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A systematic review of comorbidity between cerebral palsy, autism spectrum disorders and Attention Deficit Hyperactivity Disorder

  • Francesco Craig
    Affiliations
    Scientific Institute I.R.C.C.S, “Eugenio Medea”, “La Nostra Famiglia”, Unit for Severe Disabilities in Developmental Age and Young Adults (Developmental Neurology and Neurorehabilitation), Brindisi Research Centre, Brindisi, Italy
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  • Rosa Savino
    Affiliations
    Scientific Institute I.R.C.C.S, “Eugenio Medea”, “La Nostra Famiglia”, Unit for Severe Disabilities in Developmental Age and Young Adults (Developmental Neurology and Neurorehabilitation), Brindisi Research Centre, Brindisi, Italy
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  • Antonio Trabacca
    Correspondence
    Corresponding author. Unit for Severe Disabilities in Developmental Age and Young Adults (Developmental Neurology and Neurorehabilitation), Scientific Institute I.R.C.C.S., “Eugenio Medea”, “La Nostra Famiglia”, Brindisi Research Centre, Ex Complesso Ospedaliero “A. Di Summa” - Piazza “A. Di Summa”, 72100, Brindisi, Italy. Fax: +39 0831349612.
    Affiliations
    Scientific Institute I.R.C.C.S, “Eugenio Medea”, “La Nostra Famiglia”, Unit for Severe Disabilities in Developmental Age and Young Adults (Developmental Neurology and Neurorehabilitation), Brindisi Research Centre, Brindisi, Italy
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Published:November 02, 2018DOI:https://doi.org/10.1016/j.ejpn.2018.10.005

      Highlights

      • The NICE Guideline stresses the importance of investigating the prevalence of ASD and ADHD in CP.
      • The aim of this study was to examine the prevalence of ASD and ADHD in the CP population.
      • ASD seems to be more common in children with CP than in the general population.
      • ADHD shows a higher prevalence in CP than the general population.
      • Recognizing other NDDs might help to develop improved therapies for children with CP.

      Abstract

      Objectives

      The aim of this systematic review was to examine the incidence and prevalence of comorbidity between Cerebral Palsy (CP), Autism spectrum disorders (ASDs) and Attention-Deficit/Hyperactivity Disorder (ADHD).

      Methods

      We searched for articles indexed in PubMed, EBSCOhost, Scopus, Web of Science and other potentially relevant internet sources using a combination of expressions including “cerebral palsy” AND “autism” OR “ASD” OR “pervasive development disorder” AND “Attention Deficit Hyperactivity Disorder” OR “ADHD”.

      Results

      We identified 2542 studies on CP and ASD and 998 studies on CP and ADHD. After screening titles and abstracts and removing duplicated studies, 47 full papers (CP and ASD n = 28; CP and ADHD n = 19) were downloaded and screened for eligibility. Twenty-eight (CP and ASD n = 16; CP and ADHD n = 12) studies were identified in the peer-review literature. Based on this systematic review, ASD and ADHD seem to be more common in people with CP than in the general population, yet the gold standard methods for diagnosing ASD or ADHD are not suitable for children with motor problems.

      Conclusions

      Assessing the occurrence of ASD and ADHD would improve the significant cost of healthcare, therapies, and overall daily living for families with children affected by CP. However, psychometric studies are needed in the future to promote development of measures suitable for individuals with CP. In addition, this review highlights the paucity of peer-reviewed studies investigating the occurrence of ASD and ADHD in children with different CP subtypes or functional abilities, and there are still some open questions about pathogenic mechanisms common to CP, ASD and ADHD.

      Keywords

      1. Introduction

      Cerebral Palsy (CP) is a group of lifelong neurological disorders and a major cause of childhood disability. According to previous population-based studies from countries around the world, prevalence estimates for CP range from 1.5 to more than 4 per 1000 live births or children of a defined age range.
      • Rosenbaum P.
      • Paneth N.
      • Leviton A.
      • et al.
      A report: the definition and classification of cerebral palsy April 2006.
      • Odding E.
      • Roebroeck M.E.
      • Stam H.J.
      The epidemiology of cerebral palsy: incidence, impairments and risk factors.
      • Stavsky M.
      • Mor O.
      • Mastrolia S.A.
      • Greenbaum S.
      • Than N.G.
      • Erez O.
      Cerebral palsy-trends in epidemiology and recent development in prenatal mechanisms of disease, treatment, and prevention.
      The Executive Committee on the Definition and Classification of Cerebral Palsy delineated the definition of this disorder with the intent of providing a common conceptualization of this clinical entity for use by a broad international audience.
      • Bax M.
      • Goldstein M.
      • Rosenbaum P.
      • et al.
      Proposed definition and classification of cerebral palsy, April 2005.
      CP was defined as a group of permanent disorders of the development of movement and posture, causing activity limitation, that are attributed to non-progressive disturbances that occurred in the developing fetal or infant brain.
      • Bax M.
      • Goldstein M.
      • Rosenbaum P.
      • et al.
      Proposed definition and classification of cerebral palsy, April 2005.
      The prevailing trend in clinical practice is to classify CP by functional independence in terms of gross motor function, fine motor function, and communication abilities through the Gross Motor Function Classification System (GMFCS),
      • Palisano R.
      • Rosenbaum P.
      • Walter S.
      • Russell D.
      • Wood E.
      • Galuppi B.
      Development and reliability of a system to classify gross motor function in children with cerebral palsy.
      the Manual Abilities Classification System (MACS),
      • Eliasson A.C.
      • Krumlinde-Sundholm L.
      • Rösblad B.
      • et al.
      The manual ability classification system (MACS) for children with cerebral palsy: scale development and evidence of validity and reliability.
      and the Communication Function Classification System (CFCS).
      • Hidecker M.J.
      • Paneth N.
      • Rosenbaum P.L.
      • et al.
      Developing and validating the communication function classification system for individuals with cerebral palsy.
      These measures were designed to better delineate the functional profile of children with CP by focusing on activity and participation levels.
      • Compagnone E.
      • Maniglio J.
      • Camposeo S.
      • et al.
      Functional classifications for cerebral palsy: correlations between the gross motor function classification system (GMFCS), the manual ability classification system (MACS) and the communication function classification system (CFCS).
      Motor disorders in CP are often associated with disturbances of sensation, perception, cognition, communication, behavior, and epilepsy.
      • Rosenbaum P.
      • Paneth N.
      • Leviton A.
      • et al.
      A report: the definition and classification of cerebral palsy April 2006.
      • Trabacca A.
      • Vespino T.
      • Di Liddo A.
      • Russo L.
      Multidisciplinary rehabilitation for patients with cerebral palsy: improving long-term care.
      In addition, a recent systematic review and meta-analysis showed increased risk rates for emotional lability, irritability, impulsiveness and behavioral problems in people with CP.
      • Downs J.
      • Blackmore A.M.
      • Epstein A.
      • et al.
      The prevalence of mental health disorders and symptoms in children and adolescents with cerebral palsy: a systematic review and meta-analysis.
      All these conditions are a wide range of common disorders that may be associated with other Neurodevelopmental Disorders (NDDs) such as Attention Deficit/Hyperactivity Disorder (ADHD), Autism Spectrum disorder (ASD), Learning Disabilities (LD), Intellectual Disability (ID), Speech and Language Delay, Developmental Delay (DD), and Developmental Coordination Disorder (DCD).
      • Zhang D.L.
      • Chen S.Z.
      • Liu X.M.
      Recent perspectives of pediatric neurodevelopmental disorders.
      • Schiariti V.
      • Mahdi S.
      • Bölte S.
      International classification of functioning, disability and health core sets for cerebral palsy, autism spectrum disorder, and attention-deficit-hyperactivity disorder.
      Indeed, comorbidity with other NDDs could directly or indirectly influence habilitation and rehabilitation of children or adults with CP. For this reason, it is very important to establish the impact of comorbidities in CP patients in order to promote their adjustment and participation as well as subjective and relational well-being. Currently, there is an unambiguous link between CP and other NDDs.
      • Tollånes M.C.
      • Wilcox A.J.
      • Stoltenberg C.
      • Lie R.T.
      • Moster D.
      Neurodevelopmental disorders or early death in siblings of children with cerebral palsy.
      Based on previous studies, the same genetic risk factors could underlie different pathological phenotypes.
      • Tollånes M.C.
      • Wilcox A.J.
      • Stoltenberg C.
      • Lie R.T.
      • Moster D.
      Neurodevelopmental disorders or early death in siblings of children with cerebral palsy.
      • Kim Y.S.
      • State M.W.
      Recent challenges to the psychiatric diagnostic nosology: a focus on the genetics and genomics of neurodevelopmental disorders.
      Yet, similar phenotypes could have different genetic risk factors.
      • Tollånes M.C.
      • Wilcox A.J.
      • Stoltenberg C.
      • Lie R.T.
      • Moster D.
      Neurodevelopmental disorders or early death in siblings of children with cerebral palsy.
      • Hu W.F.
      • Chahrour M.H.
      • Walsh C.A.
      The diverse genetic landscape of neurodevelopmental disorders.
      Therefore, many NDDs – rather than being distinct conditions – may be part of a continuum of clinical expression. As suggested by Zwaigenbaum, injury-related processes versus genetically influenced developmental processes in the comorbidity between CP and other NDDs remain an interesting and challenging question.
      • Zwaigenbaum L.
      The intriguing relationship between cerebral palsy and autism.
      Further studies on comorbid conditions are needed to increase our understanding of the complexity of CP.
      Recently, the National Institute for Health and Care Excellence (NICE) Guideline on diagnosing, assessing and managing CP
      • Shaunak M.
      • Kelly V.B.
      Cerebral palsy in under 25 s: assessment and management (NICE Guideline NG62).
      underlined the importance of investigating the prevalence of ASD and ADHD in children and young people with CP. According to the Diagnostic and Statistical Manual of Mental Disorders – Fifth Edition (DSM-5), the diagnosis of ASD relies on persisting deficits of social communication and interaction and restricted and repetitive behaviors, interests, activities, while ADHD is characterized by a persistent pattern of inattention and/or hyperactivity-impulsivity interfering with functioning or development.
      • American Psychiatric Association
      Diagnostic and statistical manual of mental disorders (DSM-5®).
      ASD and ADHD are common NDDs in the pediatric population with a prevalence of 1% and 5%, respectively.
      • American Psychiatric Association
      Diagnostic and statistical manual of mental disorders (DSM-5®).
      Recent studies on epidemiological, clinical, neuroimaging and biological risk factors showed high rates of comorbidity and support several overlapping traits between ASD and ADHD.
      • Craig F.
      • Lamanna A.L.
      • Margari F.
      • Matera E.
      • Simone M.
      • Margari L.
      Overlap between autism spectrum disorders and attention deficit hyperactivity disorder: searching for distinctive/common clinical features.
      • Taurines R.
      • Schwenck C.
      • Westerwald E.
      • Sachse M.
      • Siniatchkin M.
      • Freitag C.
      ADHD and autism: differential diagnosis or overlapping traits? A selective review.
      • Simonoff E.
      • Pickles A.
      • Charman T.
      • Chandler S.
      • Loucas T.
      • Baird G.
      Psychiatric disorders in children with autism spectrum disorders: prevalence, comorbidity, and associated factors in a population-derived sample.
      Furthermore, given the link between mental and physical health, detection and management of specific comorbid diagnoses such as ASD and ADHD could improve planning for service and treatment of people with CP. The main aim of this systematic review was to explore the relationship between CP, ASD and ADHD and to investigate how these disorders overlap. This review starts with a discussion of the incidence and prevalence of CP and ASD and then presents research findings focusing on the incidence and prevalence of CP and ADHD.

      2. Methods

      2.1 Study selection and data collection

      PRISMA guidelines were followed.
      • Liberati A.
      • Altman D.G.
      • Tetzlaff J.
      • et al.
      The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration.
      The search strategy included research databases such as PubMed, Scopus, Web of Science, EBSCOhost and other potentially relevant internet sources such as Google®. All database searches were performed on January 6th, 2018 using a combination of the following free-text terms: “cerebral palsy” AND “autism” OR “ASD” OR “pervasive development disorder” AND “Attention Deficit Hyperactivity Disorder” OR “ADHD”.
      After this initial literature search, each single study title and abstract was screened by the first author. All references with duplicate data were excluded. Based on eligibility criteria, two reviewers (FC and RS) independently screened an abstract of available citations to identify potentially eligible studies. The full text of all potentially relevant studies was subsequently retrieved and further examined for eligibility. All references included in the papers identified as relevant from the database search were also examined for possible inclusion in this review. Data were extracted independently by two authors (FC and RS) and disagreements were resolved by negotiation with a third author (AT). Agreement as to whether or not the study met the inclusion criteria was 100%.

      2.2 Eligibility criteria

      All the studies included in this review met the following five criteria: They 1) investigated the prevalence of ASD in CP or vice versa; 2) investigated the prevalence of ADHD in CP or vice versa; 3) enrolled children, adolescents and young adults (18–35 years); 4) were published in English; and 5) were published in peer-reviewed journals. No restrictions were placed on the date of publication. Review articles and single clinical reports were excluded.

      2.3 Data extraction

      Studies meeting the inclusion criteria were summarized in terms of: I) type of study; II) number of participants (sample size); III) diagnosis-related groups; III) country of data collection; IV) participants’ age; V) diagnostic criteria and assessment tools; VI) rates of comorbidity.

      3. Results

      We identified 2542 studies on CP and ASD (PubMed n = 817, Scopus n = 840, Web of Science n = 738, EBSCOhost n = 120, and other sources n = 27) and 998 studies on CP and ADHD (PubMed n = 425, Scopus n = 265, Web of Science n = 184, EBSCOhost n = 108, and other sources n = 17). The screening phase involved the examination of titles and abstracts of all identified studies. 2411 studies (CP and ASD n = 1639; CP and ADHD n = 772) were excluded as they were not deemed suitable. After adjusting for duplicates, 533 studies on CP and ASD and 135 studies on CP and ADHD were screened to identify potentially eligible studies. 47 studies (CP and ASD n = 28; CP and ADHD n = 19) were selected for the eligibility phase. Out of these, 12 studies on CP and ASD and 7 studies on CP and ADHD were excluded as they did not provide sufficient data on ASD or ADHD in children or young people with CP. Following this, 16 empirical studies on CP and ASD and 12 empirical studies on CP and ADHD fully met the previously stipulated eligibility criteria for inclusion in the systematic review process. The PRISMA flow diagram (Fig. 1) provides more detailed information on the study selection process.
      Fig. 1
      Fig. 1The PRISMA flow diagram provides more detailed information regarding the selection process of studies.

      3.1 Study characteristics

      The main methodological features and general characteristics of all reviewed studies are summarized in Table 1, Table 2.
      Table 1Summary of the epidemiologic evidence on CP and ASD.
      AuthorsYear of publicationType of studyNumber of participants (N)Diagnosis-related groupsCountryAgeDiagnostic criteria and assessment toolsPrevalence of ASD or CP n (%)
      Goodman and Graham1996cross-sectional149CPUK6–10 yearsQuestionnaire measures of psychiatric caseness4 (3%)
      Nordin & Gillberg1996epidemiological38CPSwedenschool-ageABC, CARS, DSM-III-R4 (10.5%)
      Fombonne et al.1997epidemiological174AutismUK6–16 yearsADI-R5 (2.9%)
      Ek et al.1998population-based27Autistic Disorder + blindnessSweden7–17 yearsCARS, DSM-IV8 (29.6%)
      Chakrabarti & Fombonne2001cross-sectional97PDDUK2.5–6.5 yearsADI-R2 (2%)
      Steffenburg & Gillberg2003population-based37CPSweden8–16 yearsABC, CARS, ADI, DSM-III-R6 (16.2%)
      Kielinen et al.2004population-based study187Autistic DisorderTurkey4–18 yearsDSM-IV8 (4.3%)
      Lindquist et al.2006population-based study18CP + hydrocephalusSweden5–12 yearsCARS6 (33%)
      Mukaddes et al.2007case–control30CP + visually impairedTurkey7–18 yearsABC, CARS, DSM-IV10 (33%)
      Carlsson et al.2008population-based study34CP + epilepsySweden8–12 yearsSDQ5 (14%)
      Kilincaslan & Mukaddes2008case–control126CPFinland3–18 yearsABC, CARS, DSM-IV19 (15%)
      Himmelmann and Uvebrand2011population-based186CPSweden4–8 yearsDSM-IV, GMFCS9 (4.8%)
      Kirby et al.2011population-based476CPUSA8 yearGMFCS, DSM-IV-TR39 (8.2%)
      Christensen et al.2013population-based451CPUSA9 yearGMFCS, DSM-IV-TR31 (6.9)
      Delobel-ayoub et al.2017population-based1225CPIceland, Sweden, France, UK0–19 yearsICD-10-R; GMFCS107 (8.7%)
      Hirschberger et al.2018multicenter, prospective cohort follow-up93CPUSA10 yearsSCQ, ADI-R, ADOS-28 (20%)
      Cerebral Palsy (CP), Autism spectrum disorders (ASD), Pervasive Development Disorder (PDD), Autism Behavior Checklist (ABC), childhood Autism Rating Scale (CARS), diagnostic and statistical manual of mental disorders (DSM), Autism Diagnostic Interview (ADI), Strength and Difficulties Questionnaire(SDQ), Autism Diagnostic Observation Schedule-2 (ADOS-2), Social Communication Questionnaire (SCQ), Gross Motor Function Classification System (GMFCS), International Classification of Diseases (ICD).
      Table 2Summary of the epidemiologic evidence on CP and ADHD.
      AuthorsYear of publicationType of studyNumber of participants (N)Diagnosis-related groupsCountryAGEDiagnostic criteria and assessment toolsPrevalence of ADHD or CP n (%)
      McDermott et al.1996population-based47CPUSA4–17 yearsBehavior Problem Index12 (25.5%)
      Goodman1998prospective328hemiplegiaUK2.5–4.9 yearsCTRS; Rutter questionnaires
      Gross-Tsur et al.2002prospective, double-blind, placebo controlled, crossover116CP + ADHDIsrael3.9–20.0 yearsCRS; DSM-IV29 (33%)
      Schenker et al.2005cross-sectional study148CPIsrael6.1–13.6 yearsGMFCS28 (19%)
      Symons et al.2007double-blind, placebo-controlled, randomized, single-case3CP + ADHDUSA8–11 yearsDSM-IV3 (100%)
      Parkes et al.2008crosssectional multi-centre survey818CPEngland, Sweden, Northern Ireland, France, Ireland,Denmark, Italy8–12 yearsSDQ253 (31%)
      Bottcher et al.2009population-based33CPDenmark9.11–13.6 yearsTEA-Ch
      Sigurdardottir et al.2010case–control36CPIceland4–6 yearsCBCL, TRF3 (6%)
      Shank et al.2010case–control33CPUSA8–16 yearsCPRS-R, GMFCS
      Brossard-Racine et al.2011cross-sectional76CPCanada6–12 yearsSDQ23 (30.3%)
      Bjorgaas et al.2012population-based67CPNorway8–12 yearsICD-10, GMFCS, Kiddie-SADS, DSM-IV, MACS28 (18%)
      Gabis et al.2015Population-based90CPIsrael1.8–15.4 yearsGMFCS20 (22.5%)
      Cerebral palsy (CP), attention-deficit/hyperactivity disorder (ADHD), Gross Motor Function Classification System (GMFCS), Child Behavior Checklist (CBCL), Teacher's Report Form(TRF), Conners' Rating Scale (CRS), Conners Parent Rating Scales – Revised (CPRS-R), Strengths and Difficulties Questionnaire (SDQ), Test of Everyday Attention for Children (TEA-Ch), Kiddie Schedule for Affective Disorders and Schizophrenia (K-SADS), diagnostic and statistical manual of mental disorders (DSM), Conners teacher rating-scale (CTRS), Manual Abilities Classification System (MACS).

      3.2 Countries of data collection

      Studies on the co-occurrence of CP and ASD were conducted in the United Kingdom (n = 4), Sweden (n = 7); Turkey (n = 2); Finland (n = 1); United States of America (n = 3), Iceland (n = 1) and France (n = 1).
      Studies on the co-occurrence of CP and ADHD were carried out in the United States of America (n = 3), United Kingdom (n = 1); Israel (n = 3); England (n = 1), Sweden (n = 1), Northern Ireland (n = 1), France (n = 1), Ireland, Italy (n = 1), Denmark (n = 2), Iceland (n = 1), Canada (n = 1), and Norway (n = 1).

      3.3 Characteristics of participants

      The reviewed studies included 5050 participants with a primary diagnosis of CP or ASD, and none of them included participants with a primary diagnosis of ADHD. Studies focusing on ASD in children or young people with CP involved 2770 children or young people (age range: 0–19 years) with CP, of whom 240 (8.7%) met the criteria for ASD. Studies focusing on the co-occurrence of CP in populations with ASD or Pervasive Developmental Disorders (PDDs) involved 485 children or adolescents (age range: 2–18 years) with ASD, 23 (4.7%) of whom met the criteria for CP.
      Studies evaluating the co-occurrence of CP and ADHD involved 1795 children or adolescents (age range: 1.8–20 years) with CP, 399 (22%) of whom met the criteria for ADHD.

      3.4 Diagnostic criteria and assessment tools

      NDDs can potentially be assessed both categorically and dimensionally. We found a multiplicity of assessment tools for ASD or ADHD in children and young people with CP. Thirteen studies used a categorical approach based on the DSM (n = 12) or the International Classification of Diseases (ICD; n = 2) to define ASD (n = 10) or ADHD (n = 4). One of these studies used both DSM and ICD. The gold standards for the diagnosis of ASD were used in five studies, four of which used the Autism Diagnostic Interview – Revised (ADI-R)
      • Lord C.
      • Rutter M.
      • Le Couteur A.
      Autism diagnostic interview-revised: a revised version of a diagnostic interview for caregivers of individuals with possible pervasive developmental disorders.
      and one used the Autism Diagnostic Observation Schedule (ADOS).
      • Lord C.
      • Rutter M.
      • DiLavore P.C.
      • Risi S.
      • Gotham K.
      Autism diagnostic observation schedule, volume ADOS-2.
      Eight studies used a dimensional approach to the diagnosis of ASD. The Autism Behavior Checklist (ABC)
      • Krug D.
      • Arick J.
      • Almond P.
      Autism screening instrument for educational planning.
      was used in five studies, the Childhood Autism Rating Scale (CARS)
      • Schopler E.
      • Van Bourgondien M.
      • Wellman G.
      • Love S.
      Childhood autism rating scale.
      was used in three studies and the Strength and Difficulties Questionnaire (SDQ),
      • Goodman R.
      The Strengths and difficulties questionnaire: a research note.
      the Social Communication Questionnaire (SCQ),
      • Rutter M.
      • Bailey A.
      • Lord C.
      The social communication questionnaire: Manual.
      and the Questionnaire measures of psychiatric caseness
      • Goodman R.
      • Graham P.
      Psychiatric problems in children with hemiplegia: cross sectional epidemiological survey.
      were used in three studies separately.
      Six studies used a dimensional approach to the diagnosis of ADHD. The Conners' Rating Scale (CRS)
      • Conners C.K.
      • Sitarenios G.
      • Parker J.D.
      • Epstein J.N.
      The revised conners' parent rating scale (CPRS-R): factor structure, reliability, and criterion validity.
      was used in three studies, the SDQ was used in two studies, and the Child Behavior Checklist (CBCL)
      • Achenbach T.M.
      • Ruffle T.M.
      The child behavior checklist and related forms for assessing behavioral/emotional problems and competencies.
      and the Teacher's Report Form (TRF)
      • Achenbach T.M.
      • Rescorla L.
      ASEBA school-age forms & profiles.
      were used in one study. The Behavior Problem Index (BPI),
      • Zill N.
      Behavior problem index based on parent report. National health Interview survey, child health supplement.
      the Rutter questionnaires,
      • Goodman R.
      A modified version of the Rutter parent questionnaire including extra items on children's strengths: a research note.
      the Kiddie Schedule for Affective Disorders and Schizophrenia (K-SADS)
      • Kaufman J.
      • Birmaher B.
      • Brent D.
      • et al.
      Schedule for affective disorders and schizophrenia for school-age children-present and lifetime version (K-SADS-PL): initial reliability and validity data.
      and the Test of Everyday Attention for Children (TEA-Ch)
      • Manly T.
      • Anderson V.
      • Nimmo-Smith I.
      • Turner A.
      The Differential assessment of children's attention: the test of everyday attention for children (TEA-Ch), normative sample and ADHD performance.
      were used in four studies separately.
      The functional levels measured by GMFCS were provided in eight studies (CP and ASD n = 4; CP and ADHD n = 4), while only one study measured fine motor function in children with CP by MACS.

      3.5 Comorbidity of CP and ASD

      Sixteen studies were eligible for inclusion. The literature review revealed two groups of studies on the co-occurrence of CP and ASD. The first group comprises twelve studies focusing on ASD in children or young people with CP. In 1996, Goodman & Graham found that 4 (3%) out of 149 hemiplegic children had ASD and suggested that this rate was ten times higher than in the general population.
      • Goodman R.
      • Graham P.
      Psychiatric problems in children with hemiplegia: cross sectional epidemiological survey.
      One hundred seventy-seven children were screened for autistic-type symptoms by Nordin and Gillberg and ASD was found in 4 (10.5%) of the 38 children with CP.
      • Nordin V.
      • Gillberg C.
      Autism spectrum disorders in children with physical or mental disability or both. I: clinical and epidemiological aspects.
      Of these, two children had an autistic disorder, one had an autistic-like condition and one had PDD-NOS. Ek et al. recruited 29 Swedish children diagnosed with blindness due to bilateral retinopathy of prematurity (ROP) stage 5 (i.e. total retinal detachment). 15 children (8 boys, 7 girls) had an autistic disorder, however only 8 children (29.6%) met two of the DSM-IV criteria for this disorder.
      • Ek U.
      • Fernell E.
      • Jacobson L.
      • Gillberg C.
      Relation between blindness due to retinopathy of prematurity and autistic spectrum disorders: a population-based study.
      Steffenburg et al. examined 98 children with active epilepsy and learning disability and reported that 6 (16.2%) children with concurrent CP had a diagnosis of ASD.
      • Steffenburg S.
      • Steffenburg U.
      • Gillberg C.
      Autism spectrum disorders in children with active epilepsy and learning disability: comorbidity, pre- and perinatal background, and seizure characteristics.
      A population-based study comprised 67 children with hydrocephalus, 18 of whom with CP.
      • Lindquist B.
      • Carlsson G.
      • Persson E.K.
      • Uvebrant P.
      Behavioural problems and autism in children with hydrocephalus : a population-based study.
      Among children with additional impairments in the form of CP, 6 (33%) subjects out of 18 had autism. This was significantly more common than in the 3 children with autism among the 49 (6%) without these additional impairments. Carlsson et al. described and compared behavioral problems in a group of children with CP, with and without epilepsy.
      • Carlsson M.
      • Olsson I.
      • Hagberg G.
      • Beckung E.
      Behaviour in children with cerebral palsy with and without epilepsy.
      Five out of the 34 children (14%) enrolled had autism, all in the epilepsy group, suggesting that behavioral problems (incl. autism) are common in CP, and this is even more so when epilepsy is present. In 2009, Kilincaslan & Mukaddes assessed the prevalence of autistic disorder and PDD-NOS in a group of 126 children with CP, with 19 (15%) children diagnosed with autism (11% autistic disorder and 4% PDD-NOS).
      • Kilincaslan A.
      • Mukaddes N.M.
      Pervasive developmental disorders in individuals with cerebral palsy.
      PDD was more common in children with tetraplegic, mixed, and hemiplegic CP as well as in children with epilepsy, learning disability, and low level of speech. In a functional neuroimaging study, Himmelmann & Uvebrant found that nine out of 186 children with CP had a diagnosis of autism or ASD (n = 3 with an intelligence quotient in the lower normal range, n = 1 with a mild learning disability, and n = 5 with a severe learning disability). In children diagnosed with autism, the authors found periventricular white-matter lesions in 3 subjects, cortical/subcortical and basal ganglia lesions in 2 subjects, a malformation in one child, and normal imaging in three subjects.
      • Himmelmann K.
      • Uvebrant P.
      Function and neuroimaging in cerebral palsy: a population-based study.
      The Autism and Developmental Disabilities Monitoring (ADDM) Network published two studies to monitor CP prevalence in different USA regions and evaluate socio-demographic correlates and characteristics of children with CP. Based on these two reports, it is possible to estimate the rates of comorbid ASD in children with CP. In Kirby et al.‘s study, 39 (8.2%) out of 476 children with CP were diagnosed with ASD.
      • Kirby R.S.
      • Wingate M.S.
      • Van Naarden Braun K.
      • et al.
      Prevalence and functioning of children with cerebral palsy in four areas of the United States in 2006: a report from the autism and developmental disabilities monitoring network.
      They found that ASD co-occurred in 24 (6.2%) children with spastic subtype, 7 (6.4%) of whom with unilateral subtype and 17 (6.2%) with bilateral subtype, and in 4 (14.8%) children with non-spastic subtype as well as 11 (17.7%) children with other subtypes (spastic-ataxic, spastic-dyskinetic, and cerebral palsy not otherwise specified). The authors concluded that comorbid ASD was present in approximately 8% of children with CP across all sites. They also found that, as walking ability decreased, the proportion of children with a comorbid ASD also declined – from 12.9% among children who walked independently to 3.4% among those with limited or no walking ability. In the second report of the ADDM Network, Christensen et al. found that 31 (6.9%) of the 451 children with CP were diagnosed with ASD.
      • Christensen D.
      • Van Naarden Braun K.
      • Doernberg N.S.
      • et al.
      Prevalence of cerebral palsy, co-occurring autism spectrum disorders, and motor functioning - autism and developmental disabilities monitoring network, USA, 2008.
      ASD co-occurred in 21 (6%) children with spastic subtype, 7 (5.5%) of whom with unilateral subtype and 14 (6.3%) with bilateral subtype, and in 7 children (18.4%) with non-spastic subtype and 3 children (4.7%) with mixed/not otherwise specified subtype (the authors included: spastic-ataxic, spastic-dyskinetic, and cerebral palsy not otherwise specified).
      • Christensen D.
      • Van Naarden Braun K.
      • Doernberg N.S.
      • et al.
      Prevalence of cerebral palsy, co-occurring autism spectrum disorders, and motor functioning - autism and developmental disabilities monitoring network, USA, 2008.
      Recently, Delobel-Ayoub et al. evaluated the prevalence of comorbid ASD among children with CP and described their characteristics.
      • Delobel-Ayoub M.
      • Klapouszczak D.
      • van Bakel M.M.E.
      • et al.
      Prevalence and characteristics of autism spectrum disorders in children with cerebral palsy.
      A total of 1225 children with CP were included in the study, 107 (8.7%) of whom had an associated diagnosis of ASD. 6.4% of children with CP without intellectual disability presented with comorbid ASD, a proportion obviously higher than in the general population. The authors concluded that children with CP appear to be at greater risk of ASD than the general population, independently of their intellectual level. A recent study by Hirschberger et al. investigated the prevalence of neurodevelopmental impairments in children aged 10 who were born extremely preterm.
      • Hirschberger R.G.
      • Kuban K.C.K.
      • O'Shea T.M.
      • et al.
      Co-occurrence and severity of neurodevelopmental burden (cognitive impairment, cerebral palsy, autism spectrum disorder, and epilepsy) at age 10 years in children born extremely preterm.
      A total of 93 out of 849 children (11%) had CP, 8 (20%) of whom presented with comorbid ASD. At age ten years, children who had been diagnosed with CP at age two years had a +1.71 risk of having ASD compared with children without CP.
      The second group comprises four studies focusing on comorbid CP in populations with autistic disorder or PDDs. In an epidemiological survey on 325,347 children including 174 subjects diagnosed with autism, Forbonne et al. found a 2.9% rate for CP among children with autism, suggesting that the rate of CP in children with autism was higher than the population rate but twice as low as that in the comparison group (children without autism suffered from a range of different medical and developmental problems as well as intellectual deficits).
      • Fombonne E.
      • Du Mazaubrun C.
      • Cans C.
      • Grandjean H.
      Autism and associated medical disorders in a French epidemiological survey.
      Subsequently, in a group of 97 children, Chakrabarti & Fombonne found two females (2%) with CP diagnosed with PPD and autism, respectively.
      • Chakrabarti S.
      • Fombonne E.
      Pervasive developmental disorders in preschool children.
      A population-based study by Kielinen et al. investigated associated medical disorders and disabilities in 187 children with autistic disorder.
      • Kielinen M.
      • Rantala H.
      • Timonen E.
      • Linna S.L.
      • Moilanen I.
      Associated medical disorders and disabilities in children with autistic disorder: a population-based study.
      The rate of CP –4.3% (eight subjects out of 187)– is almost 10 times the population rate of 5.7 per 1000 in northern Finland (von Wendt et al., 1985b). In addition, this study reported comorbid ASD in 4 (2.1%) children with diplegia, 2 (1.1%) with triplegia and 2 (1.1%) with tetraplegia. Finally, a case–control study compared 227 children with visual impairments and 30 children with visual impairments plus ASD.
      • Mukaddes N.M.
      • Kilincaslan A.
      • Kucukyazici G.
      • Sevketoglu T.
      • Tuncer S.
      Autism in visually impaired individuals.
      Mukaddes et al. found that the two groups differed significantly in terms of CP (13% vs. 33%), concluding that subjects with blindness plus autism have a greater neurological impairment such as intellectual level and cerebral palsy.
      Full details of these studies are shown in Table 1.

      3.6 Comorbidity of CP and ADHD

      We found twelve studies evaluating the comorbidity between CP and ADHD. Our review of the literature revealed three groups of studies on the co-occurrence of ADHD and CP.
      The first group of studies investigated the prevalence of ADHD symptoms in CP populations. In a population-based research, McDermott el al. measured behavioral problems in children with CP in a non-clinical setting.
      • McDermott S.
      • Coker A.L.
      • Mani S.
      • et al.
      A population-based analysis of behavior problems in children with cerebral palsy.
      They reported that 12 (25.5%) children with CP out of a group of 47 children presented with hyperactive problems including concentration difficulty, forgetfulness, and impulsive behavior. Motor and cognitive or behavioral problems were examined in 148 children with CP.
      • Schenker R.
      • Coster W.J.
      • Parush S.
      Neuroimpairments, activity performance, and participation in children with cerebral palsy mainstreamed in elementary schools.
      The most frequently co-occurring neuropsychiatric impairments were ADHD (19%) and learning disorders (46%). To describe psychological symptoms in children with CP aged 8–12-years, Parkes et al. conducted a cross-sectional multi-centre survey
      • Parkes J.
      • White-Koning M.
      • Dickinson H.O.
      • et al.
      Psychological problems in children with cerebral palsy: a cross-sectional European study.
      using a dimensional approach to evaluate emotional and behavioral problems. The authors used the parent form of the SDQ and found that approximately 31% of children with CP (N = 818) showed hyperactivity disorders. Sigurdardottir et al. assessed emotional and behavioral problems in 33 pre-school children with congenital CP by the CBCL.
      • Sigurdardottir S.
      • Indredavik M.S.
      • Eiriksdottir A.
      • Einarsdottir K.
      • Gudmundsson H.S.
      • Vik T.
      Behavioural and emotional symptoms of preschool children with cerebral palsy: a population-based study.
      Two of these children presented with ADHD. In children with CP, attention problems and withdrawal were the most problematic symptoms both at home and at preschool. In a cross-sectional study, Brossard-Racine et al. explored behavioral problems in school-aged children with CP (N = 76) and identified modifiable factors associated with problematic behavior.
      • Brossard-Racine M.
      • Hall N.
      • Majnemer A.
      • et al.
      Behavioural problems in school age children with cerebral palsy.
      Hyperactivity-inattention problems affected 30.3% of them. In this group, 18 children (23.7%) fell in the hyperactivity abnormal range and 5 (6.6%) in the hyperactivity borderline range. Furthermore, the authors suggested that the presence of hyperactivity problems in children with CP is predictive of later peer-related problems. Recently, in a population-based study, Bjorgaas et al. assessed the rate of psychiatric disorders using a diagnostic interview.
      • Bjorgaas H.M.
      • Hysing M.
      • Elgen I.
      Psychiatric disorders among children with cerebral palsy at school starting age.
      Among the 56 children identified with GMFCS level I–IV, 32 subjects (57%) met the criteria for a child psychiatric disorder. Specifically, 28 children met the criteria for ADHD/ADD. These children had a GMFCS level III–IV and a MACS level III–V. In another study, Gabis et al. investigated the association between functional level and mental comorbidity in a large cohort of children with CP
      • Gabis L.V.
      • Tsubary N.M.
      • Leon O.
      • Ashkenasi A.
      • Shefer S.
      Assessment of abilities and comorbidities in children with cerebral palsy.
      by stratifying a sample of 90 children by GMFCS level and CP subtype. ADHD was prevalent in 22.5% of the children. Among children with ADHD, three (50%) children were categorized into GMFCS Level I, 3 children (30%) into GMFCS Level II, 4 children (33%) into GMFCS Level III, 7 children (44%) into GMFCS Level IV, and 6 children (14%) into GMFCS Level V. In addition, ADHD was found to co-occur in 11 (12.9) children with quadriplegia, 4 (4.8%) children with hemiplegia, 3 (3.5%) children with athetoid CP, and 4 (4.8%) children with spastic diplegia.
      Studies in the second group evaluated the effect of methylphenidate on ADHD in children with CP. Goodman found that hyperactivity was particularly predictive of continuing psychiatric problems in school-age children (N = 240) with hemiplegia
      • Goodman R.
      The longitudinal stability of psychiatric problems in children with hemiplegia.
      and suggested that use of stimulants could prevent the emergence of other psychiatric problems. Two studies explored the use of methylphenidate for ADHD in children with CP. In a prospective, cross-over, double-blind study, Gross-Tsur et al. treated twenty-nine patients with CP and ADHD (33% on 116 subjects) with methylphenidate or placebo, each for 4 weeks.
      • Gross-Tsur V.
      • Shalev R.S.
      • Badihi N.
      • Manor O.
      Efficacy of methylphenidate in patients with cerebral palsy and attention-deficit hyperactivity disorder (ADHD).
      The effect of methylphenidate on attentional skills were evaluated using parent and teacher reports. The study showed the efficacy of methylphenidate in children with dual diagnosis of CP and ADHD, at least in the short term. Symons et al. evaluated methylphenidate administration in 3 school-aged children with CP and comorbid ADHD symptoms and found that low-dose vs. high-dose methylphenidate resulted in clinically significant reductions in directly observed stereotyped and disruptive behavior.
      • Symons F.J.
      • Tervo R.C.
      • Kim O.
      • Hoch J.
      The effects of methylphenidate on the classroom behavior of elementary school-age children with cerebral palsy: a preliminary observational analysis.
      Studies belonging to the third group assume that children with CP present with impairments in attention and executive function similar to ADHD children. Bottcher et al. tested attention and executive functions with standardized neuropsychological measures in a group of children with unilateral (n = 15) or bilateral (n = 18) spastic CP, highlighting that children with CP had particular difficulties on measures of sustained and divided attention, while no significant differences on attention tasks were found between participants with unilateral and bilateral spastic CP.
      • Bottcher L.
      • Flachs E.M.
      • Uldall P.
      Attentional and executive impairments in children with spastic cerebral palsy.
      Shank et al. hypothesized that children with CP and control peers would show positive correlations between visual inspection time (IT) task duration thresholds and parent/guardian ratings of ADHD symptom severity.
      • Shank L.K.
      • Kaufman J.
      • Leffard S.
      • Warschausky S.
      Inspection time and attention-deficit/hyperactivity disorder symptoms in children with cerebral palsy.
      Children with CP exhibited significantly slower IT, with more symptoms of inattention and hyperactivity than the control group. However, while correlations between IT durations and reported ADHD symptoms were significant in the control group, no such finding were observed in the CP group.
      Studies included in this section are summarized in Table 2.

      4. Discussion

      The purpose of this systematic review was to establish the incidence and prevalence of comorbid NDDs in the CP population. According to the NICE Guideline on diagnosing, assessing and managing CP (Shaunak & Kelly, 2017), we focused on ASD and ADHD, as these NDDs are interrelated and may share pathological mechanisms and clinical features.
      • Craig F.
      • Lamanna A.L.
      • Margari F.
      • Matera E.
      • Simone M.
      • Margari L.
      Overlap between autism spectrum disorders and attention deficit hyperactivity disorder: searching for distinctive/common clinical features.
      • Taurines R.
      • Schwenck C.
      • Westerwald E.
      • Sachse M.
      • Siniatchkin M.
      • Freitag C.
      ADHD and autism: differential diagnosis or overlapping traits? A selective review.
      • Craig F.
      • Margari F.
      • Legrottaglie A.R.
      • Palumbi R.
      • de Giambattista C.
      • Margari L.
      A review of executive function deficits in autism spectrum disorder and attention-deficit/hyperactivity disorder.
      • Jang J.
      • Matson J.L.
      • Williams L.W.
      • Tureck K.
      • Goldin R.L.
      • Cervantes P.E.
      Rates of comorbid symptoms in children with ASD, ADHD, and comorbid ASD and ADHD.
      The ASD prevalence estimates in CP vary widely from 2% to 30%. This may in part be due to the variety of the populations studied. We found a higher prevalence of ASD (from 29% to 33%) in studies where CP was associated with other medical conditions such as visual impairment, retinopathy of prematurity, and hydrocephalus, which suggests that these additional medical conditions increased the risk of ASD. Studies focusing on comorbid CP in populations with ASD revealed a prevalence from 2.9% to 4.3%. Similarly, the prevalence of ASD in populations with CP varies from approximately 3%–16%, suggesting a higher frequency of ASD in children with CP compared with the estimated prevalence (ca. 1.5%–2%) in the ASD population.
      • Boat T.F.
      • Wu aJT.
      Mental disorders and disabilities among low-income children.
      Regarding the comorbidity between CP and ADHD, we found that ADHD prevalence in CP ranged from 19% to 35%. A recent meta-analysis on ADHD prevalence in children up to 18 years of age found an overall pooled estimate of 7.2%.
      • Thomas R.
      • Sanders S.
      • Doust J.
      • Beller E.
      • Glasziou P.
      Prevalence of attention-deficit/hyperactivity disorder: a systematic review and meta-analysis.
      These findings suggest that ADHD seems to be more common in children with CP than in the general population.
      Taken together, the studies discussed in this review point out that children and young people with CP are clearly at increased risk of ASD and ADHD. However, differences in prevalence rates between studies could be due to the different diagnostic tools used. Traditionally, the question of whether ASD and ADHD are best classified using categorical or dimensional approaches is a contentious one and has profound implications for clinical practice and scientific enquiry alike. Both categorical and dimensional solutions appear to be valuable and this varies according to the disorder considered.
      • Coghill D.
      • Sonuga-Barke E.J.
      Annual research review: categories versus dimensions in the classification and conceptualisation of child and adolescent mental disorders--implications of recent empirical study.
      However, many neurodevelopmental conditions are better described as dimensional rather than categorical disorders.
      • Cuthbert B.N.
      • Workgroup N.R.
      The RDoC framework: continuing commentary.
      This has been suggested for both ASD and ADHD, as dimensional approaches can be used to identify discrete subgroups of individuals within each disorder. Thus, in the current review, we reported the empirical literature into studies taking a categorical and dimensional approach to evaluate the comorbidity between CP and ASD or ADHD.
      Although diagnostic procedures for ASD have improved, diagnosing this disorder in children with CP remains a complex issue. Probably the gold standards for diagnosis such as the ADOS and ADI-R are not suitable for some children with CP. Assessing communication impairments in CP is difficult owing to common oral-motor disorders.
      • Kilincaslan A.
      • Mukaddes N.M.
      Pervasive developmental disorders in individuals with cerebral palsy.
      Besides, diagnostic measures for ASD include complex motor tasks that are not suitable to the motor skills of children with CP. Most studies relied on DSM or ICD criteria for the diagnosis of ASD, whereas only three studies used DSM criteria for ADHD diagnosis. Most studies used a dimensional approach to evaluate attention or behavioral problems associated with ADHD. Some studies employed the revised CRS-R, which is considered the gold standard for assessing ADHD, others evaluated ADHD symptoms using tools tapping emotional and behavioral aspects such as the SDQ or CBCL. Compared with the DSM- or ICD-based categorical approach, these dimensional tools tend to generate higher prevalence rates for ADHD.
      • Hamed A.M.
      • Kauer A.J.
      • Stevens H.E.
      Why the diagnosis of attention deficit hyperactivity disorder matters.
      It should be noted that the SDQ and the CBCL are not diagnostic measures for ADHD but only reflect parental or teachers' perceptions of a child's specific disruptive behaviors. Parent and teacher reports on a screening questionnaire cannot replace clinical validation of a diagnosis. Furthermore, these dimensional tests (CRS-R, SDQ, and CBCL) include a significant number of questions irrelevant to the level of motor activity and behavior of children or adults with CP. Therefore, there are still diagnostic challenges to overcome in order to successfully implement a screening approach for other NDDs in people with CP. Early identification of ASD or ADHD symptoms through a dimensional approach in children with CP could help clinicians improve management decisions and lead to targeted treatment and therefore better outcomes. In addition, our review highlights the paucity of published studies on the occurrence of ASD and ADHD in children with different CP subtypes or functional abilities. Only two studies reported that ASD was more frequent in children with non-spastic CP, particularly hypotonic CP.
      • Kirby R.S.
      • Wingate M.S.
      • Van Naarden Braun K.
      • et al.
      Prevalence and functioning of children with cerebral palsy in four areas of the United States in 2006: a report from the autism and developmental disabilities monitoring network.
      • Christensen D.
      • Van Naarden Braun K.
      • Doernberg N.S.
      • et al.
      Prevalence of cerebral palsy, co-occurring autism spectrum disorders, and motor functioning - autism and developmental disabilities monitoring network, USA, 2008.
      No studies report the prevalence of ASD based on functional levels measured by GMFCS, CFCS and MACS. Regarding the comorbidity between CP and ADHD, only two recent studies evaluated the prevalence of ADHD symptoms in children with CP based on GMFCS functional levels: One study reported ADHD symptoms, and comorbid ADHD was found to be more frequent in children with quadriplegia.
      • Gabis L.V.
      • Tsubary N.M.
      • Leon O.
      • Ashkenasi A.
      • Shefer S.
      Assessment of abilities and comorbidities in children with cerebral palsy.
      The other study reported a prevalence of ADHD in children with GMFCS level III–IV and MACS level III–V, while no differences in ADHD symptom prevalence were found in children with different CP subtypes.
      • Bjorgaas H.M.
      • Hysing M.
      • Elgen I.
      Psychiatric disorders among children with cerebral palsy at school starting age.
      This would be a fruitful area for further research, in order to establish whether occurrence of other NDDs in CP varies according to CP subtypes or functional abilities. In fact, the precise quantification of comorbidity between ASD or ADHD in children or young people with CP could help determine the effectiveness of medical and physical therapeutic interventions.
      Some studies indicate some overlap of cognitive deficits between ADHD and CP.
      • Bottcher L.
      • Flachs E.M.
      • Uldall P.
      Attentional and executive impairments in children with spastic cerebral palsy.
      • Shank L.K.
      • Kaufman J.
      • Leffard S.
      • Warschausky S.
      Inspection time and attention-deficit/hyperactivity disorder symptoms in children with cerebral palsy.
      Attention and executive functions seem to be more commonly affected in children with CP or ADHD than typically developing children. Improving attention and executive functions such as working memory may be beneficial for both patients and their families, reduce the need for special education and improve social and daily life functioning.
      • Roy A.
      A more comprehensive overview of executive dysfunction in children with cerebral palsy: theoretical perspectives and clinical implications.
      Nevertheless, there is a lack of evidence-based knowledge regarding cognitive function and the effects of cognitive interventions in CP.
      The studies included in our review also addressed the effects of stimulant therapy in children with CP and ADHD. Methylphenidate showed to be beneficial in ADHD, even when associated with other neurologic disorders such as intellectual disabilities, fragile X syndrome, autism spectrum disorder, and epilepsy.
      • Gross-Tsur V.
      • Shalev R.S.
      • Badihi N.
      • Manor O.
      Efficacy of methylphenidate in patients with cerebral palsy and attention-deficit hyperactivity disorder (ADHD).
      However, pharmacological treatments targeting ADHD symptoms in CP have received little attention. Two studies reported that methylphenidate is effective in children with dual diagnosis of CP and ADHD
      • Gross-Tsur V.
      • Shalev R.S.
      • Badihi N.
      • Manor O.
      Efficacy of methylphenidate in patients with cerebral palsy and attention-deficit hyperactivity disorder (ADHD).
      • Symons F.J.
      • Tervo R.C.
      • Kim O.
      • Hoch J.
      The effects of methylphenidate on the classroom behavior of elementary school-age children with cerebral palsy: a preliminary observational analysis.
      and emphasized that low-dose (0.3 mg/kg/dose) methylphenidate was associated with clinical significant reductions of ADHD symptoms in children with CP, at least in the short term. However, caution is recommended as findings cannot be generalized given the small sample size.

      5. Conclusion and future directions

      Based on our systematic review, people with CP are clearly at increased risk of other NDDs such as ASD or ADHD. The complexity of the CP condition is a challenge when diagnosing ASD or ADHD. Children with CP should specifically be screened for both these conditions; however, future psychometric studies are needed to promote the development of measures suitable for individuals with CP, particularly when sensory impairments and motor deficits limit use of gestures such as pointing, that may complicate differential diagnosis. Measures tapping ASD or ADHD symptoms need to be valid, reliable, sensitive, and able to detect change over time, and they also need to be appropriate for use in CP. Characteristics associated to ASD or ADHD such as social communication, attention, executive function and behavior problems may be overlooked or thought of as being part of the disorder. Therefore, ASD or ADHD may go undiagnosed in individuals with CP. In order to avoid this risk, health care professionals need to be more informed and knowledgeable about the symptoms of ASD or ADHD. Assessing the presence of these conditions would improve the significant cost of healthcare, therapies, and overall daily live for families with children affected by CP. A comorbidity between NDD and a disabling condition such as CP could be either a pathology, an impairment, a functional limitation, or an additional disability. Further studies are needed to ensure that appropriate services are in place to provide parents and carers with information on the diagnosis and management of CP and that this information is tailored to their individual needs and learning styles.
      Unfortunately, no attempts were made to understand the common pathogenic mechanisms linking CP, ASD and ADHD. One may argue that the brain lesion itself causes an increased prevalence of ASD and ADHD in CP people, pointing to a direct brain behavior link, and it would be reasonable to assume that CP may be a risk factor for other NDDs. Thus, a possible hypothesis could be that the CP-related brain damage or malformation could affect the same brain areas involved in the etiopathogenetic mechanisms of ASD or ADHD. However, it is well known that CP may occur in the absence of clear and definitive lesions on the current neuroimaging techniques.
      • Benini R.
      • Dagenais L.
      • Shevell M.I.
      Consortium RdlPCaQQCPR. Normal imaging in patients with cerebral palsy: what does it tell us?.
      So far, it would be reasonable to assume that a neural connectivity impairment rather than a localized deficit is involved in the pathophysiological process of NDDs. This could also apply to CP individuals, in whom aberrant brain connectivity was demonstrated not only at the injury's site, but also in the normally-appearing perilesional cortex.
      • Hall K.D.
      • Lifshitz J.
      Diffuse traumatic brain injury initially attenuates and later expands activation of the rat somatosensory whisker circuit concomitant with neuroplastic responses.
      In addition, the associations between excessive risks of a wide range of ASD and ADHD in the CP population reveal the presence of unmeasured shared causes. Such shared causes may be of genetic or environmental nature, or a combination of the two factors. However, genetic risk factors for CP and other neurodevelopmental conditions present with considerable heterogeneity and complexity. Researchers have demonstrated a number of quite heterogeneous genetic variants and have documented causal relationships between different NDDs through advanced methods.
      • Oskoui M.
      • Gazzellone M.J.
      • Thiruvahindrapuram B.
      • et al.
      Clinically relevant copy number variations detected in cerebral palsy.
      • Zarrei M.
      • Fehlings D.L.
      • Mawjee K.
      • et al.
      De novo and rare inherited copy-number variations in the hemiplegic form of cerebral palsy.
      • van Eyk C.L.
      • Corbett M.A.
      • Gardner A.
      • et al.
      Analysis of 182 cerebral palsy transcriptomes points to dysregulation of trophic signalling pathways and overlap with autism.
      These findings corroborate the hypothesis of a common underlying disturbance for comorbid CP, ASD and ADHD. Further research is needed to determine the extent of genetic or neuroimaging overlap between individuals with CP and ASD and ADHD.
      In conclusion, improved characterization of behavioral phenomenology and comorbidity complexes might be taken as starting point for the development of emerging methods of brain imaging and genetics, and ultimately lead to the development of optimized treatment approaches to ease the burden of children and young people with CP and their caregivers who struggle daily with these devastating conditions.

      Conflict of Interest

      I confirm that there is no financial or others conflict of interest that may be related to the authors.

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