Nonconvulsive status epilepticus in dialysis patients: In Reply

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NONCONVULSIVE STATUS EPILEPTICUS IN DIALYSIS PATIENTS To the Editor: The article of Chow et al1 in the August 2001 issue of the Journal reporting 4 cases of nonconvulsive status epilepticus (NCSE) in peritoneal dialysis patients shows us the importance of the early detection of the first signs of nonconvulsive status and emphasizes the utility of the electroencephalogram (EEG) in the differential diagnosis of confusion in uremic patients to detect NCSE. In this article, 3 of 4 patients were receiving antibiotics; the fourth was taking tuberculostatic drugs. The dosage of cefepime of the first patient described (2 g/d) was too high for patients on peritoneal dialysis, as discussed later, while another patient also received cefepime. Although the doses of antibiotics administered to the other patients were not stated in the paper, they may have been inappropriately high for peritoneal dialysis patients. The neurotoxicity of cefepime at high doses in chronic renal failure patients has been previously reported.24 In a recently published article, we have reported 2 cases of NCSE in patients with end-stage renal disease on maintenance hemodialysis that were treated with cefepime at the doses recommended for chronic renal failure patients.4 In both cases, the patients initially developed confusion followed by myoclonus, causing us to suspect the possibility of NCSE, which was confirmed by EEG. The clinical symptoms disappeared after antibiotic withdrawal and intensive hemodialysis. Beta-lactams and quinolones are drugs with known neurological side effects, such as convulsions. The proconvulsivant effect of selected antibiotics, similar to that of many other drugs and toxins with epileptogenic potential, is secondary to their effects on central neuroinhibitory tone. Gamma-aminobutyric acid (GABA) is the principal inhibitory central neurotransmitter present in an estimated 30% of all central synapses.5 Cephalosporins and fluorquinolones prevent GABA binding to GABAA receptor, while isoniazid prevents GABA synthesis by competing with pyridoxine. We would also like to emphasize the importance of using these potentially epileptogenic antibiotics at the doses recom440

mended for renal failure. In a recent update, the recommended dose of cefepime for peritoneal dialysis patients was 250 mg per 48 hours, which is even lower than that for hemodialysis patients, because the drug is removed to a lesser extent in peritoneal dialysis than in hemodialysis.6 Nevertheless, in our experience, NCSE can be observed even with the use of cefepime at adjusted dosages in uremic patients. In summary, we agree with Chow et al1 about the importance of including an EEG among the diagnostic tests of confusion in chronic renal failure patients and that NCSE should be considered in the differential diagnosis of this disorder in these patients. Furthermore, we believe that the safety of cefepime in chronic renal failure patients, with special attention to neurotoxicity, needs to be confirmed in prospective clinical trials. Anna Saurina, MD Manel Vera, MD Monica Pou, MD Aleix Cases, MD Dialysis Unit, Hospital Clinic Barcelona, Spain REFERENCES 1. Chow KM, Wang A Y-M, Hui A Ch-F, Wong T Y-H, Szeto Ch Ch, Li P K-T: Nonconvulsive status epilepticus in peritoneal dialysis patients. Am J Kidney Dis 38:400-405,2001 2. Chetaille E, Hary L, De Cagny B, Gras-Champel V, Decocq G, Andrejak M: Crises convulsives associees ä un surdosage en cefepime. Therapie 53:167-168, 1998 3. Wong KM, Chan WK, Chan Y-H, Li Ch-S: Cefepime related neurotoxicity in a haemodialysis patient. Nephrol Dial Transplant 14:2265-2266, 1999 4. Saurina A, Vera M, Pou M, Lopez-Pedret J, Darnell A, Campistol JM, Cases A: [Non-convulsive status epilepticus secondary to adjusted cefepime doses in patients with chronic renal failure]. Nefrologia 20:554-558, 2000 5. Wallace KL: Antibiotic-induced convulsions. Crit Care Clin 4:741-762, 1997 6. Lacy CH: Cefepime: Drug information. Up To Date, 2001 © 2002 by the National Kidney Foundation, Inc. doi:J0.J053/ajkd.2002.31J92 In Reply: We are glad to hear comments from Saurina et al on our article1 of nonconvulsive status epilepticus (NCSE) among patients undergoing peritoneal dialysis. It is noteworthy that not all of our patients suffering from nonconvulsive status epilepticus had received cefepime. We have no dispute that antibiotic neurotoxicity could have contributed to lowering seizure threshold in uremic patients, and special attention should therefore be paid to altered drug removal with renal insufficiency. Cefepime dosage recommendation has been derived from previous pharmacokinetic studies.2"4 With nor-

American Journal of Kidney Diseases, Vol 39, No 2 (February), 2002: pp 440-443

CORRESPONDENCE

mal renal function, it has been shown to undergo minimal metabolism and hence excreted unchanged in urine.2 In an advanced renal insufficiency population undergoing continuous ambulatory peritoneal dialysis,3·4 the estimated elimination half-life and steady-state volume of distribution of cefepime was independent of the dose. Roughly 26% of the dose had been demonstrated to be excreted intact into the peritoneal dialysis fluid over 72 hours. It follows that parenteral dose of 1 or 2 g of cefepime every 24 to 48 hours would be adequate to maintain the plasma and peritoneal fluid cefepime levels above the minimal inhibitory concentration MIC90s for most susceptible bacteria in systemic and intraperitoneal infections.3 The contemporary guidelines have been followed in our patients.5"7 We share the position of Saurina et al about "the importance of using these potentially epileptogenic antibiotics at the doses recommended for renal failure."8 Dosage reduction that results in ineffectively low plasma concentrations, nevertheless, is another pitfall in prescribing antimicrobial agents for the uremic patients.6 To balance the risk of antimicrobial therapy underdosing against neurotoxicity, adjustment of maintenance dosing after achieving the therapeutic level and timely recognition of the condition by early electroencephalogram would therefore be indicated. Kai Ming Chow, MRCP Teresa Yuk-Hwa Wong, MRCP Cheuk Chun Szeto, MRCP Philip Kam-Tao Li, FRCP, FACP Department of Medicine and Therapeutics The Chinese University of Hong Kong Hong Kong SAR, China REFERENCES 1. Chow KM, Wang AY, Hui CF, Wong TY, Szeto CC, Li PK: Nonconvulsive status epilepticus in peritoneal dialysis. Am J Kidney Dis 38:400-405, 2001 2. Barbhaiya RH, Knupp CA, Forgue ST, Matzke GR, Halstenson CE, Opsahl JA, Pittman KA: Disposition of the cephalosporin cefepime in normal and renally impaired subjects. Drug Metab Dispos 19:68-73, 1991 3. Barbhaiya RH, Knupp CA, Pfeffer M, Zaccardelli D, Dukes GM, Mattern W, Pittman KA, Hak LJ: Pharmacokinetics of cefepime in patients undergoing continuous ambulatory peritoneal dialysis. Antimicrob Agents Chemother 36:1387-1391, 1992 4. Barbhaiya RH, Knupp CA, Forgue ST, Matzke GR, Guay DR, Pittman KA: Pharmacokinetics of cefepime in subjects with renal insufficiency. Clin Pharmacol Ther 48: 268-276, 1990 5. Aronoff GR, Berns JS, Brier ME, Golper TA, Morrison G, Singer I, Swan SK, Bennett WM: Drug Prescribing in Renal Failure: Dosing Guidelines for Adults (ed 4). Philadelphia, PA, American College of Physicians, 1999, pp 43-46 6. Cutler RE, Forland SC: Drugs in renal failure, in Massry SG, Glassock RJ (eds): Massry & Glassock's Textbook of Nephrology (ed 4), chap 85. Philadelphia, PA, Lippincott Williams & Wilkins, 2001, pp 1564-1598 7. Aronoff GR, Brier ME, Erbeck KM, Ouseph R: Drug dosing in dialysis patients, in Owen WF, Pereira BJG, Sayegh MH (eds): Dialysis and Transplantation: A Compan-

441 ion to Brenner & Rector's The Kidney, chap 19. Philadelphia, PA, Saunders, 2000, pp 358-372 8. Saurina A, Vera M, Pou M, Lopez Pedret J, Darnell A, Campistol JM, Cases A: Non-convulsive status epilepticus secondary to adjusted cefepime doses in patients with chronic renal failure. Nefrologia 20:554-558, 2000 © 2002 by the National Kidney Foundation, Inc. doi:W.1053/ajkd.2002.31816 IS VITAMIN D RECEPTOR GENE POLYMORPHISM AN INDEPENDENT PREDICTOR OF MORTALITY IN HEMODIALYSIS PATIENTS? To the Editor: We read with great interest the article by Marco et al.1 They studied a very interesting issue (influence of vitamin D receptor [VDR] gene polymorphism on mortality risk) and concluded that Bsml polymorphism influences survival in hemodialysis (HD) patients. As Marco et al1 pointed out, this is the first study to show the influence of genetic factors on mortality of HD patients. However, we would like to comment on the study. Marco et al1 studied 143 patients, 60 of whom died after a follow-up period of 4 years. It is obvious from the data that approximately 55% of the deaths resulted from cardiovascular disease, which is the leading cause of mortality in HD patients. Relevant literature has demonstrated that anemia and hypertension are the major causes of cardiovascular disease in HD patients.2·3 In addition, anemia has been shown to be related to mortality in these patients.3·4 However, the authors did not include these factors in the Cox model. Therefore, VDR genotype cannot be suggested as an independent risk factor influencing survival in HD patients unless adjustments were made for both hemoglobin/hematocrit and blood pressure levels. Moreover, such an attempt could serve as a clue for the mechanisms by which VDR genotype influences survival. More recently, we showed that VDR gene Bsml polymorphism independently affects both hemoglobin/hematocrit levels and dose of erythropoietin in HD patients.5 In our study, the patients with BB genotype had the lowest hemoglobin/hematocrit levels, despite the highest erythropoietin doses. Therefore, the higher mortality seen in BB genotype may be a consequence of the more severe anemia. In conclusion, further clinical research on the possible association of VDR gene polymorphism with mortality in HD patients appears warranted. Sehsuvar Ertürk, MD Sim Kutlay, MD Kenan Keven, MD Department of Nephrology Ankara University Medical School Ankara, Turkey REFERENCES 1. Marco PM, Craver L, Betriu A, Fibla J, Fernandez E: Influence of vitamin D receptor gene polymorphism on