Rapid Onset Metronidazole Induced Sensory Neuropathy: Case series and Review of Literature

Background: Metronidazole has been widely used to treat various anaerobic infections for many years without producing major side effects. Some of its new therapeutic indications, however, necessitate prolonged treatment with relatively high doses. Peripheral neuropathy is clearly one of the complications that can arise with such use. Case Report: Four young male patients with history of intake of metronidazole for treatment of amoebic liver abscess and diarrhoea developed very rapid onset distal symmetrical sensory neuropathy. Patients being treated with metronidazole particularly those on high doses even for short period should be monitored for neurotoxicity Conclusion: This drug which is widely and empirically prescribed and is an over the counter (OTC) drug for any types of diarrhoea in our country is clearly associated with neurotoxicity. Metronidazole should be used with some caution and with clear indications even when is prescribing for short course and low doses.


Introduction
Metronidazole is a 5-nitroimidazole derivative and has potent activity against anaerobic bacteria, several protozoa including Entamoeba, Giardia, Trichomonas and B. coli, H. pylori and Guinea worm and hepatic encephalopathy. Common side-effects of metronidazole include mild abdominal pain, headache, nausea, and a persistent metallic taste. Other serious and rare side-effects include pseudomembranous colitis, seizures, and encephalopathy [1][2][3]. It is generally well tolerated and peripheral neuropathy is its rare side effect [4]. We are presenting a case series of patients who developed acute sensory neuropathy after intake of short course of metronidazole.

Case Report
Four male patients with history of intake of metronidazole for treatment of liver abscess and diarrhoea presented with distressing paresthesia in form of tingling and burning pain in glove and stocking distribution. Symptoms started first in soles and dorsa of feet and gradually progressed. They have distressing paresthesia in form of tingling, burning and severe tearing pain from toes up to knees in lower limbs and in glove distribution in upper limbs. Patients were taking metronidazole for different disease, dose and duration. (Table1). All were non-alcoholic. Family history was negative. Neurological examination revealed no abnormalities in the cranial nerves and no focal weakness or wasting in the limbs. There were graded impaired sensation for tactile and pain over knees and down in lower limbs and mid of forearm and down (20 to 80%) in upper limbs, but postural sense and deep pain sense were well preserved. Vibration sense was absent at the malleoli and over the tibial tuberosities. Both ankle jerks were absent, but all other tendon reflexes were preserved and symmetrical. The plantar responses were flexor. There were no stigmata of malnutrition.
They were unable to walk unassisted due to intolerable paresthesia. No cerebellar sings were present. Haematological investigations (Complete Blood Count, Blood sugar, Urea/ creatinine, thyroid profile tests and serum Vitamin B12) including CSF examination were unremarkable (     Table 3: Nerve conduction parameters of patients, Distal Latency im milliseconds (ms), Nerve conduction velocity in meters per second(m/s) and, amplitude in millivolts (mV) and microvolts (uV) They were asked to stop metronidazole intake and put on combination of drugs for neuropathic pain such as pregabalin, duoloxitine and amitriptylene. They started showing improvement in all symptoms within 2 to 3 days and was discharged after about a week. At 6 month of follow-up symptoms resolved up to 90% in 1st two patients while 3rd and 4th patient's symptoms resolved less than 30%.

Discussion
Identification of a toxic effect is simplest when acute or sub-acute onset of symptoms occurs soon after the initial drug exposure or a change of medication dosage. Most patients fall into this category. In contrast, it is much more problematic to diagnose a slowly progressive neuropathy starting many months or years after starting a chronic agent. Full investigation failed to elicit any possible cause for their neuropathy other than the drug they have been taking. The exact mechanism of metronidazole induced neuropathy is controversial and presumed to be probably the result of toxic accumulation of metronidazole leads to axonal degeneration. Most reported cases developed neuropathy following metronidazole doses of 1,000 -2,400 mg/day, total doses of at least 50 gm and treatment duration of at least 30 days [7][8][9][10]. In my series patients took very low dose (range 11-18 gm) of metronidazole over a period of 7-15days and presented with rapid onset (range 3-12 days) distal symmetrical axonal sensory neuropathy. It is noteworthy that, in case reports from India, the cumulative dose of metronidazole was low (8 -20 gm), and latency of symptoms onset very short (10-18 days) when compared to patients from the West [11,12]. This may reflect a genetic susceptibility to neurotoxic effects of metronidazole or a genetic variation in the metabolism of metronidazole in Indian patients. Most toxic neuropathies, including medication-induced forms, principally induce axonal degeneration in a "dying back" pattern disproportionately affecting the distal segments of the most vulnerable, usually longest nerves. Electron microscopic studies of human sural nerve biopsy specimen have also confirmed axonal degeneration of both the myelinated and unmyelinated fibers [13]. Complete or partial resolution may occur after discontinuation of therapy. However symptoms may take up to two years to completely resolve [10]. Neuropathic symptoms improved up to 90% in next 6 month after withdrawn of metronidazole and giving supportive treatment.
To sum up I suggest that a careful neurological examination and studies of sensory and motor nerve conduction should be performed in patients who complain of paresthesia, pain, muscle cramps, weakness or other abnormal sensation during treatment with metronidazole.