DOUTORAMENTO

INVESTIGAÇÃO CLÍNICA E EM SERVIÇOS DE SAÚDE

Stereotypies in Autism Spectrum Disorder

Prevalence, clinical determinants, and kinematic analysis

Cláudia Melo

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2022
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Stereotypies in Autism Spectrum Disorder
Prevalence, clinical determinants, and kinematic analysis

Cláudia Raquel Ferrão de Melo

Porto, 2022

Tese de candidatura ao grau de Doutor apresentada à Faculdade de Medicina

da Universidade do Porto

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Art.º 48º, § 3º - “A Faculdade não responde pelas doutrinas expendidas na

dissertação.” (Regulamento da Faculdade de Medicina da Universidade do Porto

– Decreto-Lei nº 19337 de 29 de janeiro de 1931)

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 Orientadora Professora Doutora Teresa Maria Pereira Padrão Temudo

Professora Catedrática Convidada do Instituto de Ciências

Biomédicas Abel Salazar da Universidade do Porto

Co-orientadora Professora Doutora Guiomar Gonçalves Oliveira

Professora Associada com Agregação Convidada da Faculdade de

Medicina da Universidade de Coimbra

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Corpo Catedrático da Faculdade de Medicina da Universidade do Porto

Professores Catedráticos Efetivos

Doutor Patrício Manuel Vieira Araújo Soares Silva

Doutor Alberto Manuel Barros da Silva
Doutor José Henrique Dias Pinto de Barros
Doutora Maria Fátima Machado Henriques Carneiro
Doutora Maria Dulce Cordeiro Madeira
Doutor Altamiro Manuel Rodrigues Costa Pereira
Doutor Manuel Jesus Falcão Pestana Vasconcelos
Doutor João Francisco Montenegro Andrade Lima Bernardes
Doutora Maria Leonor Martins Soares David
Doutor Rui Manuel Lopes Nunes
Doutor José Manuel Pereira Dias de Castro Lopes
Doutor Joaquim Adelino Correia Ferreira Leite Moreira
Doutora Raquel Ângela Silva Soares Lino
Doutor Fernando Manuel Mendes Falcão dos Reis
Doutor Francisco José Miranda Rodrigues Cruz
Doutor José Paulo Alves Vieira de Andrade
Doutor Jorge Manuel Silva Junqueira Polónia
Doutor José Luís Dias Delgado
Doutora Isaura Ferreira Tavares
Doutor Fernando Carlos de Landér Schmitt
Doutor Acácio Agostinho Gonçalves Rodrigues
Doutora Maria de Fátima Moreira Martel
Doutor João Tiago de Sousa Pinto Guimarães
Doutor José Carlos Lemos Machado
Doutor José Carlos de Magalhães Silva Cardoso

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Professores Jubilados ou Aposentados

Doutor Alexandre Alberto Guerra Sousa Pinto

Doutor Álvaro Jerónimo Leal Machado de Aguiar
Doutor António Albino Coelho Marques Abrantes Teixeira
Doutor António Carlos de Freitas Ribeiro Saraiva
Doutor António José Pacheco Palha
Doutor António Manuel Sampaio de Araújo Teixeira
Doutor Belmiro Dos Santos Patrício
Doutor Cândido Alves Hipólito Reis
Doutor Carlos Rodrigo Magalhães Ramalhão
Doutor Cassiano Pena de Abreu e Lima
Doutora Deolinda Maria Valente Alves Lima Teixeira
Doutor Eduardo Jorge Cunha Rodrigues Pereira
Doutor Fernando Tavarela Veloso
Doutor Francisco Fernando Rocha Gonçalves
Doutora Isabel Maria Amorim Pereira Ramos
Doutor Jorge Manuel Mergulhão Castro Tavares
Doutor José Agostinho Marques Lopes
Doutor José Carlos Neves da Cunha Areias
Doutor José Eduardo Torres Eckenroth Guimarães
Doutor José Fernando Barros Castro Correia
Doutor José Manuel Costa Mesquita Guimarães
Doutor José Manuel Lopes Teixeira Amarante
Doutor Levi Eugénio Ribeiro Guerra
Doutor Luís Alberto Martins Gomes de Almeida
Doutor Manuel Alberto Coimbra Sobrinho Simões
Doutor Manuel António Caldeira Pais Clemente
Doutor Manuel Augusto Cardoso de Oliveira
Doutor Manuel Machado Rodrigues Gomes
Doutor Manuel Maria Paula Barbosa
Doutora Maria Amélia Duarte Ferreira
Doutora Maria da Conceição Fernandes Marques Magalhães
Doutora Maria Isabel Amorim de Azevedo
Doutor Rui Manuel Almeida Mota Cardoso
Doutor Rui Manuel Bento de Almeida Coelho
Doutor Serafim Correia Pinto Guimarães
Doutor Valdemar Miguel Botelho dos Santos Cardoso
Doutor Walter Friedrich Alfred Osswald

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Júri da Prova de Doutoramento

Doutora Isaura Ferreira Tavares (Presidente)

Faculdade de Medicina da Universidade do Porto

Doutora Belén Pérez Dueñas

Universitat Autònoma de Barcelona, Espanha

Doutor António de Quinhones Levy Gomes

Universidade de Lisboa

Doutora Teresa Maria Pereira Padrão Temudo (orientadora)

Instituto de Ciências Biomédicas Abel Salazar da Universidade do Porto

Doutor Fernando Alexandre Pereira Mendes

Instituto de Ciências Biomédicas Abel Salazar da Universidade do Porto

Doutor Luís Filipe Ribeiro Azevedo

Faculdade de Medicina da Universidade do Porto

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Esta tese foi desenvolvida no Centro Materno Infantil do Norte do Centro

Hospitalar Universitário do Porto, sob orientação da Professora Doutora Teresa

Temudo (Instituto de Ciências Biomédicas de Abel Salazar e Centro Hospitalar

Universitário do Porto), e coorientação da Professora Guiomar Oliveira

(Faculdade de Medicina da Universidade de Coimbra e Centro Hospitalar

Universitário de Coimbra).

Esta investigação foi financiada pelo Fundo Europeu de Desenvolvimento

Regional (FEDER) através do Programa Operacional Competitividade e

Internacionalização e por fundos nacionais através da Fundação para a Ciência

e a Tecnologia (PTDC/NEU-SCC/0767/2012, FCOMP-01-0124-FEDER-

029673).

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Ao abrigo do Art.º 8º do Decreto-Lei n.º 388/70, fazem parte desta tese as

seguintes publicações e manuscritos submetidos para publicação:

1. Melo C, Ruano L, Jorge J, Pinto Ribeiro T, Oliveira G, Azevedo L,

Temudo T. Prevalence and determinants of motor stereotypies in autism

spectrum disorder: A systematic review and meta-analysis. Autism. 2020

Apr;24(3):569-590.

2. Melo C, Pinto Ribeiro T, Prior C, Gesta C, Martins V, Oliveira G, Temudo

T. Motor stereotypies in autism spectrum disorder: Clinical random-sample

study and classification proposal. Autism. 2022:13623613221105479.

3. Melo C, Gonçalves N, Pinto Ribeiro T, Machado L, Cunha JP, Temudo

T. Clinical and kinematic analysis of hand stereotypies in autism

spectrum disorder, intellectual disability and Rett syndrome. Em

preparação para submissão.

Participei ativamente na definição dos objetivos de todos os trabalhos que

constituem esta tese, na aquisição dos dados dos estudos descritos nos artigos

1, 2 e 3, e fui responsável pela análise dos dados, interpretação dos resultados

e redação da versão inicial de todos os manuscritos.

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Agradecimentos

Ao meu Pai, que já não está comigo, mas está presente em todos os meus melhores

atos e pensamentos.

À minha Mãe, Irmã e Sobrinho, pelo apoio e amor incondicional.

À minha orientadora, Professora Teresa Temudo, por todo o apoio, por acreditar em

mim, por todas as aventuras que vivemos. Ensinou-me Neurologia Pediátrica, mas

acima de tudo a importância da observação. Despertou em mim o fascínio pelo

Autismo. No fim, ficou uma Amizade única.

À Professora Guiomar Oliveira, por tudo o que me ensinou sobre o Autismo e pelo

apoio e aconselhamento.

Ao Professor Luís Azevedo, por me inspirar a acreditar no meu trabalho e a continuar,

bem como por todo o apoio científico.

Ao Tiago, o meu grande colaborador, durantes muitas e longas horas de trabalho, por

me ter ajudado a ultrapassar os obstáculos, e pelo seu apoio pessoal e profissional.

A todos os colaboradores deste projeto pelo seu apoio e paciência.

Ao Marco e à Maria, as pessoas que trazem o arco-íris à minha vida e me fizeram

recomeçar a sonhar.

À Té, minha melhor amiga e “irmã mais nova”.

À Nani, minha melhor amiga, para sempre.

A todos os meus amigos, em especial aos de sempre e para sempre.

À Matilde e à Teresa, por todo o aconselhamento e apoio científico.

À Iva, que apareceu no meu caminho como uma estrelinha, por todo o apoio.

Aos doentes e às suas famílias por permitirem este trabalho.

A todos os que fizeram parte da minha vida e que tiveram o seu valioso papel.
Table of contents

ABBREVIATIONS................................................................................................................................... 1
ABSTRACT ............................................................................................................................................ 2
RESUMO .............................................................................................................................................. 6
1. INTRODUCTION......................................................................................................................... 12
1.1. AUTISM ...................................................................................................................................... 12
1.1.1. The autism history in review ............................................................................................... 12
1.1.2. Epidemiology of ASD........................................................................................................... 15
1.1.3. Risk factors and etiologies of ASD ...................................................................................... 16
1.1.4. Diagnosis of ASD and coexistent features .......................................................................... 18
1.2. MOTOR STEREOTYPIES .................................................................................................................. 21
1.2.1. Definitions .......................................................................................................................... 21
1.2.2. Epidemiology and natural history of stereotypies .............................................................. 22
1.2.3. Pathophysiology – insights from biochemical, animal, and human studies ....................... 24
1.2.4. Etiology – genes versus nature, or both?............................................................................ 27
1.2.5. Stereotypies’ classification ................................................................................................. 28
1.2.6. Stereotypies: to treat or not to treat .................................................................................. 30
1.3. STEREOTYPIES IN ASD ................................................................................................................... 31
1.3.1. Clinical determinants of stereotypies ................................................................................. 31
1.3.2. Clinical versus kinematic analysis of stereotypies .............................................................. 32
2. AIMS ......................................................................................................................................... 36
3. METHODS ................................................................................................................................. 38
4. PAPERS ..................................................................................................................................... 40
4.1. PREVALENCE AND DETERMINANTS OF MOTOR STEREOTYPIES IN AUTISM SPECTRUM DISORDER: A SYSTEMATIC
REVIEW AND META-ANALYSIS (PAPER I) .......................................................................................................... 40
4.2. MOTOR STEREOTYPIES IN AUTISM SPECTRUM DISORDER: CLINICAL RANDOMIZED STUDY AND CLASSIFICATION
PROPOSAL (PAPER II) .................................................................................................................................. 72
4.3. CLINICAL AND KINEMATIC ANALYSIS OF HAND STEREOTYPIES IN AUTISM SPECTRUM DISORDER AND INTELLECTUAL
DISABILITY (PAPER III) ................................................................................................................................. 92

5. DISCUSSION AND CONCLUSIONS ............................................................................................. 112

5.1. MAIN ACHIEVEMENTS ................................................................................................................. 112
5.2. DISCUSSION .............................................................................................................................. 115
5.2.1. Prevalence of motor stereotypies in ASD.......................................................................... 117
5.2.2. Stereotypies’ definition(s) and nomenclature................................................................... 118
5.2.3. Determinants of motor stereotypies in ASD ..................................................................... 119
5.2.4. Motor stereotypies classification...................................................................................... 122
5.2.5. Kinematic analysis ............................................................................................................ 125
5.2.6. Implications for clinical practice ....................................................................................... 125
5.2.7. Limitations ........................................................................................................................ 127
5.2.8. Future directions ............................................................................................................... 129
5.3. CONCLUSIONS ........................................................................................................................... 130
6. REFERENCES ...........................................................................................................................132
Abbreviations

ADI-R Autism Diagnostic Interview-Revised

ADOS-2 Autism Diagnostic Observation Schedule – second edition
AD Autistic disorder
ADDM Autism and Developmental Disabilities Monitoring
ADHD Attention Deficit and Hyperactivity Disorder
ASD Autism Spectrum Disorder
CDC Center for Disease Control and Prevention
CHUPorto Centro Hospitalar Universitário do Porto
CHUSJ Centro Hospitalar Universitário São João
CNVs Copy Number Variations
DD Developmental Delay
DSM Diagnostic and Statistical Manual of Mental Disorders
GQ General Quotient
GIQ Global Intelligence Quotient
ID Intellectual Disability
IQ Intelligence Quotient
M-CHAT Modified Checklist for Autism in Toddlers
NVIQ Non-verbal Intelligence Quotient
OR Odd ratio
PPD Pervasive Developmental Disorder
PDD-NOS Pervasive Developmental Disorder Not Otherwise Specified
RBS-EC Repetitive behavior scale for early childhood
RBS-R Repetitive behavior scale-revised
RTT Rett syndrome
VIQ Verbal Intelligence Quotient
WISC-III Wechsler Intelligence Scale for Children – Third Edition

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Abstract

Background

Motor stereotypies are one of the most frequently identified features in

people with autism spectrum disorder (ASD) and simultaneously one of the

least understood phenomena. Stereotypies can interfere on children's

functioning, and they are a major source of stress for families. When treatment

is indicated, it relies primarily on behavioral intervention and, more rarely, on

medication. A deeper understanding about the real prevalence of stereotypies,

its phenomenology, and determinants that influence their onset and severity,

can help to program monitoring and intervention.

Objectives, methods, and results

The global aim of this thesis was to contribute for a better understanding of

the prevalence and determinants of stereotypies in ASD. We also meant to

develop a model for classifying stereotypies and to contribute to the use of a

more clear and consistent nomenclature. The following paragraphs describe

the objectives defined for the thesis, along with the corresponding methods and

results.

. To estimate the reported prevalence and main determinants of motor

stereotypies in ASD

We performed a systematic review and a meta-analysis, to estimate the

reported prevalence of motor stereotypies in ASD and to explore the factors

that may influence this prevalence. Thirty-seven studies were included and the

median prevalence of motor stereotypies in ASD was 51.8%, ranging from

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21.9% to 97.5%. The most frequent determinants associated with a higher

prevalence of stereotypies in ASD were a young age, a low intelligence

quotient, and a higher severity of ASD. Moreover, sex did not seem to influence

the prevalence of stereotypies. Meta-analytic study showed that lower

intelligence quotient (IQ) and ASD diagnosis (independent of IQ) were

associated with a higher prevalence of motor stereotypies (odds ratio of 2.5 and

4.7, respectively).

. To describe the prevalence and determinants of motor stereotypies in a

randomized clinical sample of children with a diagnosis of ASD

One hundred and thirty-four children diagnosed with ASD (age 2.3−17.6 years;

79.1% male) were randomized from a sample of 309 individuals observed

during the year of 2013 at CHUPorto. The 134 participants underwent a

standardized protocol with video recording. Stereotypies were identified and

classified by two independent observers using a new classification model.

Clinical and demographic factors were analyzed to identify determinants of

stereotypies. The prevalence of stereotypies was 56.7%. A total of 1,198 motor

stereotypies were captured with a median of 5.5 stereotypies per session.

Univariate analysis identified an association between motor stereotypies and a

young age (OR=0.74), developmental delay or intellectual disability (OR=5.25),

being nonverbal (OR=0.06), epilepsy (OR=3.89), ADIR-A score (OR=1.17),

ADIR-C score (OR=1.25) and ADOS-2 score (OR=1.65). After multivariate

analysis, only young age (OR=0.76), being nonverbal (OR=0.11), ADIR-A

(OR=1.16) and ADOS-2 scores (OR=1.64) were associated with stereotypies.

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Being nonverbal and ADOS-2 severity score were also associated with a higher

number of stereotypies.

. To develop a clinical classification model for stereotypies

We developed a new operational classification model based on previous

classification frameworks and on the group experience. This model also

presents definitions for each classification factor and adds a glossary and video

samples of stereotypies morphologies. The classification model implies

distinguishing between primary and secondary stereotypies; topography (head,

hand/arm, foot/leg, trunk/body); and complexity (simple/complex) of motor

stereotypies. Also, hand/arm or foot/leg stereotypies may be classified

according to body position in midline or out of midline, laterality

(unilateral/bilateral), movement extension (small versus large), the presence or

absence of dystonic features, and the use of objects.

. To explore clinical and kinematic parameters of motor stereotypies in ASD

comparing to non-autistic children with DD/ID and RTT

We have designed a clinical and kinematic analysis protocol to study hand

stereotypies in a sample of 45 children divided into three groups: I - 20 children

with a diagnosis of ASD and ID; II – 15 children with a diagnosis of ID; III – 10

children with a diagnosis of Rett syndrome (RTT). Participants were recorded

during standardized sessions and two independent examiners reviewed the

videos, identified, and classified the hand stereotypies. Kinematic parameters

included velocity, acceleration, frequency, and amplitude of stereotypies. Hand

stereotypies in RTT group were more frequent, had longer duration, and were

more often performed in the midline comparingly with the ASD or ID groups.
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Hand stereotypies’ velocity, acceleration, and frequency were significantly

lower in the RTT group comparing to the ASD group.

Conclusions

In this thesis, we were able to provide new insights into the epidemiology

and determinants of motor stereotypies in patients with a diagnosis of ASD.

The wide range of reported prevalence of stereotypies found on our systematic

review and meta-analysis, is revealing of the ASD and stereotypies definitions

multiplicity, but also of the samples and studies methodology’s heterogeneity.

Through meta-analytical methodology we were able to ascertain a prevalence

value for motor stereotypies in ASD close to 50%. Our clinical randomized study

of stereotypies in ASD, based on DSM-5 criteria, reached a similar prevalence

value.

The main determinants for presenting stereotypies seem to be a young age and

the severity of ASD. In this thesis we also showed that language skills seem to

be associated with stereotypies. Population based studies or longitudinal

cohorts would be relevant to validate these findings.

We were able to develop a new clinical classification model, a glossary for

motor stereotypies and a sample set of videos, that may be used in clinical

practice and research. Altogether, the present thesis provides original data on

motor stereotypies and can help guide future research in the area, multicentre

prospective studies and clinical trials of interventions or drugs used in the

treatment of stereotypies. Additionally, the proposed classification model will

facilitate the approach to stereotypies in clinical practice.

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Resumo

Introdução

As estereotipias motoras são uma das características mais frequentes nas

pessoas com diagnóstico de Perturbação do Espetro do Autismo (PEA) e,

simultaneamente, um dos fenómenos menos compreendidos. As estereotipias

podem perturbar o desenvolvimento e o funcionamento das crianças, e são

uma importante fonte de stress para as famílias. Quando o tratamento é

necessário, baseia-se principalmente na intervenção comportamental e, mais

raramente, em medicação. Uma compreensão mais profunda sobre a

prevalência real das estereotipias, da sua fenomenologia, e dos determinantes

que influenciam o seu início e/ou severidade, pode ajudar na sua

monitorização e intervenção terapêutica.

Objetivos, métodos e resultados

O objetivo global desta tese foi o de contribuir para uma melhor

compreensão da prevalência e determinantes das estereotipias na PEA.

Pretendemos também desenvolver um modelo de classificação de

estereotipias e promover a utilização de uma nomenclatura mais clara e

consistente. Os parágrafos seguintes descrevem os objetivos definidos para a

tese, juntamente com os métodos e resultados correspondentes.

. Estimar a prevalência reportada e os principais determinantes das

estereotipias motoras na PEA

Realizámos uma revisão sistemática e uma meta-análise, com o objetivo de

estimar a prevalência de estereotipias motoras na PEA e de explorar os fatores

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que influenciam esta prevalência. Foram incluídos 37 estudos e a prevalência

mediana de estereotipias motoras na PEA foi de 51,8%, variando entre 21,9%

e 97,5%. Os determinantes mais frequentes associados a uma maior

prevalência de estereotipias na PEA foram uma idade mais jovem, um

quociente de inteligência (QI) mais baixo e uma maior severidade da PEA.

Adicionalmente, o sexo não pareceu influenciar a prevalência de estereotipias.

O estudo meta-analítico mostrou que um menor QI e o diagnóstico de PEA

(independente do QI) estão associados a uma maior prevalência de

estereotipias motoras (odds ratio de 2,5 e 4,7, respetivamente).

. Descrever a prevalência e os determinantes das estereotipias motoras

numa amostra clínica aleatorizada de crianças com diagnóstico de PEA

Foram aleatorizadas 134 crianças com diagnóstico de PEA (idade 2,3-17,6

anos; 79,1% do sexo masculino) a partir de uma amostra de 309 indivíduos

observados durante o ano de 2013 no CHUPorto. Os 134 participantes foram

submetidos a um protocolo estandardizado com gravação por vídeo. As

estereotipias foram identificadas e classificadas por dois observadores

independentes utilizando um novo modelo de classificação. Os fatores clínicos

e demográficos foram analisados para identificar os possíveis determinantes

de estereotipias. A prevalência de estereotipias foi de 56,7%. Foi captado um

total de 1198 estereotipias motoras, com uma mediana de 5,5 estereotipias por

sessão. A análise univariada identificou uma associação entre estereotipias

motoras e uma idade mais jovem (OR=0,74), atraso no desenvolvimento ou

perturbação de desenvolvimento intelectual (OR=5,25), ausência de

linguagem verbal (OR=0,06), epilepsia (OR=3,89), pontuação na ADIR-A

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(OR=1,17) e na ADIR-C (OR=1,25), e pontuação de severidade da ADOS-2

(OR=1,65). Após análise multivariada, apenas se associaram a estereotipias a

idade mais jovem (OR=0,76), ausência de linguagem verbal (OR=0,11),

pontuação na ADIR-A (OR=1,16) e a severidade na ADOS-2 (OR=1,64). Ser

não verbal e a pontuação de severidade na ADOS-2 também se associaram a

um número mais elevado de estereotipias.

. Desenvolver um modelo de classificação clínica para as estereotipias

Desenvolvemos um novo modelo de classificação operacional baseado em

esquemas de classificação anteriores e na experiência do grupo. Este modelo

apresenta também definições para cada fator de classificação e acrescenta um

glossário de morfologias e um conjunto de amostras de vídeo de estereotipias.

O modelo de classificação implica a distinção entre estereotipias primárias e

secundárias; e a identificação da topografia (cabeça, mãos/braços,

pés/pernas, tronco/corpo); e complexidade (simples/complexas) das

estereotipias motoras. Além disso, as estereotipias das mãos/braços ou

pés/pernas podem ser classificadas de acordo com a posição relativamente ao

corpo, na linha média ou fora da linha média, lateralidade

(unilaterais/bilaterais), amplitude do movimento (pequena versus grande),

presença ou ausência de características distónicas, e utilização de objetos.

. Explorar parâmetros clínicos e cinemáticos de estereotipias motoras na

PEA em comparação com uma amostra de crianças sem PEA, com atraso

de desenvolvimento psicomotor / perturbação do desenvolvimento

intelectual ou com síndrome de Rett

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Elaborámos um protocolo de análise clínica e cinemática para estudar

estereotipias das mãos numa amostra de 45 crianças divididas em três grupos:

I - 20 crianças com diagnóstico de PEA e atraso de desenvolvimento

psicomotor / perturbação do desenvolvimento intelectual (ADPM/PDI); II - 15

crianças com ADPM/PDI; III - 10 crianças com síndrome de Rett (RTT). Os

participantes foram gravados em vídeo durante sessões estandardizadas e

dois examinadores independentes reviram os vídeos, identificaram, e

classificaram as estereotipias das mãos. Os parâmetros cinemáticos incluídos

foram a velocidade, aceleração, frequência e amplitude. As estereotipias das

mãos no grupo RTT foram mais frequentes, com maior duração, e realizadas

mais frequentemente na linha média em comparação com o grupo de PEA ou

de ADPM/PDI. A velocidade, aceleração, e frequência das estereotipias das

mãos foram significativamente mais baixas no grupo de RTT em comparação

com o grupo de PEA.

Conclusões

Nesta tese, fornecemos novos dados sobre a epidemiologia e os

determinantes das estereotipias motoras em doentes com PEA. O vasto

intervalo de prevalência de estereotipias identificado na nossa revisão

sistemática e meta-análise, é revelador da multiplicidade das definições de

PEA e estereotipias, mas também da heterogeneidade das amostras e

metodologias dos estudos. Através de métodos meta-analíticos, conseguimos

determinar um valor de prevalência de estereotipias na PEA próximo dos 50%.

O estudo clínico com aleatorização de estereotipias na PEA, baseado nos

critérios do DSM-5, revelou um valor de prevalência semelhante.

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Os fatores que parecem determinar uma maior probabilidade de exibir

estereotipias parecem ser a idade mais jovem e a gravidade da PEA. Nesta

tese mostramos também que os níveis mais baixos de linguagem parecem

estar associados a estereotipias. Estudos de base populacional ou coortes

longitudinais serão relevantes para validar estes resultados.

Desenvolvemos um modelo de classificação clínica, um glossário de

estereotipias motoras e um conjunto de vídeos de estereotipias que poderão

vir a ser utilizados na prática clínica e na investigação.

No seu conjunto, a presente tese fornece dados originais sobre estereotipias

motoras e pode ajudar a orientar futuras investigações na área, estudos

prospetivos multicêntricos e ensaios clínicos de intervenções ou de fármacos

utilizados no tratamento de estereotipias. Adicionalmente, o modelo de

classificação proposto facilitará a abordagem às estereotipias na prática

clínica.

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1. Introduction

1.1. Autism

Talking about stereotypies in autism spectrum disorder (ASD) implies

looking into the evolution of the concepts of ASD over time. From being an

almost neglected area to the so-called “autism epidemic era”, a lot has

happened. From this foundation, we present a summary of the history of ASD,

as well as the state of the art of the epidemiology, the risk factors and etiologies,

diagnosis, and the comorbidities of ASD. Subsequently, the following sections,

describe the current knowledge about the pathophysiology, etiology,

epidemiology, and treatment of motor stereotypies. We also explore the present

knowledge of the determinants of stereotypies in ASD and data about their

natural history.

This thesis seeks to provide information to some of the many unanswered

questions regarding stereotypies and to promote uniformity in the terminology

and classification of stereotypies to facilitate their clinical and research

approach.

1.1.1. The autism history in review

The word autism is derived from the Greek word “autos” which means “self”.

Despite the etymological roots of the word autism, its concept has varied

considerably over the past century. The term autism was first coined in 1911

by a Swiss psychiatrist named Eugen Bleuler, to designate a symptom of

schizophrenia (1). He described autistic thinking as infantile thoughts that

aimed to avoid unsatisfying realities and replace them with fantasies. To

12
Bleuler, autism was an attempt to escape from symptoms of schizophrenia into

a state of profound self-absorption (1). In 1930, psychoanalytic theories

emerged connecting autism with social or emotional deprivation. This line of

thought welcomed as many followers as opponents until the 1940s, when the

first description of autism came close to the current one. This first report of

autism was described in 1943 by Leo Kanner, an Austrian child psychiatrist

working at Johns Hopkins Hospital at the time. In his paper, “Autistic

Disturbances of Affective Contact”, he presented 11 children who lacked the

predisposition to be social, and had “resistance to change” or “insistence of

sameness” (2). Almost coincidently, between 1938 and 1944, Hans Asperger,

an Austrian paediatrician, reported four cases of “autistic psychopathy of

childhood”, who had special abilities in some fields, such as mathematics, but

presented deficits on social and communication areas. He described this

condition as a spectrum, from individuals with severe intellectual disabilities and

behavioral problems, to children with extraordinary capabilities (3). In 1967,

Bruno Bettelheim, in his book “The Empty Fortress”, blamed autism on the

emotional coldness of “refrigerator mothers”. Unfortunately, this theory has

taken root for decades despite opposing concepts.

Subsequent studies by Kolvin (1972) and Rutter (1972) showed that autism

was different from schizophrenia or psychosis, regarding onset, clinical

features, and family history. The first studies of twins with autism suggested a

strong genetic basis (4). In 1978, Rutter presented a model for autism

classification that included marked social problems, language issues and

unusual behaviors and rigidities (5).

13
In 1980, infantile autism was finally recognized in the third version of the

Diagnostic and Statistical Manual of Mental Disorders (DSM), with a major

revision in DSM-III-R in 1987. Autism was then termed “autistic disorder” and

implied qualitative impairment in reciprocal social interaction and

communication, and restricted interests. Due to some problems with this

version, in 1994, another revision was presented in DSM-IV. According to DSM-

IV, pervasive developmental disorder (PDD) included: autistic disorder (AD),

Asperger’s disorder, pervasive developmental disorder not otherwise specified

(PDD-NOS), childhood disintegrative disorder and Rett’s disorder. One of the

criticisms raised with the DSM-IV criteria for ASD was the reduced diagnostic

stability before age three (6). Another issue was the validity of PDD subtypes.

Lord et al. (2011) reported that the assessment location influenced more the

diagnosis of Asperger syndrome than the children’s characteristics, suggesting

inconsistencies in diagnosis. Also, with genetic advances, PDD-NOS was

recognized as being at a milder point of the autism spectrum and Rett’s disorder

was taken off the list of PDD (7).

More recently, in 2013, the Neurodevelopmental Disorders Work Group

proposed a new concept for autism diagnosis, merging the previous PDD

subgroups into one group of ASD, and adding a related disorder named social

communication disorder. ASD encompasses the previously coined autistic

disorder, Asperger’s disorder, and PDD-NOS. In DSM-5, diagnosis of ASD

implies persistent impairment in the three areas of communication and social

interaction (social-emotional reciprocity, nonverbal communicative behaviors,

and relationships) and at least two of four types of restrictive or repetitive

14
behavior, such as motor stereotypies, echolalia, or highly restricted, fixated

interests. Information on etiology, severity, presence of intellectual impairment,

and the presence of catatonia should be added to complete the diagnosis.

1.1.2. Epidemiology of ASD

The prevalence of ASD has been an issue of growing interest for the clinical

and academic communities, but also for the general public and on social media.

Reports show an increased prevalence of ASD in the last two decades, giving

rise to the so-called “autism epidemic”.

Looking into the literature, we find a high variability in the prevalence of ASD

across the world, ranging from 1.76 per 1,000 in the Middle East, to 7.18 per

1,000 in North America (8). Differences inside the same continent are also

described, for example, the prevalence of ASD was 15.3 per 1,000 in Lebanon

and 1.1 per 1,000 in Iran; or 4.3 per 1,000 in Italy and 17.4 per 1,000 in Sweden

(8). The estimated prevalence of ASD is derived primarily from surveillance

systems or population studies, however methodological issues, such as case

identification methods (administrative, ad hoc, surveys based on

questionnaires), the population involved or case definition, may in part explain

this variability (8). A Swedish longitudinal prevalence study showed an increase

of almost 250% in prevalence, going from 4.2/1,000 in 2001 to 14.4/1,000 in

2011 (9). Data from the Centers for Disease Control and Prevention’s Autism

and Developmental Disabilities Monitoring (ADDM) network (CDC-ADDM)

revealed an increase of prevalence of ASD from 6.7/1,000 in 2000 to 18.5/1,000

children aged eight years in 2016 (8).

15
In Portugal, the estimated prevalence of ASD was 0.92/1,000 children in the

mainland and 1.56/1,000 in the Azores. This study was based on a national

school survey and included children between six and nine years old (10).

Considering the numbers presented, it is easily understandable that ASD is

associated with a substantial economic burden (11, 12). Therefore, basic,

clinical, and translational research will be required to better understand its

causes, to improve intervention and reduce its social and economic impact.

1.1.3. Risk factors and etiologies of ASD

ASD is not a disease. ASD is a behavioral and neurodevelopmental

syndrome. The pathophysiology behind the constellation of symptoms that

define ASD probably includes several mechanisms, neuronal networks, and

neurotransmitters. Currently, the influence of genetic factors on ASD is

undeniable. A recent meta-analysis of the data from studies of autistic twins

showed an estimated heritability between 64% and 91%, which is in agreement

with previous studies (13). This study also added that, even when shared

environmental effects become significant, they did not explain most of the

variance in ASD (13). Recently, a multinational population-based cohort study

followed 29,998 individuals with a diagnosis of ASD and monitored their older

siblings or cousins for an ASD diagnosis (14). They reported a 17.4-fold

increase in the risk of childhood ASD in children who had an older sibling with

childhood ASD, and a two-fold increase in the risk of cousin recurrence (14).

Since 2007, many de novo and rare copy number variants (CNVs) have been

associated with ASD risk (15). One of the hypotheses is that genes disrupted

16
by those CNVs disturb several neural networks, leading to broad phenotypic

manifestations (16). Satterstrom et al. (2020) performed exome sequencing of

11,986 individuals with a diagnosis of ASD and identified 102 risk genes. Most

of the risk genes have roles on gene expression regulation or neuronal

communication (17). CHD8 is the most reported gene in which these variants

are found (18, 19). Another fact suggesting the strong influence of genetics in

ASD is numerous well-known genetic conditions associated with an increased

risk of ASD, such as Fragile X syndrome (20), tuberous sclerosis complex (21)

or Angelman syndrome (22, 23).

Nevertheless, the less than 100% agreement in the ASD diagnosis of

monozygotic twins suggests an epigenetic or environmental influence (24).

Several environmental risk factors have been proposed from case control and

cohort studies. A recent systematic review explored the associations between

ASD and 119 possible environmental risk factors (25). Risk factors with higher

grade evidence were maternal age >= 35 vs. 25-29 years, maternal chronic or

gestational hypertension, being overweight during pregnancy, pre-pregnancy

maternal antidepressant use, and selective serotonin reuptake inhibitors use

during pregnancy. Also, higher paternal age, maternal autoimmune disease or

acetaminophen use during pregnancy were graded as highly suggestive.

Factors, such as prenatal or postnatal exposure to mercury, neonatal jaundice

or birth by caesarean section were considered to have weak evidence (25).

Rapin I. and Tuchman R. in their book “Autism: A Neurological Disorder of Early

Brain Development” advanced the theory that, in autism, multiple causes

converge on a common neuropathogenesis. This theory may explain why,

17
depending on the dysfunctional networks (involving a complex system of

neurons, neurotransmitters, and receptors), different cascading consequences

will affect different networks implicating certain symptoms or deficits (26).

Dementia might be a good example of a similar disease model, considering that

many different causes are associated with a neurological, cognitive, and

behavioral pattern.

1.1.4. Diagnosis of ASD and coexistent features

The diagnosis of ASD is based essentially on behavioral criteria (27).

Independently of the phenotypical heterogeneity, individuals with a diagnosis

of ASD must display deficits on two central core areas: social communication

and restricted, repetitive sensory–motor behavior (28). According to the

American Psychiatric Association’s DSM-5 criteria, the diagnosis of ASD

implies that the individual should have or has had deficits on the three social

communication subdomains (social–emotional reciprocity, non-verbal

communicative behaviors and in developing, maintaining, and understanding

relationships); and must have or has had problems in two of the four different

restricted, repetitive sensory–motor behaviors (stereotyped or repetitive motor

movements, use of objects, or speech; insistence on sameness; inflexible

adherence to routines; ritualised patterns of verbal and non-verbal behavior;

highly restricted, fixated interests that are abnormal in intensity or focus;

hyperreactivity or hyporreactivity to sensory input; or unusual interests in

sensory aspects of the environment) (28). Additionally, these deficits must have

started in the early developmental period (28).

18
Screening instruments like the Modified Checklist for Autism in Toddlers (M-

CHAT) allow an early diagnosis, between 16 and 30 months of age, and are

easily applicable to the clinical practice (29). Diagnosis of ASD can be

supported by diagnostic tools such as the Autism Diagnostic Observation

Schedule (ADOS) or the Autism Diagnostic Interview-Revised (ADI-R). ADOS

is a standardized observational scale, adaptable for language level and age,

where the clinician observes and characterises the behaviors of the individual

suspected to have ASD (30). The ADI-R is a structured interview with the

caregivers, focused on the developmental history of the child.

It is estimated that about 80% of children and adolescents with a diagnosis of

ASD in the US have at least one other developmental disorder, and 70% exhibit

a co-occurring psychiatric illness (31, 32). The most frequent comorbidities in

people with a diagnosis of ASD include developmental delay (DD) or ID, ADHD,

stereotypies, tics, epilepsy, mood disorders, obsessive-compulsive disorders,

anxiety disorders, disruptive behaviors, and sleep disorders. Intellectual

disability prevalence in ASD varies between 11 to 65% in school-age children,

reflecting the heterogeneity of the studies (33). It is estimated that among young

people with a diagnosis of ASD, about 39.6% have at least one anxiety

disorder, the most frequent being a specific phobia (29.8%) followed by

obsessive compulsive disorder (17.4%) and social anxiety disorder (16.6%)

(34).

Epilepsy is also a common comorbidity in ASD, with an estimated prevalence

ranging from 2.7 to 44.4% (35-38). Ewen JB et al. (2019) studied 6,975 children

with a diagnosis of ASD included in two cohorts, and found that ID was a factor
19
associated with epilepsy in children with a diagnosis of ASD, however language

impairment, score ASD symptom severity, and motor dysfunction were also risk

factors for epilepsy (39).

The coexistence of ASD and tics ranges from 9 to 12% and the co-occurrence

of ASD and Tourette Syndrome is around 4 to 5% (40). The prevalence of tics

in ASD appears to vary with the level of ASD severity, the sample size (smaller

sample sizes had higher prevalence rates), and with the recruitment setting

(population or clinic-based); and may be influenced by the difficulty in

distinguishing tics from stereotypies (40). Zablotsky et al. (2020) analyzed data

from the 2014 National Survey of the Diagnosis and Treatment of ADHD and

Tourette Syndrome to compare children diagnosed with ADHD with and without

ASD. According to this study one in eight children currently diagnosed with

ADHD were also diagnosed with ASD. Those children had more comorbidities

and needed more treatment (41).

Management of ASD is mainly focused on behavioral and educational

interventions. Clinicians should consider medications for the management of

comorbid conditions, such as epilepsy, anxiety disorders, mood disorders,

sleep disorders, ADHD, and disruptive behavior disorders (42). Feroe AG et al.

(2021) conducted a cohort study and reported that, among the 26,722

individuals with a diagnosis of ASD, polypharmacy (≥3 medications at a given

time) ranged from 28.6% to 31.5%. Between the 24 assessed medications, 15

were associated with at least a 15% prevalence of a mood disorder and 11

were associated with at least a 15% prevalence of attention-deficit/hyperactivity

20
disorder. They concluded that the use of prescription medications by US

clinicians varied and changed considerably (43).

1.2. Motor stereotypies

1.2.1. Definitions

Movement disorders are defined as “neurologic syndromes that include

impaired performance of voluntary movements, dysfunction of posture, the

presence of abnormal involuntary movements, or the performance of normal-

appearing movements at inappropriate or unintended times” (44). They may be

divided into hyperkinetic (tics, stereotypies, dystonia, chorea, myoclonus, and

tremor) and hypokinetic (parkinsonism). In children, hyperkinetic movement

disorders are far more common, with tics and stereotypies among the most

frequently occuring (45).

This thesis focuses only on stereotypies, since it is the most frequent movement

disorder in ASD and the least understood. The first definition of stereotypies

seems to date back to 1907, when Meige and Feindel in their book entitled:

''Tics and their Treatment'' identified repetitive movements other than tics and

defined them as "motor disturbances in which the characters of the muscular

contraction are identical with those of normal acts" (46). The definition of a

stereotypy has been controversial over time. According to Jankovic, a

stereotypy is an “involuntary or unvoluntary, coordinated, patterned, repetitive,

rhythmic, purposeless but seemingly purposeful or ritualistic movement,

posture or utterance” (47). The DSM-5 defines a stereotypy as a motor disorder

with onset in childhood involving repetitive, nonfunctional motor behavior, that

21
markedly interferes with normal activities or results in bodily injury that requires

medical treatment, stressing that the movement should be not better

accounted for by a compulsion or a tic (48). More recently Edwards et al. (2011)

proposed a new definition with the aim of establishing a more cohesive group

of conditions that may be linked by a common pathophysiology. According to

this group, a stereotypy should be defined as a “non-goal-directed movement

pattern that is repeated continuously for a period of time in the same form and

on multiple occasions, and which is typically distractible” (49). They argue that

this definition would allow to exclude brief intermittent movements reducing the

confusion between stereotypies and tics. Also, stereotypies are likely to be

confounded with mannerisms, dyskinesias or repetitive behaviors (49). In

addition, various terms have been used to designate stereotypies, such as

repetitive movements, repetitive motor behaviors, or stereotypic behavior,

sometimes leading to confusion with other types of repetitive behaviors.

1.2.2. Epidemiology and natural history of stereotypies

Children with typical development often show stereotypies in the first two

years of life (50, 51). In 1979, Thelen E. presented one of the most

comprehensive works on the analysis and taxonomy of stereotypies in typically

developing children, which continues to be one of the papers most cited in the

field. She observed 20 children longitudinally and identified 16,000 episodes of

stereotypies, corresponding to 47 movement patterns, involving the head,

hand/arm, foot/leg, and the whole torso. According to this work, children

showed a higher number of stereotypies by six months of age and this number

22
decreased significantly by 12 months old (50). Sifre R et al. (2021) collected

information from the Repetitive Behavior Scales for Early Childhood on 180

typically developing children and described that stereotypies (as well as other

repetitive motor and self-directed behaviors) displayed a linear decline from

eight to 36 months old (52).

It is estimated that approximately 7% of typically developing children may

exhibit stereotypies, which are called primary stereotypies (53). Harris et al.

(2008) followed a group of 100 children with primary stereotypies for up to 10

years and reported that stereotypies typically started under three years of age

and persisted for more than five years in 62% of participants (54, 55). In a group

of 49 typically developing individuals between the ages of nine and 20, primary

complex motor stereotypies started under the age of three in 98% and the

resolution rate was 2%, suggesting that this may be a chronic condition (56).

Freeman RD et al. (2010) studied a group of 41 children with primary

stereotypies and also reported that all stereotypies started before the age of

three (57).

Data on the epidemiology and natural history of secondary stereotypies is

scarcer. A systematic review reported an average prevalence of stereotypies

in developmental disorders of 61%, and of 88% in ASD (58). Bishop et al.

(2013) described that, in a sample of 1,825 children with a diagnosis of ASD,

the prevalence of stereotypies was 51% (59). Goldman et al. (2008) described

a prevalence of stereotypies of 70.6% in a low-functioning ASD group and

63.6% in a high-functioning ASD group (60). Many other examples could

23
illustrate the widely variable prevalence of stereotypies through literature,

demonstrating the need for more consistent data.

Although it is often described that secondary stereotypies appear typically

before the age of two and that they tend to persist during adulthood (61), it is

particularly difficult to find studies that demonstrate this data. Nevertheless,

stereotypies seem to be less frequent and less severe among older individuals

(62). A study based on a sample of 405 individuals between the ages of 10 and

53 years, used ADI-R to assess the pattern of ASD symptoms in adolescence

and adulthood, and reported that one quarter of those who previously

presented hand stereotypies were not currently symptomatic, showing a

tendency for stereotypies to decrease with age (63).

1.2.3. Pathophysiology – insights from biochemical, animal, and human studies

Stereotypies are not exclusive to humans, being frequently observed in

primates and other animals, such as mice and horses (64). In fact, most of the

information about the pathophysiology of stereotypies comes from animal

models.

The cortico-striatal-thalamic-cortical loop has been pointed out as the main

pathway associated with several movement disorders, such as tics and

Parkinson's disease, but also with stereotypies. This circuit includes two main

input structures, the striatum (caudate, putamen and nucleus accumbens) and

the subthalamic nucleus (STN). The striatum receives input from the cerebral

cortex and the pars compacta of the substantia nigra (SNc), while the STN only

24
receives input from the cortex. From the striatum come inhibitory signals to the

globus pallidus externus (GPe) that lead to disinhibition of the globus pallidus

internus (GPi) and in turn inhibition to the thalamus. These connections are

mediated by the dopamine receptor D2, adenosine A2A receptor, and the

muscarinic acetylcholine receptor M. Conversely, the striatum can also inhibit

the GPi resulting in disinhibition of the thalamus. The thalamus, has excitatory

connectivity with the cortex, thus establishing the cortico-striatal-thalamic-

cortical loop. These connections depend on the dopamine D1 receptor, the

adenosine A1 receptor, and the muscarinic acetylcholine M4 receptor. The

projections back through the thalamus to the cortex, form the motor,

associative, and limbic pathways.

Stereotypies may be induced by drugs that stimulate dopamine release,

dopamine reuptake inhibitors, or dopamine receptor agonists (65, 66). In a

study using the deer mouse model of spontaneous and persistent stereotypy,

the bilateral striatal infusion of NMDA or dopamine D receptor antagonists led

to a substantial reduction in jumping stereotypies without affecting non-

stereotypic motor behavior. These findings support the hypothesis that

stereotypies are a consequence of raised feedback activity at the motor circuits

of the basal ganglia (67). Aliane et al. (2011) showed that raclopride, a

dopamine D2 antagonist, stopped stereotypies when injected in the prefrontal

dorsal striatum, with no effect when injected in the sensorimotor area of the

dorsal striatum (66) Increased levels of extracellular dopamine in the dorsal

striatum were associated with diminished acetylcholine release within the

corticostriatal circuit of animals with drug induced stereotypies (66). The

25
severity of motor stereotypies seemed to correlate with this dopamine and

acetylcholine imbalance (66). Moreover, patients treated with risperidone, a

dopamine receptor D2 (DRD2) antagonist, showed a decrease in stereotypies

(68).

γ-Aminobutyric acid (GABA)ergic systems also seem to be associated with

stereotypies. Chao et al. (2010) reported that mice lacking Mecp2 from GABA

releasing neurons initially exhibit normal behavior, but later develop forepaw

stereotyped movements and compulsive grooming. In children with primary

complex motor stereotypies lower levels of GABA in the anterior cingulate

cortex and striatum were found compared to normal controls (69).

Stereotypies are also described in patients after autoimmune encephalitis,

post-infectious disorders, and strokes (70-72). In the Lausanne stroke registry,

7% of post-stroke hyperkinetic movement disorders were stereotypies (73). The

most frequent locations of strokes were parietal, lenticulo-striatal, thalamic,

midbrain, or left middle cerebral artery territory (73-76). Lesions were most

often unilateral with contralateral stereotypies (77).

Imaging data also support the involvement of the cortico-striatal-thalamic-

cortical loop in the genesis of stereotypies. Goldman et al., 2013, performed a

structural MRI study in children diagnosed with ASD and described a

decreased striatal volume in individuals with stereotypies (78). A reduced

bilateral caudate nucleus volume in individuals with primary stereotypies has

also been reported, adding an inverse correlation between symptom severity

26
and the volume of frontal and temporal white matter when adjusted for cerebral

size (79).

1.2.4. Etiology – genes versus nature, or both?

Over the years it has been debated whether stereotypies are the result of

psychogenic or neurobiological mechanisms. Some researchers, including our

group, believe that specific neurobiological mechanisms and genes are

implicated in the cortico-striatal-thalamic-cortical loop, but psychogenic

mechanisms may have an additional relevant role.

In contrast to tics, where genetic variants being a risk factor have already been

identified, genes or genetic variants that are associated with an increased risk

of developing stereotypies are not yet known. The high prevalence of motor

stereotypies in some genetic disorders, such as RTT, supports a central role

for genetics (80). It is striking that an Australian cohort study of 144 patients

with RTT reported that 94.4% presented hand stereotypies (81). Stereotypies

are frequent findings in many other genetic disorders, such as Wilson

syndrome, neuroacanthocytosis, Angelman syndrome, Fragile X syndrome,

Pitt-Hopkins syndrome, or congenital disorders of glycosylation (80, 82-87).

The positive family history of individuals with primary stereotypies also

strengthens this hypothesis (88). To date, the frequency of family history of

secondary stereotypies is unclear and should probably be analyzed accordingly

with the genetic etiology rather than overall.

The influence of environmental factors has been also extensively studied, with

social deprivation highlighted as a main risk factor for stereotypies (89). Kanner
27
considered that movements like hand flapping or body rocking were autistic

self-stimulatory behaviors to “maintain sameness”. According to his theory,

stereotypies improve sensory processing and attention by regulating brain

rhythms, either directly from the rhythmic motor command, or via rhythmic

sensory feedback generated by the movements (90). Stereotypies may be

mechanisms to preserve states of arousal to balance for sensorial deficits such

as deafness or blindness (91, 92). Other theories claim that stereotypies are

learned behaviors which are sustained through continuous reinforcement (91,

93); or that stereotypies are a consequence of arrested neurologic maturation

(50).

1.2.5. Stereotypies’ classification

Motor stereotypies may be classified as primary stereotypies when they

occur in typically developing individuals, or secondary stereotypies in the

setting of a neurological or developmental disorder (54). Although primary

stereotypies occur in children displaying a normal cognitive profile, more and

more literature reports that these children frequently present ADHD or language

problems (55, 94). Secondary stereotypies are historically associated with a

diagnosis of ASD, but they may be found also in individuals with DD/ID and

sensory disorders (53).

Disagreement begins with the subdivision into simple or complex stereotypies

since the definition of complex stereotypy is not consensual. Whereas simple

stereotypies are defined as single movements (e.g., tapping, clapping, body

rocking) (54), complex stereotypies consist of clusters of different single

28
coordinated movements, always performed in the same sequence, including

any simple hand/arm movement occurring with other movements that used

another group of muscles (facial, mouth, legs, body contortions) (95). Singer et

al. (2009) divides primary stereotypies into common, head nodding and

complex. Complex stereotypies include handshaking, posturing, waving, and

arms flapping, which, according to many authors, can be classified as simple

stereotypies. Therefore, authors present one definition of complex stereotypies

when we talk about primary stereotypies and another definition when referring

to secondary stereotypies.

The classification schemes for stereotypies have differed widely despite having

some common aspects. Goldman S et al. (2009) classified stereotypies into

eight types: face, head/trunk, arm/leg, hand/finger, hand/finger with an object,

gait, self-directed, and vision. They also added that stereotypies could be

characterized according to rhythmicity, laterality and topography (60). Later,

Goldman S and Temudo T (2012) applied a different classification framework

to a group of 20 children with RTT and 20 children with a diagnosis of ASD.

This framework was exclusively applied to hand stereotypies which could be

classified into simple or complex, and according to topography, amplitude and

rhythmicity.

Currently, a common operational classification model for stereotypies seems

essential to obtain comparable data, monitor responses to intervention or

medication and increase knowledge about the phenomenology of stereotypies.

29
1.2.6. Stereotypies: to treat or not to treat

Stereotypies can interfere with social interaction and the performance of

activities of daily living (96-98). They also seem to be an important stressor for

families (99, 100). Treatment of stereotypies is usually encouraged when

stereotypies are self-injuring or disabling (54). A behavioral approach is

typically preferred however, it is limited by the availability of human and

technical resources. Methods include mechanical restraints, response

blocking, habit reversal and differential reinforcement of other behaviors,

response interruption and redirection (54).

Pharmacological treatment may involve the use of antipsychotics, such as

risperidone, aripiprazole, or clonidine, however the potential adverse effects

must be taken into consideration (45). Risperidone has been proved to be

beneficial in the decrease of stereotypies in children with a diagnosis of ASD

(101, 102). Aripiprazole can also be effective as a short-term medication

intervention for stereotypies in children with a diagnosis of ASD (103). Patients

with stereotypies post-stroke may be treated with benzodiazepines,

amantadine, and anticholinergics (75). Tetrabenazine has been used in the

treatment for stereotypies and tics associated with dementia and Tourette

Syndrome (104, 105).

In the next sections, we will discuss challenges and relevant research questions

that pertain to stereotypies in ASD.

30
1.3. Stereotypies in ASD

1.3.1. Clinical determinants of stereotypies

Although stereotypies are not unique to ASD, it is recognized that they are a

frequent finding in individuals with this diagnosis. In this context, several

research groups over the past few years have tried to identify factors that may

explain an increased risk of stereotypies in ASD. The most frequently

suggested factors are the age, IQ, sex, ASD diagnosis and ASD severity.

Several studies point to an association between motor stereotypies and a

young age (106-109). A lower nonverbal intelligence quotient (NVIQ) seems to

be associated with a higher chance of exhibiting stereotypies (60, 61, 106, 110-

113). However, recently a cohort of children with a diagnosis of ASD from

preschool age to 11 years of age did not show an association between NVIQ

and ADI-R items related with stereotypies (114). Regarding sex, most of the

studies failed to identify a significant association between sex and stereotypies

(61, 108, 115, 116).

Comorbidities of ASD, such as epilepsy, ADHD and anxiety disorder, among

others may also represent determinants of stereotypies. A possible association

between epilepsy or ADHD and stereotypies has not been explored. Baribeau

DA et al. studied a longitudinal cohort of 421 children with a diagnosis of ASD,

comparing restricted/repetitive behavior severity from ADI-R with the anxiety

symptoms defined by a Child Behavior Checklist. They reported that moderate

and severe restricted/repetitive behavior were both associated with increased

odds of elevated anxiety (117).

31
Stereotypies seem to be preceded or exacerbated by triggers. Harris et al.

(2008) studied a sample of 100 typically developing children with motor

stereotypies and reported that the most frequent trigger was excitement,

followed by engrossment, anxiety/stress and tiredness (55). In secondary

stereotypies the same triggers have been reported.

1.3.2. Clinical versus kinematic analysis of stereotypies

The identification and characterization of motor stereotypies in children has

traditionally been carried out by indirect methods, such as questionnaires or

interviews with caregivers, or direct methods like observation during

evaluations with or without video recording.

The instruments most frequently reported in the literature are the repetitive

behavior scale-revised (RBS-R) (118) and the repetitive behavior scale for early

childhood (RBS-EC) (119). These instruments are validated for the ASD

population and consist in questionnaires measuring repetitive behaviors in

which stereotypies are included. Diagnostic scales for ASD, such as the ADOS

(120, 121) or the ADI-R (122), also aim to identify whether children present

stereotypies or not. When applying the ADOS, the examiner observes if the

child exhibits stereotypies during the assessment and whether they are

infrequent or very frequent. During ADI-R, the caregiver is asked about the

previous or current existence of stereotypies. One of the problems with

questionnaires is the subjectivity since respondents may not identify

stereotypies or may overstate them. In addition, they do not give an accurate

idea of the frequency of stereotypies or their characteristics.

32
Direct assessments using video have the advantage of allowing the

assessment in a natural context and the reviewing of the recorded data.

Additionally, video recording, allows to characterize and classify the

stereotypies by one or more raters. Possible disadvantages of this methodology

include the fact that they are time and resource consuming.

Hence, there is a need for more efficiently and objective methods for measuring

and monitoring stereotypies in naturalistic settings. More recently, kinematic

analysis techniques have emerged allowing to collect the information in a

blinded fashion with higher objectivity. These methods also allow to extract

information that cannot be accurately extracted by observation such as velocity

or amplitude of movements.

Kinematic analysis is the study of motion without regard to the forces that cause

it (123). Movement analysis technology systems are currently used in several

fields of medicine to identify and monitor movement patterns, including gait

problems (123-126), tremor (127), epilepsy (128). Several research groups

have been working on systems that can automatically identify motor

stereotypies. The most used systems for movement acquisition include marker-

based motion capture systems, equipment which integrate different sensor

types attached to the individual body, and marker-free motion capture systems

such as Kinect and Xtion (129). Accelerometers and pattern recognition

algorithms have also been used to identify and monitor stereotypies in ASD

(129, 130). Gonçalves N et al. (2012) developed a methodology to

automatically detect stereotypies in individuals with a diagnosis of ASD, using

the Microsoft Kinect sensor and gesture recognition algorithms. They studied
33
nine children with a diagnosis of ASD and showed that Kinect sensor detected

in 83% of the stereotypies (131). The Kinect sensor implies that the participants

are close to the sensors. An alternative would be more wearable 3-axis

accelerometers. Min et al. (2010) collected three-axis acceleration data from

the wrists and torso of four individuals with a diagnosis of ASD and they

achieved highest accuracy rates of 93.5% for flapping, and 95.5% for rocking

(132). Goodwin et al. gathered three-axis acceleration data from the wrists and

torso of six individuals with a diagnosis of ASD and reported an overall

recognition accuracy of 88.6% (130). Gilchrist et al. (2018) used a commercially

available accelerometers attached to the body and a generalizable detection

algorithm with a sensitivity of 93% for hand flapping, and 80% for body rocking

(133). Both methodologies implied the tolerance of wearable devices, which

may be a problem due to sensorial hyper or hyposensitivity, or even due to the

cognitive impairment and the afraid from those equipment’s.

Motor stereotypies go far beyond hand flapping or body rocking and to date

there are no accelerometers and pattern recognition algorithms prepared to

recognize the wide range of stereotypy types. Moreover, one of the great

potentials of these technologies may be the identification of patterns of velocity,

frequency, amplitude, or even topographic location of stereotypies. Over time,

some attempts have been made to identify whether there are characteristics of

stereotypies in ASD that allow them to be distinguished from stereotypies in ID.

Other studies tried to identify distinguishing characteristics of stereotypies in

certain genetic disorders. Goldman et al. (2008) reported that a group of

children with a diagnosis of ASD displayed a wider variety of stereotypies

34
comparing to the groups with DD and language disorder (60). Goldman S and

Temudo T (2012) compared a group of 10 autistic children and 10 children with

RTT and found that stereotypies in RTT were predominantly continuous and at

the midline, whereas in ASD, they were intermittent and away from the body

(134). Wright M et al. (2003) studied the hand movements of a 10-year girl with

RTT using a computerized motion analysis system and compared to a video

when she was 3 years of age which showed the same kinematic characteristics

(135). With these results, authors suggested that automated video analysis

could be useful for screening and intervention evaluation.

35
2. Aims

The global aim of this thesis is to contribute for a better understanding of the

prevalence and determinants of motor stereotypies in ASD by using a

systematic review and meta-analysis, a clinical randomized study, and a clinical

and kinematic study.

The specific objectives are the following:

1. To estimate the reported prevalence of motor stereotypies in ASD (Paper I)

2. To identify the main reported determinants of motor stereotypies in ASD

(Paper I)

3. To describe the prevalence and determinants of motor stereotypies in a

randomized sample of children with a diagnosis of ASD (Paper II)

4. To identify, name and classify motor stereotypies in a randomized sample

of children with a diagnosis of ASD (Paper II)

5. To develop a new operational model for the classification of stereotypies

that combines tools useful in clinical practice and research (Paper II)

6. To identify clinical and kinematic parameters that may help to distinguish

motor stereotypies in individuals with and without a diagnosis of ASD (Paper

III)

36
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3. Methods

This thesis includes several studies with different research methodologies

and study designs. The work was conducted with the support of a

multidisciplinary team and involved different research institutions. We present

a brief overview of the methods for each of the studies. The detailed methods

will be described along with the papers.

In Paper I we describe the prevalence of motor stereotypies in ASD and the

main determinants of motor stereotypies in ASD based on a systematic review

and meta-analysis study.

In Paper II we studied the prevalence of stereotypies in a randomized sample

of children with a diagnosis of ASD, using the videorecording of participants

during a standardized session and an extensive clinical evaluation protocol. We

characterized the stereotypies according to a new stereotypy classification

model. We also present a glossary of stereotypy types to aid in the

reproducibility of the assessments. We compared the individuals with and

without motor stereotypies to understand if the determinants reported in the

literature behaved as determinants of stereotypies in our sample. In this context

we also intended to identify other possible clinical determinants of stereotypies.

In Paper III we analyzed the motor stereotypies of three different groups: ASD,

ID and RTT. We conducted a clinical characterization of their stereotypies

based on our stereotypies classification model and used a kinematic analysis

protocol to study and compare the kinematic parameters of the stereotypies.

38
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4. Papers

4.1. Prevalence and determinants of motor stereotypies in autism

spectrum disorder: a systematic review and meta-analysis (Paper I)

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4.2. Motor stereotypies in autism spectrum disorder: Clinical

randomized study and classification proposal (Paper II)

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4.3. Clinical and kinematic analysis of hand stereotypies in autism

spectrum disorder and intellectual disability (Paper III)

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Title: Clinical and kinematic analysis of hand stereotypies in autism spectrum disorder,

intellectual disability and Rett syndrome

Authors and affiliations:

Cláudia Meloa,b
a
Child Neurology Unit, Pediatric Department, Centro Hospitalar Universitário São João, Porto

Portugal.
b
Centre for Health Technology and Services Research (CINTESIS) & Department of

Community Medicine, Information and Health Decision Sciences (MEDCIDS), Faculty of

Medicine, University of Porto, Porto, Portugal.

Tiago Pinto Ribeiroc

c
Child and Adolescent Psichiatry and Mental Health Department, Centro Materno-Infantil do

Norte, Centro Hospitalar Universitário do Porto, Porto, Portugal.

Nádia Gonçalvese
e
Institute for Systems Engineering and Computers - Technology and Science (INESC TEC),

and Faculty of Engineering (FEUP), University of Porto, Porto, Portugal.

Leandro Machadof,g
f
Center of Research, Education, Innovation and Intervention in Sport (CIFI2D), Faculty of

Sport, University of Porto, Porto, Portugal.

g
Porto Biomechanics Laboratory (LABIOMEP-UP), University of Porto, Porto, Portugal.

João Paulo Silva Cunhae

e
Institute for Systems Engineering and Computers - Technology and Science (INESC TEC),

and Faculty of Engineering (FEUP), University of Porto, Porto, Portugal.

Teresa Temudoh,i

94
h
Child Neurology Unit, Centro Materno-Infantil do Norte, Centro Hospitalar Universitário do

Porto, Porto, Portugal.

i
Instituto de Ciências Biomédicas Abel Salazar, University of Porto, Porto, Portugal.

Corresponding author:

Cláudia Melo

Rua Professor Correia de Araújo, n738, 2º esq, 4200-205, Porto, Portugal

crferrao.melo@gmail.com

Present address:

1 - Pediatric Department, Centro Hospitalar Universitário São João, Porto, Portugal

95
Abstract

Background: Motor stereotypies are typically associated with autism spectrum disorder (ASD)

and with intellectual disability (ID). There seem to be some differences between the

stereotypies of individuals diagnosed with ASD and ID. The present study aimed to describe

and compare the clinical and kinematic characteristics of hand stereotypies in individuals

diagnosed with ASD, ID and Rett syndrome (RTT).

Methods: A total of 45 patients, with a median age of 11.28 years-old, were included in the

study; among them, 60% were female. They were organized into 3 groups: I - 20 children with

ASD and ID; II – 15 children with ID; III – 10 children with RTT. Participants were filmed during

standardized sessions in which the ADOS-2 tool was administered. Two independent

examiners reviewed the videos, identified, and classified the hand stereotypies. Kinematic

parameters of hand stereotypies included: velocity (cm/s2); acceleration (cm/s3), frequency (Hz)

and amplitude (cm3).

Results: Hand stereotypies in the RTT group were more frequent, with longer duration, and

more often performed in the midline comparing to the ASD or ID groups. Velocity, acceleration,

and frequency were significantly lower in RTT comparing to the ASD group.

Conclusions: This study showed relevant differences between clinical and kinematic features

of stereotypies in RTT comparing to ASD. Stereotypies’ distinctive features between ASD and

ID remain to be confirmed. Future studies may use kinematic and clinical analysis to compare

motor stereotypies between etiological subgroups.

Key-words: Autism Spectrum Disorder, Intellectual Disability, Rett syndrome, Stereotypies,

Kinematic analysis

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Introduction

Motor stereotypies are hyperkinetic movement disorders, defined as repetitive, patterned,

coordinated, involuntary, and rhythmic seemingly purposeless movements (54). Even though

motor stereotypies are traditionally associated with autism spectrum disorder (ASD), they may

be also found in individuals with developmental delay (DD), intellectual disability (ID), sensorial

deficits and in typically developing children (88, 136). Motor stereotypies have been reported

in some specific genetic disorders such as Rett syndrome (RTT), fragile X syndrome, STXBP1

encephalopathy with epilepsy, Angelman syndrome, among many others (80, 137-140). The

pathophysiology of stereotypies is still unknown, however it seems to be related to the

dopaminergic pathways and cortical-striatal-thalamo-cortical brain circuit (141). Stereotypies

can interfere with the individual's performance in activities of daily living and social interaction,

as well as being a relevant stress factor for families (142). Their identification and follow-up

may allow monitoring the impact of pharmacological or behavioral treatment.

Most studies describing stereotypies are based on questionnaires or interviews applied to

caregivers or through observation of children using instruments measuring repetitive behaviors

such as repetitive behavior scale-revised (RBS-R) (118) or repetitive behavior scale for early

childhood (RBS-EC) (119). Other instruments frequently used to measure stereotypies include

Autism Diagnostic Observation Schedule version 2 (ADOS-2) (120) or Autism Diagnostic

Interview-Revised (ADI-R) (122). These methods are supported by information obtained from

caregivers which can be subjective and biased. Also, these tools identify the presence of

stereotypies without giving additional information about their features. Studies based on video

recording allow the evaluators to review the assessments, can improve their identification and

allow a more detailed characterization of the stereotypies. This option is however more

resource and time consuming. Hence, there is a need for a more efficiently and objective

method to measure and monitor stereotypies in the natural context.

Kinematic analysis allows to collect information in a blinded fashion with higher objectivity and

to extract data, such as velocity or amplitude of the movements, that cannot be accurately

obtained by direct observation. Kinematic analysis is the study of motion without regard to the

forces that cause it (123). Movement analysis technology systems are currently used in several

97
fields of medicine to identify and monitor movement patterns. Gait analysis is one of the areas

in which kinematic analysis has had the greatest applicability, both in research and in clinical

practice (123-126). Tremor frequency, for example, may help distinguish between essential

tremor and Parkinson’s tremor, which have frequency ranges of 5-12 Hz and 3-6 Hz

respectively (127). In epilepsy, kinematic analysis can be used for quantitative analysis of

seizure patterns in epilepsy monitoring units (128).

Regarding motor stereotypies, automatic systems may allow to detect and characterize

stereotypies. Systems for movement acquisition include marker-based motion capture (mocap)

systems (which integrate sensor types attached to the individual body), and marker-free mocap

systems such as Kinect and Xtion (129). Accelerometers and pattern recognition algorithms

have also been used to identify and monitor stereotypies in ASD (130, 143). Gonçalves N et

al. (2012) developed a methodology to automatically detect stereotypies in individuals with

ASD, using the Microsoft Kinect sensor and gesture recognition algorithms. They studied nine

children with ASD and showed that Kinect sensor detected in 83% of the stereotypies (131).

The Kinect sensor implies that the participants are close to the sensors therefore an alternative

would be wearable three-axis accelerometers. Min et al. (2010) collected three-axis

acceleration data from the wrists and torso of four individuals with ASD and they achieved

highest accuracy rates of 93.5% for flapping, and 95.5% for rocking (132). Goodwin et al.

gathered three-axis acceleration data from the wrists and torso of six individuals with ASD and

reported an overall recognition accuracy of 88.6% (144). Gilchrist et al. (2018) used a

commercially available accelerometers attached to the body and a generalizable detection

algorithm with a sensitivity of 93% for hand flapping, and 80% for body rocking (133). These

methodologies imply that participants tolerate the equipment. This can be an obstacle since

individuals diagnosed with ASD often present with sensorial hyper or hyposensitivity, cognitive

impairment and may be afraid to use these wearable equipment’s. Motor stereotypies go far

beyond hand flapping or body rocking and, to date, there are no accelerometers or pattern

recognition algorithms prepared to recognize the wide range of stereotypies morphologies so

there still seems to be a long way to go in this area.

98
One of the great potentials of these technologies may be the identification of patterns of

velocity, frequency, amplitude, or even topographic location of stereotypies. This knowledge

may help to identify whether there are characteristics of stereotypies in ASD that allow to

distinguish them from the stereotypies in ID.

Goldman S and Temudo T (2012), compared a group of 10 children with ASD and 10 children

with Rett syndrome (RTT) and found that stereotypies in RTT were predominantly continuous

and at the midline, whereas in ASD, they were intermittent and away from the body (134).

Wright M et al. (2003) studied the hand movements of a 10-year girl with RTT using a

computerized motion analysis system and compared to a video when she was 3 years of age

which showed the same kinematic characteristics (135). With these results, the authors

suggested that automated video analysis of stereotypies could be useful for screening and

intervention evaluation.

Our group aimed to develop a methodology that combines the identification of hand

stereotypies by trained examiners, their clinical classification and kinematic characterization.

The aim of the study was to compare hand stereotypies between a group of individuals with

ASD and ID, a group of individuals with ID (non-autistic and non-RTT) and a third group of

individuals with RTT.

Patients and Methods

Participants

Participants were recruited in the Child Neurology and Child Psychiatry Clinics of a tertiary

health center. We randomly selected 20 individuals with a diagnosis of ASD and ID, from a

cohort of patients diagnosed with ASD (145). In addition, we recruited 15 non-autistic children

with ID and 10 children with clinical and molecular diagnosis of RTT. All participants had

previously been identified as having motor hand stereotypies.

This work was carried out in accordance with the ethical standards of the responsible committee

on human experimentation and with the Declaration of Helsinki as revised in 2000. Parents or

tutors of all the participants signed an informed consent allowing participation and use of the

images.

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Evaluation protocol

Participants were evaluated by a multidisciplinary team composed by a child neurologist, a

child psychiatrist, a pediatrician and two clinical psychologists. ASD diagnosis was reevaluated

by the review of DSM-5 criteria, administration of the ADOS-2 and ADI-R. Developmental delay

and intellectual disability were confirmed through the application of Griffith’s Mental

Development Scale, for children younger than 6-years-old and Wechsler Intelligence Scale for

Children III (WISC-III) or Wechsler Preschool and Primary Scale of Intelligence (WPPSI) for

those 6-years-old or older. All the patients with RTT fulfilled the revised criteria for Rett

syndrome (146).

The clinical evaluation of participants included an interview and a neurological evaluation. In

the clinical interview children’s past medical history; comorbidities (febrile seizures, epilepsy,

sleep problems, ADHD, self-aggressivity, developmental delay, learning disorder, intellectual

disability); language; drug history; and family history of neurological or psychiatric disorders

were retrieved.

Video protocol

Participants were filmed during the administration of ADOS-2 tool, always on the same

room, with a uniform environment to ensure the reproducibility of the physical stimulus (a room

with green wallpaper and floor, one table, three chairs, ADOS-2 equipment and four

synchronized partially hidden video cameras). Videos were independently reviewed and

analyzed by two researchers to identify the hand stereotypies during the first 30 minutes of

ADOS-2. The diagnosis of stereotypy implied: 1) repetitive, purposeless, rhythmic movements

with a fixed pattern; 2) movements not better characterized as tics; 3) presence for a minimum

of 4 months. Also, to be classified as a stereotypy, the movement had to be seen at least twice

in each session, to meet the distinctive feature of repetitiveness implied in the definition of

stereotypy. The motor stereotypies were classified according to a classification model

developed by the group (145).

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Kinematic analysis

We used a three-dimension (3D) acquisition system, composed by four Red, Green and

Blue (RGB) cameras GoProÒ Hero3+ with liquid crystal displays (LCD) screens attached, one

Wi-Fi remote and a local workstation to save the videos and upload them to the server.

Resolution was set to 1080p (1920x1080 pixels) and framerate to 48frames/s. We developed

high-brightness light emitting diode (LEDs) for use in children that would allow markers to be

placed on their bodies to use an automatic tracking algorithm. These LEDs, with a size of

around 3x3x1,5 cm, were attached to their jugular notch, elbows, radio (distal epiphysis) and

to the middle finger (interphalangeal joint). Videos were synchronized based on the audio’s

signal pattern between cameras. Each video was cut to remove the delays and exported

through MATLAB R2015a (The Mathworks, Inc.) and the library of FFmpeg. To convert pixel

coordinates to the 3D world coordinates space, we used a static calibration approach. After

room calibration, stereotypies tracking was performed using a 4-cameras optic system and

semi-automatic tracking software (Maxtraq 2D and 3D). The segments with stereotypies were

cropped from the videos and analyzed. The output files were analyzed using a custom, made

program, running on Matlab platform. The manual tracking option was required when the

children did not tolerate the LED’s markers. During the tracking step, each marker was digitized

at least two times in different views for the 3D reconstruction. Two experts validated every point

digitized either by a manual or an automatic tracking. Reconstruction of the 3D real coordinates

of points corresponding to each tracking point was performed with MaxTRAQ 3D. The velocity

is defined as the number of centimeters traversed by second (cm/s); acceleration is the rate of

change of the velocity by second (cm/s2), frequency corresponds to the number of times that

the stereotypy is executed per time unit (Hz), amplitude is the volume covered by each

stereotypy (cm3) and correlation measures the movement dependence between the left and

right side. For each one of these kinematic quantities, the following features were extracted:

maximum, median, minimum, energy, and median standard deviation (MAD). MAD is a more

robust feature to measure the values dispersion and less sensible to outliers than standard

deviation (29). The amplitude was measured mainly by the volume occupied by the

101
stereotypies. We focused our kinematic analysis only in hand stereotypies (middle finger -

interphalangeal joint) to validate our method.

It was agreed whenever the participants presented more than five stereotypies, we proceeded

to the randomized selection of half of their stereotypies to proceed to their analysis.

Nevertheless, some of the selected stereotypies could not be analyzed due to factors such as

visualization hampered by obstacles or inadequate marking or automated caption. Kinematic

analysis was performed with blinding for the diagnosis.

Statistical analysis

Quantitative data was summarized by means ± SD when there was a normal distribution or

by median and range values. Categorical data were summarized by absolute and percent

frequencies. Group differences for demographic, clinical and neuropsychological measures

were explored using unequal variance t-tests for continuous variables and χ2 analyzes for

categorical variables. Fisher’s exact test was used in cases of small cell counts. For group

comparisons and correlations, assumptions for parametric analyzes were assessed using

Kolmogorov–Smirnov tests for normality of distributions, with non-parametric analyzes used as

indicated. Significance was set at p<0.05. Statistical analyzes were performed using SPSS

24.0.

Results

The main demographic and clinical characteristics of the 45 participants are depicted in

Table 1. The group of individuals with RTT has some core characteristics related to the

syndrome, namely the fact that the group was composed only of females; and, since the

participants were non-verbal, the non-verbal IQ was considered lower than 20 and IQ values

were not compared. Epilepsy was significantly more common in the RTT group (p<0.05). The

group of children with ASD was younger than the others (p<0.05) (Table 1).

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Clinical characteristics of hand stereotypies

The participants showed a total of 956 hand stereotypies. The total number of stereotypies

was not significantly different between groups (p=0.895). The number of stereotypies per

minute was higher in RTT group compared to ASD and ID groups (both with p <0.05) (Table

2). The median duration of each stereotypy and the total stereotypies duration were also higher

in RTT group compared to the other two (Table 2).

The morphologies of stereotypies were more diverse in the group of ID comparing to the group

of RTT. Stereotypies with an object were less frequent in the RTT group (Table 2).

In RTT, stereotypies were mainly bilateral, performed at the midline and simple (Table 2).

Simple stereotypies were more frequent in ASD than in ID (p<0.05). No additional differences

with statistically significant values were identified between the stereotypy’s characteristics of

ASD and ID groups.

Kinematic characteristics of hand stereotypies

Kinematic analysis was performed on 337 hand stereotypies, which corresponded to 35%

of the total number of stereotypies. The number of stereotypies analyzed per participant ranged

from 5 to 16, with a median value of 6 stereotypies. The number of stereotypies for which it was

possible to perform kinematical analysis was similar among the three groups (p= 0.119).

Stereotypies of ASD group exhibited greater velocity and acceleration comparing to ID and

RTT groups (p=0.008 and p<0.001 respectively). Acceleration was also higher in ID group

comparing to RTT group (p=0.036).

The frequency of stereotypies was lower in RTT group when compared to ASD and ID groups

(p=0.001 and p=0.023, respectively). The amplitude of the stereotypies did not differ with

statistically significant values; however, it tended to be higher in ASD group (Table 3).

Discussion

At the best of our knowledge, this is the first study which used a clinical and kinematic

analysis to characterize and compare hand motor stereotypies in individuals with ASD, ID and

RTT.

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Even though the total number of stereotypies did not differ between groups, RTT group stood

out by showing a higher number of stereotypies per minute and a longer duration of

stereotypies. These findings are in accordance with the work of Goldman S and Temudo T

(2012) where they compared the hand stereotypies of 20 children with RTT and 20 children

with ASD, and found that stereotypies in RTT were frequently continuous comparing to brief

intermittent stereotypies in ASD (134). In their study, they report that RTT group displayed a

greater variety of hand stereotypies compared to the ASD group. We did not find a difference

between RTT and ASD groups concerning the variety of stereotypies. In our work, ID group

showed a marginally higher variety of stereotypies when compared to RTT group, however,

this difference may not be valuable and may be worth exploring in future studies.

Stereotypies with an object have been associated with ASD in some studies (60), however in

our study, there was no difference in the proportion of stereotypies with an object between the

ASD and ID groups. We found a near absence of stereotypies with an object in the RTT group,

easily explained by the progressive loss of hand functionality characteristic of this syndrome.

Our study reinforces the finding that one of the main differences between stereotypies in RTT

is that they are performed in the midline (80, 81, 134). We add that stereotypies in RTT also

appear to be predominantly bilateral and simple.

Among the 337 hand stereotypies analyzed through kinematic, we were able to conclude that

stereotypies in ASD are faster and with a greater acceleration than in ID or RTT, with greater

differences when compared to the RTT group. As far as we know, this finding has not been

explored in previous papers. One hypothesis is that, in RTT patients, lower speed and

acceleration of stereotypies may be related with greater neurological dysfunction. However, we

also found that the ASD group presented stereotypies with greater speed and acceleration than

the ID group. It is hypothesized that the pathophysiological mechanisms involved in the

stereotypies in these three groups may be different, justifying the differences identified in the

kinematic parameters.

The frequency of stereotypies in the RTT group was also lower than in the ASD and ID groups.

Although the RTT patients were not on antipsychotic medication, we cannot exclude some

influence of antiepileptic drug use since this group had a higher frequency of epilepsy.

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Implications

The exact measuring of the kinematic parameters allowed to characterize motor

stereotypies in a more precise and detailed way. Traditional methods for identification and

characterization of motor stereotypies rely on questionnaires/interviews to caregivers, direct

observation, and video-based coding. All these methods present advantages and limitations.

Questionnaires to caregivers may allow to reach to information that could not be identified

during direct observation due to the limited time or artificial environment of the evaluation. On

the opposite, direct observation and video-coding may allow gathering more precise and

reliable information but may be time consuming. Kinematic analysis with automatic detection

of stereotypies may represent a more objective and accurate method, however, we are still

facing many technological limitations. Multi-camera marker-based reference systems are not

suitable for clinical practice; however, it could be possible to use a single camera during clinical

evaluations such as with ADOS-2 administration and capture the motor stereotypies in a more

naturalistic environment. In future studies, the combination of clinical and kinematic methods

may enable to distinguish stereotypies of different subgroups of patients, for example,

accordingly with their genetic etiology.

Limitations

In this work we avoided wearable devices since the participants were children with

intellectual disability who presumably would not tolerate such equipment. Hence, we used LED

markers attached to their bodies, as we considered that they would be well tolerated.

Nevertheless, these markers were not tolerated by all the children, consequently part of the

motion detection analysis was done manually, making the work much more time consuming.

The sample size used in this study is limited. We are aware that studies with larger samples

will be necessary to analyze whether these results are reproducible, however, the

methodological issues associated with kinematic analysis did not allow us to study a higher

number of patients.

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Also, only the ASD group was randomly selected from a larger group. The ID and RTT groups

were selected by consecutive convenience sampling. To avoid sampling bias, ideally, all

participants should be selected by randomization. We could also have grouped the participants

in pairs according to sex, IQ, or age. However, RTT patients were exclusively female, and their

IQs were low or difficult to evaluate, hindering a matched pair methodology.

Finally, ideally, we should have analyzed all the hand stereotypies, however considering

methodological issues we believe that analyzing 337 of 956 of the stereotypies was a

satisfactory goal. In this study, intra- and intersubject variability of stereotypies parameters were

not explored, this should be a concern in future studies with larger sample sizes.

Conclusions

This clinical and kinematic study of hand stereotypies showed relevant differences between

stereotypies in ASD, ID and RTT. RTT stereotypies seem to be longer, predominantly in the

midline and bilateral. Stereotypies in ASD had higher velocity, acceleration and frequency

comparing to RTT. Those differences may be related with differences in the pathophysiological

mechanisms or may be related to the greater severity of neurological impairment in the RTT

group. Stereotypies’ velocity and acceleration were also higher on ASD comparing to ID and

frequency was tendentially higher.

Future works should aim to develop a multifunctional, affordable, and portable system which

may be used in research and clinical practice to measure stereotypies parameters. Ideally this

method should be able to automatically detect motor stereotypies, however this can be a

difficult target to hit. Experienced observers will always be crucial to properly identify or validate

stereotypies diagnosis. The inclusion of these technical systems into clinical protocols may be

complex due to certification procedures, equipment and software costs and resources.

However, we believe that these methodologies of kinematic analysis in the study of stereotypies

should first be explored and replicated in the research context. Such studies may allow

elucidating whether there are clinical and kinematic features that can help distinguish

stereotypies between certain developmental disorders, or even to identify kinematic markers

that may help differentiate stereotypies among different genetic disorders.

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Tables

Table 1 – Baseline demographic and clinical characteristics of the 45 study participants.

Group I Group II Group III

ASD ID RTT p
n=20 n=15 n=10
Female sex n (%) 9 (45.0) 8 (53.3) 10 (100) 0.011*
Age mean (SD) 7.48 (3.12) 11.28 (4.99) 11.89 (4.82) 0.006*
Language n (%)
Non-verbal 9 (45.0) 5 (33.3) 8 (80.0) 0.052
Words 7 (35.0) 6 (40.0) 2 (20.0)
Sentences 4 (20.0) 4 (26.7) 0
Febrile seizures n (%) 2 (10.0) 4 (26.7) 0 0.139
Epilepsy n (%) 6 (30.0) 7 (46.7) 8 (80.0) 0.034*
ASD – autism spectrum disorder; ID – intellectual disability; RTT – Rett syndrome; SD – standard deviation, *p<0.05

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Table 2 – Clinical characteristics of the 956 hand stereotypies.

Group I Group II Group III

ASD ID RTT ASD vs ID ASD vs RTT ID vs RTT
n=20 n=15 n=10 p p p

Number of ST 18.00 (4.00; 65.00) 21.00 (11.00; 44.00) 20.50 (6.00; 43.00) 0.364 0.502 0.978
median (range)
Number ST/min 0.93 (0.15-4.60) 1.10 (0.44; 2.00) 2.55 (0.70; 3.60) 0.479 <0.010* 0.014*
median (range)
Median duration 3.00 (2.00; 8.00) 3.00 (2.00; 15.00) 10.00 (4.00; 35.00) 0.610 <0.001* 0.001*
of each ST (s)
median (range)
ST duration sum 74.00 (9.00-282-00) 103.00 (24.00; 795.00) 226.00 (80.00; 541.00) 0.107 <0.001* 0.016*
(s) median (range)
ST morphologies 2.50 (1.00; 7.00) 3.00 (1.00; 5.00) 2.00 (1.00; 6.00) 0.657 0.131 0.048*
median (range)
ST with an object 0.50 (0; 25.00) 1.00 (0; 20.00) 0 (0; 1.00) 0.987 0.049* 0.023*
median (range)
Bilateral ST (%) 61.00 54.00 84.00 0.464 0.099 0.004*
Midline ST (%) 31.00 59.00 73.00 0.073 0.035* 0.338
Simple ST (%) 88.00 100.00 96.00 0.013* 0.356 0.216
ASD – autism spectrum disorder; ID – intellectual disability; RTT, Rett syndrome; ST – stereotypies; * p<0.05

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 Table 3 – Kinematic characteristics of hand stereotypies.

Group I Group II Group III

ASD ID RTT ASD vs ID ASD vs RTT ID vs RTT
n=20 n=15 n=10 p p p
Velocity (cm/s) 56.53 (16.80; 105.99) 27.10 (10.10; 69.55) 14.27 (8.20; 42.35) 0.008* <0.001* 0.091
median (range)
Acceleration (cm/s2) 838.38 (319.65; 2026.77) 479.23 (174.34; 1152.26) 216.25 (145.70; 689.04) 0.008* <0.001* 0.036*
median (range)
Frequency (Hz) 0.56 (0.19; 2.81) 0.38 (0.19; 2.44) 0.23 (0.09;0.61) 0.240 0.001* 0.023*
median (range)
Amplitude (cm3) 3891.16 (204.20; 1112.60 (170.68;22681.42) 1491.25 (185.20; 0.064 0.183 0.935
median (range) 41677.94) 10799.85)
ASD – autism spectrum disorder; ID – intellectual disability; RTT, Rett syndrome; * p<0.05

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Acknowledgements

We acknowledge the patients, parents, families, or guardians who allowed to accomplish this

work by their participation. This work was supported by Fundação para a Ciência e Tecnologia

(grant number PTDC/NEU-SCC/0767/2012, project FCOMP-01-0124-FEDER-029673), which

had no other role in the article.

Conflict of interest

No conflicts of interests to declare.

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5. Discussion and conclusions

5.1. Main achievements

This thesis aimed to expand the knowledge of motor stereotypies in ASD.

The main results of this work are the following:

. Based on the systematic review and meta-analysis of studies with data on

the prevalence of motor stereotypies in ASD we conclude that the median

prevalence of motor stereotypies in ASD was 51.8% (Paper I). A previous

systematic review study, without meta-analysis, reported values close to

80%, which may be justified by the inclusion of repetitive movements without

criteria for stereotypies and by the inclusion of studies with very

heterogeneous convenience samples.

. We found a wide range of prevalence values reported in the included studies

(from 21.9% to 97.5%) which probably reflects the diversity of sampling

methods, selection biases, and the variability of ASD diagnostic criteria used

through time (Paper I).

. The systematic review study mirrors the great heterogeneity regarding ASD

diagnostic criteria, instruments used to assess stereotypies, stereotypies

definition, as well as for the nomenclature used to term stereotypies.

Additionally, we identified frequent confusion between motor stereotypies

and other types of repetitive behaviors not classifiable as stereotypies

(Paper I).

. The main determinants of stereotypies identified in the systematic review

and meta-analysis were the independent diagnosis of ASD, the severity of

112
 ASD, a low NVIQ, and young age. The associations between stereotypies

and independent diagnosis of ASD, and low NVIQ were the most striking

and were confirmed by meta-analytic study (Paper I).

. Sex did not seem to influence the prevalence of stereotypies however the

predominance of males in most samples may make the analysis of this

variable more complex and warrants further investigation (Paper I). Also,

anxiety and stereotypy triggers should be further explored since data

through studies was scarce.

. We conducted the first study with a randomized sample of children with a

diagnosis of ASD, in which a comprehensive evaluation and classification

protocol were applied, to identify the prevalence and determinants of motor

stereotypies (Paper II). The prevalence of motor stereotypies identified in

this sample was 56.7%, a value close to the one identified in the meta-

analysis carried out by the group (Paper II).

. We characterized the motor stereotypies according to a new operational

classification model and rated 1,198 motor stereotypies (Paper II). We

present the study with the largest number of motor stereotypies analyzed in

an ASD group.

. Hand/arm stereotypies were by far the most frequent, however the number

of stereotypies of the head, legs, trunk or whole-body is relevant and

warrants more focus in future studies (Paper II).

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. Motor stereotypies in ASD seem to be predominantly simple, bilateral and

with small amplitude (Paper II). These findings are in accordance with the

previous literature.

. A large number of stereotypies' morphologies were identified and classified

on the basis of a glossary prepared by the team which could be used in

clinical practice and future studies.

. Young age and ASD severity score were the main determinants of

stereotypies prevalence (Paper II) in accordance with the findings of the

systematic review and meta-analysis. This study adds that being nonverbal

is also a determinant of stereotypies prevalence (Paper II).

. The association between being nonverbal and presenting stereotypies has

been little studied so far and warrants exploration. Additional language

assessment tools would be valuable in future studies, preferably with

longitudinal studies design (Paper II).

. Being diagnosed with DD/ID or epilepsy, presenting echolalia or prosody

abnormalities, and the use of antipsychotic or antiepileptic drugs were also

associated with higher odds of presenting stereotypies (Paper II).

. We were interested in exploring what factors might influence the number of

stereotypies per individual, the duration and time spent performing

stereotypies, and the variability of stereotypies. Interestingly, we identified

that: 1) being nonverbal and a higher ADOS-2 CSS, were associated with a

higher number of stereotypies; 2) a higher ADOS-2 CSS was associated

with longer time performing stereotypies; 3) longer stereotypies duration

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 correlated with being diagnosed with DD/ID or epilepsy; and 4) diagnosis of

DD/ID was associated with a higher variability of stereotypies morphologies

(Paper II).

. Trunk/body and head stereotypies may be indicative of lower language level

or lower cognitive abilities; however, this hypothesis should be further

explored (Paper II).

. RTT group showed a higher number of stereotypies per minute and a longer

duration of stereotypies when compared to ASD and ID (Paper III).

. Although stereotypies with an object have been previously associated with

ASD, in our study, there was no difference in the proportion of stereotypies

with an object between the ASD and ID groups (Paper III).

. Stereotypies in ASD were faster and had greater acceleration than in ID or

RTT, with greater differences when compared with RTT (Paper III).

5.2. Discussion

Motor stereotypies are one of the most frequent findings in individuals with a

diagnosis of ASD and one of the diagnostic criteria for ASD (28). Although mild

in some, stereotypies may be frequent or persistent, interfering with

psychomotor development, social interaction, and activities of daily living (142,

147, 148). Moreover, motor stereotypies are often a major source of concern

and stress for the family (99). Thus, in the case of stereotypies with significant

impact on the individual's function, there is an indication for treatment. Given

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the lack of knowledge on the physiopathological mechanisms behind

stereotypies, the treatment involves behavioral therapy or antipsychotic drugs

(149).

The knowledge about the epidemiology and determinants of motor stereotypies

in ASD may help to identify which individuals are more likely to present

stereotypies, requiring earlier and more targeted treatment. This may also help

us recognize the factors which we can influence to reduce the prevalence,

frequency, and duration of stereotypies.

Our group began to identify the reported prevalence of motor stereotypies in

ASD to better illustrate the real magnitude of this problem. Therefore, we

conducted a systematic literature review and meta-analysis of the prevalence

of motor stereotypies in ASD. Considering that, over the years, several studies

have identified possible determinants of motor stereotypies, we assumed that

it would also be essential to start by identifying the main reported determinants

and the consistency of the data.

We found that the prevalence data on motor stereotypies in ASD was based on

convenience samples, therefore we decided to identify the prevalence of motor

stereotypies in a randomized sample of patients with a diagnosis of ASD. We

also aimed to assess whether the previously identified determinants of

stereotypies were associated with an increased prevalence, frequency,

duration, and variability of stereotypies in our sample. In addition, we explored

other factors that from a clinical point of view seemed to us to be potentially

linked to stereotypies, such as being nonverbal, drugs, ADHD, and epilepsy.

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Another main goal of the group was to develop a more comprehensive

stereotypies classification model that could be used in both research and

clinical practice allowing for a more systematic and reproducible assessment.

To achieve this objective, we used three classification schemes of stereotypies,

two of which were proposed by a member of our group. The new classification

model includes the definition of the classification domains, a glossary of

stereotypies morphologies and a collection of video samples.

The expectation of the group is to lay the groundwork so that the diagnosis of

motor stereotypies and its classification can be more consensual and

homogeneous, facilitating the comparison of research and clinical data.

5.2.1. Prevalence of motor stereotypies in ASD

The prevalence of motor stereotypies in ASD has been described with great

variability in the literature (58-60). We performed a systematic review and meta-

analysis of data on the prevalence of stereotypies in ASD derived from studies

that included subjects with a diagnosis of ASD and where stereotypies were

defined as repetitive body movements. This study included 8,124 participants

diagnosed with ASD being, to our knowledge, the only systematic and meta-

analytic study in this field.

The included studies reported a widely varying prevalence of stereotypies, from

21.9% to 97.5%, with a median of 51.8%. The prevalence of hand/finger

stereotypies was similar and again showed a wide value range. These wide

ranges may be due to the heterogeneity of methods regarding ASD and

stereotypies definitions, sampling and data collection methods. Also, since

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most of the included studies were conducted prior to DSM-5, the individuals

with a diagnosis of ASD were categorized into subgroups such as PDD-NOS,

AD and HFA and many of the studies included only some of these subgroups.

Considering the limitations of the studies included in the meta-analysis and the

fact that the data was obtained from studies using diagnostic criteria for ASD

prior to DSM-5, we decided to analyze the prevalence of motor stereotypies in

a randomized sample of individuals with a diagnosis of ASD using the DSM-5

criteria. Therefore, we designed a clinical protocol that allowed us to establish

the diagnosis of ASD using several diagnostic instruments, with cognitive and

adaptive function evaluation, and using a video recording of the participants

during a standardized evaluation to confirm the presence of stereotypies, their

frequency and phenomenology. To our knowledge this was the first study with

this purpose, based on a randomized sample. The prevalence of motor

stereotypies was 56.7%, a value close to the median prevalence identified in

our systematic review and meta-analysis (150), suggesting that this may be a

reliable number.

5.2.2. Stereotypies’ definition(s) and nomenclature

The definition of stereotypies is far from being consensual. In the systematic

review we identified the use of 10 different definitions. In our studies, we used

Jankovic's classic definition of stereotypies (47) and we have complied with the

recommendation of Edwards et al. (2011) who advise that the definition of

stereotypies should be narrowed so that it encompasses a consistent group of

conditions that may share the same pathophysiology (49). Hence, in our studies

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we made efforts to exclude brief intermittent movements that could be better

classified as tics, (such as grimacing, lip and tongue movements or repetitive

mouth opening), and repetitive movements that do not consistently fit to the

definition of stereotypies. We believe that this practice is essential to achieve a

cohesive group of stereotypies facilitating research advances in this field.

The range of terminology used to designate stereotypies was another topic that

stood out in our systematic review. A total of 11 different terms were identified,

including: “stereotypies”, “stereotypic movements”, “mannerisms”, and

“repetitive movements”. Accurate and reliable terminology of abnormal

repetitive behaviors is necessary to enhance the knowledge of such disorders.

The lack of uniformity in nomenclature raises confusion in research and clinical

practice. We believe that the term “stereotypies” should be consistently used

and that it could be complemented as "motor stereotypies" to distinguish it from

“vocal” or “visual” stereotypies.

5.2.3. Determinants of motor stereotypies in ASD

The reason why not all individuals with a diagnosis of ASD present with

stereotypies remains unclear. The knowledge about the factors that may

explain the presence of stereotypies may help to clarify this question. This issue

has been explored by several groups with some contradictory results.

In our systematic review and meta-analysis, we concluded that the most

frequent determinants were lower NVIQ, independent diagnosis of ASD, a

young age, and a higher severity of ASD. It was possible to confirm through

meta-analytic study that both low NVIQ and ASD severity show a significant

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association with stereotypies. Concerning age and severity, the studies did not

present enough data to proceed to a meta-analytic study. In line with these

results, in the randomized clinical study we found that a young age, ASD

severity and being nonverbal were the main determinants of stereotypies.

Regarding severity of ASD, Grossi E et al. (2021) recorded motor stereotypies

of 67 children with a diagnosis of ASD and found a significant association

between the number of stereotypies and ASD severity measured by the ADOS-

2 CSS (151). We also found an association between stereotypies and a higher

ADOS-2 CSS. We note, however, that this instrument includes topics

comprising stereotypies, which may have an influence on the results. Ideally,

future studies should include other autism severity scales to further explore this

association.

Our randomized clinical study added that verbal language can be another

important determinant of stereotypies. Being nonverbal was independently

associated with displaying stereotypies and with a higher number and duration

of stereotypies. This finding seems to be consistent with what has been

described in typically developing children, in whom stereotypies seem to

decrease when verbal language emerges (93, 152). We propose two main

hypotheses: stereotypies and verbal language may share common pathways;

and/or the absence of verbal language may be an epiphenomenon associated

with lower cognitive abilities and this may explain the presence of stereotypies.

Interestingly, echolalia and abnormal prosody were also more frequent in the

group with stereotypies, although they did not reach significance on the

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multivariate analysis. Further research should elucidate these findings, but for

now, a causal relation is difficult to establish.

In this thesis we also add that presenting echolalia or prosody abnormalities,

diagnosis of epilepsy, and the use of antipsychotic or antiepileptic drugs, may

also be associated with stereotypies. It will be important to confirm in future

studies if these are independent variables that may indicate a higher probability

of an individual diagnosed with ASD to present stereotypies.

Although sex was identified as a determinant for stereotypies by some studies,

no association between sex and stereotypies was identified in either the

systematic review study or the clinical study.

Most of the published studies have focused on the analysis of the prevalence

of stereotypies, with limited analysis of the number of stereotypies per

individual, their duration and variability. In our thesis, we add that being

nonverbal and with a higher ADOS-2 CSS are associated with a higher number

of stereotypies per individual. Also, a higher ADOS-2 CSS was associated with

longer time performing stereotypies. We consider that, in clinical practice, more

important than having or not having stereotypies, the greater number of

stereotypies and time spent performing stereotypies will certainly have a

significant impact on functioning and activities in daily life of the individual

diagnosed with ASD. Thus, these variables should be considered in quality-of-

life studies and in clinical trials related to therapeutic intervention in ASD.

In this thesis we found that a wider range of stereotypies morphologies was

associated with the diagnosis of DD/ID. The meaning of this finding is uncertain

but is supported by the work of Goldman et al. (2009) where the low functioning

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ASD subgroup showed a significantly greater variability of stereotypies

morphologies than the high functioning ASD subgroup (60). Accordingly,

Lanzarini et al. (2021) studied 35 children with a diagnosis of ASD using a video

analysis and described that patients with ID showed a higher number and

variability of motor stereotypies, mainly regarding the stereotypies involving the

head/trunk/shoulders.

5.2.4. Motor stereotypies classification

The Task Force on Childhood Movement Disorders recommends that the

phenomenology of stereotypies should include the description of duration,

speed, amplitude, jerkiness, repeatability, and the number of different

identifiable movements (Sanger et al., 2010). We consider that this

recommendation should be followed in research and in clinical practice. In this

sense, we have proposed an operational classification model where the

following steps are advisable: 1) to identify if the repetitive movement fulfils the

definition of stereotypy or if it is better classified as a tic, dyskinesia, dystonia,

or even as a repetitive behavior rather than a movement disorder; 2) to

distinguish between primary and secondary stereotypies (according to the

absence or presence of a neurodevelopmental/neurological disorder,

respectively); 3) to identify the topography (head, hand/arm, foot/leg, trunk,

whole body); 4) to classify in terms of complexity (simple if single movements,

or complex if clusters of different single coordinated movements always

performed in the same sequence, including any simple hand/arm movement

occurring with other movements using additional muscle groups); 5) if it is a

stereotypy of the hand/arm or foot/leg it should be classified according to the

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body position (midline / out of midline); movement extension or amplitude (small

/ large); presence or absence of dystonic features; and use of objects.

The classification in primary and secondary stereotypies is the most consensual

domain through literature. However, studies comparing both groups are

lacking. Some authors describe that secondary stereotypies are typically longer

and more complex than primary stereotypies (153). Our study adds that in ASD,

simple stereotypies are also clearly predominant. Further studies are needed

to elucidate the differences between primary and secondary stereotypies.

The topography, or body part involved in the stereotypies, may be a clue to the

etiological diagnosis of certain neurological disorders. In Rett syndrome, one of

the neurological disorders in which stereotypies are best documented, we

identified that the dominant stereotypies are hand stereotypies, although

stereotypies of the head, foot/leg, and trunk have also been described (80, 81).

In ASD, we confirmed that hand stereotypies are clearly the most frequent, but

the percentage of stereotypies in other topographies is not negligible and

deserves attention. Another interesting finding regarding topography was that,

in our study II, all the individuals with head stereotypies had DD or ID. In

accordance, Goldman et al. (2009) reported that head stereotypies were

independently associated with low NVIQ (60).

The performance of hand stereotypies on the midline of the body is also

classically associated with Rett syndrome (80, 81, 134, 154, 155). Interestingly,

we found that in ASD there is slight preponderance of stereotypies out of the

midline. We can assume that midline stereotypies may have some sensitivity

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for the diagnosis of RTT (in combination with other criteria), however, they are

not specific and midline stereotypies are also frequent in ASD.

Although we consider that the classification of stereotypies should include their

amplitude, dystonic character and use of objects, we did not find any distinctive

factors regarding these parameters in these studies. Nevertheless, their

characterization allows a better phenomenological description of stereotypies.

Some morphologies of motor stereotypies are associated with specific

neurological diseases. One of the classical examples is the hand-washing

stereotypy identified in RTT patients (80, 81). The head stereotypy termed as

“figure-8 head stereotypy” has been associated with two entities: STXBP-1

encephalopathy(139) and in the rhombencephalosynapsis (156, 157). These

stereotypies should alert clinicians to the possibility of these diseases.

We developed a list of stereotypies morphologies and their definitions which

may help to clarify whether there are indeed certain morphologies of

stereotypies that may be associated with certain neurodevelopmental disorders

or even specific diseases. This glossary is not intended to be a closed list but

can be completed and updated. We have identified 35 morphologies of

stereotypies in the randomized sample of ASD. The most frequent were hand

flapping, tapping, jumping and fidgeting. This repertoire is similar with the one

described by Freeman et al. (2010) in 42 non-autistic children in whom

hand/arm flapping, pacing, running, and jumping were the most common

morphologies (57). We also found similar morphologies in the ID and RTT

groups in our study III. Our hypothesis is that, globally, the stereotypies

repertoires may be similar in typically developing individuals and in those with

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neurological disorders, although some of the stereotypies may be particularly

common in certain genetic disorders due to shared pathophysiological

mechanisms. Ideally, a comparable terminology and classification will enable

us to uncover specific stereotypy morphologies according to specific etiologies.

5.2.5. Kinematic analysis

Our group performed one of the first studies using kinematic analysis for the

assessment of stereotypies in ASD with greater differences when comparing

the groups of ASD and RTT. One of the main conclusions drawn was that the

velocity and acceleration of stereotypies were higher in ASD compared to the

group of patients with RTT or ID. One of the hypotheses we put forward is that

the greater neurological compromise and comorbidities in the RTT group may

contribute to slower movements. Further studies with larger samples and higher

numbers of stereotypies will be needed to evaluate if we can replicate these

results.

5.2.6. Implications for clinical practice

Our prevalence studies of motor stereotypies in ASD revealed that about half

of the individuals with ASD, in pediatric age, presented motor stereotypies.

Considering the impact that stereotypies may have on a child’s development

and functioning, this significantly high prevalence implies the need to identify

whether the children present stereotypies or not, to monitor the stereotypies

frequency and impact, and to early intervene whenever the stereotypies are

pervasive.

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The wide range of prevalence numbers reported in the literature demonstrates

the need for studies based on randomized samples, or ideally through

population-based studies. It is also important to reassess the ASD diagnosis in

the light of current DSM-5 criteria and to use additional methodologies with

direct observation of stereotypies rather than the exclusive use of

questionnaires.

This thesis’ findings also strengthen the idea that motor stereotypies are

strongly associated with ASD and should alert to this hypothetical diagnosis,

even though they may be present in typically developing children and in children

with other developmental/neurological disorders. In accordance, Goldman et al.

(2009) reported that the prevalence of children with stereotypies was

significantly associated with the diagnosis of ASD and that this association was

much stronger for ASD than for cognitive level (60). Hence, even though

stereotypies are not specific to ASD, they should prompt professionals to

hypothesize this diagnosis, regardless of the cognitive level.

Considering the results of our first two studies, in clinical practice, the

identification of children diagnosed with ASD, who present a lower age, a lower

NVIQ and are non-verbal should alert to a higher probability of developing

stereotypies. Additionally, these factors may also be associated with a higher

number and longer duration of stereotypies and also with more time spent

performing stereotypies, which should warrant further attention. Ideally,

parameters such as prevalence, number, duration, and the variability of

stereotypies can be used as outcomes in the therapeutic intervention of these

individuals. Clinical trials of drugs used to treat stereotypies, or other ASD

126
therapies trials, should include these parameters and could benefit from our

classification model.

Our investigation suggests that clinical evaluation of stereotypies may provide

clues to the comorbidities and severity of ASD and that children with

stereotypies and with a greater number and diversity of stereotypies could be

the subject of an appropriate intervention program and even of a directed

etiological study.

The lack of consensus and standardization regarding the definition and

classification of stereotypies has hindered the advancement of knowledge in

this area. Unlike tics and other movement disorders, there is no consensual

classification or standardized tool to assess stereotypies. We believe that our

stereotypies’ classification model may enhance communication between

clinicians, researchers and families. This classification may also be applied and

useful in primary stereotypies.

5.2.7. Limitations

The results obtained through the systematic review and meta-analysis of

stereotypies in ASD were limited by the heterogeneity of ASD classification

criteria, a lack of or heterogeneous definition of stereotypies, the variety of

classifications of stereotypies, and by the nature of the samples. The scarcity

of data related to some of the potential determinants of stereotypies also

hindered meta-analytic study for these variables. Additionally, we have tried to

exclude the studies that did not clearly distinguish between stereotypies and

repetitive behaviors; however, we cannot be sure that they all met criteria for

127
motor stereotypies due to the heterogeneity of definitions and instruments used.

This may have contributed to an overestimation of the prevalence of motor

stereotypies. Future studies should use a clear and recognized definition of

motor stereotypies to exclude other repetitive movements or behaviors from the

analysis.

In our clinical randomized study of stereotypies in ASD, participants were

recruited from hospital clinics which may have decreased the

representativeness of individuals with milder or less symptomatic ASD. We

acknowledge that a population-based study would be the ideal study design to

address the aims of the study. Nevertheless, most of the previous studies used

non-consecutive convenience samples. We used a randomized sample, which

allowed to decrease sample selection biases and had a participation rate after

randomization of around 70% which we find adequate considering the

methodology used. Also, the participants were followed by different specialties

(child and adolescent psychiatry, neurodevelopment and child neurology),

which contribute to a more representative sample. Future studies should also

account for the imbalance between the number of females and males to allow

a better analysis of sex as a determinant of motor stereotypies.

Regarding the study of clinical and kinematic analysis of stereotypies in the

ASD, ID and RTT groups, we present two types of limitations. The limited size

of the sample makes it difficult to generalize the results and reinforces the need

to replicate the study in a larger and preferably randomized sample. Also, the

technological issues associated with the kinematic analysis limited the number

of stereotypies analyzed. The methodology used should be adapted according

to the technical difficulties of its application to be properly validated afterwards.

128
5.2.8. Future directions

This study has clarified the prevalence of stereotypies in ASD as well as the

determinants that seem to be involved with the presentation of stereotypies and

with a higher number, duration and variability of stereotypies. Future studies

could replicate this methodology in a longitudinal cohort study and thus

corroborate the risk factors associated with stereotypies. It would be interesting

to study in more detail the association between language and stereotypies

using additional language assessment instruments.

An important result from the studies presented in this thesis is the proposal of

a classification model for stereotypies. Considering that classification is a

dynamic process that must follow the evolution of knowledge, we think that this

model should be applied and submitted with the necessary updates.

In an age when gene and exome panels are increasingly being placed at the

patient's bedside, this study highlights the importance of characterizing and

documenting their clinical profiles. The taxonomic work will always be a

fundamental basis for the interpretation of genetic studies.

The kinematic analysis of the stereotypies showed some potential identifying

distinguishing features between groups. Those differences may be related to

dissimilarities in the neurobiological pathways and neurotransmitters involved

and deserve further exploration. Nevertheless, there are still many challenges

ahead, such as using equipment and technology that is more adaptable to the

study population and making data analysis simpler and applicable to larger

samples.

129
5.3. Conclusions

In this thesis, we provide new insights into the epidemiology and

determinants of motor stereotypies in patients with a diagnosis of ASD.

The systematic review and meta-analysis of the prevalence of stereotypies in

ASD allowed us to identify a wide range of values, with a median of around

50%. Considering that the studies included in this meta-analysis covered mainly

studies prior to the update of ASD diagnostic criteria brought by DSM-5, we

conducted a study with a randomized sample of children with a diagnosis of

ASD and obtained a median prevalence of stereotypies of 56%, close to the

value identified in the meta-analysis. Thus, we can conclude that this seems to

be a reliable value.

The main determinants of stereotypies in ASD identified in the systematic

review and meta-analysis study were young age, ASD diagnosis and ASD

severity. We add that, the absence of verbal language appears to be an

independent factor associated with stereotypies in ASD.

One of the objectives of this thesis was to present a taxonomic classification of

motor stereotypies to promote a greater knowledge of their phenomenology.

We believe that this knowledge may facilitate the identification and

differentiation from other paroxysmal phenomena and may allow the monitoring

of stereotypies over time.

We present a new classification model for motor stereotypies, based on three

previous classification schemes and the authors' experience. This classification

aims to facilitate the identification and description of stereotypies, similar to

130
what is currently done with tics. A glossary of stereotypies morphologies and

video samples collection are also presented. The aim is to contribute to a

greater standardization of language in this area and to enable a greater

comparability of the results of research studies, as well as to facilitate the

clinical approach to stereotypies.

The kinematic analysis is proposed as a complementary approach to study

stereotypies, although potentially more relevant for research purposes. The

results of the kinematic comparative study of stereotypies in ASD, ID, and Rett

syndrome indicate that the stereotypies in ASD may display a greater speed,

acceleration, and frequency, especially when compared to Rett syndrome.

Despite the methodological limitations of this study, it seems to provide a basis

for future studies.

131
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