Increased extra-axial cerebrospinal fluid and benign external hydrocephalus in early autism

Previous studies have reported that some children with Autism Spectrum Disorder (ASD) below the age of 3-years-old exhibit increased extra-axial cerebrospinal fluid (EA-CSF) volumes, suggesting that transient early CSF circulation abnormalities may characterize a unique etiology in a sub-group of ASD children. Specifically, this sub-group was proposed to exhibit an EA-CSF to total brain volume (TBV) ratio >0.14. It is unknown whether such findings may correspond to an early radiological diagnosis of Benign external hydrocephalus (BEH), which is defined as an enlargement of CSF volumes within the subarachnoid space (SAS) during the first two years of life. Here we examined a retrospective clinical sample extracted from the National Autism Database of Israel. In 2020, ~14% of ASD children in the database (n= 102) had completed clinical brain MRI scans at different ages before or after ASD diagnosis. Scans of 83 ASD children fulfilled quality control criteria and were compared to those of 53 age and sex matched typicality developing (TD) children who were referred to the same clinical center for similar clinical reasons. EA-CSF volume and total brain volume (TBV) were quantified from T2-weighted scans using manual labeling and compared across groups. The results revealed that ASD children scanned before the age of 2-years-old (i.e., before ASD diagnosis) exhibited significantly larger EA-CSF volumes when compared to controls (t(49)=2.89, p=0.006, Cohens d=0.82). No significant differences were apparent across groups at older ages. Of those scanned before the age of 2-years-old, ~16% of the ASD children, and none of the control children, exhibited EA-CSF/TBV ratios >0.14, thereby replicating previous findings from prospective research samples. In addition, retrospective examination of the neuroradiology assessments revealed a BEH prevalence of 33% in the ASD children scanned before the age of 2-years-old, with 80% of these children exhibiting EA-CSF/TBV ratios >0.11. These findings reveal a clear relationship between quantitative EA-CSF volume analyses and qualitative BEH radiological findings, which characterize a considerable sub-group of ASD children. Accumulating evidence, therefore, suggests that BEH diagnosis in conjunction with a high EA-CSF/TBV ratio by the age of 2-years-old may be indicative of a specific ASD etiology that warrants further research and may offer unique opportunities for intervention. ### Competing Interest Statement The authors have declared no competing interest.