Clinical, neuroimaging and pathological features of 5-nitroimidazole-induced encephalo-neuropathy in two patients: Insights into possible pathogenesis
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.86552
Source of Support: None, Conflict of Interest: None
We report two patients manifesting with involvement of central and peripheral nervous system with brain magnetic resonance imaging (MRI) changes and pathological features of neuropathy possibly due to harmful and chronic use of various nitroimidazole group of medications for recurrent diarrheal illness. Patient 1, a 21-year-old man with obsessive-compulsive disorder, impulsive behavior and harmful use of substance (tinidazole), had developed encephalopathy and biopsy-proven neuropathy with partial remission. The MRI of brain showed involvement of bilateral caudate, lentiform and dentate nuclei, and splenium, with contrast enhancement of the caudate and putaminal lesions and restricted diffusion of the splenial lesion. Patient 2 was a 50-year-old woman with irritable bowel syndrome and was on harmful use of tinidazole and metronidazole. She manifested with encephalopathy, ataxia, and neuropathy. Her MRI of brain revealed involvement of bilateral putamen, dentate nuclei and periventricular white matter with restricted diffusion. Sural nerve biopsy revealed evidence of vasculitic neuropathy. At follow-up, there was definite, though incomplete, recovery in both the patients. The MRI alterations improved completely in patient 2 and substantially in patient 1. Increasing awareness among the physicians may enable early recognition of potentially reversible neurotoxicity and avoid unwarranted prescription of such medications.
Keywords: Encephalopathy, magnetic resonance imaging, metronidazole, neuropathy, nitroimidazole, tinidazole
Metronidazole, tinidazole, secnidazole and ornidazole are 5-nitroimidazole group of drugs and are believed to be safe, widely prescribed and freely available. The most common neurological complication caused by metronidazole is peripheral neuropathy. ,,, There are few reports on metronidazole-induced encephalopathy. ,, Neurological complications ascribed to other nitroimidazole group of drugs are few. 
We describe two patients manifesting with encephalo-neuropathy and brain magnetic resonance imaging (MRI) changes following long-term use of various imidazoles.
A 21-year-old man had recurrent abdominal cramps and frequent loose stools since he was 17 years. He was diagnosed to have "Irritable Bowel Syndrome" and was advised metronidazole. He was self-medicating with tinidazole (2400 mg) followed by ornidazole plus quinolones (200 mg) for the last 4 years. The cumulative dose of tinidazole was 5.2 kg.
After 3 years of continuous medication use, he developed acute weakness and paresthesia of both lower limbs requiring support to walk. He received parenteral multivitamins with partial improvement in his motor symptoms. Over the next 1 year, paresthesia worsened with gradual progression of weakness to involve the upper limbs in spite being on multivitamins. Six months following the onset of symptoms, he had generalized tonic-clonic convulsions.
Since childhood, he had frequent anger outbursts, exhibited destructive and impulsive behaviour that affected his social interactions and scholastic performance. He also had obsessive thoughts and activities. There was no alcohol abuse.
He was overweight with a body mass index (BMI) of 28.5 kg/m 2 . The physical examination was unremarkable. Neurologically, there was normal motor power except for bilateral ankle dorsiflexors [medical research council (MRC)-4/5] (MRC-4/5) and toe grip weakness. Sensory system was intact. Upper limb reflexes were preserved while lower limb reflexes were absent bilaterally. Both plantars were flexor. There was no other deficit. Psychiatric evaluation suggested obsessive-compulsive disorder with impulsive behavior and harmful use of tinidazole.
Laboratory parameters including hemogram, liver and renal function tests, serum electrolytes, creatinine kinase, ammonia, lactate and thyroid were normal. Serum human immunodeficiency virus (HIV) and venereal disease research laboratory test (VDRL) were non-reactive. Vasculitis work up was negative. Nerve conduction and electromyography (EMG) studies suggested distal, sensory>motor axonal neuropathy. Visual evoked potential study revealed prolonged P100 (right: 134.7 ms and left: 130.8 ms; normal: <108 ms). The median and posterior tibial nerve somatosensory evoked potential study revealed absent responses. The initial MRI (brain) revealed hyperintensities (T2W/FLAIR) involving bilateral caudate, lentiform nuclei, splenium, and dentate nuclei with contrast enhancement of caudate and putaminal lesions and restricted diffusion of the splenial lesion [Figure 1]. The left sural nerve biopsy revealed a chronic indolent axonopathy with minimal regeneration, and depletion of both large and small diameter fibers with consequent endoneurial fibrosis [Figure 2]a-c.
The offending drug was stopped. He received symptomatic treatment with mutivitamins and behavioral therapy. A repeat MRI after 3 months of stopping tinidazole revealed reduction in the extent and severity of the lesions. MR spectroscopy did not reveal abnormality [Figure 1]. After 18 months, he did not have any new symptoms. He had reduced but persisting behavioral symptoms. There were no neurological symptoms except for areflexia in lower extremities.
A 50-year-old woman presented with history of recurrent diarrhea for the last 6 years, with provoked and significant anxiety. Over the years, she had been on various medications, viz. metronidazole, tinidazole, norfloxacin and loperamide for her diarrhea, with cumulative dose of 0.5 kg tinidazole and 2.0 kg metronidazole for last 5 years. During the past 8 months, she had developed progressive paresthesia involving both hands and feet with reduced sensations, followed by mild distal weakness. She had an episode of self-remitting "encephalopathy" a year ago. She was prescribed vitamin B12.
The physical examination was normal except for hyperpigmentation of both feet. Neurologically, there was mild wasting of interossei of feet with mild weakness of both feet. Kinaesthetic sensation was absent at toes bilaterally. The gait was wide-based, slow, with short steps and swaying to either side, with an impaired tandem gait. There was no other deficit.
Hemogram revealed normocytic normochromic anemia (Hb 10.7 g%) with mild leukopenia (total leukocyte count 4100/ mm 3 ). Results of liver and renal function tests, serum electrolytes, creatinine kinase, ammonia, lactate and thyroid status were in normal range. CSF analysis was normal. Serum vasculitis profile was negative. Chest X-ray was normal. Serum HIV and VDRL were non-reactive. The MRI (brain) showed hyperintensities of bilateral putamen, dentate nuclei and periventricular white matter, with restricted diffusion in putamen [Figure 3]. The nerve conduction studies revealed sensorimotor axonal neuropathy. Sural nerve biopsy showed focal acute axoplasmic swelling and degeneration with formation of myelin ovoids. In the epineurium, medium-sized arterioles showed perivascular cuff of lymphomononulcear cells with focal transmural infiltration by lymphocytes/plasma cells. Scattered macrophages were detected in the endoneurium. There was neovascularization and myelinated fiber loss in large sectorial pockets, reflecting ischemic damage [Figure 2]d-f. Features were consistent with vasculitis.
A diagnosis of nitroimidazole-induced encephalo-neuropathy was considered. In view of vasculitic neuropathy, she received steroids in addition to multivitamins, SSRI and behavioral therapy. After 12 months, she had improved remarkably and had minimal paresthesia in feet, and anxiety. Repeat MRI (brain) was normal.
Neurological adverse effects secondary to metronidazole usage are commonly reported in literature and include neuropathy, encephalopathy, seizures, cerebellar ataxia and nonspecific symptoms like headache and vertigo. , Both the patients in this report developed encephalo-neuropathy secondary to harmful use of tinidazole and metronidazole, with background premorbid personality/behavioral disorder that could have predisposed to self-medication. Other differential diagnoses were reasonably excluded.
Metronidazole-induced axonal, predominantly sensory neuropathy has been described. The cumulative dose implicated ranges from 13.2 to 228 g, with neuropathy developing 2 weeks to 6 months following initiation. ,, Rarely, painful neuropathy has been reported.  Optic neuropathy related to metronidazole has been documented.  Reversible cerebellar ataxia due to metronidazole (dosage: 25-1080 g)  and ornidazole  is on record. Patient 1 had clinical, electrophysiological and pathological evidence of sensori-motor axonal neuropathy. Patient 2 also had sensori-motor axonal neuropathy, with sural nerve biopsy showing evidence of vasculitis, which has not been previously reported.
The characteristic MRI abnormalities caused by metronidazole toxicity include hyperintensities of dentate nuclei, midbrain (tectum, substantia nigra, red nucleus, periaqueductal region), dorsal pons (vestibular, superior olivary and abducens nuclei), medulla (inferior olivary nucleus), corpus callosum (splenium), globus pallidus, putamen and caudate nuclei, and white matter (frontal). These changes could be (a)symmetrical, with(out) contrast enhancement and restricted diffusion. Interstitial edema is due to the axonal swelling with increased water content. MR spectroscopy might show an elevated lactate peak. The MRI changes reverse following withdrawal of the drug. ,,,,,,, Both the patients in this series had MRI findings similar to that described in literature. The MRI findings should always be correlated with the clinical scenario, as some of the observations could be nonspecific.
The exact pathophysiology of the neuroimaging alterations due to imidazole toxicity is unclear. Metronidazole can cross the blood-brain barrier and the postulations include direct toxicity, RNA or DNA binding of intermediate metabolites of metronidazole affecting neuronal protein synthesis and mitochondrial function. ,, Other theories include modulation of gamma aminobutyric acid (GABA). In dogs, it was found that administration of diazepam, which is a GABA inhibitor, hastens recovery from metronidazole encephalopathy.  Genetic susceptibility may play a role. Patient 2 had evidence of vasculitic neuropathy. It is unclear if this is an independent disease process or secondary to inflammatory mediators released in response to these offending agents.
Awareness of the clinical and neuroradiologic alterations in central nervous systems secondary to nitroimidazole toxicity will permit early diagnosis and thereby prevent further damage by timely withdrawal of the drug.
[Figure 1], [Figure 2], [Figure 3]