Antonella Gagliano

COSA C'E' DI NUOVO SU: DISTURBIDELLO SPETTRO AUTISTICO

COSA C'E' DI NUOVO ?

prevalenza

Le stime precedenti di prevalenza erano molto più ba sse

1970

0,5 per 1,000

1980

1 per 1,000

2000

2 per 1,000

Reports of autism cases per 1,000 children grew dra matically in the U.S. from 1996 to 2007

Newschaffer CJ, Croen LA, Daniels J et al. The epid emiology of autism spectrum disorders . Annu Rev Public Health. 2007;28:235–58.

ASD prevalence rate in the general population of 6,2/1.000

Elsabbagh M, Divan G, Yun-Joo Koh YJ et al.. Global prevalence of autism and other pervasive developme ntal disorders.

Autism Res. 2012;5(3):160–79.

Autism . Lai MC, Lombardo MV, Baron-Cohen S. Lancet. 2014 Mar.

.

Centre for Disease Control (CDC) Autism and Developmental Disabilities Monitoring Ne twork 2014

1 of 68 children aged 8  years had been diagnosed as autistic .

Prevalence of Autism Spectrum Disorders in EU: 0,62 - 0,7%

1:119 Finlandia Mattila et al., 2011

1:87 Svezia Idring et al., 2012

1:59 Gran Bretagna Russel et al., 2014

Reported frequencies for ASD across U.S. and non-U.S. countries

1% of the population

similar estimates in child and adult samples

It remains unclear whether higher rates reflect …

• an expansion of DSM-IV diagnostic criteria to include subthreshold cases

• increased awareness

• differences in study methodology

• true increase in the frequency

APA, 2013

sistemi informativi delle regioni

Piemonte ed Emilia-Romagna

presa in carico ai Servizi di NPI di minori con dia gnosi di autismo

25/10.000

20/10.000

COSA C'E' DI NUOVO ?

outcome

I disturbi dello Spettro autistico sono una condizione che

accompagna l’individuo per tutta la vita ?

1,5% of adult were function normally Rutter,1970

Introducet the idea of “best outcome” or “recovery” Lovas, 1987

17% had lost their diagnosis Sigman e Ruskin,1999

Optimal outcome in individualswith a history of autism …

Fein, D. et al.; J Child Psychol Psy, 2013

ASD represents a major public health concern as a prevalent

neurodevelopmental disorder with pronounced risk for failure of

adaptation across social, educational, and psychological outcomes

Helena Brentani et al.,

Autism spectrum disorders: an overview on diagnosis and treatment

Revista Brasileira de Psiquiatria, 2013.

But…

…about 25% of people with autism are employed

Holwerda A, van der Klink JJ, Groothoff JW, Brouwer S.

Predictors for work participation in individuals with an Autism spectrum disorder: a systematic review.

J Occup Rehabil. 2012 Sep.

Outcame

1–16% di individui con ASD migliorano a tal punto da non soddisfare

più i criteri diagnostici in adolescenza o in età adulta.

Fountain C, et al.

Six developmental trajectories characterize children with autism.

Pediatrics. 2012

Billstedt, E.et al..

Autism after adolescence: Population-based 13- to 22-year follow-up study of 120 individuals with autism diagnosed in childhood.

Journal of Autism and Developmental Disorders, 2005

Farley, M.A.,et al,..

Twenty-year outcome for individuals with autism and average or near average cognitive abilities.

Autism Research, 2009

McGovern, C.W., & Sigman, M.

Continuity and change from early childhood to adolescence in autism. Journal ofChild Psychology and Psychiatry, and Allied Disciplines,

2005.

…. educational, psychosocial, and language therapies, often combined with adjunctive treatments, such as drug therapy for specific symptoms, are wellestablished for their benefits in ASD.

Holwerda A, et al .Predictors for work participation in individuals with an Autism spectrum disorder: a systematic review.

J Occup Rehabil. 2012 Sep;

Early diagnosis and early intervention predict a

better outcome

Dawson G, et al .

Early intervention in autism: Effectiveness and common elements of current approaches. In: Guralnick Ed. The effectiveness of early

intervention: Second generation research. Baltimore: Brookes 1997;

Charman T, Baird G.

Practitioner review: Diagnosis of autism spectrum disorder in 2- and 3-year-old children.

J Child Psychol Psychiatry 2002; 43(3): 289-305.

Zachor DA, Curatolo P; Participants of the Italian-Israeli Consensus Conference.

Recommendations for early diagnosis and intervention in autism spectrum disorders: An Italian-Israeli consensus conference.

Eur J Paediatr Neurol. 2013 Sep

Daniels AM, Mandell DS

Explaining differences in age at autism spectrum disorder diagnosis: A critical review.

Autism. 2013 Jun

Zwaigenbaum L, Bryson S, Garon N.

Early identification of autism spectrum disorders.

Behav Brain Res. 2013 Aug 15;

COSA C'E' DI NUOVO ?

diagnosi

Assenza di un’età minima per fare diagnosi

Identificazione PRECOCE

Precoce…quanto?

DSM-5: esordio e decorso

• Emergenza sintomi 12-24 mesi

Ma anche evidenti…

…prima dei 12 mesi se il ritardo di sviluppo è severo

…dopo i 24 mesi se i sintomi sono sfumati

Indicazioni assolute per un immediato invio

alla valutazione sono:

•assenza di lallazione dopo i 12 mesi

•assenza di gesti quali l’indicare, mostrare, fare “ciao”, dopo i 12 mesi

•assenza di parole singole dopo i 16 mesi

•assenza di associazioni spontanee di due parole dopo i 24 mesi

•perdita di competenze già acquisite nelle aree della comunicazione, del linguaggio, della socialità

Diagnosi precoce….

COME

• screening (18 mesi)

• successivo inquadramento diagnostico strutturato

M-chat: Modified Checklist for Autism in ToddlersRobins, Fein, & Barton, 1999

Modified Checklist for Autism in Toddlers (M -CHAT) Chlebowski et al, Pediatrics 2013;131:e1121–e1127

18 989 toddlers at 18- and 24-month well child visits

2 US geographic regions

54% of children who screened positive presented with ASD

98% presented with clinically significant developmental concerns

M-CHAT total scores of 3 to 6 require follow-up with the M-CHAT/F

M-CHAT total score of 7 can bypass the M-CHAT/F and be referred directly for evaluation and intervention(82.2% of these cases continue to screen positive after the M-CHAT/F)

M-CHAT is an effective screening instrument for ASD

Sviluppo della Quantitative CHAT

� Q = Quick & Quantitative

� Questionario per i genitori

� 25 items con punteggio 0 – 4,

(range 0 – 100)

� Include sviluppo del linguaggio

� Comportamenti ripetitivi e

interessi sensoriali

1. Il vostro bambino vi

guarda quando lo chiamate

per nome?

○ sempre○ spesso ○ a volte○ raramente○ mai

Incostante risposta al nome

Contatto oculare poco sostenuto

Scarsa attenzione congiunta e

triangolazione dello sguardo

Uso dell’altro come estensione

di Se’

Assenza Pointing Protorichiestivo

Assenza Pointing Protodichiarativo

Segni d’allarme nell’interazione sociale

Linguaggio Idiosincratico

Ecolalia Immediata e Differita

Assenza di gesti convenzionalistrumentali

Far girare gli oggetti

(Spinning Object)

Accendere e spegnere gli interruttori

Allineare gli oggetti

Segni d’allarme nella comunicazione e comportamento

Leccare, annusare gli

oggetti

Ipersensibilita’ ai suoni

Sguardo assente, fissita’

Guardare gli oggetti da

molto vicino

Stereotipie e manierismi

motori

Agitare ripetutamente (es. Stringhe)

Segni d’allarme negli interessi sensoriali atipici

www.toddlerscreening.it

Q-CHAT: Quantitative CHecklist for Autism in

Toddlers

indicatori comportamentali

ancora più precoci…?

Joint attention (JA)

Mundy P, Gomes A. Individual differences in joint attention skill development in the second year. Infant Behav Dev 1998; 21: 469–482

.

Emery NJ. The eyes have it: the neuroethology, function and evolution of social gaze. Neurosci Biobehav Rev 2000; 24: 581–604.

It is the ability to coordinate

visual attention with another

person and then shift the gaze

toward an object or event

2 interrelated components:

• Responding JA: ability to shift visual

attention following other's social cues such

as gaze or pointing, whereas initiating

• Initiating JA: ability to direct another

person’s attention through gaze or gestures

with the aim of sharing an experience

They emerge at different times during development

• RJA 6 - 9 months

• IJA 9 months (with a high variability)

Mundy P, et al. Individual differences and the development of joint attention in infancy. Child Dev 2007; 78: 938–954.

Chawarska K, et alF. Automatic attention cueing through eye movement in 2-year-old children with autism. Child Dev 2003; 74: 1108–1122.

JA impairment is one of the more precocious and consistent early

sign of ASD and these impairments correlate with social-

communication impairments, as well as language delays

(Charman T. Why is joint attention a pivotal skill in autism? Philos Trans R Soc Lond B Biol Sci 2003; 358: 315–324)

difficulties in responding JA emerge during the first year of life and

that become progressively evident during the second year

Jones W, Carr K, Klin A. Absence of preferential looking to the eyes of approaching adults predicts level of social disability in 2-year-old

toddlers with autism spectrum disorder. Arch Gen Psychiatry 2008; 65: 946–954.

difficulties in initiating JA is considered a hallmark of ASD

For this reason, a multi-item joint attention factor is considered in Modules 1 and 2 of the

Autism Diagnostic Observation Schedule (ADOS)

Gotham K, Risi S, Pickles A, Lord C. The Autism Diagnostic Observation Schedule: revised algorithms for improved

diagnostic validity. J Autism Dev Disord 2007; 37: 613–627.

Eye-tracking visual patterns of toddlers during the presentation of short video sequences involving:

• Responding JA (RJA)

• Initiating JA (IJA)

� 17 children with ASD

� 15 age-matched TD children

Screen shots of the videos of the different tasks.

(a) RJA (b) IJA with 2 objects (c) IJA with 1 object.

The three tasks are divided into the 3 different phases:

looking down, interactive, joint attention (JA).

No differences were found in the responding JA task between

children with ASD and those with TD

In the initiating JA tasks, different patterns of fixation and

transitions were shown between ASD and TD

(Billeci et al, 2016)

Responding J A scan path for ASD

(red) and TD (blue )

Gaze accuracy, transitions, and fixations were analyzed.

modifica di atteggiamento nei confronti dei segni precoci di ritardo

comunicativo-linguistico e relazionale

identificazione precoce sia attraverso la segnalazione spontanea di

casi ad alto rischio sia attraverso programmi di screening

• La diagnosi precoce nei Disturbi dello spettro autistico

necessita dell’attivazione di una rete di servizi ma, soprattutto,

di un movimento culturale

• Prima dei 30 mesi, anche se si formula la diagnosi di rischio

per ASD e non di Autismo, si attivano atteggiamenti nei

genitori e negli educatori utili a stimolare le abilità linguistico-

comunicative e sociali

• L’instabilità della diagnosi non giustifica il mancato avvio di

un trattamento precoce

COSA C'E' DI NUOVO ?

etiopatogenesi

The literature supports a hereditary component in the susceptibility to ASDs

higher concordance rates of ASDs in monozygotic twin s (92%) than dizygotic twins (10%)

the sibling recurrence risk ratio is 22 for autism

Despite being highly heritable, ASDs show heterogeneous clinical symptoms and genetic architecture

Goldani et al, 2014

a large prospective study revealing a recurrence rate of 18% in siblings and of 33% in multiplex families Ozonoff S, et al (2011) Pediatrics 128:e488-e495.

Ipotesi genetica dell’autismo

Early identification of autism based on objective gene screening is a major first step towards early intervention and effective treatment

However, it is currently believed that over 50% of the risk of developing ASD is attributed to genetic var iation

De Rubeis S, Buxbaum JD (2015) Genetics and genomics of autism spectrum disorder: embracing complexity. Hum Mol Genet 24 R1:R24-R31.

DSM-5, APA 2013

- 15% dei casi sono associati con una mutazione genetica conosciuta (copy number variants o mutazioni de novo in geni specifici associati con mutazioni genetiche conosciute).

- per i restanti casi � causa poligenica

con centinaia di loci genetici con contributi relativamente piccoli.

Tra i diversi polimorfismi associati ad incremento del rischio di ASD

Methylenetetrahydrofolate-reductase (MTHFR) polymorphism

MTHFR677C>T polymorphism

riduzione dell'attività enzimatica della MTHFR enzima coinvolto nella trasformazione del 5-10 metilentetraidrofolato in 5 metiltetraidrofolato che serve come donatore di metili per la rimetilazione della omocisteina a metionina tramite l'intervento della vitamina B12.

livelli elevati nel sangue di omocisteina specie dopo carico orale di metionina.

livelli bassi di acido folico nel plasma

fattore di rischio per • malattia vascolare, (trombosi arteriosa)• difetti del tubo neurale nelle donne in gravidanza• autismo

Methylenetetrahydrofolate-reductase (MTHFR) polymorphism

• MTHFR677T-variant allele is correlated with a 2.79-fold increased risk for autism

• MTRR66A and SHMT1420T alleles demonstratedprotective roles against autism risk

MTHFR has a strong interaction with maternal folic acid intake before and during pregnancy

Children with high autism risk whose mothers carried MTHFR677 TT allele and taking prenatal vitamin show fewer diagnoses of autism

Polimorfismi si…

…ma è vero anche il contrario…

single-gene disorders

Inoltre esistono…

single-gene disorders associated with ASD (5% of cases)

1. Fragile X syndrome

2. Rett syndrome

3. Tuberous sclerosis

4. Phosphatase and tensin homolog (PTEN) mutations

Carter MT, Scherer SW: Autism spectrum disorder in the genetics clinic: A review. Clin Genet 83:399–407, 2013.

Defects of the PTEN gene (Phosphatase and tensin homolog)

PTEN protein is encoded by the PTEN gene

PTEN is a tumor suppressor gene through the action of its phosphatase protein product

involved in the regulation of the cell cycle

preventing cells from growing and dividing too rapidly

(mutations of this gene are a step in the development of many cancers)

Defects of the PTEN gene have been cited to be a po tential cause of ASD

Napoli E, Ross-Inta C, Wong S, Hung C, Fujisawa Y, Sakaguchi D, Angelastro J, Omanska-Klusek A, Schoenfeld R, Giulivi C (2012). "Mitochondrial Dysfunction in Pten Haplo-Insufficient Mice with Social Deficits and Repetitive Behavior: Interplay between Pten and p53". In Bai, Yidong. PLoSONE 7 (8): e42504

defective PTEN protein interacts with the protein o f a second gene known as Tp53 to reduce energy production in neurons

harmful mitochondrial DNA changes and abnormal levels of energy production in the cerebellum and hippocampus (brain regions critical for social behavior and cognition)

It has been estimated that there are over 500 distinct genetic loci that may be related to ASD

Genetic biomarkers in ASD

Neurexin1(NRXN1)deletion7q11.23duplication15q11-13duplication16p11.2duplicationanddeletionSHANK 3SHANK 2SNC2ACHD8DYRKIAPOG2GRIN2BKATNAL2CNTN4 deletionCNTNAP25p14.1CDH10CDH9MTHFR 677>TSEMA5ATAS2R12q22.13p26.34q1214q23NLGN4

Betancur C.. BrainRes (2011)1380:42–77.doi:10.1016/j.brainres.2010.11.078

Mutations in genes encoding neurotransmitters such as:

• Synapsin

• Dopamine transporter

• Neuroligin

• Synapse-associated proteins such as scaffold proteins

including shank and lin7B

Corradi, A.Fadda, M.Piton, A.Patry, L.; Marte, A.; Rossi, P.Cadieux-Dion, M.; Gauthier, J.; Lapointe, L.; Mottron, L.; et al. SYN2 is an autism predisposing gene: Loss-of-function mutations alter synaptic vesicle cycling and axon outgrowth. Hum. Mol. Genet . 2014, 23, 90–103]

Hamilton, P.J.; Campbell, N.G.; Sharma, S.; Erreger, K.; Herborg Hansen, F.; Saunders, C.; Belovich, A.N.; NIH ARRA Autism Sequencing Consortium; Sahai, M.A.; Cook, E.H.; et al. De novo mutation in the dopamine transporter gene associates dopamine dysfunction with autism spectrum disorder. Mol. Psychiatry 2013 , 18, 1315–1323.

Hill-Yardin, E.L.; Argyropoulos, A.; Hosie, S.; Rind, G.; Anderson, P.; Hannan, A.J.; O’Brien, T.J. Reduced susceptibility to induced seizures in the Neuroligin-3(R451C) mouse model of autism. Neurosci. Lett. 2015 , 589, 57–61.

Sala, C.; Vicidomini, C.; Bigi, I.; Mossa, A.; Verpelli, C. Shank synaptic scaffold proteins: Keys to understanding the pathogenesis of autism and other synaptic disorders. J. Neurochem. 2015 , 135, 849–858.

Leblond, C.S.; Nava, C.; Polge, A.; Gauthier, J.; Huguet, G.; Lumbroso, S.; Giuliano, F.; Depienne, C.; Mouzat, K.; et al. Meta-analysis of SHANK Mutations in Autism Spectrum Disorders: A gradient of severity in cognitive impairments. PLoS Genet. 2014 , 10, e1004580.

Mizuno, M.; Matsumoto, A.; Hamada, N.; Ito, H.; Miyauchi, A.; Jimbo, E.F.; Momoi, M.Y.; Tabata, H.; Yamagata, T.; Nagata, K. Role of an adaptor protein Lin-7B in brain development: Possible involvement in autism spectrum disorders. J. Neurochem. 2015 , 132, 61–69.

linkage studies, candidate gene association studies, and cytogenetic studies have implicated several chromosomal regions for the presence of autism susceptibility loci

But..

they have not consistently identified and replicated common genetic variants that increase the risk of A SDs

HagermanR,HendrenR. TreatmentsforNeurodevelopmentalDisorders:Tar-getingNeurobiologicalMechanisms. NewYork,NY:OxfordUniversityPress (2014).

Betancur C. Etiological heterogeneity in autism spectrum disorders: more than 100 genetic and genomic disorders and still counting . BrainRes (2011) 1380:42–77.doi:10.1016/j.brainres.2010.11.078

Autism is not a single clinical entity

it is a behavioral manifestation of tens or perhaps hundreds of genetic and genomic disorders

E se la spiegazione non fosse così lineare ?

Szpir M. Tracing the origins of autism: a spectrum of new studies. Environ Health Perspect . 2006;114(7):A412–8.

ASD is a result of complex gene –environment interactions, with strong

and clear genetic influences Hallmayer J, et al(2011) Genetic heritability and shared environmental factors among twin pairs with autism. Arch Gen Psychiatry 68:1095-1102

Although it is unknown whether autism's frequency h as increased, any such increase would suggest directing more atte ntion and funding toward changing environmental factors instead of continuing to focus on genetics…

Szpir M. Tracing the origins of autism: a spectrum of new studies. Environ Health Perspect. 2006;114(7):A412–8.

epigenetica

le mutazioni, dette epimutazioni , durano per il resto della vita della cellula e possono trasmettersi a generazioni successive delle cellule attraverso le divisioni cellulari, senza tuttavia che le corrispondenti seq uenze di DNA siano mutate

Un segnale epigenetico è un fattore non-genomico ch e provoca una diversa espressione dei geni senza alterare la seque nza nucleotidica

DSM-5, APA 2013

Fattori prognostici e di rischio

- presenza o assenza di disabilità intellettiva e linguistica (linguaggio funzionale a 5 anni è un buon fattore prognostico) e altri problemi mentali

- L’epilessia in comorbidità è associata ad una più grave disabilità intellettiva e a più ridotte abilità verbali

- Ambiente: vari fattori di rischio non specifici come età dei genitori, basso peso alla nascita, esposizione fetale a valproato

- Genetica: l’ereditabilità è stimata dal 37 al 90%

…sul DSM 6 questo

elenco sarà più lungo e

specifico?

Sealey, L.A.; Hughes, B.W.; Sriskanda, A.N.; Guest, J.R.; Gibson, A.D.; Johnson-Williams, L.; Pace, D.G.; Bagasra, O. Environmental factors in the development of autism spectrum disorders. Environ. Int. 2016 , 88, 288–298.

Several environmental factors have been associated with the development of ASD…

• Pesticides• Phthalates• polychlorinated biphenyls• Solvents• air pollutants• Fragrances• Glyphosate• heavy metals

the majority of these toxicants are some of the most common ingredients in cosmetics and herbicides to which almost all of us are regularly exposed to in the form of fragrances, face makeup, cologne, air fresheners, food flavors, detergents, insecticides and herbicides…

Ambiente esterno

Principal exogenous gestational stressor that have been

proposed to play a role in ASD

• anticonvulsants and other psychotropic medications [Christensen et al.,

2013; Wood, 2014]

• maternal infection and immune activation [Malkova et al., 2012; Mazina et al.,

2015; Patterson, 2011; Zerbo et al., 2013 ]

• environmental toxins such as air pollutants [Ehrenstein et al., 2014]

• volatile organic compounds [McCanlies et al., 2012]

• pesticides [Roberts et al., 2007; Roberts & English, 2013]

• plasticizers [Kalkbrenner et al., 2014; Stein et al., 2015; Testa et al., 2012].

Monitoring Body-Burdens

700 different synthetic chemicals or heavy metals found in human blood,

(Total amount of a harmful substance in a live body)

the chemical body

burden ..

especially in women, children,

embryos/ fetuses

Studio prospettico di coorte iniziato nel 1989 su 11 6.430 infermiere

maternal exposure to particulate matter (PM) air pollutionchildren born 1990-2002 with ASD (n = 245), and children without ASD (n = 1,522).

PM 2.5 exposure during pregnancy was associated wit h increased odds of ASD

adjusted odds ratio (OR) for ASD per interquartile range (IQR) higher PM2.5 (4.42 µg/m3) of 1.57 (95% CI: 1.22, 2.03) among women with the same address before and after pregnancy (160 cases, 986 controls).

The association between ASD and PM2.5 was stronger for exposure during the third trimester (OR = 1.42 per IQR increase in PM2.5; 95% CI: 1.09, 1.86) than during the first two trimesters (ORs = 1.06 and 1.00)

altri studi avevano mostrato una simile associazione

JAMA Psy 2013;70(1):71-7

EHP 2013;121(3):380-6

E se fosse qualcosa a cui si espone il

feto solo negli ultimi 20-30 anni ?

Webb et al,

Severity of ASD Symptoms and Their Correlation with the Presence of Copy Number Variations and

Exposure to First Trimester Ultrasound

VC 2016 International Society for Autism Research (INSAR), Wiley Periodicals, Inc.

the developing central nervous

system, particularly during the 1st

trimester may be particularly

susceptible to hyperthermic injury

[Edwards, 2006]

Es. maternal hyperthermia is associated with

increased neural tube defects

[Milunsky et al., 1992; Moretti et al., 2005].

Ultrasound consists of high frequency sound, which when absorbed may lead to thermal (hyperthermia) and non-thermal (cavitation, radiation pressure) effects within tissue. Energy absorption depends on tissue type , exposure, and ultrasound mode, such as for imaging or blood-flow monitoring

While generally considered safe, recent FDA statements regarding the use of prenatal diagnostic ultrasound as well as on-going attention in the scientific literature continue to stress its conservative use for medical purposes.

[Abramowicz, 2013]

case-control designs suggesting increased presence of speech delay [Campbell, Elford, & Brant, 1993]

….but not in randomized trials[Kieler et al., 1998a,b; Newnham et al., 2004; Salvesen et al., 1994]

There have been several reports of increased left handendess in males in

relation to fetal ultrasound exposure

[Kieler et al., 1998a,b, 2002; Salvesen et al., 1993].

The relation between ultrasound as a primary etiological factor

and ASD diagnostic outcome has not been supported jet

[Grether et al., 2010; Stoch et al,. 2012].

1749 children with ASD and an

identified CNVs (copy number variations)

Exposure to 1st trimester

ultrasound

111 male children with ASD and CNVs, had significantly decreased

non-verbal IQ and increased repetitive behaviors compared to

male children with ASD, with CNVs, and no ultrasound

Webb et al,

Severity of ASD Symptoms and Their Correlation with the Presence of Copy Number Variations and

Exposure to First Trimester Ultrasound

VC 2016 International Society for Autism Research (INSAR), Wiley Periodicals, Inc.

Ambiente interno

ASD e immunità

Bergink V1, Gibney SM2, Drexhage HA2.Autoimmunity, inflammation, and psychosis: a search for peripheral markers.

monocyte/microglia activation is the result of a combination of genetic predisposition and an immune-mediated two-hit model

Infection but also environmental stressors during

gestation/early life activate microglia, perturbing

neuronal development

endocrine changes, stress, or infection, could further

activate microglia, leading to functional abnormalities

of the neuronal circuitry in the brain and psychosis

first

second

This activation of the inflammatory response system may be suggestive for

microglia activation, as these cells are the macrophages of the brain

Bergink V1, Gibney SM2, Drexhage HA2.Autoimmunity, inflammation, and psychosis: a search for peripheral markers.

deregulation of the immune system represents an imp ortant vulnerability factor for psychosis

this activation

disturbs the

development and

function of neuronal

circuits in the brain

Microglial activation in ASD

postmortem study

microglia was found to be augmented in individuals with autism when compared with healthy controls

(Morgan et al., 2012)

PET study

young adults with ASD had had increased markers of microglial activation in a wide range of brain areas, including the cerebellum, brainstem, frontal cortex, anterior cingulate cortex, corpus callosum, temporal cortex, and parietal cortex

(Suzuki et al., 2013; Tetreault et al. , 2012)

microglial alteration in Rett syndrome(X-linked disease)

In a murine model of Rett syndrome was found that:

The brain microglial activation is inhibited by ann exin V, which blocks phosphatydilserine residues on apoptoti c targets

Derecki et al. (2012)

The damages in dendrites and synapses and the microglial activation is due to high levels of glut amate

(Maezawa and Jin, 2010)

On the contrary…

decrease in Glu levels by glutamatergic modulators could act to reduce microglial activation and pro-inflammatory cytokine pro duction.

pathophysiology of ASD and Rett syndrome

Prenatal infection with

lipopolysaccharide may lead

to microglial activation

Microglia may be

also activated by

higher levels of Glu

Elevated glutamate levels from

presynaptic neuron may increase

Glu levels in the synaptic cleft

Consequently intraneuronal Ca2+

levels are enhanced via NMDA

(N-methyl-D-aspartate) receptors

Activation of

elevation of proinflammatory

cytokine levels

vicious cycle

G. Z. Re´ us et al. Neuroscience 300 (2015) 141–154

autistic patients exhibited

• Glutamate dysfunction (higher GABA and lower GABA/g lutamate)• a decrease in TNF-a and IL-6 • an increase in IFN-c and IFI16 (a neuroinflammatory marker)

(El-Ansary and Al-Ayadhi, 2014)

an imbalance in GABA and glutamate neurotransmissio n might be related to neuroinflammation in ASD .

Could glutamatergic modulators be promising to treat ASD spectrum to ultimately reduce glutamatergic excitotoxicity and consequently microglial activation ?

Maternal immune activation and abnormal brain development across CNS disorders

Nature Reviews Neurology 10, 643–660 (2014)

Microglial priming has been proposed as a major consequence of maternal immune

activation representing a critical link in a causal chain leading to the wide spectrum of

neuronal dysfunctions and behavioural phenotypes observed in the juvenile, adult or

aged offspring.

Molte anomalie dell’immunità sono state riportate n ell’ASD

familial autoimmune disorder clustering

Comi et al, J Child Neurol 1999, 14:388–394

dysfunctional of natural killer cells

Enstrom et al, Brain Behav Immun 2009, 23:124–133

immune transcriptome alterations in the temporal co rtex

Garbett et al, Neurobiol Dis 2008, 30:303–311

auto-antibodies to the cerebellum

Goines et al, Brain Behav Immun 2011, 25:514–523.

higher levels of auto-antibodies(anti-myelin basic protein, anti-myelin-associated glycoprotein, anti-ganglioside, anti-

neuronal, anti-mitochondrial)

Mostafa et al, Eur J Paediatr Neurol 2012, 16:464–468.Zhang et al, J Neuroinflammation 2010, 7:80.

higher cytokine levels

Corbett et al, Mol Psychiatry 2007, 12:292–306.Croonenberghs et al, Neuropsychobiology 2002, 45:1–6.Croonenberghs et al, Psychol Med 2002, 32:1457–1463.Schwarz et al, Mol Psychiatry 2011, 16:1213–1220.Singh et al, Clin Immunol Immunopathol 1991, 61:448–455.Zimmerman et al, Pediatr Neurol 2005, 33:195–201.Ashwood et al,. Brain Behav Immun 2011, 25:40–45.Onore et al, J Neuroimmunol 2009, 216:126–129.Grigorenko et al, Pediatrics 2008, 122:e438–e445.Singh et al,. J Neuroimmunol 1996, 66:143–145.Sweeten et al, Biol Psychiatry 2004, 55:434–Suzuki et al, PLoS One 2011, 6:e20470.

Interleukin-1 β è la citochina più direttamente correlata ai tratti quantitativi nei soggetti ASD

(Vineland Adaptive Behavior Scale in Autism composite score, Social Responsiveness Scale total T score, head circumference, and full intelligence quotient)

.

Napolioni et al, Plasma cytokine profiling in sibling pairs discordant for autism spectrum disorder, Journal of Neuroinflammation 2013, 10:38 doi:10.1186/1742-2094-10-38

Ciò sembra attribuibile ad una predisposizione immunogenetica

ASD e Microbiota

Microbiota

insieme di microorganismi simbiotici che si trovano nel tubo digerente

Some individuals with neurodevelopmental disorders, including ASD, co-present with gastrointestinal pro blems and dysbiosis of the gut microbiota

(Bresnahan et al., 2015; Mayer et al., 2014; Parracho et al., 2005).

a bidirectional communication system between the gu t and the brain known as the gut-brain axis links gut and brain act ivities

(Cryan and Dinan, 2012; Mayer et al., 2015)

changes in the gut microbiome may be relevant to th e development of behavioral symptoms associated with ASD ?

(Hsiao et al., 2013; Mayer et al., 2014)

Maternal obesity has been associated with alterations in the gut microbiome in offspring in both human and non-human primates(Galley et al., 2014; Ma et al., 2014).

Epidemiological evidence suggests that exposure to maternal obesity in utero increases the risk of neurodevelopmentaldisorders, such as ASD

(Connolly et al., 2016; Krakowiak et al., 2012; Sullivan et al., 2014).

Buffington et al., 2016, Cell 165, 1762–1775 June 16, 2016

maternal high-fat diet induces a shift in microbial ecology that negativelyimpacts offspring social behavior

social interaction induces synapticpotentiation in the ventral tegmentalarea (VTA) of MRD, but not MHFD offspring

MHFD offspring had feweroxytocin immunoreactive neuronsin the hypothalamus

Probiotic treatment may relievespecific behavioral abnormalitiesassociated with neurodevelopmental disorders

ASD e ossitocina

polymorphisms and haplotypes in the oxytocin receptor gene are related to ASD

(Jacob et al. 2007; Lerer et al. 2008; Liu et al. 2010; Li et al. 2012)

There is one single oxytocin receptor, a 389 aminoacidpolypeptide with seven transmembrane domains, which belongs to class I of the G protein-coupled receptor family

(Kimura et al. 1992)

structural gene for oxytocin (OXT) confers individu al differences in human sociability.

What about on epigenetic modification of OXT via DN A methylation ?

Genetic data were collected via saliva samples and analyzed to target and quantify DNA methylation across the promoter region of OXT.

People that exhibit lower OXT DNA

methylation (presumably linked to

higher OXT expression) display more

secure attachment styles and a improved

ability to recognize emotional facial

expressions

They also had

• Greater superior temporal sulcus activity

during two social-cognitive functional

MRI tasks

• larger fusiform gyrus gray matter volume

epigenetic modification of OXT is linked to several overt measures of sociability in humans

COSA C'E' DI NUOVO ?

trattamento

“Our increased ability to identify and diagnose children with autism spectrum disorders at ever earlier ages provides us with both an opportunity and a challenge”

Schreibman, Dawson et al, J Autism Dev Disord(2015) 45:2411–2428

The first challenge is to design and adapt the interventions to very young children

(Dawson et al, (2008) Development and psychopathology, 20(3), 775–803.)

Dawson et al, 2010; Dawson et al., 2012; Vivanti et al., 2013; Rogers et al., 2012; Vismara, et

al, 2009; Vismara et al., 2013)

the importance of early intervention (i.e., treatme nt before the age of 4 years) has been heavily emphasized in the treatme nt of autism

(Dawson, 2008)

Efficacy …

Reichhow, et al, 2008; Makrygianni et al, 2010; Wallace & Rogers, 2010; Dawson, et al 2010;Perry et al, 2011; Eikeseth et al 2012; Koegel, et al, 2014;

Quale trattamento????

DIR

SENSORY INTEGRATION THERAPY

MUSIC

THERAPY

TOUCH

THERAPY

AIT

COMUNICAZIONE

FACILITATA

TERAPIE

ORMONALI

TERAPIE IMMUNOLOGICHETERAPIE CONTRO

i LIEVITI

TERAPIE CON VITAMINE

DIETE

ABA

ESDM

CABAS

TEACCH

CLINICAL PRACTICE GUIDELINE FOR PARENTS AND PROFESSIONALS- AUTISM/PDD

Assessment and Intervention for young children 0-3

Documento che comprende 10 anni di raccolta dati (2000-2010), rassegna bibliografica, una meta-analisi, uno study-group, analisi comparata dei dati, finanziato dal Governo Americano:

Lo studio è stato promosso dalle associazioni di familiari,per aiutare i genitori che hanno appena ricevuto la diagnosiprecoce a scegliere il più rapidamente possibile pacchettid’intervento supportati da evidenze scientifiche di efficacia

Interventi evidence-based:

• Programmi intensivi comportamentali ABA, TEACCH, ESDM : forti evidenze. Raccomandato

• DIR : evidenze inadeguate. Non raccomandato come intervento primario

• SENSORY INTEGRATION THERAPY: evidenze inadeguate. Non raccomandato come intervento primario

• MUSIC THERAPY: nessuna evidenza. Non raccomandato

• TERAPIE CONTRO I LIEVITI: evidenze inadeguate. Non raccomandato

• TERAPIE CON VITAMINE (B6+magnesio): evidenze inadeguate. Non raccomandato

• DIETE: evidenze inadeguate. non raccomandato

• AIT (Auditory Integration Training): Evidenze forti di nessuna efficacia. DA NON USARE

• COMUNICAZIONE FACILITATA: Evidenze di efficacia inadeguate e rischi di danni o regressioni. DA NON USARE

• TERAPIE ORMONALI : Evidenze di efficacia inadeguate e mancanza di evidenze sulla sicurezza di tale trattamento. DA NON USARE

• TERAPIE IMMUNOLOGICHE : Sostanziali evidenze di rischio, E’FORTEMENTE RACCOMANDATO NON USARLE

Interventi evidence-based:

L’intervento deve essere…

…. precoce

contrastare i comportamenti devianti ma al tempo stesso modificare l’organizzazione del SNC e l’espressività del disturbo, prevenendo o limitando lo stabilirsi dei comportamenti sociali devianti

Intensivo -> almeno 18 ore/settimana

L’intervento deve essere…

…. intensivo

Curriculare -> contenuti, obiettivi, monitoraggio

L’intervento deve essere…

…. curriculare

guidelines for treatments :

1] starting as early as possible

2] minimizing the gap between diagnosis and treatmen t

3] provide not less than 3/4 hours of treatment eac h day

4] being centered on family involvement

5] providing six-monthly development evaluations an d updating the goals

6] choosing among behavioral/developmental treatmen t depending on the

child's response

7] encouraging spontaneous communication

8] promoting the skills through play with peers

9] finalizing the acquisition of new skills and to t heir generalization and

maintenance in natural contexts

10] supporting positive behaviors rather than begin ning challenging behaviors

Narzisi et al, 2014

Interventi sul linguaggio

Raccomandazione

L’utilizzo di interventi a supporto della comunicazione nei soggetti con disturbi dello spettro autistico, come quelli c he utilizzano un supporto visivo alla comunicazione, è indicato, seb bene le prove di efficacia di questi interventi siano ancora parzial i.

• comunicazione aumentativa alternativa (CAA)

• training al linguaggio segnato• Picture exchange communication system

(PECS)

Schreibman L & Stahmer AC., J Autism Dev Disord. 2014 May;44(5):1244-51. A randomized trial comparison of the effects of ver bal and pictorial naturalistic communication strategies on spoken language for you ng children with autism .

Trial randomizzato che confronta

1. intervento logopedico standard (Pivotal Response T raining)

2. Picture Exchange Communication System (PECS)

Bambini autistici di 2-4 years

Tutti pre-verbali o con linguaggio molto ridotto

247 ore di trattamento per 23 settimane

Le capacità linguistiche espressive miglioraronoin entrambi i gruppi nella stessa misura

Il 78% dei bambini ha acquisito almeno 10 parole

Programmi intensivi comportamentali

Raccomandazione

Programmi intensivi comportamentali

il modello più studiato

(Applied Behaviour Analysis, ABA)

efficacia nel migliorare

1. abilità intellettive (QI)2. linguaggio3. comportamenti adattativi

Le prove a disposizione, anche se non definitive, c onsentono di consigliare l’utilizzo del modello ABA nel trattamento dei bambini con disturbi dello spettro autistico.

Raccomandazione

Applied Behaviour Analysis, ABA

intervento intensivo 6-7 ore al giorno per 6- 7 giorni settimanali senza alcuna vacanza

valutazione clinica caso-specifica per monitorare nel singolo bambino l’efficacia dell’intervento

ampia variabilità a livello individuale negli esiti del trattamento

Interventi per la comunicazione

sociale e l’interazione

imitation is considered as a foundation for learning, socialization and communication

Meltzoff A, Prinz W (2002) The imitative mind: Development, evolution, and brain bases. Cambridge: Cambridge Univ. Press.

L’imitazione…

…la cenerentola delle abilità

Jaqueline Nadel

Perception-action coupling and

imitation in autism spectrum disorder.

Dev Med Child Neurol. 2015 Apr;57

Suppl 2:55-8. doi: 0.1111/dmcn.12689.

Sept, 2014

Literally from birth, typically developing neonates are able to imitate a tongue protrusion, even if it is presented on a s creen.

They are able to relate their motor repertory to their perception with great plasticity

Nnewborn infants improve their performance throughout repeated exposure to the stimulus

Soussignan R, Courtial A, Canet P, Danon-Apter G, Nadel J. Human newborns match tongue protrusion of

disembodied human and robotic mouths. Dev Sci 2011; 14: 385–94.

Hypothesis…

A proto-mirror neuron system is already efficient at birth

It gradually develops through repeated motor activity and related sensory feedbacks

Lepage JF, Theoret H. The mirror neuron system: grasping others’ actions from birth? Dev Sci 2007; 10: 513–23.

as soon as language improves……. the imitative communication decreases

However, it does not disappear completely…

experimental settings for synchronized activities

objects in two samples

children with ASD are able to imitate spontaneously familiar actions and recognize being imitated

Nadel J, Aouka N, Coulon N, et al.

Yes they can!

An approach to observational learning in

low-functioning children with autism. Autism

2011; 15: 421–36.

reciprocal imitation is…

…a primary communicational system consisting in matching

actions that are alternately proposed by one or the other

partner as a way to switch roles between imitator and model

(Nadel-Brulfert and Baudonnie `re 1982; Nadel and Butterworth 1999; Uzg-iris et al. 1984)

Yuka Ishizuka, Jun-ichi Yamamoto, Contingent imitation increases verbal interaction in children with

autism spectrum disorders; Autism. 2016 Apr 19. pii: 1362361315622856. Epub ahead of print

contingent adult imitation increase nonverbal communication in children with

autism spectrum disorders…

And the contingent imitation on verbal communication ?

children with autism (aged 33–63 months)

in contingent imitation condition, all children increased the number of vocal

imitations, vocalization and vocal turn-takings compared with control condition

children promote

verbal interaction via

contingent imitation

Nadel J. How Imitation Boots Development in Young Infants and Children with ASD. Oxford, UK: Oxford University Press, 2014.

imitation in its two functions, learning and communication,

promotes a coordination of bottom-up and top-down

processes that constitutes a powerful booster of

development, even in case of impaired neurodevelopment…

sviluppare e potenziare le abilità di

• relazione sociale• regolazione del comportamento• reciprocità nella conversazione• sincronia delle azioni

bambini dai 2 ai 9 anni

Interventi sulla reciprocità/imitazione

Early Start Denver Model (Rogers et al. 1986)

The M.I.N.D. Institute, UC Davis

ESDMbambini con diagnosi di ASD di età 18-36 mesi

Denverbambini con diagnosi di ASD < 48

• Approccio relazionale

• Tonalità affettiva fortemente positiva

• Lavoro contemporaneo su più areedello sviluppo e team interdisciplinare

Principi base

• Focus sull’interazione basata sulla reciprocità soc iale

• Enfasi sullo sviluppo della comunicazione non verba le e verbale

• Focus sugli aspetti cognitivi del gioco (routines di gioco diadico)

Pratiche di insegnamento all’interno di routine di gioco

Trattamento…

Comprensivotrattamento rivolto a tutti i settori dello

sviluppo e non solo a quelli tipicamente deficitari nell’autismo

Intensivoalmeno 20 ore settimanali

Sono importanti le interazioni vivaci e dinamiche in cui sono implicate espressioni emotive forti e positive

• Attiva generalizzazione• Genitori coinvolti, informati, formati

Insegnamento: • precoce e intensivo• attentamente strutturato• adattato alle caratteristiche di funzionamento

Early…

…perchè ?

ridotta iniziativa sociale

i tentativi di iniziativa sociale dei genitori e dei fratelli vengono frustrati

Numero ridotto di esperienze interattive

atti comunicativi a bassa intensità e frequenza

Ridotte occasioni di apprendimento

via via i partners sociali diminuiscono le iniziative

.

Inconsapevolmente

consapevoli della

qualità anormale

dello stato

intersoggettivo del

loro bambino

E i genitori?

Inizialmente i genitori dei bambini AD e RM non differiscono dai genitori di bambini TD

Dopo si……

Risentono precocemente della mancanza di risposta quando sollecitano il loro figlio e

modificano le loro interazioni

I Bambini mostrano una

crescente deviazione dello

sviluppo della

intersoggettività

Ruolo della famiglia nell’ESDM

• I genitori partecipano a tutti i meeting e le attività

• Genitori e team stabiliscono insieme gli obiettivi

• I genitori cooperano nell’amministrare l’intervento.

• Il supporto dei fratelli e della famiglia estesa è ricerc ato e difeso

the ESDM program may be effective in improving not only core developmental domains, but also decreasing maladapt ive behaviors

32.7% of children with ASD display

• aggressive behaviors

• self-injurious behavior

• severe temper tantrums

strong negative relationship

between the ability to communicate

and the maladaptive behavior

Eapen et al. BMC Pediatrics 2013, 13:3

effectiveness of the ESDM for preschool-aged children with ASD

comprehensive early intervention program that integrates applied behaviour analysis with

developmental and relationship-based approaches

26 children (21 male)

Mean age 49.6 months

Per week

15–20 hours of group-based

1 hour of one to-one

intervention period 10 months

post-intervention improvements on

� visual reception,

� receptive language

� expressive language

� overall intellectual functioning

ESDM using predominantly group-based intervention may be an effective intervention

Obiettivi:

• Valutare l’efficacie dell’ESDM in una comunità italiana, confrontando i

risultati di un gruppo di bambini che ha ricevuto l’ ESDM e quelli di un

gruppo che ha ricevuto trattamento usuale (TAU) per un periodo di 6

mesi.

Implementation of the Early Start Denver Model in an Italian Community

Colombi C, Narzisi A, Ruta L, Cigala V, Gagliano A, Pioggia G, Siracusano R, Rogers SJ, Muratori F & Prima Pietra Team

In press

ESDM:

• 3 sessioni /settimana da 2 ore

• rapporto 1:1

Risultati scala Griffiths QS

0

10

20

30

40

50

60

70

80

90

Mean t0 Mean t1 Mean t2

(p.02**)(p .03**)

ESDM

TAU

Risultati scala Vineland

62

64

66

68

70

72

74

76

78

80

Mean t0 Mean t1 Mean t2

Punteggio composito

(P .03)

ESDM

TAU

Lo studio dimostra modifiche significative nel livello di sviluppo e di Linguaggio

QI e linguaggio all'età di 5 anni, rappresentano i migliori predittori di outcome in età adulta.

• …..L’ESDM anche consegnato a bassa intensità (meno ore di trattamento) può promuovere risultati migliori rispetto al trattamento attualmente in uso in Italia.

Il ruolo dei genitori

Raccomandazione

I programmi di intervento mediati dai genitori sono raccomandati nei bambini e negli adolescenti con disturbi dello spettro autistico, poiché sono interventi che possono migliorare la co municazione sociale e i comportamenti problema, aiutare le fami glie a interagire con i loro figli, promuovere lo sviluppo e l’incre mento della soddisfazione dei genitori, del loro empowerment e benessere emotivo

modello di Xaiz e Micheli (2011)

incontri con cadenza settimanale per sei mesi

formare nei genitori una competenza educativa tale da sostenere

un’azione riabilitativa efficace

http://www.fondazioneares.com/uploads/media/E._Mich eli___C._Xaiz_-_I_primi_passi.pdf

Gioco e interazione sociale nell'autismo, Cento ide e per favorire lo sviluppo dell'intersoggettività,

di Enrico Micheli, Cesarina Xaiz,

Ed. Erickson

Caretto Flavia, Dibattista Gabriella, Scalese Bruna –

Autismo ed autonomie personali guida per educatori, insegnanti e genitori

- Erickson ed., 2012

Genitori coinvolti, informati, formati…

trasformare la routine quotidiana in esperienze di apprendimento

Un intervento precoce per il tuo bambino con autism o.

Come utilizzare l'Early Start Denver Model in famiglia

Sally J. Rogers, Geraldine Dawson, Laurie A. Vismara

trasformare le routine

quotidiane in esperienze

di apprendimento

• indicazioni calate nella realtà della vita quotidiana di un genitore

• suggerimenti per vivere con un un bambino che non sviluppa e non impara spontaneamente quelle abilità che nello sviluppo tipico emergono autonomamente

• strategie fattibili e pratiche che il genitore può utilizzare quotidianamente per stimolare il suo bambino a entrare in relazione con gli altri

Il bambino deve usufruire di " interazioni terapeutiche " anche quando è fuori della stanza di terapia

98 toddlers at risk for ASD ages 14–24 m

randomized controlled trial comparing

• community treatment as usual

• 12-week, low intensity (one hour-per-week of therapist contact)

I bambini di entrambi i gruppi miglioravano allo stesso modo !!!

Le ore di trattamento nel P-ESDM group erano molto minori

Le due variabili correlate con il miglioramento erano

• Età più bassa

• Numero di ore di intervento

Interventi per la comunicazione

sociale e l’interazione

Raccomandazione

Interventi per la comunicazione sociale e l’interazione

• social stories• interventi basati su tecnologie (video per la proiezione di filmati, computer)• interventi mediati da pari (peer)• training in teoria della mente• interventi basati sull’imitazione (imitazione reciproca o interazione imitativa).

Gli interventi a supporto della comunicazione social e vanno presi in considerazione per i bambini e gli adolescenti con ASD ; la scelta di quale sia l’intervento più appropriato deve essere formulata sulla base di una valutazione delle caratteristiche individuali del soggetto.

Gray, C. and White, A. L. (2002). My social stories book. London: Jessica Kingsley Publishers. Available from www.autism.org.uk/amazonshop

Karkhaneh, M. et al (2010). Social stories to improve social skills with autism spectrum disorder: a systematic review. Autism, 2010, 14(6), pp.641-662. Available from the NAS Information Centre.

Kokina, A. and Kern, L. (2010). Social story interventions for students with autism spectrum. Available from www.awares.org/conferences

Ling, J. (2010). I can't do that! My social stories to help with communication, self-care and personal skills. London: Sage.

social stories were created by Carol Gray in 1991 t o teach social skills to people with autism

Brevi descrizioni di situazioni particolari, eventi, attività cheincludono specificheinformazioni su cosaaspettarsi in quellasituazione e perchè

Mindreading DVD

Educational software designed to be an interactive, systematic guide to emotions

Baron-Cohen et al. 2004; www.jkp.com/mindreading

It learns to recognize both basic and

complex emotions and mental states

from video clips of facial expressions and

audio recordings of vocal expressions

412 different emotions organized into 24 related groups

6 video clips are provided for each emotion showing

close-up performances by a wide range of people (old,

young, men, women, boys, girls, etc).

Riconoscimento di emozioni in visi schematici (test e training)

- Identificazione delle emozioni causate da situazioni (test e training)

- Identificazione delle emozioni causate da desideri (test e training)

- Identificazione delle emozioni causate da opinioni (test e training)

- Comprensione della falsa credenza di 1° ordine (test e training)

- Comprensione della falsa credenza di 2° ordine (test e training)

- Comprensione della mente dallo sguardo (test e training)

- Training per la comprensione della falsa credenza di 1° ordine: Thought-Bubble Training

Autismo e competenze cognitivo-emotive (CD-ROM)

Valutare e potenziare le capacità di riconoscere le emozioni e inferire gli stati mentali dell'altro, Marina Pinelli,

Erica Santelli, ed Erickson, 2005

“The Transporters” è un training delle abilità di

riconoscimento emotivo per bambini con ASD.

Si presenta sotto forma di un DVD contenente una serie di brevi

filmati (15 episodi di 5 minuti ciascuno) che sono organizzati in

modo da sollecitare l’attenzione dei bambini con autismo sul volto

umano.

Il suo scopo primario è quello di

migliorare le capacità di

riconoscimento e discriminazione

delle espressioni emotive presenti

sul volto dei personaggi.

I filmati raccontano le avventure di otto diversi veicoli meccanici

(tram, bus, treno, etc) animate da volti umani che esprimono

differenti emozioni.

Sono stati così concepiti perché quasi tutti i bambini con

autismo sono affascinati dai mezzi di trasporto su ruote e, più in

generale, da tutti i veicoli che percorrono traiettorie prevedibili

o che contengono parti meccaniche in movimento.

Lego therapy (LT) terapia di gioco collaborativo durante la quale i bambini lavorano insieme

per costruire dei modellini(Owens et al. 2008)

LT encourages to build Lego models in groups of three , thereby

gaining opportunities for social interaction…

Organizations researching LEGO Therapy - Autism Research Centre - University of Cambridge. Gina Gómez de la

Cuesta Owens, Director of Action Research, National Autistic Society

Lego therapy (LT)(Owens et al. 2008)

Lego (like computers) can be assembled

in predictable and repeating sequences

Children participating in Lego therapy are intrinsically

motivated by Lego because it involves constructional systems

Lego is not directly relevant:

the focus is on ‘affective computing’

LeGoff DB. Use of LEGO as a therapeutic medium for improving social competence. J Autism Dev Disord. 2004 Oct;34(5):557-71.

Legoff DB, Sherman M. Long-term outcome of social skillsintervention based on interactive LEGO play. Autism. 2006 Jul;10(4):317-29

Owens G, Granader Y, Humphrey A, Baron-Cohen S. LEGO therapy and the social use of language programme: an evaluation of two social skills interventions for children with high functioning autism and Asperger Syndrome. J Autism DevDisord. 2008 Nov;38(10):1944-57.

Huskens B, et al, Improving Collaborative Play BetweenChildren with Autism Spectrum Disorders and Their Siblings: The Effectiveness of a Robot-Mediated Intervention Bas edon Lego® Therapy . J Autism Dev Disord. 2015 Nov;45(11):3746-55.

Peckett et al, Maternal experience of Lego Therapy in familieswith children with autism spectrum conditions: What is the impact on family relationships? Autism. 2016 Feb 5. pii: 1362361315621054. [Epub ahead of print]

9 studi in tutto su Pub-med

Concordi nel rilevare l’efficacia

E i farmaci ?

Chavez B , Chavez-Brown M , Sopko MA , Rey JA . Atypical antipsychotics in children with pervasive developmental disorders. Paediatr Drugs. 2007;9(4):249-66. USA Monmouth Medical Center, Long Branch, New Jersey, USA.

“The treatment of pervasive developmental disorders is

a challenging task which should include behavioral

therapy modifications as well as pharmacologic ther apy”

Nowadays, there is no approved pharmacological therapy for thesocial symptoms of ASD

solo due farmaci (antipsicotici atipici) hanno ricevuto l’approvazione per iltrattamento dei sintomi comportamentali di pazienti con ASD

RISPERIDONEapprovato per il sintomo generico irritabilità(irritability , aggression, deliberate self-injury, and temper tantrums) (Jesner et al. 2007)

ARIPIPRAZOLO (solo negli USA) (Farmer et al. 2013)

Drugs are generally used to control the most dysfunctional behaviors in the social sphere (Dove et al. 2012)

Individuals with ASDs frequently display irritability and disruptive behaviors including tantrums, self-injurious behavior, and aggression.

The efficacy and tolerability of risperidone and aripiprazolehave been established with multi-site, randomized, controlled trials

Politte LC1, McDougle CJ, Atypical antipsychotics in the treatment of children and adolescents with pervasive developmental disorders, Psychopharmacology (Berl). 2014 Mar;231(6):1023-36. .

Atypical antipsychotics are currently the most effi cacious pharmacological interventions available for treatment of irritability associated with ASDs

Farmer et al, Pharmacotherapy for the Core Symptoms in Autistic Disorder: Current Status of the Research Drugs. 2013 March ; 73(4): 303–314.

AAPS

Most studies have recruited children specifically for irritability no study has evaluated the core symptoms as a primary outcome

Sung et al, What’s in the pipeline? Drugs in development for autism spectrum disorder, Neuropsychiatric Disease and Treatment 2014:10 371–381

Ma i farmaci

….agiscono anche sulle difficoltà sociali e comunicative ?

….sono efficaci su altri problemi correlati come l’iperattività e i disturbi del sonno?

…possono migliorare le capacità di apprendimento?

Conventional pharmacological management targets

dysfunctional behavioral

• aggression

• irritability

• stereotyped behavior

• anxiety

• hyperactivity

• sleep difficulties

Sung et al, What’s in the pipeline? Drugs in development for au tism spectrum disorder , Neuropsychiatric Disease and Treatment 2014:10 371–381

Pharmacological agents include

• antipsychotics

• antidepressant

• mood stabilizers

• psychostimulants

Sung et al, What’s in the pipeline? Drugs in development for au tism spectrum disorder , Neuropsychiatric Disease and Treatment 2014:10 371–381

What about novel treatments ?

• melatonin

• omega-3 fatty acids

• glutamate receptor related medications

• oxytocin

In the last 5 years, various retrospective studies,

open-label trials, and placebo-controlled trials

reported improvements in long sleep latency,

night waking, and settling difficulties

Andersen et al, Melatonin for insomnia in children with autism spectrum disorders. J Child Neurol. 2008;23(5):482–485.

Malow et al. Melatonin for sleep in children with autism: a controlled trial examining dose, tolerability, and outcomes. J Autism Dev Disord. 2012;42(8):1729–1737

Wright et al. Melatonin versus placebo in children with autism spectrum conditions and severe sleep problems not amenable to behaviour management strategies: a randomised controlled crossover trial. J Autism Dev Disord. 2011;41(2):175–184.

Galli-Carminati et al, Melatonin in treatment of chronic sleep disorders in adults with autism : a retrospective study. Swiss Med Wkly. 2009;139(19–20):292–296.

Wirojanan et al. The efficacy of melatonin for sleep problems in children with autism, fragile X syndrome, or autism and fragile X syndrome . J Clin Sleep Med. 2009;5(2):145–150.

omega-3 fatty acids

low levels of omega-3 fatty acids in children with ASD

Bent et al. Omega-3 fatty acids for autistic spectrum disorder: a systemic review. J Autism Dev Disord. 2009; 39(8):1145–1154.

Positive effect on hyperactivity and impulsivity

Richardson & Montgomery Pediatrics 2005Gustafsson at al. Acta Pediatrica 2010

James S, Montgomery P, Williams K.

Omega-3 fatty acids supplementation for autism spectrum disorders (ASD) [review].

Cochrane Database Syst Rev. 2011;(11):CD007992.

glutamate receptor related medications

1. Vaste disfunzioni GABAergiche nel cervello deisoggetti ASD

2. Aumentati livelli di GABA nel plasma di soggetti ASD

Fatemi et al, GABA(A) receptor downregulation in brains of subjects with autism. J Autism Dev Disord. 2009;39(2):223–230

Shimmura, et al. Alteration of plasma glutamate and glutamine levels in children with high-functioning autism. PLoS One. 2011;6(10):e25340

Eccessiva attività glutamatergica � eccitotossicità nel cervello �

anormale sviluppo neuronale � ASD

Essa et al, . Excitotoxicity in the pathogenesis of autism. Neurotox Res. 2013;23(4):393–400.

N-methyl-D-aspartate (NMDA) subtype of the glutamate receptor have been studied for their roles in treating ASD and the related symptoms

Glutamate antagonists work by blocking the glutamate receptor and moderating excessive excitation at the neuronal level

Can we use glutamate receptor-related medications in clinical populations ?

Erickson et al, A retrospective study of memantine in children and adolescents with pervasive developmental disorders. Psychopharmacology (Berl). 2007;191(1):141–147.

Owley T, et al. A prospective, open-label trial of memantine in the treatment of cognitive, behavioral, and memory dysfunction in pervasive developmental disorders. J Child Adolesc Psychopharmacol. 2006;16(5):517–524.

One of the more commonly known NMDA-receptor antagonists used in the treatment of Alzheimer’s dementia.

open-label studies with ASD

improvements in social withdrawal and inattention

but several adverse effects (sedation, irritability, rash, emesis, and increased seizure frequency)

memantine

Bumetanide

It is a diuretic, chloride-importer antagonist, which reduces intracellular chloride and enhances GABAergic inhibition

It showed significant improvements in the CARS, CGI and ADOS after eliminating the most severe cases

Lemonnier E, Degrez C, Phelep M, et al. A randomised controlled trial of bumetanide in the treatment of autism in children. Transl Psychiatry. 2012;2:e202

Acamprosat

l'acamprosato usato per il mantenimento dell'astinenza nel paziente alcoldipendente

GABA type A agonist and excitatory glutamate antagonist

improvements in • social withdrawal• Hyperactivity• Social Responsiveness Scale,• CGI–Severity scale scores.

Erickson et al, An open-label naturalistic pilot study of acamprosate in youth with autistic disorder. J Child Adolesc Psychopharmacol. 2011;21(6): 565–569.

Oxytocin.

Oxytocin and the related nonapeptide arginine

vasopressin are involved in social behavior

• Formation of mother–infant

and adult–adult pair bonds

• separation distress

• social memory and

recognition

• stress response

• Regulation of feeding

(Donaldson and Young 2008;

MacDonald and MacDonald 2010).

Peripheral indicators such as levels of salivary and plasma oxytocin, are

related to parenting behaviors in child–parent attachment relationships

(Levine et al. 2007; Feldman et al. 2011)

oxytocin administration can influence social

behavior in humans

(Kosfeld et al. 2005; Domes et al. 2007b; Guastella et al. 2008; Declerck et al. 2010),

In healthy humans, intranasal oxytocin was reported to increase

• in-group trust (reduce anxiety toward social stimuli)

• prosocial approaches (Kosfeld et al. 2005; Baumgartner et al. 2008; Andari et al. 2010),

• foster cooperation among unrelated persons (De Dreu et al. 2010; Rilling et al. 2012).

• recognition of emotional facial expressions (Kirsch et al., 2005; Bartz et al. 2010;

Hurlemann et al. 2010; Marsh et al., 2010)

• perceptual salience and/or processing of social cues (Bartz et al. 2011)

• greater empathic concern for conspecifics (MacDonald and MacDonald 2010)

• promotes gaze in the eye region (Guastella et al. 2008; Andari et al. 2010)

oxytocin abnormalities in ASD

Green JJ, Hollander E. Autism and oxytocin: new developments in translational approaches to therapeutics. Neurotherapeutics. 2010;7(3):250–257.

Early studies investigated the effects of oxytocin infusion.

reduced repetitive behaviors and improved affective speech comprehension

Hollander E, Bartz J, Chaplin W, et al. Oxytocin increases retention of social cognition in autism. Biol Psychiatry. 2007;61(4):498–503.

It shows promise as a drug targeting the core social and communication deficits in ASD

Tachibana M, Kagitani-Shimono K, Mohri I, et al. Long-term administration of intranasal oxytocin is a safe and promising therapy for early adolescent boys with autism spectrum disorders. J Child Adolesc Psychopharmacol. 2013;23(2):123–127

Stavropoulos KK, Carver LJ: Research Review: Social motivation and oxytocin in autism – implications for joint attention developmentand intervention. J Child Psychol Psychiatry 54:603–618, 2013

Guastella AJ, Einfeld SL, Gray KM, et al. Intranasal oxytocin improves emotion recognition for youth with autism spectrum disorders.

Biol Psychiatry. 2010;67(7):692–694.

Some parents report that they decided to administer the

compound themselves to their children affected by ASD

(Munesue et al. 2010; Kosaka et al. 2012)

Mancano ancora ampi studi controllati e le evidenze sono contrastanti ma…

Recent studies have focused on investigating social behaviors in ASD with intranasal oxytocin

Andari E, Duhamel JR, Zalla T, Herbrecht E, Leboyer M, Sirigu A. Promoting social behavior with oxytocin in high-functioning autismspectrum disorders. Proc Natl Acad Sci U S A. 2010;107(9): 4389–4394

Guastella AJ, Einfeld SL, Gray KM, et al. Intranasal oxytocin improves emotion recognition for youth with autism spectrum disorders.

Biol Psychiatry. 2010;67(7):692–694.

stronger interactions and increased eye gaze and social cognition

doses ranging from 12 to 48 IU

effetti avversi somministarzione intravenosa

restlessness, irritabilià, nausea, vomito, cefalea, irregolarità del polso

Somministrato per via intranasale non differisce dal placebo (MacDonald et al. 2011)

Review of 7 RCTs

the acute administration of oxytocin may produce potentially promising effects in neuropsychological measures that are related to the core symptoms of ASD

in particular repetitive behaviors and some indicators of dysfunctional social cognition (eye gaze and emotion recognition )

The improvement in social cognition was maintained after short-term administration of oxytocin (6 weeks)

…but the global clinical status of the patients was not affected

Preti et al, OXYTOCIN AND AUTISM: SYSTEMATIC REVIEW OF RCTSJOURNAL OF CHILD AND

ADOLESCENT PSYCHOPHARMACOLOGY Volume 24, Number 2, 2014

• Molecules whose mutations or polymorphisms are associated with ASD are in red.

• Stimulation and inhibitions are indicated by red and blue arrows, respectively

• Possible treatments and their target molecules are in orange boxes.

Signaling pathways and possible treatments associated with ASD

WonH,MahW,KimE.Autismspectrumdisordercauses,mechanisms,and treatments:focusonneuronalsynapses. FrontMolNeurosci (2013)

Guideline on

the management

of autism:

1] starting as early as possible;

2] minimizing the gap between diagnosis and treatment;

3] provide not less than 3/4 hours of treatment each day;

4] being centered on family involvement;

5] providing six-monthly development evaluations and updating the goals of treatment;

6] choosing among behavioral/developmental treatment depending on child's response;

7] encouraging spontaneous communication;

8] promoting the skills through play with peers;

9] finalizing the acquisition of new skills and to their generalization in natural contexts;

10] supporting positive behaviors rather than tackling challenging behaviors