A Case of Metronidazole‐Induced Encephalopathy: Can Encephalopathy be Distinguished From Delirium Like Symptoms?

ABSTRACT

Although the treatment strategies differ significantly, metronidazole‐induced encephalopathy and delirium manifest with similar clinical symptoms. Therefore, the potential risk of encephalopathy should be considered when treating patients with delirium.

1. Introduction

Encephalopathy typically arises from metabolic disturbances in the brain that affect neuropsychiatric function. It can be caused by a variety of systemic conditions, such as toxin exposure, drugs, metabolic disorders, infections, and COVID‐19 [1, 2]. Clinically, encephalopathy often presents with delirium, which is characterized by an acute onset of disorientation, hallucinations, delusions, and mood swings due to physical abnormalities or drug use, as well as seizures. The incidence of antibiotic‐induced encephalopathy is reportedly 1.0%; however, it may be underestimated [3, 4]. Therefore, it is often challenging to assess the potential causes of cognitive dysfunction. Moreover, delays in discontinuing the causative agent are not uncommon.

In this report, we describe a case of metronidazole‐induced encephalopathy in which the differential diagnosis and treatment initiation were delayed by several days. We aimed to share our experience and recommendations for managing patients with delirium‐like symptoms caused by encephalopathy.

2. Case Presentation

2.1. Case History and Examination

A 73‐year‐old man (height: 155 cm and weight: 68.2 kg) with rectal cancer and pulmonary metastases underwent robot‐assisted low anterior resection with D3 lymphadenectomy and ileostomy. Cefmetazole (2 g/day) was administered for postoperative infection prophylaxis (Figure 1). On postoperative day 3, the patient developed a fever of 37.6°C, and blood culture and abdominal drain fluid samples were collected. Computed tomography (CT) revealed an anastomotic leak. By day 4, the patient's C‐reactive protein (CRP) level had increased to 31.96 mg/dL, prompting a change in the antibiotic therapy to piperacillin‐tazobactam 18 g/day. On day 7, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels increased from 11/9 to 36/49 IU/L. Moreover, piperacillin‐tazobactam was suspected to be the cause of liver dysfunction, and Candida parapsilosis (1+) was detected in the abdominal drain fluid. Consequently, the antibiotic treatment was changed to levofloxacin 500 mg/day and metronidazole (2000 mg/day). Renal function decreased (serum creatinine level increased from 1.09 to 1.33 mg/dL); on day 13, levofloxacin was reduced to 250 mg/day. The CRP level remained stable, and the patient was discharged on day 33.

FIGURE 1.

Clinical course of the present case.

On day 35, the patient fell at home and continued to experience poor appetite and generalized fatigue. On day 37, the home nurse requested emergency transportation. On the day of emergency admission, the patient's renal function was found to have declined further, with a serum creatinine level of 1.83 mg/dL and an estimated glomerular filtration rate of 29.4 mL/min/1.73m². His blood ammonia level was stable. Unfortunately, an electroencephalogram was not performed. A head CT performed on the day of emergency admission revealed low‐attenuation areas in the midbrain, and the patient displayed gait instability but responded well to the medical instructions. On day 41, the patient made a statement indicative of disorientation: “Students are coming over now, so I need to teach them calligraphy.” He also exhibited dysarthria.

2.2. Differential Diagnosis

We initially considered dementia, cerebral infarction, and other causes of encephalopathy as potential explanations for the patient's symptoms. However, these were excluded based on head CT findings and clinical diagnosis. As delirium was suspected, treatment with ramelteon 8 mg/day and lemborexant 5 mg/day was initiated. Given the long‐term use of metronidazole, metronidazole‐induced encephalopathy was also considered. Blood dialysis was performed after the discontinuation of metronidazole. On day 43, the patient continued to display disorientation with statements such as, “There is someone downstairs. It is already 6 AM, so I need to go take out the trash. I will get changed,” along with persistent somnolence and dysarthria. Owing to continued daytime somnolence, lemborexant was discontinued. The patient had no history of delirium, alcohol use, depression, or other psychiatric disorders, at least based on our interview. In addition, he tested negative for COVID‐19

2.3. Investigations and Treatment

On day 44, magnetic resonance imaging (MRI) of the brain revealed high‐signal areas in the splenium of the corpus callosum on diffusion‐weighted, T2‐weighted, and fluid‐attenuated inversion recovery (FLAIR) imaging (Figure 2). Moreover, T2‐weighted and FLAIR imaging revealed bilateral symmetric hyperintense lesions in the cerebellar dentate nuclei. Therefore, a diagnosis of metronidazole‐induced encephalopathy was made (Figure 2).

FIGURE 2.

Brain computed tomography (CT) images of the patient's brain (A) at admission on day 37, and magnetic resonance imaging (MRI) of the brain (B–F) obtained 8 days after admission. (A) The CT scan reveals low‐attenuation areas in the midbrain; (B) diffusion‐weighted imaging shows high‐signal areas in the splenium of the corpus callosum, as do (C) T2‐weighted imaging and (D) fluid‐attenuated inversion recovery imaging. (E) T2‐weighted and (F) fluid‐attenuated inversion recovery imaging show bilateral symmetric hyperintense lesions in the cerebellar dentate nuclei.

2.4. Outcome and Follow‐Up

Dysarthria persisted, and the patient exhibited incoherent nighttime behavior; however, he responded well to medical instructions. By day 51, the dysarthria had improved, and the patient was discharged without complications on day 55.

3. Discussion

In the present case, the diagnosis of metronidazole‐induced encephalopathy was delayed owing to the difficulty in distinguishing between delirium and encephalopathy. Delirium is relatively common among hospitalized patients, particularly in older adults, those undergoing intensive treatments such as surgery or chemotherapy, or individuals in poor health, with an incidence of 10%–30% [5]. Given that it is frequently encountered by healthcare professionals, clinical practice involves conducting risk assessments and managing behaviors associated with delirium, with pharmacological interventions deemed necessary. While delirium generally improves within 1–2 weeks, it resolves as the underlying physical conditions improve. However, drug‐induced encephalopathy, which often manifests as symptoms similar to delirium, is uncommon and can be challenging to differentiate based on the clinical presentation alone. Generally, drug‐induced encephalopathy is associated with clinical findings similar to delirium and is considered reversible; however, irreversible outcomes have been reported [6]. Antibiotic‐induced encephalopathy is not well recognized. Moreover, in hospitalized patients, multiple factors may influence psychiatric symptoms, complicating the identification of antibiotic‐related encephalopathy as a cause of delirium.

Antibiotic‐associated encephalopathy can be classified into three clinical phenotypes based on clinical presentation, duration, and laboratory abnormalities (type 1, cephalosporins and penicillins; type 2, quinolones, macrolides, and procaine penicillin; and type 3, metronidazole). Type 1 presents with myoclonus and seizures, whereas type 2 presents with psychiatric symptoms such as hallucinations and delusions, with both types exhibiting normal head MRI findings [7]. Type 3 is relatively less associated with myoclonus or seizures, and metronidazole often causes cerebellar dysfunction, such as ataxia and balance disturbances, which are rare with other drugs [7]. In the present case, the patient exhibited signs suggestive of cerebellar dysfunction upon emergency admission. This raised the possibility that metronidazole‐induced encephalopathy had already developed at that time. Metronidazole‐induced encephalopathy has a median onset of 19 days (range: 1–180 days) and a median resolution of 13 days (range: 1–365 days), which is longer than that associated with encephalopathies caused by other antibiotics [7]. In our patient, dysarthria and disorientation developed on day 34 after the initiation of metronidazole therapy, and the symptoms improved by day 11 after discontinuation, following a course consistent with a previous report [7]. However, in cases of prolonged hospitalization, multiple potential factors contributing to delirium may complicate the differential diagnosis.

Although the mechanism of metronidazole neurotoxicity remains unclear, the pathogenesis appears to be related to free radical formation and altered thiamine metabolism [7]. Moreover, while metronidazole has good penetration into the cerebrospinal fluid and central nervous system, it has not been reported to directly cause disorders related to the blood–brain barrier. Abnormalities on T2‐weighted and FLAIR imaging are often observed, with hyperintense signals in the cerebellum, corpus callosum, and midbrain. Although the prognosis is generally favorable, irreversible neurological symptoms may develop, and cortical involvement is associated with a poor prognosis [6]. Similar imaging findings were observed in this case. Moreover, brain MRI is expected to be a useful tool in distinguishing metronidazole‐induced encephalopathy from delirium, which is believed to develop because of changes in neurotransmitter synthesis, function, and availability.

The primary risk factors for metronidazole‐induced encephalopathy are treatment duration and total dose. A total dosage of metronidazole ranging from 3 to 135 g is reportedly associated with the onset of encephalopathy [8]. However, in cases of severe hepatic or renal impairment, encephalopathy can develop even with relatively short treatment durations or lower total doses [9, 10]. Approximately 30%–60% of metronidazole is metabolized by the liver. In older adults or those with hepatic or renal dysfunction, metronidazole clearance is reduced, increasing central nervous system penetration [11, 12]. Thus, conditions such as hepatic encephalopathy [13], liver cirrhosis, liver abscesses [6], and malignancy are risk factors associated with the development of encephalopathy [14]. In this case, the patient's advanced age and coexisting malignancy may have contributed to the decreased metronidazole clearance. Although measuring metronidazole levels in the blood or cerebrospinal fluid could serve as a means of risk assessment, it is challenging in clinical practice. However, the relationship between the co‐administration of specific antibiotics and the risk of encephalopathy remains unclear.

In the present case, at the onset of disorientation, delirium was a reasonable diagnosis from his symptoms based on the patient's treatment history. However, the gait disturbance preceding the emergency admission may have been attributable to cerebellar ataxia. Metronidazole, which was initiated to treat an anastomotic leak, was not re‐evaluated upon emergency admission, nor was a brain MRI performed, leading to delayed discontinuation of metronidazole. Ultimately, metronidazole was discontinued 5 days after admission. However, we could have discontinued metronidazole earlier had we considered the possibility of metronidazole‐induced encephalopathy. Metronidazole‐induced encephalopathy associated with prolonged drug use has been previously reported [15], emphasizing the importance of optimizing antimicrobial therapies.

Although we conclude difficulty in distinguishing encephalopathy from delirium‐like symptoms, these symptoms improved with the discontinuation of metronidazole. Healthcare providers should carefully perform differential diagnoses considering the potential risks associated with each patient, particularly when clinical presentations common to more than one condition are noted.

Author Contributions

Maho Tanaka: conceptualization, data curation, writing – original draft. Yasushi Kojima: investigation, writing – review and editing. Takahiro Nishimura: supervision, writing – review and editing. Satoshi Numazawa: supervision, writing – review and editing. Kenji Momo: conceptualization, supervision, writing – review and editing.

Ethics Statement

The authors have nothing to report.

Consent

We obtained written informed consent from the patient for the publication of this report.

Conflicts of Interest

The Department of Hospital Pharmaceutics, School of Pharmacy, Showa University, received funds from Ono for a contract research project in accordance with a collaborative research agreement. As a potential conflicts of interest, the department also received research grants from Daiichi Sankyo, Mochida, Shionogi, Ono, Taiho, Nippon‐Kayaku, and Bayer. K.M. received an honorarium fee for presentations from Sawai, Nippon Kayaku, Hisamitsu, and Abbvie. Y.K. received an honorarium fee for presentations from Chugai, Esai, Ono, and AstraZeneca; participation on a data safety monitoring board. The other authors declare no conflicts of interest associated with this manuscript.

Tanaka M., Kojima Y., Nishimura T., Numazawa S., and Momo K., “A Case of Metronidazole‐Induced Encephalopathy: Can Encephalopathy be Distinguished From Delirium Like Symptoms?,” Clinical Case Reports 13, no. 9 (2025): e70800, 10.1002/ccr3.70800.

Data Availability Statement

All information pertaining to this case is included in this article.