Nervous system toxicity is a rare complication of metronidazole, leading to neuropathy, ataxic gait, dysarthria, seizures, and encephalopathy. These symptoms may occur from short- or long-term metronidazole use. The mechanism of neurotoxicity induced by metronidazole is unclear, and neuroimaging is the foundation of diagnosis. Reaching the appropriate diagnosis is contingent upon a high clinical index of suspicion, prompt brain imaging to identify specific imaging abnormalities, and improvement after prompt withdrawal of metronidazole. Clinical improvements typically occur after discontinuing metronidazole, but in some cases, comprehensive rehabilitation is needed to optimize mobility and activities of daily living (ADLs). Herein, we describe the diagnosis and rehabilitation of a case of metronidazole toxicity.
2. Case presentation
A 58-year-old female with a past medical history of hepatitis C, cirrhosis, esophageal varices, alcohol and intravenous drug abuse, and paroxysmal atrial fibrillation not on anticoagulation was brought to the emergency department for altered mental status secondary to drug overdose. She was unresponsive upon arrival and subsequently intubated for airway protection. Head computed tomography (CT) identified right temporal and left frontal lobe lesions with surrounding microhemorrhages, and head magnetic resonance imaging (MRI) showed multifocal, hypercellular, rim-enhancing lesions. The favored diagnosis was embolic versus hematogenous spread of bacteria resulting in multifocal abscess. Blood cultures, brain magnetic resonance angiography, CT chest, abdomen, and pelvis, lumbar puncture, and transthoracic echocardiogram were unremarkable. Given her history of coagulopathy and esophageal varices, a brain biopsy and transesophageal echocardiogram were deferred. The patient was treated empirically with metronidazole 500 mg by mouth every 6 hours, cefepime 2 g intravenously every 8 hours, and vancomycin 1 g by mouth twice daily for presumed microabscesses. She was also placed on levetiracetam 500 mg by mouth twice daily for seizure prophylaxis. Follow-up head MRI confirmed that the lesions were decreasing in size, and she was subsequently discharged with instructions to continue her seizure prophylaxis and the aforementioned antibiotic regimen orally for 7 weeks.
Two weeks after discharge, the patient returned to the emergency department with slurred speech, muscle aches, generalized weakness, inability to ambulate, and poor oral intake. Physical examination was significant for drowsiness, right upper extremity pronator drift, right-sided facial droop, and slightly diminished strength on the right. She was noted to have left greater than right-sided ataxia.
The list of differential diagnoses for a patient with new altered mental status, right-sided weakness, and right-sided facial droop includes intracranial hemorrhage, acute ischemic stroke, neurotoxicity secondary to metronidazole, seizure with associated Todd paralysis, and acute disseminated encephalomyelitis. Additionally, in a patient with a history of intracranial microabscesses such as this patient, the differential would also include worsening abscess, viral or bacterial meningitis, or infective endocarditis leading to new septic emboli. Non-contrast head CT should be ordered first, as it can identify intracranial hemorrhage and occasionally acute ischemic stroke. If findings are insignificant, head CT with angiography can be conducted to identify any vascular pathology that may have resulted in ischemic stroke. The patient is especially susceptible to an ischemic stroke because of her preexisting atrial fibrillation and intravenous drug abuse. Therefore, another transthoracic echocardiography should be ordered. Insignificant head CT with angiography findings can be followed by a head MRI, which can identify acute ischemic stroke, neurotoxicity secondary to metronidazole, and acute disseminated encephalomyelitis. The patient’s history of liver failure places her at risk of developing metronidazole toxicity. Because hypo- and hyperglycemia and Todd paralysis can present with stroke-like symptoms, blood glucose levels and electroencephalogram should be conducted while waiting for imaging.
With the patient’s altered mentation and history of liver cirrhosis, electrolyte imbalance, hyperammonemia, and systemic infection must also be considered as potential etiologies. A complex metabolic panel, which assesses liver function and electrolyte levels, should be ordered. Additionally, vital signs including blood pressure, heart rate, respiratory rate, and temperature can be ordered to screen for systemic infections.
Labs that were ordered revealed normal blood cultures, sodium, potassium, blood urea nitrogen, creatinine, calcium, alanine aminotransferase, aspartate aminotransferase, erythrocyte segmentation rate, and C-reactive protein.
Head MRI revealed ongoing improvement of the rim-enhancing lesions identified during her first admission. However, symmetric enhanced T2/FLAIR signaling in the dentate nuclei were also present bilaterally, a finding pathognomonic for metronidazole toxicity (Fig. 1). Metronidazole was discontinued per the recommendation of infectious disease.
Following the discontinuation of metronidazole, the patient’s mentation gradually improved over 2 weeks. She was subsequently admitted to Acute Inpatient Rehabilitation, where her initial physical and occupational therapy evaluations were significant for marked decline in physical function and ability to perform ADLs. The patient progressed from requiring multiple people assisting to walk short distances to being able to walk independently with a walker. She also had notable improvement in her cognitive functioning, short-term memory, and complex problem solving after working with speech therapy using cognitive-communication therapy activities. The patient did not encounter any adverse events throughout her second admission. She began inpatient rehabilitation dependent for all ADLs, and requiring moderate assistance for transfers. She could walk 10 feet with a front-wheeled walker and with 2-person assist. The patient rapidly improved and due to these improvements, she was discharged after 5 days of inpatient rehabilitation. At the time of discharge she was independent with all ADLs and could walk 160 feet independently with a front-wheeled walker.
Based on the patient’s pathognomonic MRI findings, ataxia, and drastic improvement of symptoms following metronidazole cessation and acute inpatient rehabilitation, the patient had metronidazole-induced neurotoxicity without associated peripheral neuropathy. The rehabilitation management of this patient included speech therapy to work on her impaired short-term memory and cognitive deficits as well as medication and money management, occupational therapy to improve her ability to dress and bathe herself along with other self-care tasks such as eating and oral care, and physical therapy to improve her walking ability, improve safety with turns and walking on uneven surfaces, and other tasks such as picking up objects, transferring to a commode or into a vehicle, and other instrumental ADLs. Together, these therapies improved our patient’s ability to live independently in her community.
Metronidazole-induced neurotoxicity is a rare and unpredictable adverse effect that can cause cerebellar ataxia, dysarthria, and peripheral neuropathy.[1,2] Previously believed to occur only after long-term use, cases of neurotoxicity after taking the antimicrobial for less than a week with doses as low as 5 g have been reported.[2–7] Therefore, patients’ susceptibility to developing neurotoxic symptoms cannot be reliably predicted based on the duration or dose of metronidazole therapy. Due to its rare occurrence, the incidence of neurotoxicity is unknown.[1,8]
Currently, the pathophysiology of metronidazole-induced neurotoxicity is poorly understood. The antimicrobial is suspected to cause irreversible cell damage through deprivation of metabolic processes. Interestingly, the cerebellum and brainstem—both of which have been shown to be affected by metronidazole on MRI—are particularly susceptible to energy deprivation. However, other studies propose that metronidazole may have Gamma-Aminobutyric Acid-inhibitory and subclinical Monoamine oxidase-inhibitory properties. Recent MRI studies also suggest that metronidazole may cause neurotoxicity via central nervous system vasoconstriction.[1,2] While often a diagnosis of exclusion, metronidazole-induced neurotoxicity can be diagnosed using T2/FLAIR MRI to detect bilateral dentate nuclei lesions, which is seen in 90% to 93% of patients. Lesions located within splenium and corpus callosum have also been reported.[1,5]
Metronidazole should be discontinued upon suspicion of neurotoxicity. Over 90% of patients demonstrate complete or near complete resolution of their symptoms, typically within 14 days of drug cessation.[1,4] However, peripheral neuropathy secondary to metronidazole toxicity carries a worse prognosis with only one-third of patients making a complete recovery. As stated above, fortunately this patient did not have an associated peripheral neuropathy. There are numerous examples in the literature of patients with significant long-term morbidity and in some cases mortality secondary to metronidazole toxicity.[1,5,6,10] Prompt recognition and discontinuation of the offending agent remains the only known effective treatment. A comprehensive approach to treatment and rehabilitation is achieved with an early referral to rehabilitation services. This is crucial to minimize morbidity and optimize functional outcomes in this patient population.
Conceptualization: Justin Weppner and Emily Hillaker.
Formal analysis: Justin Weppner.
Supervision: Justin Weppner.
Writing – original draft: Emily Hillaker, Jacob Boomgaardt,
James Lau, Justin Weppner.
Writing – review & editing: Emily Hillaker, Jacob Boomgaardt, James Lau, Justin Weppner.
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