Thursday, July 28, 2016

Can ultrasound diagnose autism?

Bradstreet JJ, Pacini S, Ruggiero M. A New Methodology of Viewing Extra-Axial
Fluid and Cortical Abnormalities in Children with Autism via Transcranial
Ultrasonography. Front Hum Neurosci. 2014 Jan 15;7:934.

Autism spectrum disorders (ASDs) are developmental conditions of uncertain etiology which have now affected more than 1% of the school-age population of children in many developed nations. Transcranial ultrasonography (TUS) via the temporal bone appeared to be a potential window of investigation to determine the presence of both cortical abnormalities and increased extra-axial fluid (EAF).
TUS was accomplished using a linear probe (10-5 MHz). Parents volunteered ASD subjects (N = 23; males 18, females 5) for evaluations (mean = 7.46 years ± 3.97 years), and 15 neurotypical siblings were also examined (mean = 7.15 years ± 4.49 years). Childhood Autism Rating Scale (CARS2(®)) scores were obtained and the ASD score mean was 48.08 + 6.79 (Severe).
Comparisons of the extra-axial spaces indicated increases in the ASD subjects. For EAF we scored based on the gyral summit distances between the arachnoid membrane and the cortical pia layer (subarachnoid space): (1) <0.05 cm, (2) 0.05-0.07 cm, (3) 0.08-0.10 cm, (4) >0.10 cm. All of the neurotypical siblings scored 1, whereas the ASD mean score was 3.41 ± 0.67. We also defined cortical dysplasia as the following: hypoechoic lesions within the substance of the cortex, or disturbed layering within the gray matter. For cortical dysplasia we scored: (1) none observed, (2) rare hypoechogenic lesions and/or mildly atypical cortical layering patterns, (3) more common, but separated areas of cortical hypoechogenic lesions, (4) very common or confluent areas of cortical hypoechogenicity. Again all of the neurotypical siblings scored 1, while the ASD subjects' mean score was 2.79 ± 0.93.
TUS may be a useful screening technique for children at potential risk of ASDs which, if confirmed with repeated studies and high resolution MRI, provides rapid, non-invasive qualification of EAF, and cortical lesions.

Siniscalco D. The searching for autism biomarkers: a commentary on: a new
methodology of viewing extra-axial fluid and cortical abnormalities in children
with autism via transcranial ultrasonography. Front Hum Neurosci. 2014 May

It’s worth taking a moment to appreciate how remarkable these results are. Using ultrasound, Bradstreet et al. are claiming to have found markers which are pretty much 100% predictive of the presence of autism. Compare this to the situation with structural MRI scanning: Haar et al. found that the very best methods achieved no more than 60% accuracy at predicting ASD (where 50% is chance performance) based on brain structure. So either ultrasound is much better than MRI for detecting ASD, or something’s gone wrong here.

What might have gone wrong? In Bradstreet et al.’s study, the abnormalities were rated manually by someone who reviewed the ultrasound images. It is not stated that this person was blind to the group (autism or control) of the subjects in question. If the rater wasn’t blinded, the ratings might have been influenced (consciously or subconsciously) by the rater’s expectation of finding abnormalities in the autism group.

A related concern is that no data is provided about the reliability of the EAF and cortical dysplasia ratings. Reliability means the extent to which two raters (or the same rater at two different times) assigns the same rating to the same subject. Establishing the reliability of a novel measure is considered crucial before it can be deployed to examine group differences. Neither the blinding nor the reliability issue are addressed anywhere in the paper. I’m surprised that this paper passed peer review.

Finally, it may be relevant that the authors of this paper have ‘interesting’ track records. Marco Ruggiero has published papers arguing that HIV does not cause AIDS. Stefania Pacini, along with Ruggiero, has promoted the controversial cancer therapy GcMAF and Jeff Bradstreet had (before his death last year) a long history of ‘treating’ autism with a variety of unconventional therapies, including GcMAF.

Courtesy of Doximity

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