Neurological involvement in children with familial Mediterranean fever: a systematic review

Background: Although typical findings of familial Mediterranean fever (FMF), such as brief fever episodes and abdominal or chest pain, have been largely described, little is known about the neurological manifestations of the disease in childhood. Methods: A systematic search of the literature was conducted in PubMed/Medline, Cochrane, and Web of Science databases in accordance with the PRISMA guidelines, using MeSH terms related to FMF and neurological manifestations. Studies involving patients under 18 years of age diagnosed with FMF with neurological manifestations were included. Results: Sixty-four studies, comprising 4753 children with FMF, were included. Approximately 33.9% of them had some degree of neurological involvement. Headache was the most common neurological symptom and was often associated with FMF flares, with frequencies ranging from 4.8 to 58.8%. Febrile seizures were also relevant manifestations, as expected in children with FMF since they have more and more high fever during childhood, with frequencies ranging from 1 to 15.2%. Demyelinating disorders, such as multiple sclerosis, were rarely reported, mostly in female adolescents with the homozygous M694V MEFV genotype. A few studies have shown that cochlear and retinal involvement due to chronic and recurrent inflammation may contribute to sensorineural hearing loss and retinal abnormalities. Conclusion: Although causality has not been shown and reporting bias cannot be excluded, neurological involvement appears relatively common in children with FMF and may lead to long-term disability and reduced quality of life. These findings support the need for a comprehensive neurological assessment to enable early detection, appropriate management, and better long-term outcomes.