Extra-axial cerebrospinal fluid in high-risk and normal-risk children with autism aged 2–4 years: a case-control study

Summary

Background

We previously showed, in two separate cohorts, that high-risk infants who were later diagnosed with autism spectrum disorder had abnormally high extra-axial cerebrospinal fluid (CSF) volume from age 6–24 months. The presence of increased extra-axial CSF volume preceded the onset of behavioural symptoms of autism and was predictive of a later diagnosis of autism spectrum disorder. In this study, we aimed to establish whether increased extra-axial CSF volume is found in a large, independent sample of children diagnosed with autism spectrum disorder, whether extra-axial CSF remains abnormally increased beyond infancy, and whether it is present in both normal-risk and high-risk children with autism.

Methods

In this case-control MRI study, children with autism spectrum disorder or with typical development aged 2–4 years were recruited from the community to the UC Davis MIND Institute Autism Phenome Project, based in Sacramento, CA, USA. The autism spectrum disorder group comprised children with autism spectrum disorder who were either normal risk (ie, from simplex families) or high risk (ie, from multiplex families). Measurements of extra-axial CSF volume, brain volume, head circumference, sleep problems, and familial risk status were derived from MRI and behavioural assessments. We applied a previously validated machine learning algorithm based on extra-axial CSF volume, brain volume, age, and sex to the current dataset.

Findings

Between July 20, 2007, and Dec 13, 2012, 159 children with autism spectrum disorder (132 male, 27 female) and 77 with typical development (49 male, 28 female) underwent MRI scans. The autism spectrum disorder group had an average of 15·1% more extra-axial CSF than controls after accounting for differences in brain volume, weight, age, and sex (least-squares mean 116·74 cm³ [SE 3·33] in autism group vs 101·40 cm³ [3·93] in typical development group; p=0·007; Cohen's d = 0·39). Subgroups of normal-risk (n=132) and high-risk (n=27) children with autism spectrum disorder had nearly identical extra-axial CSF volumes (p=0·78), and both subgroups had significantly greater volumes than controls. Both extra-axial CSF volume (p=0·004) and brain volume (p<0·0001) uniquely contributed to enlarged head circumference in the autism spectrum disorder group (p=0·04). Increased extra-axial CSF volume was associated with greater sleep disturbances (p=0·03) and lower non-verbal ability (p=0·04). The machine learning algorithm correctly predicted autism spectrum disorder diagnosis with a positive predictive value of 83% (95% CI 76·2–88·3).

Interpretation

Increased extra-axial CSF volume is a reliable brain anomaly that has now been found in three independent cohorts, comprising both high-risk and normal-risk children with autism spectrum disorder. Increased extra-axial CSF volume is detectable using conventional structural MRI scans from infancy through to age 3 years. These results suggest that increased extra-axial CSF volume could be an early stratification biomarker of a biologically based subtype of autism that might share a common underlying pathophysiology.

Funding

US National Institutes of Health.

Introduction

Increased extra-axial cerebrospinal fluid volume (CSF) is a brain anomaly characterised by excessive CSF in the subarachnoid space surrounding the cortical surface.1, 2, 3 We previously reported that high-familial-risk infants (based on having an older sibling with autism) who were later diagnosed with autism spectrum disorder had an increased amount of extra-axial CSF from 6 to 24 months of age, which preceded the age of diagnosis at 33 months.⁴ We reproduced this finding in a much larger independent sample of high-risk infants who developed autism spectrum disorder.⁵ The increased volume of extra-axial CSF at 6 months of age preceded the onset of autism symptoms, was predictive of later autism spectrum disorder diagnosis, and was associated with the severity of autism spectrum disorder symptoms 2 years later.⁵

The presence of increased extra-axial CSF in infancy had previously been considered to be benign because it had not been associated with a clinical syndrome. Although these two previous reports were the first to link increased extra-axial CSF in infancy to autism, past reports have associated increased extra-axial CSF volume with other neurological problems.6, 7, 8, 9 Research in the past 10 years has highlighted the importance of CSF circulation¹⁰ to transport trophic factors that regulate normal brain development,¹¹ and in turn, to clear metabolites that affect brain development and function.12, 13, 14 Altered CSF circulation has been shown to impair the clearance of neurotoxic proteins implicated in neuro-degenerative diseases (eg, amyloid-β [Aβ] protein¹⁴). This neuroprotective process is especially affected by disturbances in sleep.¹³

Research in context

Evidence before this study

We searched PubMed for published articles, using combinations of search terms that included “extra-axial fluid”, “benign extra-axial fluid”, “extra-axial fluid of infancy”, “extra-axial cerebrospinal fluid”, “subarachnoid cerebrospinal fluid”, “enlargement of subarachnoid spaces”, “benign effusions of infancy”, “external hydrocephalus”, and “communicating hydrocephalus”. Our search did not have any language or date restrictions. We also searched the reference lists of selected articles for other relevant publications. In addition, we identified a review paper on extra-axial cerbrospinal fluid (CSF; Zahl et al, 2011) and reviewed the articles listed in the reference list. None of the selected articles mentioned an association between the search terms and autism spectrum disorder, with the exception of our previous two publications that reported that high-risk infants (ie, with an older sibling with autism), who later developed autism spectrum disorder themselves, had increased extra-axial CSF volume from ages 6–24 months (Shen et al, 2013; Shen et al, 2017). It was not known whether extra-axial CSF volume remains abnormally high beyond infancy and whether it occurs in normal-risk children with autism spectrum disorder (ie, without an older sibling with autism).

Added value of this study

We have shown that extra-axial CSF volume is higher in children with autism spectrum disorder at 2–4 years of age compared with control children and remains abnormally high beyond infancy in children with autism, irrespective of family history of autism. Both extra-axial CSF volume and brain volume uniquely contributed to enlarged head circumference in the autism spectrum disorder group. Increased extra-axial CSF volume was associated with greater sleep disturbances and lower non-verbal ability. Extra-axial CSF volume correctly predicted autism spectrum disorder diagnosis with a positive predictive value of 83%.

Implications of all the available evidence

Increased extra-axial CSF volume is a reliable brain anomaly detectable using conventional structural MRI scans that has now been found in three independent cohorts from infancy through to age 3 years, comprising both high-risk and normal-risk children with autism. Increased extra-axial CSF volume could be an early stratification biomarker of a subtype of autism that shares a common underlying biology and could map on to specific, mechanistically targeted treatments.

Several outstanding questions remained from the previous studies, which used the infant sibling study design in which the participants were at high familial risk for autism because they had an older sibling with autism spectrum disorder.4, 5 The goal of the present study was to establish whether increased extra-axial CSF volume is found in a large, independent sample of children diagnosed with autism spectrum disorder and recruited from the community at age 2–4 years, comprising both normal-risk and high-risk children with autism. On the basis of our previous reports and the extant literature, we conducted this study guided by several hypotheses. First, we hypothesised that the autism spectrum disorder group would show excessive extra-axial CSF volume at age 2–4 years, irrespective of familial risk status, compared with children with typical development. Second, we expected that head circumference would be increased in the autism spectrum disorder group and that both extra-axial CSF volume and brain volume would contribute independently to head size. Third, in view of the biological evidence that normal sleep is associated with proper CSF circulation,¹³ we predicted that sleep problems would be associated with increased extra-axial CSF volume. Finally, based on our previous report that extra-axial CSF volume could predict autism spectrum disorder diagnosis among high-risk children,⁵ we hypothesised that applying the same prediction algorithm to normal-risk children could also accurately predict autism spectrum disorder diagnosis on an individual level.