Cefepime-induced Cotard syndrome: a case report

Molly Howland MD1, Chelsea Markle PharmD, BCPP1, Jennifer M. Erickson DO1, Thomas Soeprono MD1
1Department of Psychiatry and Behavioral Sciences, University of Washington School of Medicine, Seattle, WA
Corresponding author: [email protected]

DOI
doi.org/10.7244/cmj.2021.01.001
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Abstract

Background:
Cotard syndrome features nihilistic delusions about one’s body or existence and is typically related to severe depression though is rarely associated with medical or neurological insults.

Case presentation:
The patient was a 62-year-old male with no past psychiatric history and a past medical history of congestive heart failure and consequent renal failure who presented for scheduled heart and kidney transplantation. He was started on routine post-transplant ganciclovir and steroids. Due to postoperative hypotension, empiric cefepime was initiated to cover for septic shock. One week postoperatively, the patient stated “I am dead.” He elaborated that “an intern overdilated me” during transplantation and declined tacrolimus. The patient also reported visual hallucinations of green algae and bubbles. He denied depression and was attentive and oriented. He had a Bush-Francis score of 9. MRI brain revealed no acute changes. Low-dose haloperidol was initiated for psychosis. Cefepime was discontinued, but ganciclovir and steroids were continued. Two days later, the symptoms fully resolved.

Discussion:
This is the first reported case of Cotard syndrome as an acute transplant complication. Though corticosteroid-induced psychosis was initially suspected, cefepime neurotoxicity is the more likely explanation given the correlation between the antibiotic and symptom courses. Older age and renal dysfunction were risk factors.

Conclusions:
Cotard Syndrome can be an acute complication of solid organ transplantation, where renal impairment and polypharmacy are common. Transplantation teams and consult-liaison psychiatrists should work together to manage this syndrome.

 

Introduction


Cotard syndrome is a rare clinical entity that features nihilistic delusions that one is dead and may also include delusions of damnation and immortality.[1] Cotard syndrome warrants active management, as complications include medication nonadherence, self-starvation, and suicide attempts.[1,2]
 
Depression, schizophrenia, and other psychiatric diagnoses have been associated with Cotard syndrome.[1] Cotard syndrome has been occasionally demonstrated in neurological conditions such as cerebral infarction, temporal lobe epilepsy, and multiple sclerosis.[1] Due to lesions in face processing regions in some patients, Cotard syndrome is postulated to represent patients’ explanation of being unable to recognize their own face.[3] Cotard syndrome has been rarely described in case reports as an adverse drug reaction (ADR) of medications including steroids, antivirals, and amantadine via unclear mechanisms.[4,5] 

Most patients with Cotard syndrome recover, particularly when symptoms are related to a medical etiology.[4,6] Symptom resolution typically results from treatment of the underlying problem through pharmacotherapy, psychotherapy, electroconvulsive therapy, and/or withdrawing the offending medication.[1,4,6] For instance, anti-epileptic medication treats Cotard Syndrome associated with seizures.[4] Psychiatrists, neurologists, and internists should know how to recognize and manage this syndrome.

We present an older transplant patient with no prior psychiatric history who acutely developed Cotard syndrome in the setting of a recent heart and kidney transplant and cefepime treatment. Given the heterogeneity of Cotard syndrome etiologies, our objective was to present a differential diagnosis for Cotard syndrome in the post-transplantation period, highlight a unique etiology of the syndrome, and propose management considerations.

 

Case Presentation


The patient was a 62-year-old male with no past psychiatric history and a past medical history significant for congestive heart failure secondary to non-ischemic cardiomyopathy and recurrent acute kidney injury secondary to heart failure. He initially presented for scheduled heart and kidney transplantation. One week postoperatively, he stated “I am dead.”

After transplant, he was resuscitated without issue. Routine post-transplant antiviral prophylaxis was initiated on postoperative day (POD)-1 with ganciclovir 100 mg/d (renally dosed). He was started on IV cefepime (2-4 g/d, renally dosed) on POD2 and vancomycin on POD3 due to shock of unclear etiology. Diagnostic evaluation revealed shock was primarily cardiogenic, which improved over days. Methylprednisolone and tacrolimus were initiated for routine post-transplant immunosuppression. 

On POD6, he was noted by staff and his wife to trace “I’m dead” with his fingers on the bed while still intubated. After extubation later that day, he told staff he was dead and declined oral tacrolimus. He was observed to be fully oriented otherwise. 

Psychiatry was consulted for evaluation and management of the death delusion. During initial evaluation on POD7, the patient stated “I am dead” since “forever.” He did not want tacrolimus “because I’m dead” and “because it would bring me back to life.” However, he denied depression or suicidality. The patient described that “an intern overdilated me” during heart transplantation, which caused the surgery to fail. He believed he was on Earth and that we could converse because “you can speak to the dead.” He reported constantly seeing “green algae” and “bubbles” on the ceiling. The patient was calm and cooperative, though made only brief eye contact before staring upward. Orientation was intact to person, place, date, and general situation, and thought process was linear. Speech was non-spontaneous and under-elaborative. Affect was neutral and blunted. Bush-Francis score was 9 out of 23 (immobility +1, staring +2, rigidity +1, repetition of phrases +1, withdrawal +1, grasp reflex +3).

The patient was hemodynamically stable. Labs were remarkable for white count of 14 (from 11 the day before), creatinine 3.06 (from 2.41), BUN 70 (from 48), and tacrolimus <1. 

Psychiatry initially suspected steroid-induced Cotard syndrome. To address psychotic symptoms, haloperidol 2.5 mg IV daily was initiated on POD7. A lorazepam trial was considered for catatonic symptoms but not initiated. Psychiatry recommended a non-contrast CT head to rule out stroke as a cause of the delusion, which was negative for acute findings.

Cefepime was discontinued by POD8. The patient had been cooperating with care but continued to state that he was dead, which he knew because “I’m not breathing.” The same visual hallucinations persisted. Bush-Francis score was 3 (immobility +1, repetition of phrases +1, withdrawal +1). 

On POD9, the patient was certain he was alive. To explain his recent belief, he stated, “It felt like I was repeating last Tuesday over and over again” (the day he was re-intubated). He explained that “Now I have a new purpose” due to improvement of his medical situation. He denied hallucinations. The patient’s wife believed he was back to normal other than speaking slowly. Three days later, the patient’s QTc was 562, so haloperidol was discontinued. On POD12, non-contrast MRI/MRA of the brain was obtained to evaluate for an etiology of Cotard syndrome and post-transplant tongue deviation. This showed no acute changes and moderate enlargement of the ventricles and sulci. The patient remained on steroids, ganciclovir, and tacrolimus without symptom recurrence.

 

Discussion


Our older patient who underwent heart and kidney transplant with ongoing renal dysfunction experienced the acute onset of Cotard syndrome, which is the first reported instance of this rare syndrome in the acute post-transplant period. The syndrome was initially attributed to steroids; however, we believe cefepime neurotoxicity is the more likely cause. Cotard syndrome as a sequela of cefepime neurotoxicity has not been previously reported. 

Based on the Naranjo Scale,[7] cefepime caused a “possible” ADR (Table 1) given a known association between cefepime and neurotoxicity[8,9] and symptom onset and resolution occurring as expected per a recent cefepime neurotoxicity review.[8] Specifically, symptoms typically appear a median of four days after cefepime initiation and resolve a median of two days after discontinuation,8 which mirrors our patient’s course.

Cefepime antagonizes GABA receptors, creating a hyperexcitable brain state.[8] The clinical presentation typically features delirium, decreased consciousness, myoclonus, aphasia, seizures, and/or agitation.[8,9] Isolated psychotic symptoms or Cotard syndrome have not been previously reported as cephalosporin ADRs.

Our patient’s older age and renal dysfunction were significant risk factors for cefepime neurotoxicity.[8] Both acute and chronic renal dysfunction can increase a patient’s risk of cefepime neurotoxicity via increasing serum levels of cefepime and decreasing protein binding (secondary to proteinuria), leading to an increased concentration of unbound cefepime available to cross the blood-brain barrier.[9] Though our patient’s cefepime was dosed appropriately based on kidney function, renally dosed cefepime can cause neurotoxicity due to other potential pharmacokinetic factors (e.g., decreased integrity of the blood-brain barrier secondary to acute inflammation).[8,9] 

Ganciclovir and steroids have been associated with Cotard syndrome,[4,5] but ganciclovir and steroids were continued for several weeks without symptom recurrence. In the only previous report of steroid-induced Cotard syndrome, symptoms resolved only after withdrawal of steroids.[4] Delirium was improbable, as our patient’s course was not fluctuating, and attention and orientation were intact. Tacrolimus levels were undetectable, so tacrolimus neurotoxicity was unlikely. Primary neurologic etiologies were unlikely as MRI brain was unremarkable, and the duration of symptoms was too short for stroke and too long for transient ischemic attack. The patient did not have a past psychiatric history or perioperative affective symptoms, making a primary psychiatric etiology unlikely. Haloperidol was an unlikely cure given rapid symptom resolution. 

Physicians should recognize Cotard syndrome as a possible complication of cefepime use, particularly in the post-transplant period due to the risk of graft failure. In patients with renal graft failure, renally adjusted dosing (unless the patient is on continuous renal replacement therapy) and a less neurotoxic antibiotic than cefepime should be considered. Other critically ill patients (e.g., patients with suspected gram-negative infections) may require cefepime and possess risk factors for cefepime toxicity such as older age, renal dysfunction, and pre-existing brain injury.[8,9] We suggest close neurological monitoring of high-risk patients on cefepime. A clear threshold for toxic cefepime serum levels has not yet been established, so prophylactic monitoring of cefepime levels is unlikely to be helpful.[8]

In patients with Cotard syndrome suspected to be cefepime related, cefepime should be discontinued, as Cotard syndrome has resolved after withdrawal of the offending agent and/or hemodialysis in our case and other cases induced by medication toxicity.[4,5,9] If discontinuing cefepime is not medically advisable, a benzodiazepine trial could be considered given the GABA-related mechanism of cefepime neurotoxicity.[9] However, this intervention warrants systematic study. Antipsychotic medication may increase patients’ agreeability to taking antirejection medications. All patients with Cotard syndrome should be regularly monitored for suicidality.[6]

Case reports on the combination of Cotard syndrome and catatonia have described mood-related etiologies of this rare combination;[10] our patient’s medical etiology is novel. Catatonia and Cotard syndrome symptoms commonly resolve with lorazepam.[10] However, our patient’s symptoms resolved with the discontinuation of cefepime. A lorazepam trial may not be necessary for this symptom combination if the underlying medical cause is addressed.

 

Conclusions


The consequences of post-transplant Cotard syndrome may be severe since medications to prevent organ rejection may be declined due to delusional thinking or discontinued due to neurotoxicity. Though delirium or steroid psychosis are typically suspected when peritransplant mental status changes occur, physicians should be aware of other etiologies, including neurotoxicity from the commonly used antibiotic cefepime. 

References


1.    Debruyne H, Portzky M, Van den Eynde F, Audenaert K. Cotard’s syndrome: a review. Curr Psychiatry Rep 2009 Jun;11(3):197-202. doi: 10.1007/s11920-009-0031-z
2.    Moschopoulos NP, Kaprinis S, Nimatoudis J. Cotard’s syndrome: Case report and a brief review of the literature. Psychiatriki 2016 Oct-Dec;27(4):296-302. 
3.    Kudlur SNC, George S, Jaimon M. An overview of the neurological correlates of Cotard syndrome. Eur J Psychiatry 2007 Jun;21(2)
4.    Sahoo A, Josephs KA. A neuropsychiatric analysis of the Cotard delusion. J Neuropsychiatry Clin Neurosci 2018 Jun;30(1):58-65. doi: 10.1176/appi.neuropsych.17010018
5.    Hellden A, Odar-Cederlog I, Larsson K. Death delusion. The BMJ 2007 Dec;335:1305. doi: 10.1136/bmj.39408.393137.BE
6.    Enoch M, Ball H. Uncommon Psychiatric Syndromes. 4th ed. CRC Press;2001. Cotard’s Syndrome. p.116-133
7.    Naranjo CA, Busto U, Sellers EM, Sandor P, Ruiz I, Roberts EA, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther 1981 Aug;30(2):239-245. doi: 10.1038/clpt.1981.154
8.    Payne LE, Gagnon DJ, Riker RR, Seder DB, Glisic EK, Morris JG, et al. Cefepime-induced neurotoxicity: a systematic review. Crit Care 2017 Nov;21:276. doi: 10.1186/s13054-017-1856-1
9.    Appa AA, Jain R, Rakita RM, Hakimian S, Pottinger PS. Characterizing cefepime neurotoxicity: a systematic review. Open Forum Infect Dis 2017 Oct;4(4). doi: 10.1093/ofid/ofx170
10.    Basu A, Singh P, Gupta R, et al. Cotard syndrome with catatonia: Unique combination. Indian J Psychol Med 2013 Jul-Sep;35(3):314-316. doi: 10.4103/0253-7176.119490
 

Table 1

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