A case report of metronidazole-induced encephalopathy in a bowel obstruction patient with MRI findings

Abstract

Metronidazole is a widely used antimicrobial agent in the treatment of anaerobic and protozoal infections. However, excessive and prolonged use of metronidazole can lead to encephalopathy. We present a case of a 69-year-old male with bowel obstruction who was treated with metronidazole for approximately 26 days and subsequently developed neurological signs and symptoms. The magnetic resonance imaging findings were consistent with the suspected diagnosis of metronidazole-induced encephalopathy. This case highlights the necessity for careful monitoring of patients receiving metronidazole to detect central nervous system toxicity, and emphasizes the role of magnetic resonance imaging in confirming the diagnosis.

Introduction

Metronidazole, a member of the nitro-imidazole group of antibiotics, has been utilized for over three decades in the treatment of anaerobic and parasitic infections. Due to its excellent cellular penetration, it can readily reach the central nervous system. ¹ It is crucial to optimize the dosage and duration of metronidazole use, as a prolonged period of administering more than 2 g/day is associated with peripheral neuropathy and cerebellar dysfunction.^2,3 Gut translocation of bacteria with clinically significant septic complications is common in bowel obstruction. In such cases, broad-spectrum antibiotics, including metronidazole, are frequently employed as an adjunct to surgery.^4,5 Here, we present a case of metronidazole-induced encephalopathy (MIE) in a patient with bowel obstruction.

Case report

A 69-year-old male presented to the emergency department with a chief complaint of abdominal pain that had been ongoing for 3 days. He also reported experiencing multiple episodes of vomiting. The patient denied any history of loss of consciousness, seizures, or vertigo. He stated that he did not consume alcohol and was not taking any chronic medications. He stated no history of exposure to fumigant gas or working in the industries.

Of note, 6 months prior to this presentation, the patient had undergone a bilateral percutaneous nephrostomy tube insertion due to obstructive uropathy.

Upon physical examination, the patient’s abdomen appeared distended. There was tenderness noted in the epigastric and periumbilical regions. Percussion of the abdomen yielded a tympanic sound, indicating air-filled bowel loops. No obvious guarding, rigidity, or rebound tenderness was observed. Signs of dehydration were evident, including dry oral mucosa, dry eyes, and reduced skin turgor. There were no blisters in skin and no ulceration in mucosal surface was noted. Bowel sounds were hypoactive, suggesting decreased intestinal motility. Rectal examination did not reveal any abnormalities, and the hernial orifices appeared intact.

Subsequently, the patient experienced generalized tonic–clonic seizures, which are characterized by sudden loss of consciousness followed by generalized muscle contractions and rhythmic jerking movements. In addition to the seizures, the patient exhibited signs of neurological dysfunction. Impaired coordination was noted, as evidenced by the inability to perform a finger-to-nose test. The patient also demonstrated a tendency to fall to the right side while walking, indicating a balance disturbance. Furthermore, he developed dysarthria, a condition characterized by slow and slurred speech. Notably, the remaining sensory and motor examinations were within normal limits.

Ultrasound examination demonstrated dilated bowel loops with moderate ascites and echogenic contents. The contrast-enhanced computed tomography of the abdomen and pelvis report was unavailable, but features consistent with bowel obstruction and pneumatosis coli were mentioned. The patient was admitted and initiated with broad-spectrum antibiotics including metronidazole 500 mg intravenous thrice daily. Liver function tests were deranged (SGOT 60 IU/L, SGPT 62 IU/L, Gamma-glutamyl transferase 377 IU/L, alkaline phosphatase 300 IU/L, Albumin 19 gm/L, Prothrombin time 26 with INR of 2.16, Total leukocyte count 22,500). Three weeks after the admission, the patient developed agitation with focal seizure characterized by facial twitching. Normal level of serum electrolyte was noted with sodium (141 mEq/l), potassium (4.1 mEq/L), calcium (9.3 mg/dl), and phosphate(4.7 mg/dl). The serology report for Japanese encephalitis was negative. Cerebrospinal fluid (CSF) analysis was performed to rule out any infective and demyelinating etiology. CSF analysis was inconclusive showing, two lymphocytes, glucose of 60 mg/dl, protein of 39 mg/dl, and no oligoclonal bands. Urine examination shows normal findings without any sweety smell. A plain computed tomography head (not available) showed normal findings.

Further evaluation was performed with magnetic resonance imaging, which showed bilateral symmetrical high signal in the dentate nucleus and medial cerebellum in T2 and fluid attenuated inversion recovery (FLAIR) images (Figure 1(a) and (b)). T2 and FLAIR high signals are also noted in part of the middle cerebellar peduncle, dorsum of the pons, tectum of the midbrain (Figure 2(a) and (b)), and right basal ganglia (Figure 3(a) and (b)). Diffusion-weighted imaging (DWI) demonstrated high signal intensity in the bilateral medial cerebellar hemisphere, dentate nucleus, and middle cerebellar peduncle. However, the apparent diffusion coefficient (ADC) showed a high signal with a higher value of coefficient (1005 × 10⁻⁶ mm²/s) in the site of diffusion signal abnormality suggestive of T2 shine through (Figure 4(a) and (b)). Corresponding areas exhibited iso-intense signal intensity in T1-weighted images with no areas of blooming in Gradient echo images (Figure 5(a) and (b)).

Figure 1.

Sixty-nine-year-old male with metronidazole-induced encephalopathy. (a) Axial T2-weighted and (b) fluid attenuated inversion recovery images show increased signal intensities (black arrows) symmetrically involving the bilateral dentate nuclei, middle cerebellar peduncle, and part of the pons.

Figure 2.

Sixty-nine-year-old male with metronidazole-induced encephalopathy. (a) Fluid attenuated inversion recovery and (b) axial T2-weighted images show the increased signal intensity (orange arrow) in the tectum of the midbrain.

Figure 3.

Sixty-nine-year-old male with metronidazole-induced encephalopathy. (a) Axial T2-weighted and (b) fluid attenuated inversion recovery images showing high signal intensity in the right basal ganglia (black arrows).

Figure 4.

Sixty-nine-year-old male with metronidazole-induced encephalopathy. (a) Axial diffusion-weighted imaging showing the high signal intensity in bilateral dentate nucleus (blue arrow), middle cerebellar peduncle, and dorsal pons. (b) Corresponding areas in apparent diffusion coefficient also give a high signal with a higher coefficient value (1005 × 10⁻⁶ mm²/s).

Figure 5.

Sixty-nine-year-old male with metronidazole-induced encephalopathy. (a) Axial Gradient echo image shows no area of blooming in the medial cerebellar hemisphere and dentate nucleus. (b) These areas show iso-intense signal intensity in T1-weighted image.

Based on these imaging findings and the patient’s history of prolonged metronidazole use for approximately 25 days, metronidazole toxicity was suspected. Discontinuation of metronidazole was advised, resulting in the resolution of convulsive features and agitation. The patient’s legally authorized representative refused follow-up MRI. Unfortunately, the patient developed ventilator-associated pneumonia and ultimately died because of sepsis.

Discussion

The exact mechanism of MIE is not well-understood. Multiple theories have been put forward, including the interstitial edema and ischemia causing the T2 shine-through effect, or intracellular binding of metronidazole to Purkinje RNA (Ribonucleic Acid) with resultant axonal degeneration. Ahmed et al. described the first imaging finding of metronidazole toxicity with symmetrical bilateral T2 hyperintense signal in supra and infratentorial white matter and corpus callosum. They suggested that axonal swelling and edema due to metronidazole could be the possible mechanism, which is reversible upon discontinuation of the drug. ⁶ Genetic predisposition has also been proposed as a possible etiology. ⁷ Some indications for metronidazole require prolonged treatment or a higher dose, in creasing the risk of its toxicity. ⁸ Neurotoxicity is a rare adverse effect related to metronidazole, which includes peripheral neuropathy, syncope, vertigo, and confusion. Cerebellar manifestations are very uncommon and may appear at the cumulative doses ranging from 25 g to 110 g.^9,10 The metabolite of metronidazole has antimicrobial activity, crosses the blood–brain barrier and reaches the brain. ¹ In cases of liver injury with reduced clearance, the drug’s half-life is increased threefold. ¹¹ Consequently, even at low cumulative doses, there is an accumulation of drugs leading to toxic effects. In our case, there is evidence of liver dysfunction, and metronidazole was administered for longer period of 4 weeks, which could be the possible cause for seizure in this patient as other plausible cause like electrolyte disturbances are ruled out.

In a study conducted by Kato et al., ¹² dysarthria (70.6%) and ataxia (61.8%) were identified as predominant symptoms associated with MIE, which aligns with the findings in our study. Our patient exhibited non-specific symptoms such as an abnormal finger-to-nose test and dysarthria, which do not provide clear lateralization. However, the tendency to fall toward the right side suggests a higher possibility of right cerebellar hemisphere involvement compared to the left. It is worth noting that the MRI revealed high signal intensity in both dentate nuclei.

MRI plays an important role in both diagnosis and follow-up to see the resolution of signal changes. Following Ahmed’s study, many other cases have been published, demonstrating involvement of the bilateral dentate nucleus, dorsal pons, and midbrain.^13,14 These findings were demonstrated in our study as well. Hypertrophic changes in the bilateral inferior olivary nucleus were reported by Seok et al., ¹⁵ but they were not observed in our case. Similar to Seok’s findings, involvement of the right basal ganglia as well as the tectal part of the midbrain was noted in our case. MIE showing restricted diffusion due to cytotoxic effect in the corpus callosum was reported by Kim et al., ¹⁶ but no such findings were present in our case. DWI/ADC can help predict the viability of the involved tissue. Lower ADC values suggest a lower chance of reversibility upon drug discontinuation. ¹⁵

Certain differential diagnoses should be kept under consideration. Bilateral symmetrical hyperintense dentate nuclei can also be seen in maple syrup urine disease, methyl bromide intoxication, and enteroviral encephalitis. In our case, Maple syrup urine disease was ruled out due to the patient’s young age and the absence of a sweet odor. Methyl bromide intoxication was ruled out as there was no history of fumigant exposure. The possibility of the EV71 variant of enterovirus was considered, ¹⁷ but there were no outbreaks in the patient’s residential areas, and the absence of blisters and mucosal ulcers in our patient suggests a different diagnosis. Heat stroke can involve the cerebellum, but the internal capsule is the predominantly affected site. ¹⁸

The diagnosis of MIE can be made by combining MRI with clinical findings, treatment history, and resolution of clinical and imaging findings upon drug cessation. ⁶ Thus, metronidazole should always be used with proper monitoring when higher doses or prolonged duration of treatment are required, and close clinical observation should be done.

Conclusion

MRI is an essential imaging modality for diagnosing suspected MIE, as it exhibits a distinct and characteristic feature of bilateral symmetrical high signal intensity in the dentate nuclei. Considering the patient’s history of metronidazole usage, it is imperative for the radiologist to promptly notify the referring physician. It is crucial to exercise caution and prudence when prescribing metronidazole, ensuring awareness of its potential neurotoxic effects.