- Email: [email protected]
TOXICITY OF CYCLSPORIN METABOLITES
333 of the cerebral hemispheres (figure). Although generalised hypoxia could account for such changes, there was no morphological evidence of neuronal hypoxic damage in the central
directly to clinical practice since the sample was unrepresentative, or recently delivered women facing a real decision have quite different utilities. Nevertheless, we think that the may
matter
debate about intensive care of VLBW infants would benefit from a precise numerical analysis of parents’ views.
nervous
and pregnant
more
Departments of Obstetrics and Gynaecology, Welsh National School of Medicine, Heath Park, Cardiff CF4 4XN
J. G. THORNTON
St James’s University Leeds
F. C. BRYCE K. BHABRA
Hospital,
1 Pauker SP, Pauker SG. Prenatal diagnosis: a directive approach to genetic counselling using decision analysis. Yale J Biol Med 1977; 50: 275-89. 2 Thomton JG, Lilford RJ, Howel D Safety of amniocentesis. Lancet 1986; ii. 225-26. 3 Weinstein MC, Fineberg HV, eds. Clinical decision analysis. Philadelphia: Saunders, 1980
TOXICITY OF CYCLSPORIN METABOLITES
SiR,—Dr Kunzendorf and colleagues (May 28, p 1223) suggest that cyclosporin neurotoxicity may develop in patients with normal trough values of the parent compound due to the accumulation of a metabolite. This may have occurred in one of our cases. A 45-year-old woman presented with bloody diarrhoea and vomiting 5 months after renal allograft transplantation. Her immunosuppression was 400 mg cyclosporin (5-6 mg/kg) and 15 mg prednisolone daily. Benzylpenicillin and metronidazole were started after cultures had been taken. The diarrhoea persisted and her general condition deteriorated, the conscious state fluctuating between mild confusion and coma. Laparotomy revealed extensive colitis but bowel resection was not considered necessary. A single blood culture grew Clostridium septicum. Despite appropriate antibiotics, her conscious state continued to fluctuate. A computerised tomographic brain scan did not show any abnormality, and a lumbar puncture was normal except for an increased cerebrospinal fluid (CSF) protein concentration of 1-2 g/l (normal less than 0-33 g/1); the pressure was 12 cm of water and the CSF aluminium less than 0-1umol/1 (normal). 9 days after admission she suddenly became deeply unconscious with signs of a brainstem lesion. An electroencephalogram was compatible with a diffuse encephalopathy. Cerebral oedema was suspected and she was treated with mannitol, dexamethasone, and elective hyperventilation, but she died 4 days later. At necropsy there was evidence of a non-specific colitis affecting the caecum and ascending colon. The brain (1552 g) was swollen and microscopy showed widespread oedema, especially in the white
system.
Cyclosporin trough values measured with a monoclonal nonspecific antibody technique ranged between 120 and 145 ng/ml (cyclosporin toxicity would be suspected with values above 400 ng/ml). Neurotoxicity has been attributed to cyclosporin in association with acute allograft rejection,l pulse methylprednisolone therapy,2 aluminium toxicity,3 hypomagnesaemia4 and hypertension, especially in young children.s Nuclear magnetic resonance studies have shown a generalised increase in the water of cerebral white matter in association with clinical symptoms and signs in patients treated with cyclosporin.6 Our patient did receive a single 1 g dose of erythromycin parenterally on admission, but otherwise did not receive any drugs known to interfere with cyclosporin metabolism or pulse methylprednisolone therapy. The CSF aluminium level was not in the toxic ranged Although Cl septicum was grown from a single blood culture on one occasion, she was treated with penicillin, to which the organism was sensitive. At necropsy none of the characteristics of clostridial infection in the central nervous system were found.8 She did become transiently hypertensive at the time of the brainstem lesion, but otherwise mean arterial pressure had been normal. Although the clinical and necropsy findings were in accord with cyclosporin neurotoxicity, this diagnosis was in dispute because of the normal trough values of the parent drug. However, the suggestion made by Kunzendorf and colleagues that the 17 metabolite had a role in the development of cyclosporin neurotoxicity might explain our findings. The clostridial sepsis or the initial dose of erythromycin could have interfered with cyclosporin hepatic metabolism, resulting in an increase in cyclosporin metabolites. Although liver function tests were normal on presentation, as with the patient of Kunzendorf et al, increases in both serum alanine transferase (peak value 46 IU/1, normal below 35) and bilirubin (peak value 75 umol/1, normal below 15) occurred during her admission. It would therefore seem prudent to measure cyclosporin metabolites in patients with liver disease and those with systemic illnesses during which hepatic metabolism may be disturbed. content
Department of Renal Medicine, St James’s University Hospital, Leeds LS9 7TF; and Department of Neuropathology, Leeds General Infirmary
A. DAVENPORT E. J. WILL A. M. DAVISON J. W. IRONSIDE
1. Gross
MLP, Sweny P, Pearson RM, Kennedy J, Femando OM, Moorhead JF. Rejection encephalopathy, an acute neurological syndrome complicating renal transplantation. J Neurol Sci 1982; 56: 23-34. 2. Durrant S, Chipping PM, Palmer S, Gordon-Smith EC. Cyclosporin A, methyl prednisolone and convulsions Lancet 1982; ii: 829-30. 3. Nordal PK, Talseth T, Dahl E, et al Aluminium overload, a predisposing condition for epileptic seizures in renal transplant patients treated with cyclopsorin? Lancet 1985; ii: 153-54. 4. Thompson CB, June CH, Sullivan KM, Thomas GD. Association between cyclosporm neurotoxicity and hypomagnesaemia. Lancet 1984; ii. 1116-20. 5. Joss DV, Barrett AJ, Kendra JR, Lucas CF, Desai S. Hypertension and convulsions in children receiving cyclosporin A. Lancet 1982; i: 906. 6. DeGroen PC, Aksamtt AJ, Rakele J, Frobes GS, Krom RAF. Central nervous system toxicity after liver transplantation. N Engl J Med 1987; 317: 861-66. 7. Adhemar JP, Laedrich J, Jaudon MC, et al. Dialysis encephalopathy, diagnostic and prognostic value of clinical and EEG signs, and aluminium levels in serum and cerebrospinal fluid. Proc EDTA 1980; 17: 234-39. 8. King A, Rampling A, Wight DGD, Warren RG. Neutropenic enterocolitis due to Clostridium septicum infection. J Clin Pathol 1984; 37: 335-43.
QUALITY OF LIFE ON ANGINA THERAPY SIR,-Dr Fletcher and colleagues (July 2, p 4) report on the use of transdermal glyceryl trinitrate versus placebo in angina. In the four years since we were involved in the design of this trial our Extensive vacuolation within white matter of the brain, due to oedema accumulating between nerve fibre bundles and around small blood vessels. Luxol fast
blue/haematoxylin and eosin,
x
200.
recommendations for the use of ’Transiderm-Nitro’ have been amended on the basis of further experience. We now recommend that 10 mg patches should be used for patients not responding to the lower dose. This is especially so in patients with severe disease such as those suffering 8 attacks per week despite 0-blocker therapy, as was the case in this study.
directly to clinical practice since the sample was unrepresentative, or recently delivered women facing a real decision have quite different utilities. Nevertheless, we think that the may
matter
debate about intensive care of VLBW infants would benefit from a precise numerical analysis of parents’ views.
nervous
and pregnant
more
Departments of Obstetrics and Gynaecology, Welsh National School of Medicine, Heath Park, Cardiff CF4 4XN
J. G. THORNTON
St James’s University Leeds
F. C. BRYCE K. BHABRA
Hospital,
1 Pauker SP, Pauker SG. Prenatal diagnosis: a directive approach to genetic counselling using decision analysis. Yale J Biol Med 1977; 50: 275-89. 2 Thomton JG, Lilford RJ, Howel D Safety of amniocentesis. Lancet 1986; ii. 225-26. 3 Weinstein MC, Fineberg HV, eds. Clinical decision analysis. Philadelphia: Saunders, 1980
TOXICITY OF CYCLSPORIN METABOLITES
SiR,—Dr Kunzendorf and colleagues (May 28, p 1223) suggest that cyclosporin neurotoxicity may develop in patients with normal trough values of the parent compound due to the accumulation of a metabolite. This may have occurred in one of our cases. A 45-year-old woman presented with bloody diarrhoea and vomiting 5 months after renal allograft transplantation. Her immunosuppression was 400 mg cyclosporin (5-6 mg/kg) and 15 mg prednisolone daily. Benzylpenicillin and metronidazole were started after cultures had been taken. The diarrhoea persisted and her general condition deteriorated, the conscious state fluctuating between mild confusion and coma. Laparotomy revealed extensive colitis but bowel resection was not considered necessary. A single blood culture grew Clostridium septicum. Despite appropriate antibiotics, her conscious state continued to fluctuate. A computerised tomographic brain scan did not show any abnormality, and a lumbar puncture was normal except for an increased cerebrospinal fluid (CSF) protein concentration of 1-2 g/l (normal less than 0-33 g/1); the pressure was 12 cm of water and the CSF aluminium less than 0-1umol/1 (normal). 9 days after admission she suddenly became deeply unconscious with signs of a brainstem lesion. An electroencephalogram was compatible with a diffuse encephalopathy. Cerebral oedema was suspected and she was treated with mannitol, dexamethasone, and elective hyperventilation, but she died 4 days later. At necropsy there was evidence of a non-specific colitis affecting the caecum and ascending colon. The brain (1552 g) was swollen and microscopy showed widespread oedema, especially in the white
system.
Cyclosporin trough values measured with a monoclonal nonspecific antibody technique ranged between 120 and 145 ng/ml (cyclosporin toxicity would be suspected with values above 400 ng/ml). Neurotoxicity has been attributed to cyclosporin in association with acute allograft rejection,l pulse methylprednisolone therapy,2 aluminium toxicity,3 hypomagnesaemia4 and hypertension, especially in young children.s Nuclear magnetic resonance studies have shown a generalised increase in the water of cerebral white matter in association with clinical symptoms and signs in patients treated with cyclosporin.6 Our patient did receive a single 1 g dose of erythromycin parenterally on admission, but otherwise did not receive any drugs known to interfere with cyclosporin metabolism or pulse methylprednisolone therapy. The CSF aluminium level was not in the toxic ranged Although Cl septicum was grown from a single blood culture on one occasion, she was treated with penicillin, to which the organism was sensitive. At necropsy none of the characteristics of clostridial infection in the central nervous system were found.8 She did become transiently hypertensive at the time of the brainstem lesion, but otherwise mean arterial pressure had been normal. Although the clinical and necropsy findings were in accord with cyclosporin neurotoxicity, this diagnosis was in dispute because of the normal trough values of the parent drug. However, the suggestion made by Kunzendorf and colleagues that the 17 metabolite had a role in the development of cyclosporin neurotoxicity might explain our findings. The clostridial sepsis or the initial dose of erythromycin could have interfered with cyclosporin hepatic metabolism, resulting in an increase in cyclosporin metabolites. Although liver function tests were normal on presentation, as with the patient of Kunzendorf et al, increases in both serum alanine transferase (peak value 46 IU/1, normal below 35) and bilirubin (peak value 75 umol/1, normal below 15) occurred during her admission. It would therefore seem prudent to measure cyclosporin metabolites in patients with liver disease and those with systemic illnesses during which hepatic metabolism may be disturbed. content
Department of Renal Medicine, St James’s University Hospital, Leeds LS9 7TF; and Department of Neuropathology, Leeds General Infirmary
A. DAVENPORT E. J. WILL A. M. DAVISON J. W. IRONSIDE
1. Gross
MLP, Sweny P, Pearson RM, Kennedy J, Femando OM, Moorhead JF. Rejection encephalopathy, an acute neurological syndrome complicating renal transplantation. J Neurol Sci 1982; 56: 23-34. 2. Durrant S, Chipping PM, Palmer S, Gordon-Smith EC. Cyclosporin A, methyl prednisolone and convulsions Lancet 1982; ii: 829-30. 3. Nordal PK, Talseth T, Dahl E, et al Aluminium overload, a predisposing condition for epileptic seizures in renal transplant patients treated with cyclopsorin? Lancet 1985; ii: 153-54. 4. Thompson CB, June CH, Sullivan KM, Thomas GD. Association between cyclosporm neurotoxicity and hypomagnesaemia. Lancet 1984; ii. 1116-20. 5. Joss DV, Barrett AJ, Kendra JR, Lucas CF, Desai S. Hypertension and convulsions in children receiving cyclosporin A. Lancet 1982; i: 906. 6. DeGroen PC, Aksamtt AJ, Rakele J, Frobes GS, Krom RAF. Central nervous system toxicity after liver transplantation. N Engl J Med 1987; 317: 861-66. 7. Adhemar JP, Laedrich J, Jaudon MC, et al. Dialysis encephalopathy, diagnostic and prognostic value of clinical and EEG signs, and aluminium levels in serum and cerebrospinal fluid. Proc EDTA 1980; 17: 234-39. 8. King A, Rampling A, Wight DGD, Warren RG. Neutropenic enterocolitis due to Clostridium septicum infection. J Clin Pathol 1984; 37: 335-43.
QUALITY OF LIFE ON ANGINA THERAPY SIR,-Dr Fletcher and colleagues (July 2, p 4) report on the use of transdermal glyceryl trinitrate versus placebo in angina. In the four years since we were involved in the design of this trial our Extensive vacuolation within white matter of the brain, due to oedema accumulating between nerve fibre bundles and around small blood vessels. Luxol fast
blue/haematoxylin and eosin,
x
200.
recommendations for the use of ’Transiderm-Nitro’ have been amended on the basis of further experience. We now recommend that 10 mg patches should be used for patients not responding to the lower dose. This is especially so in patients with severe disease such as those suffering 8 attacks per week despite 0-blocker therapy, as was the case in this study.