Background and importance Ivermectin is a broad-spectrum antiparasitic. It was tested to treat COVID-19 but no benefit was found through large studies. Severe encephalopathy occurrence is known in patients treated with ivermectin and coinfected by a large number of Loa loa microfilariae but there is a growing concern due to severe encephalopathy reports in other contexts.

Aim and objectives Assess the evidence about severe neurological toxicity cases after ivermectin use.

Material and methods Following the PRISMA recommendations for systematic reviews, a search combining terms associated with ‘ivermectin’ and ‘drug toxicity’ was conducted using the MEDLINE and LILACS databases for all relevant English- and Spanish-language articles from inception through 30 September 2021. Cases and case–control reports were included. We excluded articles not mentioning at least minimal information on ‘ivermectin’ or ‘neurotoxicity’ in a first screening phase. In a subsequent selection phase, articles were excluded if they reported data on paediatric or pregnant patients, intoxications, non-oral route administration or animal data. The outcome of interest was cases of severe neurotoxicity (SN) in adult/adolescent patients (>11 years) treated with ivermectin. Data were synthesised narratively.

Results 266 articles were assessed and 17 met the inclusion criteria. 6 cases and 11 cases series reports in patients treated for strongyloidiasis, onchocerciasis, loiasis and scabies infections reported SN occurrence such as consciousness disorders, seizure or convulsion, encephalopathy and coma. SN not only was associated with Onchocerciasis treatment in Loa loa coinfected patients. Chandler RE reported 28 SN cases after ivermectin use outside the Onchocerciasis indication and Nzolo D et al reported cases of SN even with low blood levels of Loa loa microfilaria. 2 studies associated SN with the presence of ABCB1 mutation. Baudou E et al reported the case of patient with two human ABCB1 mutations who suffered SN and Bourguinat C et al showed homozygotic haplotypes associated with alterations in drug disposition in 2 cases.

Conclusion and relevance Although SN has traditionally been reported after extensive Loa loa infections this occurs in other contexts. SN after ivermectin use must be detected early to avoid fatal consequences. Authors related this toxicity with human ABCB1 nonsense mutations that allow ivermectin penetration into the central nervous system. This could be a future field of research.

Conflict of interest No conflict of interest