Imipenem-associated encephalopathy: alert to physicians

Encefalopatia associada a impanem: alerta aos médicos

LETTER

Imipenem-associated encephalopathy: alert to physicians

Encefalopatia associada a impanem: alerta aos médicos

Alessandro Finkelsztejn^I; Lucas Cabral^II; José Augusto Bragatti^I; Aline Vitali da Silva^III; Arthur Francisco Schumacher Schuh^II

^IHospital de Clínicas de Porto Alegre, Porto Alegre RS, Brazil:Neurologist, Neurology Unit

^IIHospital de Clínicas de Porto Alegre, Porto Alegre RS, Brazil:Physician, Neurology Resident

^IIIHospital de Clínicas de Porto Alegre, Porto Alegre RS, Brazil:Medical student, Federal University of Rio Grande do Sul

^{Correspondence}

Imipenem, one of the first antibiotics of the carbapenem class, was developed more than 2 decades ago and has been utilized for multi-resistant bacterial infections in more than 26 million patients¹. It also has been a life-saving drug, as some bacteria are frequently resistant to other broad-spectrum antibiotics. Imipenem-related encephalopathy was not formally reported, and can be overlooked by practitioners.

The aim of this report is to alert physicians to this condition.

CASE

A 69-year-old, diabetic and hypertense, Caucasian male who presented to our hospital with behavioral disturbances, forgetfulness and a constant new-onset headache for the previous 10 days. His physical examination disclosed a right supranuclear facial palsy. A head MRI (Fig 1) was ordered and showed a right frontal mass lesion surrounded by marked edema and signs of subfalcial herniation. A routine screening for systemic cancer was normal. He was taken to neurosurgical treatment and a subtotal resection was achieved; the final pathological diagnosis was glioblastoma. In the post-operative period the patient developed multiple respiratory infections; his general medical condition worsened, and critical care was necessary for about 2 months. After partial recovery, he started on fractionated radiotherapy. At that moment, he showed paroxysmal clonic jerks on his right hemiface, and phenytoin was successful in suppressing them. Electroencephalogram (EEG) and cranial CT were performed, and revealed no new significant abnormalities. His general medical condition substantially improved. About a month later, he developed a mixed skin / respiratory severe sepsis. ESBL-producing Klebsiella pneumoniae was isolated from skin specimens, and imipenem was started at an adjusted dose. In the next two days, an impaired level of consciousness was established, and fluctuations between sleepiness and obnubilation went on. Four days later, his relatives reported new-onset generalized movements; on clinical examination sudden, brief, shock-like, involuntary, symmetrical, synchronous and repetitive muscle contractions were observed on proximal limb muscles (positive myoclonus). Common causes of metabolic encephalopathy were excluded by means of laboratory exams (complete blood count, glucose levels, renal / hepatic function, electrolytes and phenytoin level). A new head CT (Fig 2) showed stable edema and post-operative alterations but was not particularly helpful. A wake-up EEG (Fig 3) was performed concomitantly to the hyperkinesias and disclosed irregular slow waves and non-periodic left parieto-temporal sharp waves. In light of these findings, imipenem therapy was withdrawn, and 3 days later his consciousness level was fully recovered and myoclonus had disappeared. In order to confirm the improvement and to document the electrophysiological changes, a control EEG (Fig 4) was performed and was consistent with improved background rhythms; no sharp waves were detected anymore.

DISCUSSION

This report aims to show a probable adverse drug reaction related to imipenem use. The chronological relationship between the introduction of the drug and the onset of encephalopathy, and its withdrawn and patient recovery reveal a close association with imipenem. Additionally, the combined EEG findings give support to this association.

The most recommended method for estimating the probability of an adverse drug reaction is the Naranjo Scale². Analyzed by this method, our case scored a total of 6, which represents a "probable" adverse drug reaction.

Medical literature demonstrates some articles on imipenem neurotoxicity, most of them reporting seizures. A paper from Rivera et al.³ reports a case of a 80-year-old male who developed reversible myoclonus after the beginning of Imipenem. This patient had the most common risk factor for neurotoxicity, chronic renal insufficiency.

The article from Norrby⁴ discusses the prevalence of seizures caused by imipenem to be 0.2%, while Rodloff et al.¹ refers to the prevalence of seizures to be 1.4%. All these articles present seizures as the most common neurologic adverse event caused by imipenem. Similarly as reported by Norrby⁴, our patient also had previous CNS disease as a risk factor for neurotoxicity from imipenem. The case presented here, however, is an example of encephalopathy, not of an isolated seizure.

Betalactamic-related encephalopathy is not a new clinical entity. Broadly used antibiotics such cefepime are soundly related to various abnormal mental status disorders⁵. The clinical picture and EEG findings from cefepime encephalopathy can perfectly be superimposed to our case. To our knowledge, no previous imipenem-related encephalopathy was formally reported.

Considering this patient evolution, imipenem-related encephalopathy appears to be a reversible and relevant clinical entity. We conclude that physicians should be alert about symptoms of encephalopathy. We suggest that more studies on this subject should be done.

Received 13 April 2009

Received in final form 18 April 2009

Accepted 17 September 2009

References

• 1. Rodloff AC, Goldstein EJC, Torres A. Two decades of imipenem therapy. J Antimicr Chemotherapy 2006;58:916-929.
• 2. Naranjo CA, Busto U, Sellers EM, et al. A method for estimating the probability of adverse drug reaction. Clin Pharmacol Ther 1981;30:239-245.
• 3. Rivera M, Crespo M, Teruel JL, Marcén R, Ortuño J. Neurotoxicity due to imipenem-cilastatin in patients on continuous ambulatory peritoneal dialisys. Nephrol Dial Transplant 1999;14:258-259.
• 4. Norrby RS. Neurotoxicity of carbapenem antibacterials. Drug Safety 1996; 15:87-90.
• 5. Bragatti JA, Rossato R, Ziomkowski S, Kliemann FAD. Encefalopatia induzida por cefepime: achados clínicos e eletroencefalográficos em sete pacientes. Arq Neuropsiquiatr 2005;63:87-92.

Publication Dates

• Publication in this collection
  22 Sept 2010
• Date of issue
  Feb 2010