CYCLOSPORIN-ASSOCIATED FATAL CONVULSIONS

219 with rheumatoid arthritis had greatly increased urinary levels of51Cr-EDTA after one week’s treatment with NSAIDs and concluded that the NSAIDs were responsible for the "systemically mediated" loss of intestinal integrity. What needs to be shown is that enhanced intestinal permeability does result in increased plasma concentrations of the marker molecule. In the absence of such evidence it is possible that the higher excretion of the marker simply indicates increased GFR. There are good reasons to believe that the gastric disorders as well as alcoholism are associated with abnormal blood rheology, and the enhanced excretion of 51 Cr-EDT A may simply be an expression of the effects of abnormal haemorheology on GFR. Raised erythrocyte sedimentation rates in Crohn’s disease indicate altered blood rheology. The malabsorption of both coeliac disease and Crohn’s disease results in low plasma protein concentrations and hypoalbuminaemia, a condition which is associated with increased blood viscosity.5 Dintenfass6 has pointed out that alcoholism is associated with increased blood viscosity and greater stiffness of red cells. NSAIDs inhibit prostaglandin synthesis, and for this reason it is likely that NSAID-treated patients with rheumatoid arthritis had abnormal blood rheology. Diabetics have abnormal blood associated with increased GFR and microalbuminuria.4 Altered renal function in polycythaematous patients epitomises the way in which blood viscosity can alter GFR.Similar changes in renal function, varying in degree, can be expected whenever 8 haemorheology is abnormal. Therefore unless it can be shown that urinary levels of 51 Cr-EDTA correlate with an increased concentration of marker in the blood, the possibility exists that the greater excretion of 51CR-EDTA in specific disorders merely indicates a rheologically mediated increase in GFR in those disorders rather than enhanced absorption of the marker. Until this point is clarified, the claim that the urinary levels of a small, inert molecule provide a marker of intestinal permeability will remain unsubstantiated.

patients

rheology

Pathology Department, University of Otago Medical School, Dunedin, New Zealand 1.

L. O. SIMPSON

Bjarnason I, O’Morain C, Levi AJ, Peters TJ. Absorption of 51chromium-labelled ethylenediamine-tetracetate in inflammatory bowel disease Gastroenterology 1983;

85: 318-22 2. Bjarnsason I, Peters TJ, Veall N. A persistent defect in intestinal permeability in coeliac disease demonstrated by a 51Cr-labelled EDTA absorption test. Lancet 1983, i: 323-25 3 Bjarnason I, Ward K, Peters TJ The leaky gut of alcoholism: Possible route of entry for toxic compounds. Lancet 1984, i: 179-82. 4. Viberti GC, Hill RD, Jarrett RJ, Argyropoulos A, Mahmud U, Keen H. Microalbuminuria as a predictor of clinical nephropathy in insulin-dependent diabetes mellitus. Lancet 1982; i: 1430-32. 5 Merrill EW, Margett WG, Cokelet GR. Influence of the plasma proteins on the rheology of human blood In Copley AL, ed. Proceedings of the 4th International Congress on Rheology Sydney: Interscience Publishers, 1963. 601-11 6 Dmtenfass L. Rheology of blood in diagnostic and preventive medicine. London: Butterworths, 1976 252-55 7 Simpson LO Blood viscosity induced proteinuria. Nephron 1984; 36: 280-81. 8 Simpson LO A hypothesis proposing increased blood viscosity as a cause of proteisuria Nephron 1982; 31: 89-93

CYCLOSPORIN-ASSOCIATED FATAL CONVULSIONS cases of convulsions in patients given cyclosporin prevent graft-versus-host disease (GVHD) have been reportedl-3 -one in an 18-year-old, one in a 25-year-old, and ten in children. There were no deaths directly associated with these convulsions. Durrant et al2 and Boogaerts et al3 pointed out the association of seizures with the combined use of cyclosporin and high-dose methylprednisolone given as treatment of GVHD. On the other hand, Gross et al4 argued that similar convulsions in patients with renal transplants were related to the severity of the rejection crisis and not to features such as blood pressure, fever, or steroid or cyclosporin therapy. We describe here a case of fatal epileptic seizures in a bone-marrow-transplant recipient who did not have GVHD and was not given high-dose methylprednisolone. A 19-year-old girl with acute lymphoblastic leukaemia in first relapse had never had central-nervous-system leukaemia or cranial

SiR,-Twelve

to

irradiation. She had no personal but did have a family history of epilepsy. She was prepared for transplantation with intrathecal methotrexate, cytarabine 3 g/m2every 12 h for 6 days (day -7 to day 2), and total body irradiation (800 rad) on day - 1. On day 0 she received bone marrow from her HLA-matched brother. Cyclosporin was given as a continuous intravenous infusion at the dose of 10 mg/kg on day -1and then 5 mg/kg daily. From day -11 she complained of severe headache. On day 6 she started having generalised convulsions and then status epilepticus which proved very resistant to diazepam, clonazepam, phenytoin, and dexamethasone at high doses. Computerised tomography did not show intracerebral bleeding. Her high serum cyclosporin level (900 ng/ml) was at least partly attributable to the association with ketoconazole5 (600 mg daily). Neurological function worsened and she died on day 10. Post-mortem examination of the brain revealed diffuse oedema only. A genetic predisposition to seizures and the combination of neurotoxic drugs such as intrathecal methotrexate, high-dose cytarabine, cyclosporin at high serum levels, and total body irradiation may have triggered this parent’s convulsions. -

Department of Internal Medicine, Institut Jules Bordet, 1000 Brussels. Belgium

TH. VELU L. DEBUSSCHER P. A. STRYCKMANS

AJ, Kendra JR, Lucas CF, et al Cyclosporin A as prophylaxis against graftversus-host disease in 36 patients. Br Med J 1982, 285: 162-66 2. Durrant S, Chipping PM, Palmer S, Gordon-Smith EC. Cyclosporin A, methylprednisolone, and convulsions. Lancet 1982, ii: 829-30 3. Boogaerts MA, Zachee P, Verwilghen RL Cyclosporin, methylprednisolone, and convulsions Lancet 1982; ii: 1216-17. 4 Gross MLP, Pearson RM, Kennedy S, Moorhead JF, Sweny P. Rejection encephalopathy Lancet 1982; ii 1217. 5. Ferguson RM, Sutherland DER, Simmons RL, Najarian JS. Ketoconazole, cyclosporin metabolism, and renal transplantations. Lancet 1982; ii: 882-83. 1. Barrett

SEVERE CENTRAL-NERVOUS-SYSTEM TOXICITY ASSOCIATED WITH CYCLOSPORIN

SIR,-The side-effects of cyclosporin include, besides renal and hepatic toxicity, neurological symptoms such as tremor, neuralgia, and convulsions.1-3 Atkinson et al have reported serious centralnervous-system toxicity in five bone-marrow transplant recipients treated with cyclosporin to prevent graft-versus-host disease. 20 days after renal transplantation one of our patients went into a coma that lasted 44 days. Immunosuppression consisted of cyclosporin 15-55 mg/kg body weight and prednisone 10 mg daily. Whole blood cyclosporin levels after transplantation ranged from 600 to 1000 ng/ml. At the onset of the coma cyclosporin was replaced by azathioprine. CSF analysis revealed no evidence of infection with bacteria, fungi, or neurotropic viruses; there were no increases in serum antibody titres against respiratory viruses, cytomegalovirus, measles virus, herpes simplex virus, or varicellazoster virus; and serum magnesium levels were normal. The most prominent findings during the comatose period were a pronounced, diffuse hypodensity of the white matter (16-19 Hounsfield units; normal 29-34) on the cerebral computerised tomographic (CT) scan and electromyographic signs of axonal degeneration and demyelination. Both abnormalities gradually disappeared coincident with the clinical recovery of the patient.

Hypodensity of white matter in the absence of cerebral oedema suggests leucoencephalopathy. Although we cannot prove that the leucoencephalopathy or demyelination were caused by cyclosporin, circumstantial evidence supports this view. An increased bleeding tendency precluded brain biopsy. There were no signs of infection and almost full recovery was achieved without specific antimicrobial or antiviral treatment. Cyclosporin and prednisone apart, the patient was not taking drugs. A congenital metabolic cause for the leucoencephalopathy could be excluded since all lysosomal enzymes tested in leucoytes were normal. Although the CT scans resembled those reported in progressive multifocal leucoencephalopathy,the reversibility of the hypodensity and the almost complete clinical recovery make it very unlikely that the