Elsevier

Epilepsy & Behavior

Volume 47, June 2015, Pages 172-182
Epilepsy & Behavior

Review
Structural MRI biomarkers of shared pathogenesis in autism spectrum disorder and epilepsy

https://doi.org/10.1016/j.yebeh.2015.02.017Get rights and content

Highlights

  • MRI morphometric anomalies are antecedent to disease expression in ASD and epilepsy.

  • Blunted growth trajectories indicate brain dysmaturation in ASD and epilepsy.

  • Focal cortical dysplasia is the most common substrate in ASD and pediatric epilepsy.

  • MRI morphometry improves detection of FCD in epilepsy, an application untested in ASD.

  • qMRI biomarkers could extend the range of patients who might benefit from rapalogs.

Abstract

Etiological factors that contribute to a high comorbidity between autism spectrum disorder (ASD) and epilepsy are the subject of much debate. Does epilepsy cause ASD or are there common underlying brain abnormalities that increase the risk of developing both disorders? This review summarizes evidence from quantitative MRI studies to suggest that abnormalities of brain structure are not necessarily the consequence of ASD and epilepsy but are antecedent to disease expression. Abnormal gray and white matter volumes are present prior to onset of ASD and evident at the time of onset in pediatric epilepsy. Aberrant brain growth trajectories are also common in both disorders, as evidenced by blunted gray matter maturation and white matter maturation. Although the etiological factors that explain these abnormalities are unclear, high heritability estimates for gray matter volume and white matter microstructure demonstrate that genetic factors assert a strong influence on brain structure. In addition, histopathological studies of ASD and epilepsy brain tissue reveal elevated rates of malformations of cortical development (MCDs), such as focal cortical dysplasia and heterotopias, which supports disruption of neuronal migration as a contributing factor. Although MCDs are not always visible on MRI with conventional radiological analysis, quantitative MRI detection methods show high sensitivity to subtle malformations in epilepsy and can be potentially applied to MCD detection in ASD. Such an approach is critical for establishing quantitative neuroanatomic endophenotypes that can be used in genetic research. In the context of emerging drug treatments for seizures and autism symptoms, such as rapamycin and rapalogs, in vivo neuroimaging markers of subtle structural brain abnormalities could improve sample stratification in human clinical trials and potentially extend the range of patients that might benefit from treatment.

This article is part of a Special Issue entitled “Autism and Epilepsy”.

Introduction

Shared genetic risk factors for autism spectrum disorder (ASD) and epilepsy [1] suggest the possibility of shared intermediate endophenotypes. Although substantial heterogeneity is apparent in both ASD and epilepsy at the biochemical, neurophysiological, and neuroanatomic level, endophenotypes can provide more homogenous subgroups at intermediate levels between the genotype and the much broader diagnostic phenotype (i.e., ASD and/or epilepsy). To be viewed as an endophenotype, a measure must be quantifiable, heritable, and trait-dependent, thus presenting at a higher rate among affected individuals and their unaffected relatives than among the general population [2]. A related but less stringent classification of intermediate measures is a “biological marker” or “biomarker.” Biomarkers must be associated with the disease and measurable in patients but are not yet confirmed in nonaffected family members. This article will review findings from quantitative magnetic resonance image (qMRI) morphometry studies in ASD and epilepsy with the goal of identifying neuroanatomic biomarkers associated with both of these disorders.

The identification of shared neuroanatomical biomarkers in ASD and epilepsy could provide essential links for genotype–phenotype studies. Tuberous sclerosis complex (TSC) provides a model for such an approach [1], [3]. In TSC, links have been established between the genes that are mutated (TSC, TSC1, and TSC2), disturbance in a molecular pathway (mammalian target of rapamycin: mTOR), neuroanatomic abnormalities (hamartomas/tubers), and phenotypic expression (ASD and epilepsy). The presence of tubers on MRI is the neuroanatomic biomarker associated with elevated risk of ASD (50%) [4], epilepsy (60%) [5], and cognitive impairment (45%) [6]. Tuber location and extent have been investigated as contributing factors, revealing that tubers in the frontal and temporal lobes [3] and cerebellum [7], [8] increase ASD risk. This approach has yielded a clear marker for molecularly driven drug therapies such as rapamycin, an mTOR inhibitor, in patients with TSC.

However, not all malformations of cortical development (MCDs) are as apparent on MRI as tubers. For example, focal cortical dysplasia (FCD) is an MCD that is commonly found on histopathological evaluation of epilepsy surgical tissue [9] and postmortem autism tissue [10], [11], [12], [13], [14], [15] but is often visually unappreciable on MRI [16]. Quantitative magnetic resonance image methods that utilize measurements of cortical thickness or blurring of the gray and white matter boundary improve detection of subtle FCD lesions [16], [17], [18], [19], allowing for an extension of a TSC-like model into genetic syndromes where FCD is a neuroanatomic marker, such as contactin-associated protein-like 2 (CNTNAP2) deletions. Contactin-associated protein-like 2 is a protein critical for early brain development [20]. Contactin-associated protein-like 2 mutation is associated with cortical dysplasia focal epilepsy syndrome (CDFE), a clinical phenotype that involves language regression, intellectual disability, hyperactivity, and, in two-thirds of patients, ASD [21]. Contactin-associated protein-like 2 knockout mice show stereotypic motor movements, behavioral inflexibility, social communication deficits, seizures, and neuronal migration abnormalities [20]. Migration abnormalities in CNTNAP2 knockout mice are characterized at the histopathological level as cortical dyslamination and ectopic neurons in the white matter [20]. These migrational abnormalities are also present in tissue from humans with CDFE syndrome [21]. Quantitative magnetic resonance image metrics of cortical features (e.g., cortical thickness and gray–white matter blurring), which could be obtained and compared across animals and humans, have the potential to provide an in vivo measure of these pathologic features. Importantly, abnormal motor behavior is rescued by administration of risperidone in CNTNAP2 knockout mice [20], which suggests a potential clinical application in humans. Identification of qMRI biomarkers for FCD in humans could improve sample selection for risperidone trials and potentially extend the range of patients who might benefit from mTOR inhibitor therapies targeting seizures, cognitive impairment, and autism symptoms [22].

Thus, it is an important time to survey the existing structural neuroimaging literature for neuroanatomic endophenotypes or biomarkers that may be indicators of shared pathogenesis in epilepsy and autism. These can then be used to guide future investigations in genetically derived samples at high risk of seizures and developmental delay. In the following review, findings from qMRI morphometry studies of normative life span brain growth trajectories will first be summarized to establish a baseline from which to evaluate abnormal findings in epilepsy and ASD. Then, evidence for aberrant growth trajectories and focal structural abnormalities common in epilepsy and ASD will be discussed. Correspondence with pathology will be evaluated where evidence is available. Attention will be paid to the type and location of focal abnormalities as factors that contribute to seizure risk and ASD symptoms.

Section snippets

Normative life span brain maturation

Although there is considerable neuroanatomical variance among healthy individuals, which increases with age [23], general patterns can be observed in both gray matter maturation and white matter maturation.

Aberrant brain growth trajectories in patients with epilepsy and normal MRI

An optimal method for investigating subtle structural abnormalities in patients with epilepsy and radiologically “normal” MRI is to scan participants when they first present with seizures and follow them longitudinally in comparison with typically developing controls (TDCs). This approach can address whether structural abnormalities detected with qMRI are antecedent or subsequent to seizure onset. Studies that have adopted such a methodology reveal abnormalities in gray and white matter

Focal abnormalities on neuroimaging and histology in epilepsy

Detection of a focal lesion on MRI informs epilepsy diagnosis and prognosis [61]. Practice parameters from the American Academy of Neurology, the Child Neurology Society, and the American Epilepsy Society recommend diagnostic neuroimaging for adults presenting with a first unprovoked seizure and for children with risk factors [62], [63], [64], [65]. Electroencephalography (EEG) and high-resolution MRI are the methods of choice for accurate diagnosis after a first seizure [66]. High-resolution

Aberrant growth trajectories in idiopathic ASD

Leo Kanner was the first to describe larger head circumference in autism, having observed it in five of the 11 children from his initial case series [105]. Head circumference may start off within the normal range at birth, followed by accelerated growth that peaks anywhere between six months and four years and normalizes by puberty [106]. A meta-analysis of head circumference studies revealed that using locally recruited controls results in less head size differences than population norms [107]

Focal radiologic abnormalities in idiopathic ASD

Although biomarkers are emerging from the qMRI literature, there is a major gap between findings from these group studies and studies of focal radiologic abnormalities in nonsyndromal ASD. Blinded conventional visual analysis of MRI scans has not consistently identified a higher prevalence of neuroradiologic findings in children with nonsyndromal ASD compared with TDCs despite using comprehensive imaging protocols [125]. This has contributed to a reluctance to integrate MRI in the comprehensive

Histopathological analysis of postmortem ASD brain tissue

Early histopathological investigations of postmortem autism brains [130], [131] noted a predominant pattern of “cortical dysgenesis.” Kemper and Bauman [130] noted findings of dyslamination in the anterior cingulate in five of six cases. In four of the six cases studied, Bailey and colleagues [131] observed increased cortical thickness, high neuronal density, neurons present in the molecular layer, and irregular laminar patterns. Half showed ectopic gray matter and an increased number of

Summary and conclusions

The number of shared genetic risk factors for ASD and epilepsy is expanding. Advances in chromosomal microarray analysis (CMA) technology have improved the detection of small chromosomal structural variations. Several copy number variants (CNVs) are linked to both ASD and epilepsy [1] such as 1q21.1 deletions, 7q11.23 duplications, 15q11.1-q13.3 duplications, 16p11.2 deletions, 18q12.1 duplications, and 22q11.2 deletions. However, the mechanisms through which these deleterious CNVs confer risk

List of acronyms

    AD

    autistic disorder

    ASD

    autism spectrum disorder

    CA4

    cornu ammonis subregion 4 in the hippocampus

    CC

    corpus callosum

    CDFE

    cortical dysplasia focal epilepsy syndrome

    CMA

    chromosomal microarray analysis

    CNTNAP2

    contactin-associated protein-like 2

    CNV

    copy number variant

    CPAE

    Collaborative Programs of Excellence in Autism Criteria for ASD

    CT

    cortical thickness

    DSM-IV

    Diagnostic and Statistical Manual of Mental Disorders — Fourth Edition

    EEG

    electroencephalography

    FA

    fractional anisotropy

    FCD

    focal cortical dysplasia

    FLAIR

Acknowledgments

This study was supported by grants from the Epilepsy Foundation (Award 286054 to Karen Blackmon) and the Simons Foundation (Simons Foundation Autism Research Initiative Award 291959 to Orrin Devinsky and Karen Blackmon), as well as by generous support from the Morris and Alma Schapiro foundation and the Finding a Cure for Epilepsy and Seizures (FACES) foundation. The author would like to thank Dr. Thomas Thesen, Dr. Ruben Kuzniecky, and Dr. Orrin Devinsky for discussions on earlier drafts of

References (141)

  • E. Hutchinson et al.

    Children with new-onset epilepsy exhibit diffusion abnormalities in cerebral white matter in the absence of volumetric differences

    Epilepsy Res

    (2010)
  • J.F. Téllez-Zenteno et al.

    Surgical outcomes in lesional and non-lesional epilepsy: a systematic review and meta-analysis

    Epilepsy Res

    (2010)
  • K.C. Lim et al.

    Focal malformations of cortical development: new vistas for molecular pathogenesis

    Neuroscience

    (2013)
  • J. Liu et al.

    Evidence for mTOR pathway activation in a spectrum of epilepsy-associated pathologies

    Acta Neuropathol Commun

    (2014)
  • E. Russo et al.

    mTOR inhibition modulates epileptogenesis, seizures and depressive behavior in a genetic rat model of absence epilepsy

    Neuropharmacology

    (2013)
  • X. Huang et al.

    Pharmacological inhibition of the mammalian target of rapamycin pathway suppresses acquired epilepsy

    Neurobiol Dis

    (2010)
  • E. Raffo et al.

    A pulse rapamycin therapy for infantile spasms and associated cognitive decline

    Neurobiol Dis

    (2011)
  • A. Sliwa et al.

    Post-treatment with rapamycin does not prevent epileptogenesis in the amygdala stimulation model of temporal lobe epilepsy

    Neurosci Lett

    (2012)
  • S. Erlich et al.

    Rapamycin is a neuroprotective treatment for traumatic brain injury

    Neurobiol Dis

    (2007)
  • D.N. Franz et al.

    Efficacy and safety of everolimus for subependymal giant cell astrocytomas associated with tuberous sclerosis complex (EXIST-1): a multicentre, randomised, placebo-controlled phase 3 trial

    Lancet

    (2013)
  • M. Perek-Polnik et al.

    Effective everolimus treatment of inoperable, life-threatening subependymal giant cell astrocytoma and intractable epilepsy in a patient with tuberous sclerosis complex

    Eur J Paediatr Neurol

    (2012)
  • Z.I. Wang et al.

    The pathology of magnetic-resonance-imaging-negative epilepsy

    Mod Pathol Off J U S Can Acad Pathol Inc.

    (2013)
  • S.S. Jeste et al.

    Disentangling the heterogeneity of autism spectrum disorder through genetic findings

    Nat Rev Neurol

    (2014)
  • I.I. Gottesman et al.

    The endophenotype concept in psychiatry: etymology and strategic intentions

    Am J Psychiatry

    (2003)
  • P.F. Bolton et al.

    Neuro-epileptic determinants of autism spectrum disorders in tuberous sclerosis complex

    Brain J Neurol

    (2002)
  • P. De Vries

    What can we learn from tuberous sclerosis complex (TSC) about autism?

    J Intellect Disabil Res

    (2008)
  • R. Guerrini et al.

    Epilepsy and malformations of the cerebral cortex

    Epileptic Disord Int Epilepsy J Videotape

    (2003)
  • A.M. Weber et al.

    Autism and the cerebellum: evidence from tuberous sclerosis

    J Autism Dev Disord

    (2000)
  • T.J. Eluvathingal et al.

    Cerebellar lesions in tuberous sclerosis complex: neurobehavioral and neuroimaging correlates

    J Child Neurol

    (2006)
  • I. Blümcke et al.

    Cause matters: a neuropathological challenge to human epilepsies

    Brain Pathol

    (2012)
  • J. Wegiel et al.

    The neuropathology of autism: defects of neurogenesis and neuronal migration, and dysplastic changes

    Acta Neuropathol

    (2010)
  • J. Wegiel et al.

    Differences between the pattern of developmental abnormalities in autism associated with duplications 15q11.2-q13 and idiopathic autism

    J Neuropathol Exp Neurol

    (2012)
  • J. Wegiel et al.

    Brain-region-specific alterations of the trajectories of neuronal volume growth throughout the lifespan in autism

    Acta Neuropathol Commun

    (2014)
  • J. Wegiel et al.

    Stereological study of the neuronal number and volume of 38 brain subdivisions of subjects diagnosed with autism reveals significant alterations restricted to the striatum, amygdala and cerebellum

    Acta Neuropathol Commun

    (2014)
  • M.F. Casanova et al.

    Focal cortical dysplasias in autism spectrum disorders

    Acta Neuropathol Commun

    (2013)
  • R. Stoner et al.

    Patches of disorganization in the neocortex of children with autism

    N Engl J Med

    (2014)
  • A. Bernasconi et al.

    Advances in MRI for ‘cryptogenic’ epilepsies

    Nat Rev Neurol

    (2011)
  • B. Ahmed et al.

    Hierarchical conditional random fields for outlier detection: an application to detecting epileptogenic cortical malformations

    J Mach Learn Res

    (2014)
  • T. Thesen et al.

    Detection of epileptogenic cortical malformations with surface-based MRI morphometry

    PLoS One

    (2011)
  • S.J. Hong et al.

    Automated detection of cortical dysplasia type II in MRI-negative epilepsy

    Neurology

    (2014)
  • K.A. Strauss et al.

    Recessive symptomatic focal epilepsy and mutant contactin-associated protein-like 2

    N Engl J Med

    (2006)
  • P. Curatolo et al.

    mTOR inhibitors as a new therapeutic option for epilepsy

    Expert Rev Neurother

    (2013)
  • J.H. Gilmore et al.

    Longitudinal development of cortical and subcortical gray matter from birth to 2 years

    Cereb Cortex

    (2012)
  • G. Li et al.

    Mapping region-specific longitudinal cortical surface expansion from birth to 2 years of age

    Cereb Cortex

    (2013)
  • M.S. Panizzon et al.

    Distinct genetic influences on cortical surface area and cortical thickness

    Cereb Cortex

    (2009)
  • A.B. Storsve et al.

    Differential longitudinal changes in cortical thickness, surface area and volume across the adult life span: regions of accelerating and decelerating change

    J Neurosci

    (2014)
  • Y. Ostby et al.

    Heterogeneity in subcortical brain development: a structural magnetic resonance imaging study of brain maturation from 8 to 30 years

    J Neurosci

    (2009)
  • Brain Development Cooperative Group

    Total and regional brain volumes in a population-based normative sample from 4 to 18 years: the NIH MRI study of normal brain development

    Cereb Cortex

    (2012)
  • M. Wu et al.

    Development of superficial white matter and its structural interplay with cortical gray matter in children and adolescents

    Hum Brain Mapp

    (2014)
  • P. Shaw et al.

    Neurodevelopmental trajectories of the human cerebral cortex

    J Neurosci

    (2008)
  • Cited by (18)

    • Quantitative magnetic resonance imaging traits as endophenotypes for genetic mapping in epilepsy

      2016, NeuroImage: Clinical
      Citation Excerpt :

      Identifying genetic variants that influence HV is less likely to elucidate susceptibility variants unique to each brain condition, but may provide an opportunity to characterize biological pathways shared by such complex brain-related disorders, which themselves may be co-morbid. Shared underlying mechanisms between epilepsy and other neurologic and psychiatric disorders, including genetic processes, have been suggested by the observation that epileptic seizures form part of the wide phenotype of some brain-related conditions, such as autism spectrum disorder (Blackmon, 2015). Over the last two decades, the search for neuroimaging endophenotypes has expanded.

    View all citing articles on Scopus
    View full text