ESSENCE: What is it and does it matter?

2. ESSENCE: What is it and does it matter? • Christopher Gillberg, MD, PhD • Gillberg Neuropsychiatry Centre at the Sahlgrenska Academy, University of Gothenburg, and Queen Silvia Hospital (Sweden and Japan) • University of Glasgow and University of Strathclyde, and YorkhillHospital (Scotland) • Institute of Child Health, University College London, and Young Epilepsy (England) • UniResearch, Bergen (Norway) Luleå, augusti 2012

3. ESSENCE – What is it? Not a diagnosis, but a new concept (for an old “truth”) that will make you want to go beyond the DSM-5 and ICD-11 and accept that nature smudges all clinical boundaries • ESSENCE - Early Symptomatic Syndromes Eliciting Neurodevelopmental Clinical Examinations • Predictors of empathy disorders (ASD), antisocial disorders (ADHD+CD), anxiety and depression (ASD/ADHD/TS/DCD), SUD (ADHD), “psychosis” (ASD/ADHD/DCD), and memory problems (ADHD) • ASC (Autism Spectrum Conditions, including Disorders) • ADHD (Attention-Deficit/Hyperactivity Disorder Spectrum) with or without ODD/CD (Oppositional Defiant Disorder/Conduct Disorder) • TS (Tic Spectrum Conditions including Tourette Syndrome) • SLI/LI (“Specific” Language Impairment), never specific? • IDD/LD/MR (Intellectual Developmental Disorder/Learning Disability) • DCD (Developmental Coordination Disorder) • BPS (Behavioural Phenotype Syndromes, including FAS and VAS) • Preschool depression and BD (Bipolar Spectrum Conditions including Disorder) and RAD? • EpilepsySyndromes and other neurological disorders (HC, CP, neurometabolic): Landau-Kleffner Syndrome, CSWS, FS+, FS?

4. ESSENCE – symptoms and where to find cases? • Major symptoms lasting more than 6 months from one or more of the following domains before age 5 years are the markers of ESSENCE; the symptoms lead to concern and “specialist” consultation • General development (community pediatrics, neurology, GP) • Motor control/Perception-Sensory (community pediatrics, neurology, GP) • Communication/Language (audiology, ENT, SLT, community pediatrics, CAMHS, GP) • Activity/Impulsivity (CAMHS, psychology, community pediatrics) • Attention/”Listening” (audiology, ENT, SLT, CAMHS, neurology) • Social interaction/Reciprocity (community pediatrics, audiology, ENT, SLT, CAMHS, autism centres) • Behaviour(community pediatrics, CAMHS, GP) • Mood (CAMHS) • Sleep (community pediatrics, GP) • Feeding (community pediatrics, dieticians, GP, CAMHS) • Odd facial features/Minor physical anomalies (plusWELL-BABY-CLINICS/CHILD HEALTH, PRE-SCHOOLS, SCHOOLS, NEW-BORN UNITS, SOCIAL WORK, CLINICAL GENETICS) - Gillberg2010

5. Early symptoms (age 0-4 years) in ASD • Motor control problems first year of life (Moebius-like “serious” face, relatively little smiling (but social smile can be elicited, strange movements from back to front, compartmentalised motor development), limpness, partial hypotonia50-100% • Perceptual abnormalities/preferences in 90-100% • Language problems/pragmatic problems/strange voice in 90-100% • Repetitive movements in 80-100% • Behaviourproblems (including insistence on sameness) in 90-100% • No/little reaction to own name 30-100% • No or limited initiation of joint attention ( => major social interaction problems), no pointing to attract attention 80-100% • Hyperactivity and impulsivity (often extreme) in 40-50% • Hypoactivity in 10-25% • Sleep problems in 40% • Food fads and other feeding problems in 50% • Delayed general development in 20% • Major mood swings in 10% • One or several of the above could be presenting complaint • Coleman and Gillberg 2011

6. Early symptoms (age 0-4 years) in ADHD/ODD • Motor control problems first year of life 50-100% (but possibly different from those in ASD?) • Perceptual-sensory abnormalities in 50-100% • Language problems/pragmatic problems in 50% • Behaviour problems in 50-100% • Mood problems, including inability to control temper, in 50-100% • Inattention/brief focused attention/non-purposeful 100%? • Hyperactivity (rarely extreme) in 10-30% • Hypoactivity problems and inattention in 25% • Major sleep problems in 40% • Delayed general development in 15% • Major mood swings in 5% • One or several of the above could be presenting complaint • Gillberg 2010

7. Scope of problem • At least 10% of children under 18 years of age are or have been affected by “neuropsychiatric/neurodevelopmental disorders” (ESSENCE)(12% of boys, 8% of girls) - including ADHD, ASD, TS, CD, BD (and psychosis, eating disorder, depression, RAD and anxiety disorders) – half this group “discovered” by age 6 years • Overlap/”Comorbidity”/Co-existence is the rule; almost never “one problem only” • When looking back: vast majority had symptoms <5 years • Girls usually are not recognized until adolescence/adult age (and usually as non-ESSENCE) • Half or more of all adult psychiatry?

8. Scope of problem: pre-school, school and adolescence • If at least 10% of children under 18 years of age are or have been affected by ESSENCE (12% of boys, 8% of girls), then this is • Clearly a public health problem • For some of the subgroups we think we “know what to do” (IDD, ADHD, autism, SLI) • For a few of the subgroups we “know that it helps” (ADHD, autism) • For some of the subgroups there are good screening instruments with high PPV and sensitivity (autism, SLI) • So, really, for some of these, should we not screen? (autism, SLI, conduct disorder/ODD)

9. Screening and then? • After screening, is there a treatment? Is there a cure? • Not really, except in rare circumstances/cases • But there is help to be had in almost all cases • Psychoeducation, parent expertise (“parent training”), adaptive skills training, autism-friendly environment (including early reading training?), individualisedprogrammes, remedial education, and, sometimes medication (for “comorbidities”)

10. The autisms: summary biological background factors • The autisms are a group of multifactorially determined conditions, that are always comorbid in cases with impairment, and there are possibly only slightly fewer causes than there are cases. Synapse and clock genes probably play a major role (and often affect synapse formation and function, e.g. neuroligin, neurexin, SHANK 2 and 3, melatonin genes), but environmental factors contribute to clinical presentation in many cases and can themselves cause ASD in some instances. There is decreased and abnormal intra- and internetwork connectivity. The medial prefrontal, medial temporal, brainstem and cerebellar regions of the central nervous system are almost always affected, singly or in various combinations. These areas constitute a functional network, “the default network”, which appears to be critically differently functioning in ASD • Iacoboni 2006, Buckner and Vincent 2007, Bourgeron 2007, Monk et al 2009, Gillberg 2010, Dinnstein et al 2010, Coleman and Gillberg 2011, Lundström et al 2012, Leblond et al 2012

11. ASD: diagnostic assessment and work-up • Observation outside clinic (pre-school/school), ADOS-structure, JA-OBS • M-CHAT plus follow-up interview • DSM-interview/DISCO and Vineland by doctor/psychologist • A-TAC/FTF/BIB-Q (to screen for comorbidity) and ASSQ • Medical/neuromotor/psychiatric examination (incl skin, nails, hair, MPA, height, weight, head size) • Hearing, ABR, vision, CNV, FMR-1, EEG including sleep, screening for thyroid and metabolic disorders • Griffiths, Wechsler (Leiter, Raven, Reynell, NEPSY)

12. ASD: important issues for intervention planning • ASD is always a signal that comorbidities MUST BE SCREENED for • Any ASD intervention programme MUST be individually tailored • Parent “training” and education plan most important of all (“understanding autism”) • ADHD in ASD is often responsive to treatment, both pharmacotherapy and computerized training programmes • Epilepsy MUST be treated as a top priority • BD and MDD should be treated with mood stabilizers and/or psychotherapies • DCD can be responsive to focused motor training • Catatonia may need very intensive specialist interventions • OCD can be responsive to SRI, old tricyclics may be better • Sleep disorders often responsive to melatonin • Violent behaviours/SIB can be responsive to low-dose atypical neuroleptics • Psychoeducation, communication enhancement, autism-friendly environment and behavioural approaches first and foremost throughout life

13. ASD: some issues • Severe cases (“autistic disorder”, usually signalling a number of “comorbidities”) should all be recognized in preschool (majority under 3 years of age) • DSM-5 will not have separate code for Asperger syndrome (but will probably be mentioned as “a clinical presentation”) • Asperger syndrome will not usually be diagnosed until school age (risk that some of these and quite a few with PDDNOS will be missed under DSM-V) • Severe hyperactivity/”ADHD” often major presenting symptom in ASD, can be “secondary” to ASD or a true “comorbidity”

14. ADHD: background factors • ADHD is largely genetic, and almost always comorbid in cases with clinical impairment; similar phenotype results after various types of environmentally caused brain dysfunction. Atypical brain development in children with ADHD; loss of prefrontal component of normal asymmetrical brain development. Growing evidence that dopamine-dependent reward systems deviant in ADHD. Executive functioning poor, but may not be caught on specific EF-tests. ASD and ADHD are related in some families. CNS connectivity genes involved in ASD relevant for development of ADHD symptoms • Curatolo et al 2008, Strang-Karlsson et al 2008, Melke et al 2008, Mulligan et al 2009, Kopp et al 2009, Sharp et al 2009, Shaw et al 2009, Volkow et al 2009, Bourgeron et al 2010, Shen et al 2012

15. ADHD: diagnostic assessment • ADHD-RS (DSM-5 will have 22 symptoms, not 18) • Conners parents and teachers • A-TAC/FTF/BIB-Q • Medical/neuromotor/psychiatric examination (incl skin, nails, hair, MPA, height, weight, head size) • Hearing, ABR, vision, CNV, FMR-1, EEG including sleep, screening for thyroid and metabolic disorders • Griffiths, Wechsler, TOVA/QB-test (Leiter, Raven, Reynell, NEPSY)

16. ADHD: implications • ADHD is always a signal that comorbidities SHOULD BE SCREENED for • Most of the comorbidities (except ODD and DCD) are probably unresponsive to stimulants • Some of the comorbidities respond to physiotherapy (DCD), CBT (OCD, anxiety), psychoeducation/remedial education/phonological awareness training (autism, academic failure, dyslexia) or other medications (depression, tics, OCD)

17. ADHD: intervention • Diagnosis, information (child, family, school, parent “training”) • Individualized programme • Educational changes, long-term perspective • Cognitive training (e.g. Robo-Memo) • Diverse activitieshavebeenshown to improvechildren'sexecutivefunctions: computerizedtraining, noncomputerized games, martial arts, yoga, mindfulness, and schoolcurricula • Most of the comorbidities (except ODD and DCD) are probably unresponsive to stimulants • Some of the comorbidities respond to physiotherapy (DCD), CBT (OCD, anxiety), psychoeducation/remedial education/phonological awareness training (autism, academic failure, dyslexia) or other medications (depression, tics, OCD)

18. Comorbidity in ADHD in males

19. Hyperactivity as a predictor of chronic pain • Children who were consistently overactive (“ADHD”?) during middle childhood and adolescence were those who 30 years later had chronic widespread pain • Pang et al 2010

20. 100 girls with social and/or attention deficits • Two of 100 girls (3-18 years) refererrd for social and/or attention deficits to a specializedneuropsychiatricclinichadreceived a diagnosis of autism beforecoming to the clinic. In the other 98 a diagnosis of autism or ADHD had not beenconsidered • 47 of the girlshadASD (80% of whomalsometcriteria for ADHD) • 47 othergirlshad ADHD ”only” • Virtually all of thesegirlshadbeendiagnosed as having MD, GAD or ”familyrelationship problems” • Kopp et al 2010

21. ADHD in adult psychiatric patients • Of all 400 adult psychiatric outpatients coming for more than one visit, c. 25% met criteria for ADHD (but only one per cent of these had been given a clinical diagnosis of ADHD by the adult psychiatrist) • MD, GAD, and SUD were the mostcommonclinicaldiagnoses • At least 15% of youngoffenders in a forensicunithave ADHD, in some studies the rate found has been up to 72% • Many postmenopausal women with MD and GAD (and memory problems) have ADHD (that wasmasked by estrogen and dopamineduring the fertile period) • Nylander et al 2009, Sipponmaa et al 2001, Vermeiren 2003, Asherson 2008, Inagaki et al 2010

22. ASD, ADHD and tic disorders in severe ED and in OCD • Thirty adult ED patients in a specialist clinic were assessed • Not one of them had been considered from the point of view of ASD, ADHD or tic disorders • 53% (n=16) had one or more of these disorders • ADHD, OCD and tics very often comorbid/sometimes described as “Tourette syndrome” • ADHD and OCD “in Tourette syndrome” usually warrant intervention, tics themselves often do not (other than information and tips for “everyday management”) • Wentz et al 2005, Gillberg et al 200

23. ASD and ADHD in schizophrenia and personality disorder in ASD • A large proportion of all with a diagnosis of schizophrenia have a developmental and symptom history consistent with classic Asperger syndrome • A very large proportion of men with Asperger syndrome meet criteria for schizoid personality disorder • It is likely that adult psychiatric patients with ASD will get diagnoses of schizophrenia and personality disorder rather than Asperger syndrome and autism • Lugnegård, Hallerbäck, Gillberg 2011

24. ADHD in incarcerated men • In a Swedish study of 315 male long-term prison inmates, 40% had ADHD, most of whom had been diagnosed with SUD and depression but not previously with ADHD • Ginsberg et al 2010

25. Conclusions • ASD and ADHD are two of a group of ESSENCE that overlap genetically, symptomatically and as regards neural circuitry (default network, brainstem, decreased connectivity, and mirror neurons) • Both disorders persist into adult life (as do most of the other ESSENCE) • Autism is a relatively common disorder (c. 1%), ADHD very common (c. 5%), but is only “severe” variant (c. 3%) relevant? • Other psychiatric disorders/problems emerge or become diagnosable over time (MD, GAD, SUD, psychopathy, personality disorder) – these are the diagnoses that adult psychiatrists will make • ASD and ADHD (and other ESSENCE) are clearly genetically based in many cases (and often affect synapse formation and function, e.g. neuroligin, neurexin, SHANK1, SHANK2 SHANK3, glutamate, dopamine, and also clock genes), but environmental factors play an important role (to be studied: how important) • Autism in itself has a different outcome, not necessarily poor • Girls are missed or misdiagnosed • Early diagnosis makes a difference

26. ESSENCE • In clinicalpractice and research • ESSENCE is of the essence!

27. Early signal symptom (language) • Example: delayed language at 2.5 years • Screen takes no more than 5 minutes (deviance if comprehension difficulties, fewer than 25 communicative words, major dysarticulation) • About 2-6% of all children screen positive and have “confirmed” language delay at 2.5 years • Screen positive and confirmed language delay at 2.5 years => 70% have “neuropsychiatric/neurodevelopmental” diagnosis (with clinical impairment) at age 7 years (ADHD, ASD, LD, DCD), virtually all have remaining speech-language problems or dyslexia • i.e. all children with “SLI”/LI at 2.5 years need to be followed carefully and vast majority will need services • Miniscalco et al 2005, 2006, 2007, 2009, Nygren et al 2012

28. Other early signal symptom (autism) • Example: suspected ASD under age 3 years • 28 children followed for several years from under age 3 years with suspected ASD: 75% met criteria for autistic disorder at age 6 years, and remainder had other neuropsychiatric diagnosis (other ASD, ADHD, LD) • Gillberg et al 1990 • 208 children with ASD diagnosis made by clinicians at age 0-4 years: 52% met criteria for autistic disorder at follow-up, 39% met criteria for other ASD, 9% had other neuropsychiatric diagnosis (ADHD, LD) - prevalence of ASD in this age group 0.6% • Fernell et al 2009, 2011 • ASD diagnosis around age 2-4 years highly stable in 90% of cases, virtually no “over-diagnosis”, many Asperger cases missed

29. Yet another early signal symptom (ADHD) • Example: suspected ADHD under age 5 years • 131 children followed for several years from age 3 years with suspected – and diagnostically confirmed - ADHD: 60% met criteria for oppositional defiant disorder (ODD) at age 3, 4, 5, 6 and 7 years, only 10% of all with ADHD had no symptom of ODD, ODD symptom (often loses temper) most common individual symptom of all in ADHD-group • Kadesjö et al 2003 • ADHD diagnosis around age 3-7 years confers highly stable risk of ODD in 60% of cases – risk of violence, aggression criminal, antisocial behaviour, and SUD in adult age much increased in this group

30. ASD as an example of ESSENCE • At least one per cent of the general population of children and almost one per cent of the adult population, increased mortality in ASD group with IDD • ASD predicts ASD throughout life (but maybe not terrible outcome “in itself”) • Half of all with ASD recognized in children under 6 years of age (almost all with IDD) • M-CHAT (23 items)+JA-OBS (5 items) at 2-3 years • Main presenting symptoms: motor-perceptual-sensory, attention, activity, (no response to name, maybe only US?), no initiation of joint attention, learning, sleep, social, and language (and macrocephalus?? and stigmata) • (Gillberg et al 1991, Gillberg and Wing 1999, Wing and Potter 2002, Baird et al 2006, Gillberg et al 2007 a and b, Baron-Cohen et al 2009, Fernell et al 2010, Kocovska et al 2011, Brugha et al 2011, Nygren et al 2011, 2012, Cederlund et al 2012)

31. ASD as an example of ESSENCE • The JA-OBS • Does the child: • react to ownname (turns to person addressing)? • try to establisheye-contact with you? • gaze at something that you point to furtheraway? • useindex-finger to point at something? • interact with you or parent in pretend play (e.g. duringfeeding a doll, or putting the doll to bed; does the childuseeyecontact to monitor that you are watching)? • Nygren et al 2012

32. ASD and co-existingdisorders: whatshouldwe be looking for? Earlyindicators of associated problems? • Epilepsy 20% (pooroutcomeifleftundertreated) • Other ”medical disorders” 20% • MPA 30% • Big head/smallhead 15% • IDD/MR 15-20% (negative outcome marker) • Language disorder 20% (negative outcome marker) • ADHD 31-50% (negative outcome marker?) • VLD or NLD in 60% (persistent NLD negative outcome marker) • Tic disorders 40% (best positive outcome marker?) • OCD 10% • Depression 20% • BPD 15% • Catatonia 15% (pooroutcome marker?) • Anxiety (disorder) 20-41% • Sleep disorder 50% • No co-existing disorder 0% • Gillberg and Coleman 2000,Billstedt and Gillberg 2000, Billstedtet al 2005, Gjevik et al 2010, Mukkades et al 2010, Zappella2010, Coleman and Gillberg 2011, Lugnegård et al 2011

33. ESSENCE conclusions • ESSENCE is not a diagnosis • ASD, ADHD, TS, bipolar disorder, IDD, (S)LI, DCD etc. overlap to a marked degree throughout life and are often not clearly separable under age 5 years • All children presenting with major and impairing ESSENCE symptoms (developmental delay, language delay, motor control problems, perceptual-sensory problems, activity problems, inattention, social interaction, general behaviour, mood or sleep problems) need to be followed up – ESSENCE clinics of the essence! • Even though refined diagnosis is needed in all cases, at early stages ESSENCE may be the only “safe” label • Never proclaim: “He/she will grow out of it” - no evidence that this is likely to happen in more than a small minority of cases

34. ESSENCE conclusions • ESSENCE is an extreme risk factor for adolescent/adult ODD/CD/Antisocial personality disorder/Social exclusion/ Academic failure (and drug abuse, criminality and depression/GAD) – and for “non-handicapping” ASD?? • Only an antenatal birth cohort study addressing the whole range of ESSENCE (and its genetic and pre-, peri- and postnatal predictors/intermediating effects) will help address the issues of how to apply preventive measures in society generally • We still know VERY little about early intervention • For some of ESSENCE we know how to screen at early ages

35. Research projects that need to be done (and that are currently underway) • Scottish ABCD (Antenatal Birth Cohort Development) study including neurosocialassessment, genetics, ultrasound, and imaging • Japanese BC (Birth Cohort) (JECS) study • AUDIE study (Autism Diagnosis and Intervention in Early life) • Early intervention in autism in 208 children (ABA) • Follow-up of autism from 2 years of age to 40 years • GAP (Gothenburg Autism Project, epidemiology, genetics, neurophysiology, neurochemistry) • Febrile seizures/epilepsy in under 5-year-olds, cross-cultural • Epilepsy in autism and autism in epilepsy (with Brian Neville) • Behaviour in school children who had status epilepticus (with Brian Neville) • ADHD and ODD in preschool children • Girls with social and/or attention problems: follow-up in adult age • RAD and autism in (pre-school and) school-age children • Stress in maltreated and communication impaired children • Faroe Islands autism study from 7-25 years • BCS (Bergen Child Study) of school children followed to late adolescence

36. Research projects continued • Genetic studies on ESSENCE with Thomas Bourgeron/Pasteur Institute • The Young Swedish twin study of ESSENCE with HenrikAnckarsäter, Maria Råstam, Sebastian Lundström, and Paul Lichtenstein • Neuroimaging of ESSENCE with NouchineHadjikhani/Harvard • Vitamin D, CMV, ultrasound studies on ESSENCE in Sweden, Japan and Faroe Islands • Follow-up of Asperger syndrome males from childhood to 40 years • ESSENCE in anorexia nervosa from adolescence to 40 years • Autism and schizophrenia in adults • ESSENCE in adult psychiatric patients • Behavioural and psychosocial effects of mild IDD • Behavioural phenotype studies (22q11, FraX, TS, Moebius) • Stimulant and non-stimulant intervention for ADHD

37. New proposed “categories” or new criteria for old categories in DSM-5 • Neurodevelopmental disorders/syndromes • ASD will be the “only” coded autism category (7 symptoms from 2 domains, rather than 12 from 3 domains) – three severity levels based on need for support • ADHD will be one coded category with subtypes (22 rather than 18 symptoms, 4 “new” hyperactive/impuslive symptoms • DCD and TS will both be in the same, new “motor disorder” category • Language impairment, “specific” language impairment and social communication disorder (!) will be grouped in a new “communication disorder” category • IDD will not be subdivided into mild and severe, diagnosis based on both IQ-test and adaptive test • ODD and conduct disorder will be in a separate category (“disruptive, impulse control and conduct disorders”) – not in the same neurodevelopmental disorder section with ADHD, ASD, DCD, TS etc.

38. ESSENCE and the DSM-5 • Not in the DSM-5 • ESSENCE is “Early Symptomatic Syndromes Eliciting Neurodevelopmental Clinical Examinations” • But many named ESSENCE will be in the DSM-5 • Not a diagnosis but a way of thinking • ESSENCE are predictors of empathy disorders (“ASD”), conscience disorders (“ADHD”, “ODD”, “CD”, “Psychopathy”), anxiety, depression, SUD (“ADHD”), “psychosis”, personality disorders, and memory problems