Elevated Extra-Axial Cerebrospinal Fluid in Toddlers with Autism Spectrum Disorder

Background: Extra-axial fluid is characterized by excessive cerebrospinal fluid in the subarachnoid space, particularly over the frontal lobes. We previously reported that infants who later developed autism spectrum disorder (ASD) had an elevated amount of extra-axial fluid at 6-9 months of age, which persisted and remained elevated through 24 months of age. The amount of extra-axial fluid in infancy was predictive of more severe ASD symptoms at the age of diagnosis. It is unknown whether excessive extra-axial fluid remains abnormally elevated beyond infancy and if its presence is associated with clinical or medical factors.

Objectives: The objectives of the current study was to replicate and extend these findings in a large, independent sample of toddlers with ASD and to identify clinical and medical factors associated with this brain anomaly. Our hypothesis was that toddlers with ASD would continue to show a persistent elevation of extra-axial cerebrospinal fluid, compared to age-matched typically developing control children (TD).

Methods: This study was conducted as part of a larger multidisciplinary study at the UC Davis MIND Institute aimed at identifying subtypes of ASD. The current sample included all children who had a successful structural MRI between 2-4 years of age (mean age 38.2 months, SD=6.46). The total sample included 277 children, 187 with ASD (153 male, 34 female) and 90 with TD (59 male, 31 female). High-resolution, T1-weighted structural MRI scans were acquired during sleep. Quantitative measurements of extra-axial fluid were obtained using an anatomical protocol developed by our laboratory and validated in a previous study. Medical examinations and medical history reviews were conducted by a board-certified developmental behavioral pediatrician. Behavioral and clinical assessments were conducted by a team of developmental and clinical psychologists.

Results: The ASD group had significantly greater volume of extra-axial cerebrospinal fluid compared to the TD group (p<0.005). This effect remained significant (p=0.03) when taking brain size into account, which indicated that extra-axial fluid was elevated out of proportion to overall brain volume. Both male and female toddlers with ASD had greater extra-axial fluid compared to their typically developing counterparts. 

Conclusions: This finding in a large, independent sample of toddlers with ASD suggests that elevated extra-axial cerebrospinal fluid is a structural brain anomaly that is detectable from infancy through early childhood in ASD. There is mounting evidence from neurobiological studies that persistently excessive cerebrospinal fluid in the subarachnoid space surrounding the developing brain alters the concentration of neural growth factors and potentially harmful metabolites that may have a pathological effect on normal brain development. We will examine several clinical and medical factors that might relate to the phenotypic variation of this brain anomaly in ASD, including ASD symptoms and cognitive function, prenatal and perinatal medical history, immune function, sleep problems, and other MRI brain measures.