Closantel toxicity

  1. Eimear O Leary ,
  2. Sara Gasior and
  3. Elizabeth McElnea
  1. Ophthalmology, Galway University Hospitals, Galway, Ireland
  1. Correspondence to Dr Eimear O Leary; eimoleary1912@gmail.com

Publication history

Accepted:26 Jan 2023
First published:09 Feb 2023
Online issue publication:09 Feb 2023

Case reports

Case reports are not necessarily evidence-based in the same way that the other content on BMJ Best Practice is. They should not be relied on to guide clinical practice. Please check the date of publication.

Abstract

Closantel is a broad-spectrum antihelminthic agent. It is a veterinary drug used only in animals—usually cattle, sheep and goats. A man in his 60s accidentally ingested approximately 1500 mg closantel. His visual acuity deteriorated. Optical coherence tomography (OCT) showed disruption of the outer retinal layers. Electroretinography identified abnormalities in macula and inner retinal function. He received methylprednisolone 1 g daily intravenously for 3 days. Improvements in both his visual acuity and OCT appearance followed. This case illustrates the profoundly destructive effect of this drug on humans even when consumed in low dose. We provide a concise summary of the small number of cases of closantel toxicity in humans, previously reported, for future reference as needed by others.

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.

Figure 1

Optical coherence tomography 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 of the right (A) and left (B) eyes. Following treatment with methylprednisolone 1 g daily intravenously for 3 days, the disruption of the outer retinal layers is reduced so that each of the aforementioned layers is identifiable at the macula of the right (C) and left (D) eyes.

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.

Discussion

Closantel poisoning in humans can occur from the consumption of milk and/or meat from animals treated with the drug, by accident or misuse.9 The volume of closantel ingested was estimated based on the patient’s history of having swallowed two mouthfuls of the same—approximately 15 mL each. Mebendazole was also ingested. It has been used safely to treat human central nervous system infections and was not expected to have an effect.

In Lithuania, in 1993, donated closantel was mistakenly given to 11 women to treat endometritis.14 15 A summary of those cases of closantel poisoning in humans previously described is given in table 1.3 8 9 15–21

Table 1

Previously reported cases of closantel poisoning

Case Gender Age in years Origin Reason given for consumption Dose Time to presentation Symptoms Ocular signs Abnormalities in systemic investigations Right, left eye visual acuity at presentation unless otherwise stated Right, left eye visual acuity at time after presentation unless otherwise stated Treatment Reference
ALT, alanine aminotransferase; aPTT, activated partial thromboplastin time; AST, aspartate aminotransferase; CF, counting fingers; CK, creatine kinase; HgB, haemoglobin; HM, hand movements; IV, intravenously; NPL, no perception of light; PL, perception of light; PT, prothrombin time.
1 Male 20s India Mistaken for cough syrup 2250 mg 3 days Sudden painless defective vision Mild temporal optic disc pallor CF, CF 6/9, 6/9 at 1 month Methylprednisolone 1 g daily IV for 3 days followed by prednisolone 40 mg orally daily and tapered 17
2 Male 30s Iran Accidental ingestion 1500 mg 10 days Progressive loss of vision;
mild headache		 Left optic disc swelling Normocytic, normochromic anaemia with serum HgB 11 g/L;
increase in ALT and AST more than 2×		 PL, NPL NPL, NPL at 26 days Methylprednisolone 1 g daily IV for 3 days followed by prednisolone 1 mg/kg orally for 2 weeks
Erythropoietin 20 000 units daily IV for 3 days		 3
3 Male 50s Iran For sore throat, as an antibiotic 1000 mg 15.15 mg/kg 14 days Sudden vision loss in both eyes Mid-dilated, poorly reactive pupils; mild peripapillary whitening and right>left eye nerve fibre layer oedema Liver enzyme test 2× normal range; multiple bright foci at periventricular and paraventricular, centrum semiovale and junctional areas at MRI brain, T2 weighted without gadolinium CF, CF CF, CF Methylprednisolone 1 g daily IV for 3 days
Erythropoietin 10 000 IU two times per day for 3 days		 18
4 Male 40s Iran Mistaken for another medicine 1000 mg 15.87 mg/kg 4 hours Dizziness; nausea; progressive vision loss Mild optic disc swelling bilaterally 20/200, 20/200 3 days after ingestion
HM, HM 14 days after ingestion		 20/20, 20/20 28 days after ingestion
20/20, 20/20 3 years after ingestion		 Gastric lavage 4 hours after ingestion
Methylprednisolone 250 mg IV once for 5 days after ingestion		 19
5 Male 50s Germany Helminth fearing 1800 mg over 3 days 4 days Visual impairment;
tongue dysesthesia		 20/63, 20/50
HM, HM 3 days later		 20/25, 20/25 Five sessions on alternate days therapeutic membrane plasma exchange with the OctaNova system Diamed Medizintechnik using a Plasmaflo OP-08W(L) filter (Asahi Kasei Kuraray Medical Co)
A 1.5 plasma volume exchange was performed using human albumin 20 g/100 mL and crytalloids in a 20%–80% distribution, respectively, as placement		 8
6 Male 50s Germany On purpose to treat himself 1800 mg over 3 days ‘Several’ days Scotomata in both visual fields ‘Complete vision loss’ at 10 days after presentation 60% of vision regained at 6 weeks Plasmapheresis more than 1 week after ingestion 20
7 – 40s Morocco Accidental ingestion Unknown amount 7 days Blindness Normal fundus Unknown Lost to follow-up 16
8 – 40s Morocco To treat intestinal parasitosis Unknown amount 7 days Blindness Normal fundus Unknown Lost to follow-up 16
9 Female 20s Iran Inadvertently dispensed as an alternative to triclabendazole 3000 mg
500 mg two times per day for 3 days		 3 days Bilateral blurred vision; bilateral decreased colour vision Sluggish pupillary reaction to light;
bilateral pale optic disc		 HM, HM 20/30, 20/30 at both 18 months and 2.5 years Methylprednisolone 1 g daily IV for 3 days
Plasmapheresis commenced on the third day of drug ingestion
Five sessions completed		 21
10 Female Early childhood Morocco Accidental ingestion Unknown amount 1 day Blindness Bilateral mydriasis with abolition of pupillary reflex;
severe papilloedema		 Regained vision after 2 months Oral vitamins B1, B6 and B12 16
11 Female Early childhood Morocco Mistaken administration 4000 mg
500 mg daily for 8 days		 4 Acute blindness Bilateral mydriasis with loss of pupillary light reflex and absence of blinking to threat
bilateral papilloedema		 Normocytic, normochromic anaemia with HgB 10.7 mg/L;
AST 120 IU/L;
52% increase PT; 1.3× prolongation of aPTT;
CK 904 IU/L;
leucocytosis with lymphocytic predominance		 ‘Partial recovery’ at 2 months
Advised to attend school for visually impaired children		 Glucocorticoids, vitamin B12 and vitamin K 9
12 Female 20s Lithuania Mistaken administration to treat endometritis Not stated 7 days Blurred vision;
photopsia		 20/250, 20/250 20/63, 20/200 at 22 years 15
13 Female 20s Lithuania Mistaken administration to treat endometritis Not stated 3 days Haze;
black spots		 20/32, 20/63 20/25
20/40 at 22 years		 15
14 Female 20s Lithuania Mistaken administration to treat endometritis Not stated 5 days Blurred vision; decrease in vision 20/32, 20/20 20/20, 20/20 at 22 years 15
15 Female 30s Lithuania Mistaken administration to treat endometritis Not stated 1 day Blurred vision 20/20, 20/20 20/40, 20/40 at 22 years 15
16 Female 20s Lithuania Mistaken administration to treat endometritis Not stated 3 days Photopsia 20/20, 20/20 20/25, 20/25 at 22 years 15

Ethics statements

Patient consent for publication

Footnotes

  • Contributors EOL identified the ocular toxicity in the patient on presentation, researched initial management options and created this report. SG made research and designed the table summarising previous reported cases of closantel poisoning. EM guided the treatment plan and monitored the patient, and supervised the writing of this case report.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Case reports provide a valuable learning resource for the scientific community and can indicate areas of interest for future research. They should not be used in isolation to guide treatment choices or public health policy.

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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