Clin Exp Nephrol (2009) 13:138–144 DOI 10.1007/s10157-008-0115-9
ORIGINAL ARTICLE
Non-convulsive status epilepticus following antibiotic therapy as a cause of unexplained loss of consciousness in patients with renal failure Savas Ozturk Æ Gonenc Kocabay Æ Baris Topcular Æ Halil Yazici Æ Arif Atahan Cagatay Æ Gulistan Bahat Æ Betul Baykan Æ Aydin Turkmen Æ Alaattin Yildiz
Received: 28 March 2008 / Accepted: 2 October 2008 / Published online: 17 December 2008 Ó Japanese Society of Nephrology 2008
Abstract Background Non-convulsive status epilepticus (NCSE): a condition that may be associated with different levels of altered consciousness without any apparent motor signs. There are published reports that it may be associated with antibiotic use patients with renal failure.
S. Ozturk (&) Division of Nephrology, Department of Internal Medicine, Haseki Training and Research Hospital, Istanbul, Turkey e-mail:
[email protected] G. Kocabay Istanbul Faculty of Medicine, Department of Internal Medicine, Istanbul University, Istanbul, Turkey B. Topcular B. Baykan Istanbul Faculty of Medicine, Department of Neurology, Istanbul University, Istanbul, Turkey H. Yazici A. Turkmen A. Yildiz Istanbul Faculty of Medicine, Division of Nephrology, Department of Internal Medicine, Istanbul University, Istanbul, Turkey A. A. Cagatay Istanbul Faculty of Medicine, Department of Clinical Bacteriology and Infectious Disease, Istanbul University, Istanbul, Turkey G. Bahat Istanbul Faculty of Medicine, Division of Geriatrics, Department of Internal Medicine, Istanbul University, Istanbul, Turkey S. Ozturk Haseki Egitim ve Arsatirma Hastanesi, Ic Hastaliklari, 5. dahiliye servisi, Haseki, Fatih, Istanbul, Turkey
123
Method This is a retrospective analysis of our 12 NCSE (2 men, 10 women, a mean age: 58.4 ± 17.5 range of 29–85 years) patients with renal failure who have used antibiotics. Results Twelve patients were receiving a total of 19 antibiotics including mainly beta-lactams. The mean duration of time between start of antibiotic treatment and NCSE was 8.0 (3–21) days. In all of the patients, neurological symptoms were slowly progressive and consisted of depression of consciousness and/or disorientation. Diazepam administration resulted in marked reduction or completely disappears of epileptic activity. Four of 12 patients (33%) died, but none of were associated with NCSE but primarily associated with infection developed secondary to the preexisting disease and with congestive heart failure which patients already had. Conclusion Antibiotics, especially beta-lactams could be neurotoxic and may cause of NCSE. NCSE should be considered in patients with unexplained loss of consciousness; EEG must be a part of investigations in patients with uraemia receiving antibiotics. Keywords Antibiotic therapy Beta-lactam Loss of consciousness Non-convulsive status epilepticus Renal failure
Introduction Non-convulsive status epilepticus (NCSE): a condition that may be associated with different levels of altered consciousness status without any apparent motor signs where continuous or intermittent epileptic seizure discharges are detected in electroencephalography (EEG).[1] Although there are not definite diagnosis criteria, clinic
Clin Exp Nephrol (2009) 13:138–144
features, EEG findings and response to antiepileptics therapy are important in diagnosis. Of all status epilepticus cases, 5–20% are NCSE; moreover, in comatose patients NCSE incidence has been found to be 8.2%. [2, 3] While there may be several metabolic, toxic or neurological causes, uremic milieu may also decrease convulsive threshold. There are published reports that it may be associated with antibiotic use patients with renal failure. This paper presents a retrospective analysis of our 12 NCSE patients with renal failure who have used antibiotics.
Results Between 2001 and 2005, diagnosis of NCSE was made in 12 patients (2 men, 10 women, a mean age: 58.4 ± 17.5 range of 29–85 years) who have been followed up by Istanbul University Istanbul Medical Faculty, Internal Medicine, Division of Nephrology. Demographic features and outcome results were given in Table 1. Five of the patients were acute renal failure (ARF), and the others were chronic renal failure (CRF). Two of the CRF patients were receiving hemodialysis (HD), one of them was receiving peritoneal dialysis (PD). When NCSE developed the mean creatinine levels were 4.3 mg/dl (1.5–8.0 mg/dl) [only for patients with ARF: 3.5 mg/dl (2.0–5.1 mg/dl)]. Twelve patients were receiving a total of 19 antibiotics either as mono- or combined therapy (cefepime nine patients, ciprofloxacin three patients, vancomycin two patients and ceftazidime, cefoperazone/sulbactam, imipenem/cilastatin, clarithromycin, amikacin one patient each). Only patient number 3 was receiving a medication (cyclosporine-A) known to be neurotoxic other than antibiotic. Cyclosporine-A levels determined during NCSE were within normal limits. Although this medication was continued, NCSE was decreased when the antibiotic was discontinued. The mean duration of time between start of antibiotic treatment and NCSE development was 8.0 (3–21) days. In six of the patients (50%), the first clinical sign of NCSE recognized was altered consciousness only, and myoclonus and/or impairment of consciousness was detected in the others. None of the patients had history of epilepsy and, during NCSE, and there was no change in blood chemistry to explain neurological findings. Only two uremic patients who had antibiotic-related convulsive (not nonconvulsive) status epilepticus were revealed during our research phase, and these patients were excluded from the study.
139
Diagnosis of nonconvulsive status epilepticus In all of the patients, neurological symptoms were slowly progressive and consisted of depression of consciousness and/or disorientation. Only one patient had accompanying agitation. Of the seven patients, whom we could observe more closely, three had coexisting automatisms, one patient had myoclonic jerks and only one patient had generalized tonic clonic seizure. None of the patients had new-onset focal neurological signs except for one patient had sequels due to a hemorrhagic cerebrovascular disease. None of the patients had cranial computerized tomography findings which could be responsible for NCSE. The EEGs showed generalized slowing with superimposed continuous or periodic bursts of sharp waves or sharp and slow wave activity (Fig. 1). One patient had continuous myoclonic activity associated with epileptiform discharges. Diazepam administration during EEG recordings resulted in suppression or marked reduction or completely disappears of epileptic activity in eight patients (Fig. 2). Outcomes Four of 12 patients (33%) died (one with renal transplantation, one with congestive heart failure—CHF—and sepsis and two with hematologic malignity and febrile neutropenia), but none of these deaths were associated with NCSE. Mortality was primarily associated with infection developed secondary to the pre-existing disease and with congestive heart failure which patients already had. All the patients who died had ARF (in patient no. 4, it was ARF developed on CRF background). Six patients were treated with phenytoin, whereas two received clonazepam. No antiepileptic drug was given to four patients who clinical improvement after withdrawal of ongoing antibiotic treatments (Table 1). There was no difference between survivors (eight patients) and non-survivors (four patients) groups in terms of age, sex, acute/chronic renal failure, latent time of appearance of NCSE, serum creatinine, response to i.v. diazepam. In addition antibiotics that were used were similar.
Discussion It’s known that convulsions can develop due to uraemia itself or due to many other reasons (e.g. cerebrovascular accident, electrolyte imbalance, and epileptogenic drugs) in patients with uraemia. However, there is limited data about NCSE development in these patients and almost all of them
123
123
55/F
61/F
52/M
67/F
85/F
29/M
75/F
83/F
1
2
3
4
5
6
7
8
Chronic
Acute (HD?)
Chronic (HD?)
Chronic
Chronic (acute HD?)
Chronic
Chronic (HD?)
Acute
Age/ Renal failure Gender (acute/chronic)
Patient no.
Lung tuberculosis, chronic atrial fibrilation
Congestive heart failure
Operated brain abscess
DM ? HT, late hemorrhagic CVA
Multiple myeloma
Transplanted kidney (chronic rejection), TRAS, HD (?)
Multiple myeloma (MM)
Polycystic kidney, cholecystectomy and bile duct operation
Other diagnoses
?/6.1
55/2.2
62/2.4
22/1.5
64/4.8
75/2.8
81/8.0
Cefepime 2 9 1 g
Cefepime 2 9 2 g, Vancomycin 191g
Cefepime 2 9 2 g
Cefepime 2 9 2 g
Ceftazidime 3 9 2 g/ead, Ciprofloxacin 2 9 200 mg
Imipenem/ Cilastatin 2 9 0.5 g
Cefepime 291g
Pneumonia
Pneumonia
Brain abscess
Pneumonia
Febrile neutropenia
Pneumonia
Febrile neutropenia
Acute pyelonephritis
56/3.7
Cefoperazone/ sulbactam 291g
Indication for antibiotic therapy
BUN/ Antibiotic creatinine (name, dose)
Table 1 Demographic features and outcome results of patients
7
3
21
7
12
4
8
10
Disappeared
Response of epileptic activity to i.v. diazepam
Stupor
Confusion
Stupor
Stupor
Stupor, rare limb contractions
Contractions of face muscles, stupor
Partial
Patient was on CsA, blood levels were normal, died of heart failure after 15 days
Phenytoin
Phenytoin
Consciousness improved completely, then taken into four antibiotic treatment and chronic HD program
Died of sepsis ? congestive heart failure on day 4
General anesthesia applied to the patient whose status presentation and mental state did not improve and was admitted to ICU
Clonazepam HD administrated to the patient again, after 3 days died of CPA
Phenytoin
NonePhenytoin responsive
Disappeared
Admitted to ICU, resolved with discontinued drug
Clonazepam Still on 3/7 HD program, MM is not in complete remission
Phenytoin
Maintenance Outcome antiepileptic drug
None– responsive
Disappeared
???
Disappeared Contractions of eyelids, chin, hands and arms
Contractions of face and neck/ generalized convulsion
Latent Clinical signs time (days)
140 Clin Exp Nephrol (2009) 13:138–144
33/F
48/F
58/F
55/F
9
10
11
12
End stage renal failure (amyloidosis?)
Chronic allograft nephropathy, febrile neutropenia, cellulitis, DM
Other diagnoses
Refractory lymphoma, pancytopenia (after chemotherapy)
71/5.1
Cefepime 2 9 2 g, Amikacin 191g
Febrile neutropenia
Transplanted kidney pyelonephritis
Cefepime 2 9 2 g, Clarithromycin 2 9 500
75/2.0
4
5
6
Disappeared
Response of epileptic activity to i.v. diazepam
Loss of consciousness
Impaired consciousness
–
–
Phenytoin
Consciousness did not improve and died of sepsis
Antibiotic discontinued, underwent HD, consciousness improved immediately
Antibiotic discontinued, consciousness improved
Cytopenia improved, creatinine decreased to 2.8 mg/dl. MMF was started again. He was not receiving CsA
Maintenance Outcome antiepileptic drug
None– responsive
Disappeared
Agitation, speech Partial difficulty, hand tremor, loss of consciousness
Disorientation, loss of consciousness
9
Febrile neutropenia, cellulitis
Ciprofloxacin Exacerbated 2 9 200 mg (day bronchiectasis 4), Cefepime 2 9 1 g (day 6)
Cefepime 2 9 1 g, Ciprofloxacin 2 9 200 mg (Vancomycin 1 9 1 g 2/7)
Latent Clinical signs time (days)
Indication for antibiotic therapy
56/7.5
74/6.0
BUN/ Antibiotic creatinine (name, dose)
ICU intensive care unit, HD hemodialysis, PD peritoneal dialysis, TRAS transplanted renal artery stenosis, CsA cyclosporine_A, CPA Cardiopulmonary arrest, CVA Cerebrovascular accident, ead every other day, DM diabetes mellitus, HT hypertension, MMF mycophenolate mofetil
Acute
Acute on chronic Transplanted kidney ? urinary infection, acute rejection
Chronic (PD?)
Chronic
Age/ Renal failure Gender (acute/chronic)
Patient no.
Table 1 continued
Clin Exp Nephrol (2009) 13:138–144 141
123
142
Clin Exp Nephrol (2009) 13:138–144
Fig. 1 EKG showing slowing with superimposed continuous or periodic bursts of sharp waves or sharp and slow wave activity
had been reported only in patients who had received antibiotic treatment. There are some reports that blame particularly beta-lactams among these antibiotics. The relation between b-lactam antibiotics and epilepsy is known for many years [4, 5]. Recently there are case reports especially about cefepime that it causes NCSE in renal failure in children and adults [6–15]. In the largest series of NCSE reported by Martinez-Rodriguez et al. [11], authors presented 10 NCSE patients associated with antibiotic therapy in patients with renal failure and cefepime again has been implicated in most of the cases (60%). In our series, nine of the patients (75%) have been receiving cefepime as mono-therapy or combined with other antibiotics. In addition, one of the patients has been receiving imipenem/cilastatin, and NCSE in this patient was considered to be related to its use. This patient was also receiving cyclosporine, which blood levels were within the normal limits. Mental status impairment and myoclonus in this patient disappeared after imipenem/cilastatin treatment was switched to meropenem treatment. Although mental confusion related to imipenem/cilastatin has been reported
123
before, this is the first imipenem/cilastatin related NCSE case shown by EEG. In addition, the majority of our patients had to receive high dose antibiotics due to severity of the clinical conditions; therefore it is likely that the serum levels of the drug increased and neurotoxicity occurred more easily. But it should be kept in mind that, it is observed that NCSE developed also in patients who were receiving the drug at the renal doses recommended [11–13]. We ordered the drugs according to the recommended dose but the changes of central nervous system in uraemia (e.g. accumulated guanidine compounds in uremia acts like GABA inhibitor, or changes in blood–brain barrier) [5, 16–19] may cause side effects in these patients. Although it is generally recognized that etiologic factors and co-morbidities are also important for prognosis of NCSE, it has been suggested that age of the patient, NCSE duration and response to treatment are effectual in prognosis [20]. Whereas in non-uremic patient groups, as a result of a retrospective analysis of a NCSE series of 100 cases; it was noted that primarily the etiologic cause was responsible for mortality, NCSE could rarely be fatal,
Clin Exp Nephrol (2009) 13:138–144
143
Fig. 2 EKG following administration of diazepam
etiology and altered mental state were independent risk factors, there was no relationship between NCSE duration before the diagnosis and overall duration of NCSE, and the most important complications were infectious, neurological and respiratory complications; [3] in this study, mortality due to all reasons was 18%. In addition to all these, survival in NCSE is mainly dependent on the respective patient group; while deaths are rare in ambulatory patients without a major comorbidity, mortality rate in comatose patients in intensive care units may be as high as 50% [21, 22]. However, due to quite limited number of reported cases, it is difficult to make comments about the mortality rate in patients with renal failure. In our series, mortality rate was 33% and, sepsis was the leading cause of deaths (50%). As the major cause of mortality is related to the seriousness of the underlying disease in NCSE, the patients died were generally those who had infections that could not be controlled with treatment due to their severe immunosuppressant comorbidities (e.g. hematological malignities, renal transplantation). As previously reported in the literature, sepsis appears to be the major cause of death in NCSE cases with renal failure [10, 11].
It is controversial whether NCSE causes sequalae neurological dysfunction in non-uremic group and the effect of antiepileptic treatment on prognosis [23]. There are no data that shows squeal signs remaining after NCSE in uremic NCSE cases. In our group as well, no sequalae signs that were considered to be related to NCSE remained in any patients. There are some limitations of our study. The analysis is only made on the patients with NCSE and uremia, and no patients groups are settled to compare the nephrological and neurological status with our patients. The comparisons between our reported group and the NCSE patients without uremia (either with or without antibiotic treatments), or antibiotic treated uremic patients without NCSE but comatose or other neurological disorders, require more information. In the largest series of NCSE patients published by Shneker et al. [3], only two of 100 patients had renal failure. We did not research all NCSE patients (including non-uremic patients) of our hospital, and we do not claim that NCSE is more prevalent in uremic patients in our paper. On the other hand, during our research phase, we discovered only two uremic
123
144
patients who had antibiotic-related convulsive (not nonconvulsive) status epilepticus. As a result our study did not answer these questions fully. Another issue is that the uremia status of patients is not described enough. The disorders by uremic compounds are much different in the patients with ARF, CRF and CRF on HD or PD. To relate the uremic status with the high incidence of NCSE, more details should be given. However, it was not possible to get these stated details extensively. Although there was no any change in biochemical analyses, which might explain the neurological findings, this is a heterogeneous group of patients. Hence it is not possible to give more details in a single paper.
Conclusion Due to high risk of infection in patients with ESRD, antibiotics have been commonly prescribed in this group of patients. Antibiotics, especially b-lactams could be neurotoxic and its use result in development of NCSE. Diagnosis of NCSE should be considered in all patients with unexplained loss of consciousness and EEG must be routine part of investigations in the assessment of loss of consciousness in patients with uremia receiving antibiotics.
References 1. Krumholz A, Sung GY, Fisher RS, Barry E, Bergey GK, Grattan LM. Complex partial status epilepticus accompanied by serious morbidity and mortality. Neurology. 1995;45:1499–504. 2. Towne AR, Waterhause EJ, Boggs JG. Prevalence of nonconvulsive status epilepticus in comatose patients. Neurology. 2000;54:340–5. 3. Shneker BF, Fountain NB. Assessment of acute morbidity and mortality in nonconvulsive status epilepticus. Neurology. 2003;61:1066–73. 4. Johnson H, Walter A. Intraventricular penicillin. A note of warning. JAMA. 1945;127:217–9. 5. Curtis DR, Game CA, Johnston GAR, et al. Convulsive action of penicillin. Brain Res. 1972;43:242–5. 6. Jackson GD, Berkovic SF. Ceftazidime encephalopathy. Absence status and toxic hallucinations. J Neurol Neurosurg Psychiatry. 1992;55:333–4. 7. Klion AD, Kallsen J, Cowl CT, Nauseef WM. Ceftazidimerelated nonconvulsive status epilepticus. Arch Intern Med. 1994;154:586–9.
123
Clin Exp Nephrol (2009) 13:138–144 8. Chetaille E, Masmoudi K, et al. Convulsions associated with the administration of excessive dose of ceftazidime in patients with renal failure. Therapie. 1994;49:435–8. 9. Dixit S, Kurle PK, Buyant-Dent L, Sheth RD. Status epilepticus associated with cefepime. Neurology. 2000;54:2153–5. 10. Chow KM, et al. Nonconvulsive status epilepticus in peritoneal dialysis patients. Am J Kid Dis. 2001;38:400–5. 11. Martinez-Rodriguez JE, Barriga FJ, et al. Nonconvulsive status epilepticus associated with cephalosporins in patients with renal failure. Am J Med. 2001;111:115–9. 12. Ferrara N, Abete P, Giordano M, Ferrara P, Carnovale V, Leosco D, et al. Neurotoxicity induced by cefepime in a very old hemodialysis patient. Clin Nephrol. 2003;59:388–90. 13. 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. 2000;20:554–8. 14. Alpay H, Altun O, Biyikli NK. Cefepime-induced non-convulsive status epilepticus in a peritoneal dialysis patient. Pediatr Nephrol. 2004;19:445–7. 15. Fishbain JT, Monahan TP, Canonico MM. Cerebral manifestations of cefepime toxicity in a dialysis patient. Neurology. 2000;55:1756–7. 16. De Deyn PP, Macdonald RL. Guanidino compounds that are increased in cerebrospinal fluid and brain of uremic patients inhibit GABA and glycine responses on mouse neurons in cell culture. Ann Neurol. 1990;28:627–33. 17. D’Hooge R, Pei YQ, Marescau B, De Deyn PP. Convulsive action and toxicity of uremic guanidino compounds: behavioral assessment and relation to brain concentration in adult mice. J Neurol Sci. 1992;112:96–105. 18. De Sarro A, et al. Relationship between structure and convulsant properties of some b-lactam antibiotics following intracerebroventricular microinjection in rats. Antimicrob Agents Chemother. 1995;39:232–7. 19. Schliamser SE, Cars O, Norrby SR. Neurotoxicity of beta-lactam antibiotics: predisposing factors and pathogenesis. J Antimicrob Chemother. 1991;27:405–25. 20. Krumholz A. Epidemiology and evidence for morbidity of nonconvulsive status epilepticus. J Clin Neurophysiol. 1999; 16:314–22. 21. Cockerell OC, Walker MC, Sander JW, Shorvon SD. Complex partial status epilepticus: a recurrent problem. J Neurol Neurosurg Psychiatry. 1994;57:835–7. 22. Young GB, Jordan KG, Doig GS. An assessment of nonconvulsive seizures in the intensive care unit using continuous EEG monitoring: an investigation of variables associated with mortality. Neurology. 1996;47:83–9. 23. Kaplan PW. No, some types of nonconvulsive status epilepticus cause little permanent neurologic sequelae (or: ‘‘the cure may be worse than the disease’’). Review. Neurophysiol Clin. 2000;30:377–82.
