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ESSENCE: Early recognition of autism and related disorders – can it improve outcomes?

• Christopher Gillberg, MD, PhD• Gillberg Neuropsychiatry Centre at the Sahlgrenska Academy,

University of Gothenburg, and Queen Silvia Hospital and Kochi Prefecture (Sweden and Japan) – GO TO www.gnc.gu.se

• University of Glasgow and University of Edinburgh, and Yorkhill Hospital (Scotland)

• Institute of Child Health, University College London, and Young Epilepsy (England)

• Diferenças, Lisboa (Portugal)• Genetic Biobank, Torshavn (Faroe Islands, Denmark)• Institut Pasteur, Paris (France)

VANCOUVER APRIL 2017

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ESSENCE (neurodevelopmental/psychiatric disorders)• ESSENCE - Early Symptomatic Syndromes Eliciting

Neurodevelopmental Clinical Examinations – ADHD with or without ODD/CD (Oppositional Defiant Disorder/Conduct Disorder) 5-7%– SLI (Language disorder inlcuding antecedents of dyslexia) 5%– DCD (Developmental Coordination Disorder) 5%– IDD (Intellectual Disability/Intellectual Developmental Disorder) 2%– ASD (Autism Spectrum Disorder) with or without regression 1.2% (20% regression)– TD/TS/OCD (Tic disorders/Tourette syndrome/OCD) 1%– RAD (Reactive Attachment Disorder/Disinhibited Social Engagement Disorder) 0.5-1.5%– (BIF (Borderline Intellectual Functioning) 10%)– (BPS (Behavioural Phenotype Syndromes, including FAS and VAS) 2%)– (EP/NEUROMUSC (Epilepsy syndromes and other neurological/neuromuscular disorders

(HC, CP, Sturge-Weber, Duchenne, myotonic dystrophy, neurometabolic): Landau-Kleffner Syndrome, CSWS, FS+, FS? 0.6%)

– (PANS (Pediatric Acute-onset Neuropsychiatric Syndrome)? 0.1%)• Predictors of academic failure, other school adjustment problems, social exclusion,

substance use, psychiatric disorder, eating disorders including obesity, accidents empathy problems, antisocial lifestyle and criminality later in life, persistent autistic features “only”, early death through accidents, criminality, substance abuse and physical health problems

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What are the “symptoms” of ESSENCE?

• Major childhood onset symptoms either lasting more than 6 months or of extremely abrupt onset from one or more of the following domains are the markers of developmental disorder/ESSENCE; the symptoms lead to concern and “specialist” consultation– General development – delayed mental development– Motor coordination – delayed gross or fine motor development– Perception/Sensory – hyper- or hyposensitive to sensory stimuli– Communication/Language – delayed speech, few or no gestures– Activity/Impulsivity – too active or too passive– Attention – inattention, not listening, “not hearing”, distracted– Social interaction/Reciprocity – little interest in (most) adults, children, play – Behaviour including stereotypic, insistence on sameness, tics, and OCD– Mood swings/emotional dysregulation – inability to control temper– Sleep – disrupted sleep-wake cycle, sleep onset problems, night waking problems– Feeding – food fads, selective or consistent food refusal

- Gillberg 2010, revised Gillberg 2013, Hatakenaka et al 2016, Mina et al 2017

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ASD: The Autisms• The autisms are a group of multifactorially determined conditions, that ALWAYS

coexist with other developmental/neurological problems in cases with earlyimpairment (SLI, DCD, ADHD, IDD, tics, “OCD”, epilepsy, other medicaldisorders), and there are almost as many causes as there are cases. Cases with nocomorbidity at all are not recognized or impairing early in life, or may beacknowledged as “loners”, “nerds”, “weirdos”, “geniuses”. The prevalence of thephenotype is not increasing! Synapse and clock genes play a major role in cases withimpairment, but environmental factors (prematurity, fetal drug and toxin exposure,infections, trauma, vitamin D deficiency?) contribute to or are associated with theclinical presentation in many cases and can themselves cause autism in someinstances. Abnormalities/variations of default network and decreased connectivity (?)almost universal finding. Impaired social facial perception in large subgroup, relatedto specific brain areas. Arousal and sleep problems important in subgroup. No sharpboundary between ASD and autistic traits or between autistic traits and “normality”.You do not grow out of it, but impairment may increase or decrease and is usually,at least partly, an “effect” of comorbidities. No good evidence that base rate ofautism symptoms has increased in the population, but diagnosis has gone throughthe roof (heavily overdiagnosed in some parts of the world), fewer and fewersymptoms required for diagnosis

– Iacoboni 2006, Buckner and Vincent 2007, Bourgeron 2007, Monk et al 2009, Gillberg 2010, Dinnsteinet al 2010, Coleman and Gillberg 2012, Lundström et al 2012, Leblond et al 2012, Delorme et al 2013,Kocovska et al 2013, Zürcher et al 2013, Lundström and Gillberg 2014, Toro et al 2014, Lundström etal 2015; Posserud et al 2016, Arvidsson et al 2017

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ADHD• The ADHDs are a group of multifactorially determined conditions, that almost

ALWAYS coexist with other developmental problems in cases with early impairment(SLI, DCD, ASD, IDD, tics, “OCD”, epilepsy, other medical disorders), and thereare probably almost as many causes as there are cases. Cases with no comorbidityat all are usually not recognized or impairing early in life, or may beacknowledged as “hyper”, “early walkers”, “never listening”, “emotionallylabile”. The prevalence of the phenotype is not increasing! Dopamine andglutamate genes possibly play a major role in cases with impairment, butenvironmental factors (prematurity, asphyxia, fetal drug and toxin exposure,infections, trauma, vitamin D deficiency?) contribute to or are associated with theclinical presentation in many cases and can themselves cause ADHD in someinstances. Abnormalities/variations of default network, reward system and brainvolume (slightly reduced) in certain areas almost universal finding. Arousal and sleepproblems important in large subgroup. Real-life executive dysfunction almostuniversal (not necessarily “validated” on tests). Inattention (and possibly impulsivity)core features of all with poor outcome, hyperactivity not. No sharp boundarybetween ADHD and “ADHD features” or such features and “normality”. You donot grow out of it, but impairment may increase or decrease and is often, at leastpartly, an “effect” of comorbidities. 20-80% of adults with SUD, GAD, psychosis,bipolar disorder, personality disorder or criminality have ADHD or met criteria forADHD when younger. Highly treatable at all ages

– Gillberg 2013

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The autisms

Regressive autism

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Early symptoms of ASD ( 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 2012, Allely et al 2013, Höglund-Carlsson et al 2013, Barnevik-Olsson et al 2013, 2014, Hatakenaka et al 2016, Höglund-Carlsson et al 2016

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How many people are affected by ESSENCE?• At least 10% of school age children are or have been

affected by “neuropsychiatric/neurodevelopmental disorders” (ESSENCE) (12% of boys, 8% of girls) -including ADHD, ASD, TS, CD, DCD, IDD – half this group “discovered” by age 6 years; many more than half this group will have persistent problems in adult life

• Overlap/”Comorbidity”/Co-existence is the rule; almost never “one problem only”

• When looking back: vast majority had symptoms

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PARENT REPORTS ON AUTISM SYMPTOMS (ASSQ)IN 6200 CHILDREN AGED 7-9 YEARS DATA FROM

(LARGE GENERAL POPULATION) BERGEN CHILD STUDY

ASSQ score (Range 0-54, here shown 0-42)

Chart1

00

11

22

33

44

55

66

77

88

99

1010

1111

1212

1313

1414

1515

1616

1717

1818

1919

2020

2121

2222

2323

2424

2525

2626

2727

2828

2929

3030

3131

3232

3333

3434

3535

3636

0

3838

3939

4040

4141

4242

2

ASSQ-score

825

787

696

530

474

403

300

344

202

239

136

152

99

148

85

84

66

68

41

51

28

51

31

37

30

34

18

33

16

23

13

14

12

15

13

15

8

13

4

11

9

6

4

4

4

8

4

4

3

8

2

9

1

4

1

10

1

3

0

3

2

3

3

2

0

1

1

0

1

0

0

0

0

1

0

0

1

Sheet1

Girls Parent, ASSQa

FrequencyPercentValid PercentCumulative Percent

Valid082518.526.326.3787

169615.622.248.5530

247410.615.163.7403

33006.79.673.3344

42024.56.479.7239

51363.14.384.0152

6992.23.287.2148

7851.92.789.984

8661.52.192.068

941.91.393.351

1028.6.994.251

1131.71.095.237

1230.71.096.234

1318.4.696.733

1416.4.597.323

1513.3.497.714

1612.3.498.115

1713.3.498.515

188.2.398.713

194.1.198.911

209.2.399.16

214.1.199.34

224.1.199.48

234.1.199.54

243.1.199.68

252.0.199.79

261.0.099.74

271.0.099.710

281.0.099.83

2903

302.0.199.83

313.1.199.92

3201

331.0.0100.00

341.0.0100.00

35313370.3100.00

Missing36132529.70

374458100.00

380

391

400

410

421

Sheet1

2

Sheet2

Jenter Teacher ASSQa

FrequencyPercentValid PercentCumulative Percent

Valid0261158.658.658.6

185819.219.277.8

23588.08.085.8

31944.44.490.2

41152.62.692.8

5882.02.094.8

6431.01.095.7

739.9.996.6

827.6.697.2

924.5.597.7

1025.6.698.3

1115.3.398.6

129.2.298.8

137.2.299.0

1411.2.299.2

157.2.299.4

165.1.199.5

173.1.199.6

184.1.199.7

191.0.099.7

213.1.199.8

232.0.099.8

243.1.199.9

251.0.099.9

260

272.0.099.9

281.0.0100.0

290

300

311.0.0100.0

320

330

340

351.0.0100.0

Total4458100.0100.0

Sheet3

Boys Parent, ASSQa

FrequencyPercentValid PercentCumulative Percent

Valid078717.025.225.2

153011.517.042.2

24038.712.955.1

33447.411.066.2

42395.27.773.8

51523.34.978.7

61483.24.783.5

7841.82.786.1

8681.52.288.3

9511.11.690.0

10511.11.691.6

1137.81.292.8

1234.71.193.9

1333.71.194.9

1423.5.795.7

1514.3.496.1

1615.3.596.6

1715.3.597.1

1813.3.497.5

1911.2.497.9

206.1.298.0

214.1.198.2

228.2.398.4

234.1.198.6

248.2.398.8

259.2.399.1

264.1.199.2

2710.2.399.6

283.1.199.6

293.1.199.7

303.1.199.8

312.0.199.9

321.0.099.9

330

340

350

360

370

380

391.0.0100.0

400

410

421.0.0100.0

Total311967.4100.0

MissingSystem150632.6

Total4625100.0

Sheet4

Boys Teacher ASSQa

FrequencyPercentValid PercentCumulative Percent

Valid0213346.146.146.1

171415.415.461.6

246810.110.171.7

32705.85.877.5

41994.34.381.8

51242.72.784.5

61222.62.687.1

7811.81.888.9

8801.71.790.6

9621.31.392.0

1042.9.992.9

11491.11.193.9

1233.7.794.6

1328.6.695.2

1422.5.595.7

1519.4.496.1

1619.4.496.5

1722.5.597.0

1818.4.497.4

1924.5.597.9

2014.3.398.2

2111.2.298.5

2211.2.298.7

2310.2.298.9

245.1.199.0

256.1.199.2

2612.3.399.4

272.0.099.5

282.0.099.5

294.1.199.6

303.1.199.7

313.1.199.7

323.1.199.8

333.1.199.8

342.0.099.9

351.0.099.9

361.0.099.9

371.0.0100.0

401.0.0100.0

421.0.0100.0

Total4625100.0100.0

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Autism• Once (Kanner 1943, Rutter 1994), autism was considered a discrete disorder

– the best and most clearly delineated in child psychiatry, also the most severe

• Gillberg (1983) found autistic traits to be very common in ADHD with DCD and found ASD in 0.7% of 7-year-olds in the mid 1970s

• Wing and Gillberg in the 1980s proposed a continuum/spectrum of autism• Coleman and Gillberg proposed several different autism spectra (later

“many different varieties of autisms”) in the 1980s• Gillberg (1991 and 1992) proposed that autism was on a spectrum with

normally distributed empathy skills and that some variants even of the “disorder” could be considered mild, others moderate, yet others severe

• Gillberg (2010) proposed that autism is “hundreds of spectra” and a subgroup of ESSENCE

• Some (=marked) scorn because of this proposition• Gillberg proposed Autism Plus as a clinically meaningful category (2013)• Regressive autism something completely different? – neuroinflammation?

– Kanner 1943, Gillberg 1983, Coleman and Gillberg 1985, Wing 1979, Gillberg 1983, Gillberg 1992, Rutter 1994, Gillberg 2010, Coleman and Gillberg 2012, Gillberg and Fernell 2014, Gillberg et al 2017

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Autism• L v Beethoven• A Bruckner• B Bartok• E Satie• HC Andersen• S Kierkegaard• A Conan Doyle• I Kant• L Wittgenstein• A Einstein• A Robbe-Grillet• W Kandinskij• P Klee• E Hopper• G Garbo• A Warhol• D Springfield• S Kubrick • S Boyle• “ALL THE LONELY PEOPLE – WHERE DO THEY ALL COME FROM”

– Gillberg 1992, Baron-Cohen 2003, Fitzgerald 2005, Wing 2011

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From preschool to school and into adult life: what predicts what in autism?

• In virtually all studies of the outcome of autism, language disorder/problems/delay and low IQ predict poor outcome

• Medical disorders, including epilepsy, predict poor outcome• ADHD/EF dysfunction in ASD predicts poor outcome• Persistent NVLD in ASD predicts poor outcome• Intervention may or may not predict the very long-term outcome, the

jury is out, but we know it helps to do something (diagnosis + info) in the early years as regards intermediate-term outcomes; can early diagnosis prevent schizophrenia?

• But autism preschool or school “load” in itself does not predict long-term outcome, maybe later persistence does, adolescent load does though

• SO IT IS AUTISM PLUS THAT MATTERS IN EARLY LIFE• REGRESSIVE AUTISM ALWAYS MATTERS – neuroinflammation?

– Gillberg and Steffenburg 1987, Billstedt et al 2007, Cededrlund et al 2008, Fernell et al 2011, Eriksson et al 2013, Hagberg et al 2013, Helles et al 2014, 2016, Gillberg et al 2016, Thompson et al 2017

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Girls and women• IT IS LIKELY THAT ADOLESCENT AND ADULT FEMALES (AND

SOME MALES) WHO HAVE HAD ASD AND/OR OTHER ESSENCE ALL THEIR LIVES ARE OFTEN MISDIAGNOSED AS SUFFERING FROM (ONLY):

DEPRESSION (OFTEN IN ASD OR DCD, SOMETIMES IN ADHD)EATING DISORDER (ASD COMMON IN AN, ADHD IN BULIMIA

AND OBESITY)ANXIETY (CATASTROPHIC CONFUSION IN ASD, GAD IN ADHD)BORDERLINE/OTHER PERSONALITY DISORDER/SELF-HARMOPPOSITIONAL DEFIANT BEHAVIOURSNOT SO FEW REFERRED TO SOCIAL SERVICES

– Kopp et al 2010, Gillberg et al 2017

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Girls and women may have a different ASD/ESSENCE phenotype or different associated “symptoms” or “traits” or “personality styles”

• Females are biologically less aggressive, less violent, less insistent on sameness as compared with males

• Females are also not as obviously motorically active as males• Females generally show more social interest and are more talkative than men• HOWEVER INDIVIDUAL VARIATION IS ENORMOUS, AND ALL THE

DIFFERENCES OUTLINED ARE AT A GROUP LEVEL

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Schizophrenia and autism: some Swedish studies

• 30-year-olds with schizophrenia have a prior history of (usually undiagnosed) autism/Asperger syndrome in about half the cases (even higher among those with paranoid disorders)

• 30-year-olds with an early diagnosis of autism/Asperger syndrome do not meet criteria (and have never met criteria for schizophrenia

• Both schizophrenia and autism are at about 1% prevalence rates in the population• So how can early diagnosed autism not lead to schizophrenia in about half the cases when

half of all cases with schizophrenia have a background history of autism?• Could the answer be that early autism diagnosis means stress reduction throughout

adolescence and early adult life, and this protects from the development of schizophrenia?

– Lugnegård et al 2011, Unenge Hallerbäck et al 2012, Helles et al 2016

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How should we proceed if we suspect ESSENCE?

• Observation inside and outside clinic (if at all possible)• Parent (and teacher) questionnaires plus follow-up interview – e.g.

FTF (Five To Fifteen) or TTF (Two To Five), ATAC, SDQ, SNAP, ASSQ, most of these can probably be used for adults retrospectively

• Parent interview by doctor/psychologist• Medical/neurologic/psychiatric examination of child• Hearing, vision, height, weight, head circumference, MPA screen

including FASD screen, genetic discussion, screening for thyroid and metabolic disorders, EEG sometimes (more often than currently), more if needed

• Assessment of intellectual functioning/neuropsychological/speech and language strengths and weaknesses

– Kadesjö et al 2004, Hansson et al 2005, Coleman and Gillberg 2012, Miniscalco et al 2013, Gillberg 2013, Marinopoulou et al 2016

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How should we plan for best intervention in clinics and research ASD PLUS, i.e. Autism with comorbidity (and ESSENCE more generally)?

• We need to recognize all the problems as early as possible - not just “the autism”, “the ADHD”, “the DCD”, “the Tourette syndrome”, “the IDD”, “the SLI” and all interventions must be individually tailored THROUGHOUT THE LIFESPAN

• Parent “training” and education plan perhaps most important of all (“understanding the condition”), but parent ESSENCE problem needs to be taken into account (!)

• ADHD – whether or not combined with ASD, tic disorders, epilepsy or IDD - is usually responsive to treatment (meds and computer/cognitive training, possibly small effect of Omega-3)

• DCD is usually responsive to focused motor training regardless of comorbidity• Epilepsy (possibly including “subclinical”), when present, should be treated as a top priority

in all ESSENCE• Schizophrenia might be prevented by stress reduction through early autism diagnosis• Sleep disorders sometimes responsive to melatonin or dose adjustment of other meds• Violent behaviours/SIB can be responsive to low-dose neuroleptics or mood stabilizers• Do not treat tics per se unless extreme• Do not treat autism per se with meds (Bumetanide? Oxytocin?)• Psychoeducation, communication enhancement, ESSENCE-friendly environment

(“understanding the condition”), school and work place “adjustment”, and behavioural approaches - sometimes only possible with medication - first and foremost throughout life

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ASD and ESSENCE preliminary conclusions• ESSENCE (not autism per se) is an extreme risk factor for

adolescent/adult social exclusion, academic failure, other school adjustment problems, problems in the work-place antisocial personality disorder (and depression/anxiety, drug abuse, and criminality) – and for “non-handicapping” autistic traits?

• We still know VERY little about early intervention• The OVERFOCUS on ASD ONLY in young children is possibly a

big mistake; but AUTISM PLUS HAS HUGE IMPLICATIONS, SO HAS REGRESSIVE AUTISM and PANS

• For some ESSENCE we can screen and intervene early• All advanced societies need to increase/spread knowledge about

ESSENCE, including ADHD and IDD, not just ASD• In research following children over time all aspects of ESSENCE

need to be taken into account – with screeners such as ESSENCE-Q, A-TAC or TTF

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Final conclusions: What we need to think about when setting up clinical and research routines

• ASD is but one of a group of ESSENCE that overlap genetically, symptomatically and as regards brain dysfunction/variation, enivronmental factors also play a role, but it is unclear how much of the variance they account for

• AUTISM PLUS (i.e. with comorbidity) is a severe disorder, AUTISM ONLY?• ASD persists into adult life (as do most other ESSENCE), re-assessments needed• ADHD is common (c. 5%), ASD is relatively common (c. 1%)• Other psychiatric disorders/problems/academic failure emerge or become

“diagnosable” over time – these are the diagnoses that adult psychiatrists will make• Autism in itself has different outcome, not necessarily poor, current focus on

autism only in screening, assessment and intervention programs a big mistake• IDD has “poor” outcome, ADHD probably has worse outcome (including obesity,

pain syndrome, substance use, MCI?) than ASD “in itself”, SLI may also have partly “poor outcome”

• Regressive autism, Landau Kleffner, CSWS,, FASD, and PANS need to better assessed and worked up, better researched as regards neuroinflammation, perhaps even FS+

• Girls still usually missed or misdiagnosed

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ESSENCE CONFERENCE 2018GOTHENBURG SWEDEN- APRIL 10-11

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Slide Number 1ESSENCE: Early recognition of autism and related disorders – can it improve outcomes?ESSENCE (neurodevelopmental/psychiatric disorders)What are the “symptoms” of ESSENCE?ASD: The AutismsADHDSlide Number 7Slide Number 8Early symptoms of ASD (