blank count = 511cpm). A skin patch test for phenobarbital was negative 48 days after the onset, but 3 months later the test was strongly positive. Liver function continued to improve without any specific treatment. Renal dysfunction lasted over 3 weeks and prednisolone (lmg/kg per day) was administered orally. Following a 4-week
71
Fig. 3. Microscopic appearance of the kidney, showing an interstititial oedema and an extensive inflammatory infiltration (H&E, x 100). Renal tubules were partly degenerated and blood vessels appeared normal
course of prednisolone, renal function improved gradually and returned to normal by 8 weeks. Discussion Allergic reactions to phenobarbital such as exfoliative dermatitis and liver failure are rare [6, 8, 9, 11, 12]. Our patient presented typical clinical symptoms compatible with those of the previously reported cases, i.e. highgrade fever, pruritic skin rash, generalized lymphadenopathy and liver dysfunction after receiving phenobarbital for 4 weeks. Serial investigations of lymphocyte transformation study and skin patch test revealed increasing reactions of phenobarbital, supporting the pathogenic contribution of allergic mechanisms. The levels of Nacetyl-[3-D-glucosaminidase and 132-microglobulin in urine were elevated in the acute phase, indicating the subclinical existence of renal tubular dysfunction. Proteinuria on admission was too mild to explain hypoproteinaemia which might be caused by hyponutrition, liver dysfunction and inflammatory exudation. Hypocalcaemia seemed to be related to hypoproteinaemia and the level of serum ionized calcium was within normal range. Although acute aggravation of renal dysfunction in the convalescent stage of the clinical course seemed to be induced by the episodes of haemolysis, the findings of renal biopsy demonstrated rather typical tubulo-interstitial nephritis, excluding the possibility of haemolytic renal damage which is characterized by acute tubular necrosis with pigmented casts within the tubular lumens [14]. The time lag of 3 weeks between the discontinuation of phenobarbital and the exacerbation of renal function is compatible with those of other reports concerning drug-induced interstitial nephritis [1, 5]. Piperacillin, which was administerd for only 4 days, might be associated with tubulo-interstitial nephritis. However, a series of symptoms started before the treatment with piperacillin and the period of its
administration was too short compared with other reports concerning antibiotic-induced interstitial nephritis [1, 7]. Other anticonvulsants including carbamazepine [3, 10] and diphenylhydantoin [5, 13] have been occasionally reported to induce interstitial nephritis. However, only one report on phenobarbital-induced interstitial nephritis was available in a review of the English [2]. In this case IgE-containing plasma cells were observed in the perivascular area, but in our case no IgE deposits were detected by immunofluorescent studies. The combination of hepatic failure and subsequent renal dysfunction caused by phenobarbital has been only once previously described [15] and the authors did not refer to the pathogenesis of the renal dysfunction. In our case, accidental haemolysis might have precipitated and uncovered the otherwise overlooked mild interstitial nephritis. Indeed, it may be speculated that interstital nephritis may have gone unnoticed in the past because of mild clinical course and lack of precipitating factors.
References 1. Baldwin DS, Levine BB, McCluskey RT, Gallo GR (1968) Renal failure and interstitial nephritis due to penicillin and methicillin. N Engl J Med 279 : 1245-1252 2. Faarup P, Christensen E (1974) IgE-containing plasma cells in acute tubulointerstitial nephropathy. Lancet II : 718 3. Hogg RJ, Sawyer M, Hecox K, Eigenbrodt E (1981) Carbamazepine-induced acute tubulointerstitial nephritis. J Pediatr 98 : 830-832 4. Houwerzijl J, DeGast GC, Nater JP, Esselink MT, Nieweg HO (1977) Lymphocyte-stimulating test and patch tests in carbamazepine hypersensitivity. Clin Exp Immunol 29 : 272-277 5. Hyman LR, Ballow M, Knieser MR (1978) Diphenylhydantoin interstitial nephritis. Roles of cellular and hnmoral immunologic injury. J Pediatr 92 : 915-920 6. Lane T, Peterson EA (1980) Hepatitis is a manifestation of phenobarbital hypersensitivity. South Med J 77 : 94
72 7. Linton AL, Clark WF, Driedger AA, Turnbull DI, Lindsay RM (1980) Acute interstitial nephritis due to drugs. Review of the literature with a report of nine cases. Ann Intern Med 93 : 735-741 8. McGeachy TE, Bloomer WE (1953) The phenobarbital sensitivity syndrome. Am J Med 14 : 600-604 9. Menninger WC (1928) Skin eruptions with phenobarbital. JAMA 91 : 14-18 10. Nicholls DP, Yasin M (1972) Acute renal failure from carbamazepine. BmJ IV: 490 11. Sexton DL, Pike GM, Neilson A (1941) Exfoliative dermatitis and death due to phenobarbital. JAMA 116:700
12. Shapiro PA, Antonioli DA, Peppercorn MA (1980) Barbiturate-induced submassive hepatic necrosis: Report of a case and review of the literature. Am J Gastroenterol 74 : 270-273 13. Sheth KJ, Casper JT, Good T A (1977) Interstitial nephritis due to phenytoin hypersensitivity. J Pediatr 91 : 438-441 14. Tisher CC, Brenner BM (1989) Renal pathology with clinical and functional correlations. JB Lippincott Company, Philadelphia 15. Tomita H, Konno M, Ishikawa N, Kajii N (1987) A case of hepatic failure with exfoliative dermatitis due to phenobarbital hypersensitivity (abstract) Nippon Shonika Gakkai Zasshi 91 : 1465-1471
European Journal of
Pediatrics
9 Springer-Verlag 1992
A case of tubulo-interstitial nephritis with exfoliative dermatitis and hepatitis due to phenobarbital hypersensitivity Y. Sawaishi, K. Komatsu, O.Takeda, Y. Tazawa, I. Takahashi, K. Hayasaka, and G. Takada Department of Paediatrics, Akita University School of Medicine 1-1-1, Hondo, Akita 010, Japan Received December 12, 1990 / Accepted May 2, 1991
Abstract. S e v e r e exfoliative d e r m a t i t i s a n d liver dysfunction d e v e l o p e d in a 5 - y e a r - o l d girl 3 w e e k s after initiation o f p h e n o b a r b i t a l t h e r a p y . L i v e r f u n c t i o n i m p r o v e d g r a d u a l l y a f t e r d i s c o n t i n u a t i o n of p h e n o b a r b i t a l . D u r i n g t h e c o n v a l e s c e n t s t a g e an initially m i l d r e n a l d y s f u n c t i o n was e x a c e r b a t e d b y e p i s o d e s of p o s t - t r a n s f u s i o n h a e m o lysis. L i v e r b i o p s y r e v e a l e d m o d e r a t e p a r e n c h y m a l d a m age with s u b a c u t e cellular infiltration. R e n a l b i o p s y d e m o n s t r a t e d t h e c a r d i n a l findings of i n t e r s t i t i a l n e p h r i t i s , excluding the possibility of acute tubular necrosis caused by h a e m o l y s i s . Serial l y m p h o c y t e t r a n s f o r m a t i o n studies a n d skin p a t c h tests gave p o s i t i v e results for p h e n o b a r b i tal, s u p p o r t i n g t h e view t h a t t h e s e w e r e u n u s u a l c o m p l i cations of phenobarbital hypersensitivity.
Key words: P h e n o b a r b i t a l - I n t e r s t i t i a l n e p h r i t i s - T o x i c hepatitis - Exfoliative dermatitis
Introduction P h e n o b a r b i t a l has b e e n w i d e l y u s e d as an e x c e l l e n t antic o n v u l s a n t b e c a u s e o f its effectiveness a n d safety. H o w ever, s e v e r e e x f o l i a t i v e d e r m a t i t i s a n d l e t h a l h e p a t i c failu r e h a v e b e e n d e s c r i b e d i n f r e q u e n t l y in p a t i e n t s receiving p h e n o b a r b i t a l [ 6 - 8 , 11, 12]. I n t e r s t i t i a l n e p h r i t i s , an e v e n m o r e u n c o m m o n a d v e r s e effect [2], d e v e l o p e d in o u r p a t i e n t following s e v e r e e x f o l i a t i v e d e r m a t i t i s a n d liver d y s f u n c t i o n .
Case report A 5-year-old Japanese girl without allergic diathesis had two episodes of afebrile generalized convulsions and was treated with phenobarbital (4mg/kg per day). Approximately 3 weeks later, she developed intermittent high fever, generalized erythematous rash, and oedematous swelling of the face and limbs. She was admitted to a near by hospital and received intravenous administraOffprint requests to: Y. Sawaishi
tion of piperaciltin (120 mg/kg per day) for 4 days without any effect. On suspicion of a drug-induced toxic dermatitits, phenobarbital was discontinued 9 days after onset. Laboratory tests revealed liver dysfunction (serum aspartate aminotransferase 768 IU/I and serum alanine aminotransferase 682 IU/1). Thirteen days after the onset she was referred to Akita University Hospital. On admission, she was seriously ill with moderate generalized oedema and temperature over 39~ Consciousness was not disturbed. Erythematous maculopapular eruption was generalized and confluent with severe itching (Fig. 1). Perioral and buccal eruption was desquamative. No mucosal inflammation was found and Nikolsky sign was negative. The liver was tender and palpable 12 cm below the costal margin. Splenomegaly and generalized lymphadenopathy were also prominent. Heart sounds were normal and no respiratory rNes were audible. Laboratory investigations gave the following results; C-reactive protein 0.8 mg/dl, haemoglobin 10.4 g/dl, platelet count 153,000/ mm 3, white blood cell count ll,400/mm 3 (32% neutrophils, 48% lymphocytes, 13% monocytes, and 6% eosinophils), serum sodium 138 mmol/1, serum potassium 4.3 mmol/1, serum calcium 1.7 mmol/1 (serum ionized calcium 1.23 mmol/1), blood urea nitrogen 2.1 mmol/l, serum creatinine 35 gmol/1, total protein 4.9 g/dl, albumin 3.1 g/dl, ammonia 47gg/dl, serum aspartate aminotransferase 193IU/1, serum alanine aminotransferase 390IU/1, alkaline phosphatase 729 IU/I, and total serum bilirubin 25 gmol/1. Prothrombin time was 15 s and activated partial thromboplastin time was 48 s. Fibrinogen was decreased (59.8mg/dl: control 200-400) but fibrin degradation products were not increased (3.9 gg/dl: control < 10.0). Immunoglobulins were decreased (IgG 386 mg/dl, IgA 8 mg/dl and IgM 78 mg/dl). Total activity of complement system, CH50, was as low as 12.3 units/ml (control 30.0-40.0). Anti-nuclear antibody titre was not elevated. Mycoplasma titre was normal. Immunological viral studies showed no evidence of acute infection by hepatitis B virus, Ebstein-Barr virus or cytomegalovirus. Serum concentration of phenobarbital was 9.0gg/ml 4 days after withdrawal. Urinalysis showed mild proteinuria with normal sediments. Urinary N-acetyl-~3-D-glucosaminidase was 10.5 units/1 (control < 7.0) and [~2-microglobulin was over 8 000 ~tg/1(control < 250) with slightly elevated serum 132-microglobulin (2.8 gg/l: control < 2.4). Remittent high-grade fever continued over 3 weeks but skin lesions gradually improved resulting in desquamation and subsequent hyperpigmentation. Serum transaminase levels began to decrease gradually after discontinuation of phenobarbital. Haemoglobin level decreased without any sign of haemolysis within a few days after admission. One unit of packed red blood cells was transfused 3 times for 1 week. Thereafter, her course was complicated with episodes of hemolysis due to the development of anti-Rh C
70
Fig. 1. Patient on the 14th day of the disease. Note the severe generalized exfoliative dermatitis
Fig. 2. Microscopic appearance of the liver, showing hydropic hepatocytes and the infiltration of subacute inflammatory cells (H&E, x 200)
and e in I week after the first transfusion. Blood urea nitrogen and serum creatinine began to increase over 2 weeks and reached the maximum values, 82 mg/dl and 4.6 mg/dl, respectively. Urine analysis showed a 3+ reaction for protein (highest level 3.2g/day) and glucose. Significant columnar hyaline bodies were in sediments but no eosinophils. Percutaneous biopsies of the liver and the kindey were performed 40 days after the onset. Liver biopsy (Fig. 2) showed moderate parenchymal damage with diffuse hydropic hepatocytes and evidence of regeneration with slightly disturbed liver cell cords. A moderate infiltration of inflammatory cells, mainly lymphocytes, was seen in the portal areas. There was no intralobular or canalicular choelstasis and no destructive alteration of the reticulum framework. Renal biopsy (Fig. 3) revealed the presence of interstitial oedema and extensive inflammatory infiltration of plasma cells, lymphocytes, and scattered eosinopils. Neutrophils were not observed. Tubular atrophy and degeneration were seen with intratubular cast formation. The
appearance of the glomeruli was relatively normal except for mild diffuse mesangial proliferation. Arterioles appeared normal. Immunofluorescent studies for IgA, IgM, IgE, C3, C4, and fibrin were all negative. Weak staining for IgG was observed in a granular pattern within occasional glomerular mesangial regions. A lymphocyte transformation test for phenobarbital performed on the 9th day of the disease showed a borderline reaction with stimulation index [4], 2.1 (count stimulated with phenobarbital = 513 cpm and blank count = 241cpm), but the subsequent study carried out 4 weeks later indicated a positive reaction with stimulation index, 4.6 (count stimulated with phenobarbital = 2362cpm and blank count = 511cpm). A skin patch test for phenobarbital was negative 48 days after the onset, but 3 months later the test was strongly positive. Liver function continued to improve without any specific treatment. Renal dysfunction lasted over 3 weeks and prednisolone (lmg/kg per day) was administered orally. Following a 4-week
71
Fig. 3. Microscopic appearance of the kidney, showing an interstititial oedema and an extensive inflammatory infiltration (H&E, x 100). Renal tubules were partly degenerated and blood vessels appeared normal
course of prednisolone, renal function improved gradually and returned to normal by 8 weeks. Discussion Allergic reactions to phenobarbital such as exfoliative dermatitis and liver failure are rare [6, 8, 9, 11, 12]. Our patient presented typical clinical symptoms compatible with those of the previously reported cases, i.e. highgrade fever, pruritic skin rash, generalized lymphadenopathy and liver dysfunction after receiving phenobarbital for 4 weeks. Serial investigations of lymphocyte transformation study and skin patch test revealed increasing reactions of phenobarbital, supporting the pathogenic contribution of allergic mechanisms. The levels of Nacetyl-[3-D-glucosaminidase and 132-microglobulin in urine were elevated in the acute phase, indicating the subclinical existence of renal tubular dysfunction. Proteinuria on admission was too mild to explain hypoproteinaemia which might be caused by hyponutrition, liver dysfunction and inflammatory exudation. Hypocalcaemia seemed to be related to hypoproteinaemia and the level of serum ionized calcium was within normal range. Although acute aggravation of renal dysfunction in the convalescent stage of the clinical course seemed to be induced by the episodes of haemolysis, the findings of renal biopsy demonstrated rather typical tubulo-interstitial nephritis, excluding the possibility of haemolytic renal damage which is characterized by acute tubular necrosis with pigmented casts within the tubular lumens [14]. The time lag of 3 weeks between the discontinuation of phenobarbital and the exacerbation of renal function is compatible with those of other reports concerning drug-induced interstitial nephritis [1, 5]. Piperacillin, which was administerd for only 4 days, might be associated with tubulo-interstitial nephritis. However, a series of symptoms started before the treatment with piperacillin and the period of its
administration was too short compared with other reports concerning antibiotic-induced interstitial nephritis [1, 7]. Other anticonvulsants including carbamazepine [3, 10] and diphenylhydantoin [5, 13] have been occasionally reported to induce interstitial nephritis. However, only one report on phenobarbital-induced interstitial nephritis was available in a review of the English [2]. In this case IgE-containing plasma cells were observed in the perivascular area, but in our case no IgE deposits were detected by immunofluorescent studies. The combination of hepatic failure and subsequent renal dysfunction caused by phenobarbital has been only once previously described [15] and the authors did not refer to the pathogenesis of the renal dysfunction. In our case, accidental haemolysis might have precipitated and uncovered the otherwise overlooked mild interstitial nephritis. Indeed, it may be speculated that interstital nephritis may have gone unnoticed in the past because of mild clinical course and lack of precipitating factors.
References 1. Baldwin DS, Levine BB, McCluskey RT, Gallo GR (1968) Renal failure and interstitial nephritis due to penicillin and methicillin. N Engl J Med 279 : 1245-1252 2. Faarup P, Christensen E (1974) IgE-containing plasma cells in acute tubulointerstitial nephropathy. Lancet II : 718 3. Hogg RJ, Sawyer M, Hecox K, Eigenbrodt E (1981) Carbamazepine-induced acute tubulointerstitial nephritis. J Pediatr 98 : 830-832 4. Houwerzijl J, DeGast GC, Nater JP, Esselink MT, Nieweg HO (1977) Lymphocyte-stimulating test and patch tests in carbamazepine hypersensitivity. Clin Exp Immunol 29 : 272-277 5. Hyman LR, Ballow M, Knieser MR (1978) Diphenylhydantoin interstitial nephritis. Roles of cellular and hnmoral immunologic injury. J Pediatr 92 : 915-920 6. Lane T, Peterson EA (1980) Hepatitis is a manifestation of phenobarbital hypersensitivity. South Med J 77 : 94
72 7. Linton AL, Clark WF, Driedger AA, Turnbull DI, Lindsay RM (1980) Acute interstitial nephritis due to drugs. Review of the literature with a report of nine cases. Ann Intern Med 93 : 735-741 8. McGeachy TE, Bloomer WE (1953) The phenobarbital sensitivity syndrome. Am J Med 14 : 600-604 9. Menninger WC (1928) Skin eruptions with phenobarbital. JAMA 91 : 14-18 10. Nicholls DP, Yasin M (1972) Acute renal failure from carbamazepine. BmJ IV: 490 11. Sexton DL, Pike GM, Neilson A (1941) Exfoliative dermatitis and death due to phenobarbital. JAMA 116:700
12. Shapiro PA, Antonioli DA, Peppercorn MA (1980) Barbiturate-induced submassive hepatic necrosis: Report of a case and review of the literature. Am J Gastroenterol 74 : 270-273 13. Sheth KJ, Casper JT, Good T A (1977) Interstitial nephritis due to phenytoin hypersensitivity. J Pediatr 91 : 438-441 14. Tisher CC, Brenner BM (1989) Renal pathology with clinical and functional correlations. JB Lippincott Company, Philadelphia 15. Tomita H, Konno M, Ishikawa N, Kajii N (1987) A case of hepatic failure with exfoliative dermatitis due to phenobarbital hypersensitivity (abstract) Nippon Shonika Gakkai Zasshi 91 : 1465-1471
