Nephrol Dial Transplant (2004) 19: 252-254
© European Renal Association–European Dialysis and Transplant Association
Teaching Point
(Section Editor: K. Kühn)
Supported by an educational grant from 
Creutzfeldt–Jakob-like EEG in a patient with end-stage renal failure
Chiao-Lin Chuang1,
Kun-Po Chen2,
Shang-Yeong Kwan3 and
Wu-Chang Yang1
1Division of Nephrology, Department of Medicine, 3Section of Epilepsy, Neurological Institute, Taipei Veterans General Hospital and National Yang-Ming University School of Medicine and 2Taipei City Psychiatric Center, Taiwan
Correspondence and offprint requests to: Chiao-Lin Chuang, MD, Division of Nephrology, Department of Medicine, Taipei Veterans General Hospital, No. 201, Sec 2, Shih-Pai Road, Taipei 112, Taiwan. Email: clchuang{at}vghtpe.gov.tw
Keywords: ceftazidime; Creutzfeldt–Jakob disease; electroencephalogram; haemodialysis
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Introduction
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Ceftazidime is a widely used third-generation cephalosporin
with structural similarities to penicillins, and has been reported
to cause encephalopathy in the setting of inappropriate dosage.
We present here a case of ceftazidime intoxication with neurological
manifestations and electroencephalogram (EEG) patterns similar
to that seen in the Creutzfeldt–Jakob disease (CJD). All
of the patient's symptoms subsided and the EEG normalized after
drug cessation and daily haemodialysis, suggesting an adverse
response to ceftazidime.
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Case report
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A 76-year-old woman, on maintenance haemodialysis for 3 years
as a consequence of chronic glomerulonephritis, came to our
hospital with an infection of her arteriovenous fistula. On
admission, she was afebrile, mentally fully oriented and had
a blood pressure of 140/80 mmHg. Her physical examination was
remarkable for erythema and purulence on the left arm over the
arteriovenous fistula. Laboratory tests confirmed the presence
of advanced renal failure (blood urea nitrogen 76 mg/dl, creatinine
7.9 mg/dl) and anaemia (haemoglobin 9.8 g/dl). Routine biochemical
tests (including electrolytes, liver enzymes, lipids and glucose)
were normal. Empiric treatment was initiated with oxacillin,
1 g every 6 h, intravenously. Three days later, the wound culture
reports came back positive for
Pseudomonas aeruginosa with sensitivity
to ceftazidime. Parenteral ceftazidime was started, 2 g every
12 h. Unexpectedly, disturbance of consciousness as well as
myoclonic jerk involving upper extremities suddenly appeared
on the eighth hospital day. Serum urea nitrogen and creatinine
concentrations were 42 and 3.1 mg/dl, respectively. Serum glucose,
sodium, potassium, calcium, magnesium, aluminium and arterial
blood gases were all within normal limits. Blood cultures were
negative. Neurological examination documented disorientation
and myoclonic movements of the upper extremities. There was
neither fever nor hypotension. Magnetic resonance imaging (MRI)
of her brain disclosed no evidence of recent infarction or haemorrhage.
Lumbar puncture was withheld due to her family's concerns. Surprisingly,
the EEG (
Figure 1) revealed periodic short-interval diffuse
discharge (PSIDD) with a frequency of 1.6 Hz superimposed on
a diffuse, slow background activity in the theta and delta ranges,
raising the suspicion of CJD. However, her past history, clinical
course and MRI findings did not support this diagnosis. Since
her neurological status continued to deteriorate in the absence
of another obvious cause for the rapidly evolving dementia,
beginning with the ninth hospital day, the patient's pharmacotherapy
was discontinued and she underwent daily haemodialysis, given
a high suspicion of ceftazidime toxicity. In 72 h, following
the discontinuation of ceftazidime and three consecutive sessions
of haemodialysis, she was able to respond to simple commands.
An EEG repeated on hospital day 12 (
Figure 2) showed diffuse
background slowing in the theta and delta ranges with complete
disappearance of PSIDD. Serum ceftazidime was measured before
and after haemodialysis on the ninth, tenth and eleventh days,
with levels being, as expected, 480/95.8, 62/22.7 and 18.3/12.8
µg/ml (normal peak level 55 µg/ml), respectively.
On discharge (hospital day 14), she was fully alert and oriented
to person and place. Within 1 month after discharge, her mental
status and activity level had recovered.
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Fig. 1. EEG showed PSIDD with a frequency of 1.6 Hz, mostly maximal in the posterior head regions and some in anterior head regions, superimposed on a diffuse, slow background activity in the theta and delta ranges.
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Fig. 2. EEG showed diffuse background slowing in the theta and delta ranges with complete disappearance of previous PSIDD.
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Discussion
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Ceftazidime, a third-generation cephalosporin with a chemical
structure similar to penicillins, has been reported to cause
encephalopathies, with manifestations of lethargy, disorientation,
myoclonus and tonic–clonic seizure if administered in
excessive dosage [
1–
4]. The mechanism of this adverse
effect is hypothesized to be a competitive antagonism (in the
higher central brain) with the principal inhibitory neurotransmitter,
-aminobutyric acid by a portion of the antibiotic molecule that
is structurally related to bicuculline, a known (GABA) antagonist
[
5]. In addition, ceftazidime is not metabolized in the body
and is only 17% protein-binded. Glomerular filtration of unchanged
ceftazidime therefore is the major route of its elimination,
and its elimination half-life is prolonged in direct proportion
with the reduction in creatinine clearance, allowing for an
accumulation of the drug in patients with renal impairment.
For this reason, great care should be exercised in prescribing
ceftazidime to patients with renal failure. In patients with
end-stage renal disease, the elimination half-life of ceftazidime
was found to be 33.9 h during the interdialytic period and decreased
to 3.3 h during haemodialysis (
vs 1.9 h in normal adults) [
6].
Hence, ceftazidime at 1 g daily would be expected to produce
a therapeutic plasma concentration.
Five cases of ceftazidime-induced encephalopathy with similar characteristics have previously been reported in the literature [1–4]. Their EEGs showed a 3-per-second spike-and-wave activity (consistence with non-convulsive status epilepticus) in two patients [2,3], and PSIDDs with a frequency of 1–2 Hz superimposed on a diffuse, slow background activity in the theta and delta ranges, raising the suspicion of metabolic encephalopathies, in the other two patients [4]. Similarly, the EEG obtained in our patient demonstrated a PSIDD pattern with a frequency of 1.6 Hz superimposed on a diffuse, slow background activity in the theta and delta ranges, based on which we suspected CJD. Therefore, the PSIDD observed in our patient is, in fact, not pathognomonic for CJD (sensitivity/specificity: 67/86%) [7]. It could be associated with epilepsy, metabolic encephalopathy, infections of the CNS, and toxic effects of drugs. Clinical manifestations such as disorientation, rapidly progressive dementia as well as myoclonus, which are consistent with the diagnosis of ‘probable’ CJD according to WHO criteria [8], may lead to a delay in diagnosis and possibly permanent damage. Therefore, ceftazidime toxicity was not initially suspected in any of the reported cases other than ours. Fortunately, all patients recovered completely after the drug was stopped.
The Creutzfeldt–Jakob-like syndrome, with neurological features of rapidly progressive dementia along with myoclonic jerks involving limbs and characteristic EEG changes consisting of periodic sharp complexes that resemble those of the CJD, was first described by Smith and Kocen in 1988 [9]. From then on, some cases of drug-induced Creutzfeldt–Jakob-like syndrome have been reported, implicating in particular lithium. Thus, a careful drug history should be taken in any patient with rapidly progressive dementia even when the EEG suggests a diagnosis of CJD. All previous cases of ceftazidime-related encephalopathy as well as our patient had renal failure; so the need for carefully evaluating a patient's renal function to determine the appropriate dose of intravenously administered ceftazidime must be emphasized. Additionally, the patient's mental status should be monitored closely, and EEG should be obtained during ceftazidime therapy in the presence of myoclonus or altered mental status, or both. The EEG pattern, although non-specific, could prompt physicians to look for drug-induced neurotoxicity and avoid delayed diagnosis and possibly permanent sequelae. Once clinical suspicion is raised, drug cessation in combination with intensive haemodialysis is the best therapeutic option for patients with end-stage renal disease.
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Teaching points
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- Rapidly progressive encephalopathy with myoclonus and akinetic mutism may suggest the diagnosis of CJD. However, the differential diagnosis is broad and includes infections of the CNS, epilepsy, metabolic disorders and toxic effects of drugs.
- Ceftazidime-related toxicity should be suspected in any patient with encephalopathy during ceftazidime treatment, especially in patients who had pre-existing renal insufficiency.
- The typical neurological symptoms and characteristic pattern of EEG, a PSIDD with a frequency of 1–2 Hz, should prompt physicians to consider the possibility of this potentially dangerous complication.
Conflict of interest statement. None declared.
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References
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- Douglas MA, Quandt CM, Stanley DA. Ceftazidime-induced encephalopathy in a patient with renal impairment. Arch Neurol 1988; 45:936–937[Abstract/Free Full Text]
- Jackson GD, Berkovic SF. Ceftazidime encephalopathy: absence status and toxic hallucinations. J Neurol Neurosurg Psychiatry 1992; 55:333–334[Free Full Text]
- Klion AD, Kallsen J, Cowl CT, Nauseef WM. Ceftazidime-related nonconvulsive status epilepticus. Arch Intern Med 1994; 154:586–589[Abstract/Free Full Text]
- Martínez-Rodríguez JE, Barriga FJ, Santamaria J et al. Nonconvulsive status epilepticus associated with cephalosporins in patients with renal failure. Am J Med 2001; 111:115–119[CrossRef][Medline]
- Curtis DR, Game CJA, Johnston GAR, Mc Cullough RM, MacLachlan RM. Convulsive action of penicillin. Brain Res 1972; 43:242–245[CrossRef][Web of Science][Medline]
- Nikolaidis P, Tourkantonis A. Effect of hemodialysis on ceftazidime pharmacokinetics. Clin Nephrol 1985; 24:142–146[Web of Science][Medline]
- Steinhoff BJ, Racker S, Herrendorf G et al. Accuracy and reliability of periodic sharp wave complexes in Creutzfeldt–Jakob disease. Arch Neurol 1996; 53:162–166[Abstract/Free Full Text]
- Zelder M, Gibbs C Jr, Meslin F. WHO Manual for Strengthening the Diagnosis and Surveillance of Creutzfeldt–Jakob Disease. WHO, Geneva, Switzerland, 1998
- Smith SJ, Kocen RS. A Creutzfeldt–Jakob like syndrome due to lithium toxicity. J Neurol Neurosurg Psychiatry 1988; 51:120–123[Abstract/Free Full Text]
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