Closantel toxicity

Background

Closantel is a broad-spectrum antihelminthic agent used against several species and developmental stages of parasitic worm—nematodes and trematodes.1 A halogenated salicylanilide, closantel inhibits the coupling between electron transport and phosphorylation reactions, that is, oxidative phosphorylation, and thereby disrupts mitochondrial ATP production to impair parasite membrane transport mechanisms, motility and probably other processes.2 It is a veterinary drug used only in animals—cattle, sheep and goats predominantly. Its use is contraindicated in humans.3

The recommended oral dose of closantel for sheep is 7.5–10.0 mg/kg and for cattle is 10.0–15.0 mg/kg. In humans, an acceptable daily intake of closantel is thought to be ≤0.03 mg/kg. The recommended maximum residue of closantel in food products in the edible tissues of sheep is 1.5 mg/kg, and in cattle is 0.5 mg/kg for muscles, 2.0 mg/kg for kidneys and 1.0 mg/kg for liver.4

Several cases of toxicity and mortality due to closantel ingestion in animals have been reported.5–7 Closantel is neurotoxic, ophthalmotoxic and hepatotoxic in animals in overdose.5–7

Following oral intake in animals, the peak plasma concentration of closantel is reached in 8–48 hours. Its tissue distribution is limited by its strong protein binding—99.9%—to plasma albumin. It is, for the most part, eliminated unmetabolised, in faeces, with a half-life of 2–3 weeks.8 The pharmacokinetics of closantel in humans are unknown.8 The unique pharmacokinetic features of closantel in animals—rapid parenteral absorption and long elimination half-life—may however play important roles in its toxicity in both animals and humans.9

In the central nervous system, white matter and spinal cord ‘spongiosis’ are the most significant histopathological findings in cases of closantel toxicity in animals.10 These changes are symmetrical and affect the optic radiation, the periventricular white matter, the thalamic nuclei, the brainstem and the cerebellar peduncles. Optic nerve damage is thought due to the development of oedema within the surrounding myelin sheath and resultant compression of the nerve within the osseous portion of its course resulting in degeneration, fibrosis and subsequent atrophy.11 In the retina, closantel toxicity leads to necrosis and apoptosis of the outer retinal layers, in particular, the photoreceptor cells.12 Closantel can also cause fatty change and hepatocellular degeneration in the liver.13

Case presentation

A man in his 60s presented to the Eye Casualty describing a progressive deterioration in his night vision over the 10 days that followed his accidental ingestion of approximately 30 mL of a solution containing 50 mg/1 mL closantel, that is, 1500 mg and 75 mg/1 mL, that is, 2205 mg mebendazole intended for oral administration to his sheep.

He had a history of hypertension, nasal polyps, hiatus hernia, Barrett’s oesophagus, diverticular disease and varicose veins. His medications were perindopril and lercanidipine. He had a 40 pack-year history of cigarette smoking and consumed six units of alcohol weekly.

Right visual acuity (VA) was 6/45 unaided and 6/30 with pinhole (PH). Left VA was 6/30 unaided and 6/24 with PH. He could not read any of the Ishihara colour vision plates with either eye. No further abnormalities were noted at ophthalmic clinical examination. Systemic examination inclusive of a complete neurological examination was normal.

Investigations

Humphrey visual fields 30-2 with 10/17 fixation losses bilaterally could not be reliably interpreted. As can be seen from figure 1A,B, optical coherence tomography (OCT) displayed disruption of the outer retinal layers—the retinal pigment epithelium, the outer photoreceptor layer, the junction of the inner and outer photoreceptor segments, the inner photoreceptor layer and the external limiting membrane, at the macula bilaterally. Fundus autofluorescence at the macula and fundus fluorescein angiography were normal. Full blood count, and liver and renal function tests did not identify any abnormality.

At full-field electroretinography (ERG), both rod and cone-isolated responses were delayed and of reduced amplitude bilaterally. Pattern ERG indicated compromised macula and inner retinal function bilaterally. Pattern visual evoked response showed normal P100 latencies but a reduction in amplitude of the response.

Treatment

This case was discussed with the National Poisons Information Centre. The patient was admitted to the medical assessment unit where he received methylprednisolone 1 g daily intravenously for 3 days and two doses of Pabrinex I, II and IV, each containing thiamine hydrochloride 250 mg, riboflavin 4 mg, pyridoxine hydrochloride 50 mg, ascorbic acid 500 mg, nicotinamide 160 mg and glucose 1000 mg. He was discharged to take prednisolone 60 mg daily tapering by 10 mg daily every 5 days thereafter.

Outcome and follow-up

Objective improvements in visual acuity were recorded, so the day following completion of intravenous methylprednisolone, right VA was 6/6 and left VA was 6/7.5. Improvements were also noted in the appearance of the macula bilaterally at OCT. At review 6 months following his initial presentation, this man’s VA remains unchanged.