# data[].attributes.headline
Children with developmental coordination disorders: a review of approaches to assessment and intervention, 2024

# data[].attributes.subject
Children with developmental coordination disorders: a review of approaches to assessment and intervention, 2024

# data[].attributes.attachment_link.title
Frontiers | Children with developmental coordination disorders: a review of approaches to assessment and intervention

# data[].attributes.attachment_link.description
Developmental Coordination Disorder (DCD) is a neurodevelopmental disorder characterized by deficits in motor skills, with gross and fine motor dysfunction b…

# data[].attributes.headline
eTextbook of Child and Adolescent Mental Health

# data[].attributes.subject
eTextbook of Child and Adolescent Mental Health

# data[].attributes.headline
The management of sleep disturbances in children with attention-deficit/hyperactivity disorder (ADHD): an update of the literature, 2024

# data[].attributes.subject
The management of sleep disturbances in children with attention-deficit/hyperactivity disorder (ADHD): an update of the literature, 2024

# data[].attributes.attachment_link.title
ADHD Teaching Aid, Digital Publication, May 2025

# data[].attributes.attachment_link.description
This ADHD Teaching Aid is developed as an interactive clinical tool for clinicians to educate, engage and empower children, young people and families.

# data[].attributes.headline
Neurodiversity best practice guide for professionals

# data[].attributes.subject
Neurodiversity best practice guide for professionals

# data[].attributes.attachment_link.title
Neurodiversity best practice guide for professionals

# data[].attributes.attachment_link.description
Find a list of ways for health professionals to best prepare, communicate and support neurodivergent children and young people.

# data[].attributes.headline
ADHD Medications - A Guide for Healthcare Professionals

# data[].attributes.subject
ADHD Medications - A Guide for Healthcare Professionals

# data[].attributes.attachment_link.title
ADHD Medications - A guide for healthcare professionals v5 7th May 2024.pdf

# data[].attributes.attachment_link.readable_text
This guideline covers recognising, diagnosing and managing attention deficit hyperactivity disorder (ADHD) in children, young people and adults. It aims to improve recognition and diagnosis, as well as the quality of care and support for people with ADHD.

In September 2019, we amended the recommendation on assessment for people starting medication for ADHD to indicate that an ECG is not needed before starting stimulants, atomoxetine or guanfacine if cardiovascular history and examination are normal and the person is not on medicine that poses an increased cardiovascular risk. For details, see update information.

Recommendations

This guideline includes new and updated recommendations on:

It also includes recommendations on:

Who is it for?

Healthcare professionals

Commissioners and providers

People with ADHD, and their families and carers

Is this guideline up to date?

December 2021: We have found no new evidence that affects the recommendations. For more information, see the surveillance decision.

Guideline development process
How we develop NICE guidelines
This guideline updates and replaces NICE guideline CG72 (September 2008), NICE technology appraisal guidance 98 (2006) and NICE evidence summaries ESUOM8, ESNM19 and ESNM70.

Your responsibility

The recommendations in this guideline represent the view of NICE, arrived at after careful consideration of the evidence available. When exercising their judgement, professionals and practitioners are expected to take this guideline fully into account, alongside the individual needs, preferences and values of their patients or the people using their service. It is not mandatory to apply the recommendations, and the guideline does not override the responsibility to make decisions appropriate to the circumstances of the individual, in consultation with them and their families and carers or guardian.

All problems (adverse events) related to a medicine or medical device used for treatment or in a procedure should be reported to the Medicines and Healthcare products Regulatory Agency using the Yellow Card Scheme.

Local commissioners and providers of healthcare have a responsibility to enable the guideline to be applied when individual professionals and people using services wish to use it. They should do so in the context of local and national priorities for funding and developing services, and in light of their duties to have due regard to the need to eliminate unlawful discrimination, to advance equality of opportunity and to reduce health inequalities. Nothing in this guideline should be interpreted in a way that would be inconsistent with complying with those duties.

Commissioners and providers have a responsibility to promote an environmentally sustainable health and care system and should assess and reduce the environmental impact of implementing NICE recommendations wherever possible.

# data[].attributes.attachment_link.title
Attention deficit hyperactivity disorder: diagnosis and management

# data[].attributes.attachment_link.description
This guideline covers recognising, diagnosing and managing attention deficit hyperactivity disorder (ADHD) in children, young people and adults. It aims to improve recognition and diagnosis, as well as the quality of care and support for people with ADHD

# data[].attributes.headline
Digital technologies for assessing attention deficit hyperactivity disorder (ADHD), Oct 2024

# data[].attributes.subject
Digital technologies for assessing attention deficit hyperactivity disorder (ADHD), Oct 2024

# data[].attributes.headline
Canadian ADHD Practice Guidelines 4.1, Jan 2021

# data[].attributes.subject
Canadian ADHD Practice Guidelines 4.1, Jan 2021

# data[].attributes.headline
2023 European Guidelines - The management of ADHD in children and adolescents:

# data[].attributes.subject
2023 European Guidelines - The management of ADHD in children and adolescents:

# data[].attributes.body
bringingevidence to the clinic: perspective from the European ADHD

Guidelines Group (EAGG)

# data[].attributes.attachment_link.title
The management of ADHD in children and adolescents: bringing evidence to the clinic: perspective from the European ADHD Guidelines Group (EAGG) - European Child & Adolescent Psychiatry

# data[].attributes.attachment_link.description
ADHD is the most common neurodevelopmental disorder presenting to child and adolescent mental health, paediatric, and primary care services. Timely and effective interventions to address core ADHD symptoms and co-occurring problems are a high priority for healthcare and society more widely. While much research has reported on the benefits and adverse effects of different interventions for ADHD, these individual research reports and the reviews, meta-analyses and guidelines summarizing their findings are sometimes inconsistent and difficult to interpret. We have summarized the current evidence and identified several methodological issues and gaps in the current evidence that we believe are important for clinicians to consider when evaluating the evidence and making treatment decisions. These include understanding potential impact of bias such as inadequate blinding and selection bias on study outcomes; the relative lack of high-quality data comparing different treatments and assessing long-term effectiveness, adverse effects and safety for both pharmacological and non-pharmacological treatments; and the problems associated with observational studies, including those based on large national registries and comparing treatments with each other. We highlight key similarities across current international clinical guidelines and discuss the reasons for divergence where these occur. We discuss the integration of these different perspective into a framework for person/family-centered evidence-based practice approach to care that aims to achieve optimal outcomes that prioritize individual strengths and impairments, as well as the personal treatment targets of children and their families. Finally, we consider how access to care for this common and impairing disorder can be improved in different healthcare systems.

# data[].attributes.headline
Clinical practice guidelines for attention-deficit/hyperactivity disorder: recent updates, 2023

# data[].attributes.subject
Clinical practice guidelines for attention-deficit/hyperactivity disorder: recent updates, 2023

# data[].attributes.headline
The ADHD Assessment Quality Assurance Dec 2024

# data[].attributes.subject
The ADHD Assessment Quality Assurance Dec 2024

# data[].attributes.body
Standard for Children and Teenagers (CAAQAS)

# data[].attributes.headline
Common pitfalls, and how to avoid them, in child and adolescent psychopharmacology: Part I Apr 2024

# data[].attributes.subject
Common pitfalls, and how to avoid them, in child and adolescent psychopharmacology: Part I Apr 2024

# data[].attributes.headline
Common pitfalls, and how to avoid them, in child and adolescent psychopharmacology: Part II Apr 2024

# data[].attributes.subject
Common pitfalls, and how to avoid them, in child and adolescent psychopharmacology: Part II Apr 2024

# data[].attributes.headline
Females with ADHD: An expert consensus 2020

# data[].attributes.subject
Females with ADHD: An expert consensus 2020

# data[].attributes.body
statement taking a lifespan approach

providing guidance for the identification

and treatment of attention-deficit/

hyperactivity disorder in girls and women

# data[].attributes.headline
Fifteen-minute consultation - The angry child, 2017

# data[].attributes.subject
Fifteen-minute consultation - The angry child, 2017

# data[].attributes.headline
The World Federation of ADHD International Consensus Statement: 208, 2021

# data[].attributes.subject
The World Federation of ADHD International Consensus Statement: 208, 2021

# data[].attributes.body
Evidence-based conclusions about the disorder

# data[].attributes.attachment_link.description
About ScienceDirect Shopping cart Contact and supportTerms and conditionsPrivacy policy

# data[].attributes.headline
2024 Practitioner Review: Continuity of mental health care from childhood to adulthood for youths with ADHD – who, how and when?

# data[].attributes.subject
2024 Practitioner Review: Continuity of mental health care from childhood to adulthood for youths with ADHD – who, how and when?

# data[].attributes.headline
The World Federation of ADHD Guide, 2019

# data[].attributes.subject
The World Federation of ADHD Guide, 2019

# data[].attributes.attachment_link.title
Autism spectrum disorder in under 19s: recognition, referral and diagnosis | Guidance and guidelines | NICE

# data[].attributes.attachment_link.description
Evidence-based recommendations on the recognition, referral and diagnosis of autism specturm disorder (ASD) in children and young people under 19

# data[].attributes.body
"Cutting Edge Psychiatry in Practice” is a journal published by East London Foundation NHS Trust (ELFT). All the past papers are available free of charge

https://www.cepip.org/

# data[].attributes.attachment_link.description
web services to get programmatic access to ICD-11

# data[].attributes.attachment_link.readable_text
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The most up to date, comprehensive, regulated information about medicines. Easy to use, trusted and recommended by healthcare professionals

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Common Sleep Disorders in Children, 2022

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Common Sleep Disorders in Children, 2022

# data[].attributes.headline
British National Formulary for Children 

# data[].attributes.subject
British National Formulary for Children 

# data[].attributes.attachment_link.description
The NICE British National Formulary for Children (BNFc) site is only available to users in the UK (England, Scotland, Wales and Northern Ireland)

# data[].attributes.attachment_link.description
AACAP’s Resource for Clinicians helps members stay current in the field of child and adolescent psychiatry and on important clinical issues. Each AACAP Resource Center contains consumer-friendly definitions, answers to frequently asked questions, cli

# data[].attributes.headline
ADHD Treatment Response Form for Parent/Teacher

# data[].attributes.subject
ADHD Treatment Response Form for Parent/Teacher

# data[].attributes.headline
ADHD Treatment Response Form for Teenagers

# data[].attributes.subject
ADHD Treatment Response Form for Teenagers

# data[].attributes.headline
WEISS FUNCTIONAL IMPAIRMENT RATING SCALE (WFIRS)

# data[].attributes.subject
WEISS FUNCTIONAL IMPAIRMENT RATING SCALE (WFIRS)

# data[].attributes.headline
2016 Fifteen minute consultation: tics and Tourette syndrome

# data[].attributes.subject
2016 Fifteen minute consultation: tics and Tourette syndrome

# data[].attributes.headline
Management of sleep disorders among children and adolescents with neurodevelopmental disorders: A practical guide for clinicians, 2022

# data[].attributes.subject
Management of sleep disorders among children and adolescents with neurodevelopmental disorders: A practical guide for clinicians, 2022

# data[].attributes.attachment_link.title
Management of sleep disorders among children and adolescents with neurodevelopmental disorders: A practical guide for clinicians

# data[].attributes.attachment_link.description
There is a complex relationship between sleep disorders and childhood neurodevelopmental, emotional, behavioral and intellectual disorders (NDEBID). NDEBID include several conditions such as attention deficit/hyperactivity disorder, autism spectrum ...

# data[].attributes.headline
Your Child’s Sensory Differences Checklist (SDC)

# data[].attributes.subject
Your Child’s Sensory Differences Checklist (SDC)

# data[].attributes.attachment_link.title
Conners 4 - Conners 4th Edition (Conners 4) – Hogrefe - Online testing, psychometric test & training providers

# data[].attributes.attachment_link.description
Conners 4 provides a thorough assessment of symptoms and impairments associated with ADHD and common co-occurring problems and disorders in children and youths aged 6 to 18 years. The Conners 4 allows for flexibility in the administration, offering screen

# data[].attributes.attachment_link.readable_text
In 2013, the American Psychiatric Association (APA) released the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), the handbook used to diagnose of mental disorders, including autism.

The DSM-5 introduced three ASD levels of severity: level 1 ("requiring support"), level 2 ("requiring substantial support"), and level 3 ("requiring very substantial support"). The full-text of the DSM-5 severity levels for autism spectrum disorder (ASD) is provided below with permission from the APA.

Severity levels for autism spectrum disorder

Level 3 autism: "Requiring very substantial support"

Social communication

Severe deficits in verbal and nonverbal social communication skills cause severe impairments in functioning, very limited initiation of social interactions, and minimal response to social overtures from others. For example, a person with few words of intelligible speech who rarely initiates interaction and, when he or she does, makes unusual approaches to meet needs only and responds to only very direct social approaches

Restricted, repetitive behaviors

Inflexibility of behavior, extreme difficulty coping with change, or other restricted/repetitive behaviors markedly interfere with functioning in all spheres. Great distress/difficulty changing focus or action.

Level 2 autism: "Requiring substantial support"

Social communication

Marked deficits in verbal and nonverbal social communication skills; social impairments apparent even with supports in place; limited initiation of social interactions; and reduced or abnormal responses to social overtures from others. For example, a person who speaks simple sentences, whose interaction is limited to narrow special interests, and how has markedly odd nonverbal communication.

Restricted, repetitive behaviors

Inflexibility of behavior, difficulty coping with change, or other restricted/repetitive behaviors appear frequently enough to be obvious to the casual observer and interfere with functioning in a variety of contexts. Distress and/or difficulty changing focus or action.

Level 1 autism: "Requiring support"

Social communication

Without supports in place, deficits in social communication cause noticeable impairments. Difficulty initiating social interactions, and clear examples of atypical or unsuccessful response to social overtures of others. May appear to have decreased interest in social interactions. For example, a person who is able to speak in full sentences and engages in communication but whose to- and-fro conversation with others fails, and whose attempts to make friends are odd and typically unsuccessful.

Restricted, repetitive behaviors

Inflexibility of behavior causes significant interference with functioning in one or more contexts. Difficulty switching between activities. Problems of organization and planning hamper independence.

Related resources

Contact the Autism Response Team

Autism Speaks' Autism Response Team can help you with information, resources and opportunities.
Haga clic aquí para ver esta página en español.

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Read about the three levels of autism spectrum disorder (ASD) from the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5).

# data[].attributes.headline
ADHD Institute - An educational platform developed and funded by Takeda

# data[].attributes.subject
ADHD Institute - An educational platform developed and funded by Takeda

# data[].attributes.attachment_link.description
Useful resources on ASD and ADHD created by or on behalf of Flynn Pharma. For advice on personal medical matters, please consult your doctor.

# data[].attributes.attachment_link.readable_text
Our vision

Our vision is that any parent or carer, wherever they are, has information on their child's medicines that they can trust.

What we offer

Our medicines information pages cover many of the medicines that are prescribed or recommended for children by health professionals. They answer frequent questions, such as how and when to give the medicine, what to do if you forget to give the medicine, and any possible side-effects.

You can also read information or watch our short videos about giving different types of medicines, including tablets, capsules, liquid medicine, inhalers, eye drops/ointment and ear drops.

Who are we?

Medicines for Children is a partnership programme of Royal College of Paediatrics and Child Health (RCPCH), Neonatal and Paediatric Pharmacists Group (NPPG) and WellChild. Read more about us and our work.

# data[].attributes.attachment_link.title
Medicines For Children - We provide practical and reliable advice about giving medicine to your child

# data[].attributes.attachment_link.description
Our vision is that any parent or carer, wherever they are, has information on their child's medicines that they can trust. Our medicines information pages cover many of the medicines that are prescribed or recommended for children by health professionals.

# data[].attributes.headline
Working with Autistic Young People, not Around -  Video

# data[].attributes.subject
Working with Autistic Young People, not Around -  Video

# data[].attributes.attachment_link.title
EHCP Clinical Guidelines version 1.2 January 2025

# data[].attributes.headline
Learning disabilities and behaviour that challenges: service design and delivery, 2018

# data[].attributes.subject
Learning disabilities and behaviour that challenges: service design and delivery, 2018

# data[].attributes.headline
Learning disability: behaviour that challenges, 2019

# data[].attributes.subject
Learning disability: behaviour that challenges, 2019

# data[].attributes.attachment_link.title
Overview | Learning disability: behaviour that challenges | Quality standards | NICE

# data[].attributes.attachment_link.description
This quality standard covers care and support and services for children, young people and adults with a learning disability (or a learning disability and autism) and behaviour that challenges, and their families and carers. It describes high quality care in priority areas for improvement

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Disabled children and young people up to 25 with severe complex needs: integrated service delivery and organisation across health, social care and education,2023

# data[].attributes.subject
Disabled children and young people up to 25 with severe complex needs: integrated service delivery and organisation across health, social care and education,2023

# data[].attributes.attachment_link.readable_text
This guideline covers support for disabled children and young people with severe complex needs, from birth to 25 years. It aims to encourage education, health and social care services to work together and provide more coordinated support to children and young people, and their families and carers.

Recommendations

The guideline includes recommendations on:

It also covers specialist support for disabled children and young people with particular needs:

Who is it for?

Education, health and social care practitioners and service providers

Local authorities and health commissioners

Disabled children and young people with severe complex needs, their families and carers

Guideline development process
How we develop NICE guidelines
This guideline was developed by the National Guideline Alliance, which is hosted by the Royal College of Obstetricians and Gynaecologists (RCOG). The guideline was developed with complete independence from RCOG governance.

Your responsibility

The recommendations in this guideline represent the view of NICE, arrived at after careful consideration of the evidence available. When exercising their judgement, professionals and practitioners are expected to take this guideline fully into account, alongside the individual needs, preferences and values of their patients or the people using their service. It is not mandatory to apply the recommendations, and the guideline does not override the responsibility to make decisions appropriate to the circumstances of the individual, in consultation with them and their families and carers or guardian.

All problems (adverse events) related to a medicine or medical device used for treatment or in a procedure should be reported to the Medicines and Healthcare products Regulatory Agency using the Yellow Card Scheme.

Local commissioners and providers of healthcare have a responsibility to enable the guideline to be applied when individual professionals and people using services wish to use it. They should do so in the context of local and national priorities for funding and developing services, and in light of their duties to have due regard to the need to eliminate unlawful discrimination, to advance equality of opportunity and to reduce health inequalities. Nothing in this guideline should be interpreted in a way that would be inconsistent with complying with those duties.

Commissioners and providers have a responsibility to promote an environmentally sustainable health and care system and should assess and reduce the environmental impact of implementing NICE recommendations wherever possible.

# data[].attributes.attachment_link.title
Disabled children and young people up to 25 with severe complex needs: integrated service delivery and organisation across health, social care and education

# data[].attributes.attachment_link.description
This guideline covers support for disabled children and young people with severe complex needs, from birth to 25 years. It aims to encourage education, health and social care services to work together and provide more coordinated support to children and young people, and their families and carers.

# data[].attributes.headline
Blood Pressure Centiles for Boys and Girls

# data[].attributes.subject
Blood Pressure Centiles for Boys and Girls

# data[].attributes.headline
Blood Pressure and Heart Rate Monitoring in Children

# data[].attributes.subject
Blood Pressure and Heart Rate Monitoring in Children

# data[].attributes.headline
Challenges Surrounding the Diagnosis of Autism in Children

# data[].attributes.subject
Challenges Surrounding the Diagnosis of Autism in Children

# data[].attributes.headline
International Consensus on Standard Outcome Measures, 2024

# data[].attributes.subject
International Consensus on Standard Outcome Measures, 2024

# data[].attributes.body
for Neurodevelopmental Disorders

A Consensus Statement

# data[].attributes.attachment_link.title
Consensus on Standard Outcome Measures for Neurodevelopmental Disorders

# data[].attributes.attachment_link.description
This survey study of clinical and research experts and service users describes a core set of outcome measures for specific neurodevelopmental disorders.

# data[].attributes.headline
Age Based Paediatric BP Reference Chart Online with Data Input  

# data[].attributes.subject
Age Based Paediatric BP Reference Chart Online with Data Input  

# data[].attributes.body
Individual results, when compared to other children, can be affected by many factors. Thus, this software should not be used for medical diagnostic or treatment purposes.

# data[].attributes.attachment_link.readable_text
Age-based Pediatric Blood Pressure Reference Charts

Why monitor blood pressure (BP)?

Hypertension (high blood pressure) is an important health issue in children, because of its association with obesity. High blood pressure is considered a risk factor for heart disease and stroke, and high BP in childhood has been linked to high BP in adulthood.

This calculator can help to determine whether a child has a healthy blood pressure for his/her height, age and gender. In boys and girls, the normal range of blood pressure varies based on height percentile and age. This calculator automatically adjusts for differences in height, age and gender, calculating a child's height percentile along with blood pressure percentile. The normal blood pressure range, while steadily increasing with age, will shift based on the child's height.

The BP reference data include the 50th, 90th, 95th, and 99th percentiles for age and height for both boys and girls. So the graphs on this page show the upper half of the blood pressure range found in children. Normal BP is defined as systolic and diastolic blood pressures that are below the 90th percentile. The systolic number represents BP in blood vessels when a heart beats. The diastolic number is the pressure in blood vessels between beats, when the heart is at rest.

The graphs on this page have been updated to reflect the most recent guidelines from the American Academy of Pediatrics (AAP). The new normative pediatric BP tables are now based on normal-weight children. Unlike the previous tables, these BP reference values do not include children and adolescents with overweight and obesity. The strong association of both overweight and obesity with elevated BP and hypertension (HTN) was thought to bias the previous results. (See Flynn et al, Pediatrics, 2017)

The original BP calculator can still be found here: Pediatric BP Calculator, Version 1.

All values must be entered in order to calculate percentiles for BP and Height.

A percentile shows the relative position of the child's measurement (such as Blood Pressure or Height) among children of the same sex and age.
For example, a boy at the 25th percentile for height is taller than 25% of boys his age. If a girl is at the 40th percentile for height, she is taller than 40% of girls at that same age.

How do we evaluate blood pressure

Blood pressure is not always consistent, and can vary even when the child is resting. Thus, elevated BP readings should be repeated and confirmed over several visits before a child is identified as having hypertension. The most precise measure of a child's BP is an average of multiple measurements taken over several weeks (or even months) by a health professional.

A common approach is to obtain 3 assessments from different days to more reliably measure blood pressure.

Reference Data

The tools provided here are based on publicly available data from the following source:

Flynn JT, Kaelber DC, Baker-Smith CM, et al. Clinical Practice Guideline for Screening and Management of High Blood Pressure in Children and Adolescents. Pediatrics 2017; 140(3):e20171904.

BP-for-age status categories and their related percentile ranges are shown in the following table:

Definitions of BP Categories & Stages

Category

For Children Aged 1 to <13 y

For Children Aged ≥13 y

Normal BP:

<90th percentile

<120/<80 mmHg

Elevated BP:

≥90th to <95th percentile or
120/80 mmHg to <95th percentile
(whichever is lower)

120/<80 to 129/<80 mmHg

Stage 1 HTN:

≥95th to <95th percentile+12 mmHg or
130/80 to 139/89 mmHg
(whichever is lower)

130/80 to 139/89 mmHg

Stage 2 HTN:

≥95th percentile+12 mmHg or
≥140/90 mmHg
(whichever is lower)

≥140/90

Simplified BP Table

The new guidelines also include a simplified table designed to be used as a screening tool to identify children and adolescents needing further evaluation. Thus, the simplified table may be used to determine when a BP measurement should be repeated. It is not meant to be used to diagnose elevated BP or HTN. It is important to use the values in the BP reference tables or tools such as the calculators on this page to diagnose elevated BP or HTN. Depending on the child's height and age, values in the simplified table may differ from reference values.

Simplified Screening BP Table - Further Evaluation Required

Please note

Individual results, when compared to other children, can be affected by many factors. Thus, this software should not be used for medical diagnostic or treatment purposes. Additionally, the authors and their affiliated institutions are not liable for any damages to users or third parties arising from the use of this software.

This software is protected under international copyright law. Unauthorized duplication or distribution is a violation of copyright. Entering this section of the web site implies acceptance of the conditions stated above.

To cite this source

Shypailo RJ (2018) Age-based Pediatric Blood Pressure Reference Charts. Retrieved from the Baylor College of Medicine, Children's Nutrition Research Center, Body Composition Laboratory Web Site:
http://www.bcm.edu/bodycomplab/BPappZjs/BPvAgeAPPz.htm

Supporting publications

National High Blood Pressure Education Program Working Group on High Blood Pressure in Children and Adolescents. The fourth report on the diagnosis, evaluation, and treatment of high blood pressure in children and adolescents. Pediatrics 2004; 114(2 Suppl 4th Report): 555-76.

Rosner B, Cook N, Portman R, Daniels S, Falkner B. Determination of blood pressure percentiles in normal-weight children: some methodological issues. Am J Epidemiol 2008; 167(6): 653-66.

Flynn JT, Kaelber DC, Baker-Smith CM, et al. Clinical Practice Guideline for Screening and Management of High Blood Pressure in Children and Adolescents. Pediatrics 2017; 140(3):e20171904.

# data[].attributes.attachment_link.description
Why monitor blood pressure (BP)? Hypertension (high blood pressure) is an important health issue in children, because of its association with obesity. High blood pressure is considered a risk factor for heart disease and stroke, and high BP in childhood has been linked to high BP in adulthood.

# data[].attributes.headline
Hypertension UHL Children’s Medical Guideline, 2024

# data[].attributes.subject
Hypertension UHL Children’s Medical Guideline, 2024

# data[].attributes.attachment_link.description
The NICE Clinical Knowledge Summary (CKS) site is only available to users in the UK, Crown Dependencies and British Overseas Territories

# data[].attributes.headline
Epilepsies in children, young people and adults, NICE Guideline 2022

# data[].attributes.subject
Epilepsies in children, young people and adults, NICE Guideline 2022

# data[].attributes.attachment_link.readable_text
This guideline covers diagnosing and managing epilepsy in children, young people and adults in primary and secondary care, and referral to tertiary services. It aims to improve diagnosis and treatment for different seizure types and epilepsy syndromes, and reduce the risks for people with epilepsy.

MHRA advice on antiepileptic drugs in pregnancy: Recommendations in this guideline on carbamazepine, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, phenobarbital, phenytoin, pregabalin, topiramate and zonisamide are in line with the MHRA updated safety advice on antiepileptic drugs in pregnancy.

MHRA advice on valproate: Recommendations on valproate are in line with the MHRA guidance on valproate use by women and girls. Valproate must not be used in women and girls of childbearing potential (including young girls who are likely to need treatment into their childbearing years), unless other options are unsuitable and the pregnancy prevention programme is in place. The MHRA has published temporary advice on the valproate pregnancy prevention programme during the COVID-19 pandemic.

August 2023: The MHRA issued new safety advice on risks associated with valproate for the under 55s in December 2022. The valproate recommendations in this guideline will be reviewed once further advice from the MHRA is available. People currently taking valproate should not stop taking it unless they are advised by a specialist to do so.

Recommendations

This guideline includes recommendations on:

Who is it for?

Healthcare professionals in primary, secondary and tertiary care

Commissioners, providers and voluntary organisations

People with epilepsy, their families and carers

Guideline development process
How we develop NICE guidelines
This guideline updates and replaces NICE guideline CG137 (January 2012) and NICE evidence summaries ESNM7, ESNM17 and ESNM37.

Your responsibility

The recommendations in this guideline represent the view of NICE, arrived at after careful consideration of the evidence available. When exercising their judgement, professionals and practitioners are expected to take this guideline fully into account, alongside the individual needs, preferences and values of their patients or the people using their service. It is not mandatory to apply the recommendations, and the guideline does not override the responsibility to make decisions appropriate to the circumstances of the individual, in consultation with them and their families and carers or guardian.

All problems (adverse events) related to a medicine or medical device used for treatment or in a procedure should be reported to the Medicines and Healthcare products Regulatory Agency using the Yellow Card Scheme.

Local commissioners and providers of healthcare have a responsibility to enable the guideline to be applied when individual professionals and people using services wish to use it. They should do so in the context of local and national priorities for funding and developing services, and in light of their duties to have due regard to the need to eliminate unlawful discrimination, to advance equality of opportunity and to reduce health inequalities. Nothing in this guideline should be interpreted in a way that would be inconsistent with complying with those duties.

Commissioners and providers have a responsibility to promote an environmentally sustainable health and care system and should assess and reduce the environmental impact of implementing NICE recommendations wherever possible.

# data[].attributes.attachment_link.title
Epilepsies in children, young people and adults

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This guideline covers diagnosing and managing epilepsy in children, young people and adults in primary and secondary care, and referral to tertiary services. It aims to improve diagnosis and treatment for different seizure types and epilepsy syndromes, and reduce the risks for people with epilepsy

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Sleep Disturbances in Children Affected by Autism Spectrum Disorder

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Sleep Disturbances in Children Affected by Autism Spectrum Disorder

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Frontiers | Sleep Disturbances in Children Affected by Autism Spectrum Disorder

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Background: Sleep disturbances are common in children affected by Autism Spectrum Disorder (ASD). The aim of our study was to describe sleep characteristics…

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Epilepsy and Attention Deficit Hyperactivity Disorder: Connection, Chance, and Challenges, 2023

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Epilepsy and Attention Deficit Hyperactivity Disorder: Connection, Chance, and Challenges, 2023

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1. Introduction

With the advent of neuroscience, the definition of epilepsy evolved dramatically due to our better understanding of the disease's underlying mechanisms and natural history [ 5]. According to the 2014 International League Against Epilepsy (ILAE) task force, epilepsy is defined as the occurrence of two or more unproved seizures at least one day apart, one unproved seizure in patients with a high risk of recurrence in the next ten years, or presence of epilepsy syndrome [ 5]. Epilepsy is the most common neurological disorder in the pediatric age group and affects approximately 0.5-1% during childhood [ 6].

Comorbidities are common in children with epilepsy (CWE). Recent reports demonstrated that approximately 50% of people with epilepsy have at least one comorbidity and that the risk of comorbidities may reach eight times higher in people with epilepsy than in the normal population [ 11]. Broad spectrums of comorbidities can present in CWE, including neurodevelopmental, psychiatric, bone, cardiac, and digestive disorders [ 11]. Attention deficit hyperactivity disorder (ADHD) is one of the most common psychiatric disorders affecting children. Symptoms of ADHD include impaired attention, impulsivity, and hyperactivity, leading to risk-taking behavior, learning difficulties, disorganization, and difficulty completing tasks [ 12]. Large population-based studies showed a significantly higher risk of ADHD in CWE than in the general population. The prevalence of ADHD was found to be as high as 77% in CWE, compared to 3-5% in the general population [ 13]. The presence of ADHD in CWE is challenging and can negatively affect the prognosis of the patients. Previous studies showed that CWE and concurrent ADHD are at increased risk of having an abnormal neurological examination and abnormal background rhythm on the electroencephalogram (EEG) [ 14], lower ASMs adherence [ 15], and more negative outcomes in social, behavioral, and learning development compared with CWE alone [ 16].

Despite the high burden, comorbid ADHD remains unrecognized in the clinical setting. Besides, the current literature shows controversies regarding the magnitude and nature of ADHD in CWE, the connection between ADHD and ASMs, the challenges in managing epileptic children with ADHD, and the role of precision medicine in the management of ADHD in CWE. Thus, the current literature review aims to summarize the current burden of ADHD in childhood epilepsy, the possible mechanisms of association between epilepsy and ADHD, and the challenges imposed by ADHD during the management of childhood epilepsy.

2. Evolving Concepts in Epilepsy Classification and Etiologies

Epilepsy is a leading cause of disability, morbidity, and economic burden worldwide. Current data indicate a global age-standardized prevalence of epilepsy of 540.1-737 per 100,000 population [ 17]. Nevertheless, the burden of epilepsy shows notable demographic and socioeconomic disparities, with a striking difference in its incidence between developed (33-82/100,000) [ 18] and developing (up to 187/100,000) countries [ 18, 19]. The prevalence of epilepsy was reported to range from 1.5 to 40 per 1000 population [ 9]. In the pediatric age group, the estimated prevalence was 6.8 per 1000 in the USA [ 20], 3.2-5.1 per 1000 in Europe [ 21], 1.5 to 14 per 1000 in Asia [ 22], and 3.3 per 1000 in Taiwan [ 23]. The incidence of epilepsy is highest in the first year of age and decreases to adult levels by the end of 10 years of age [ 24]. Prevalence and incidence of epilepsy are relatively higher in males than in females [ 2].

Thus, with the evolving evidence of a strong correlation between the semiologic features and SEEG-recorded activated cortical zones during seizure episodes [ 29], the ILAE published a new classification in 2017 that not only heavily relies on the semiologic features but also incorporates etiology and the risks of comorbidities ( Figure 1) [ 30]. The 2017 multi-level classification begins with the clinical identification of seizure type, which is now operationally classified into focal, generalized, or unknown onsets [ 31]. The proportion of generalized and unknown seizures peaks in children less than one year and decreases with age, while the proportion of focal seizures shows its highest peak in children aged 5-9 years [ 32]. In the second classification level, generalized seizures are categorized according to the presence of motor onset, while focal seizures are classified according to the associated awareness impairment and the presence of motor or non-motor symptoms. In some instances, generalized and focal seizures co-exist in EEG and clinical presentation, such as Dravet syndrome. The third level in the 2017 ILAE classification is to identify epilepsy syndrome, referring to a distinct entity characterized by the presence of aggregate clinical, EEG, and imaging features. Besides, some epilepsy syndromes incorporate age at onset, prognosis, diurnal variations, and/or comorbidities [ 30]. Epilepsy syndromes can play a significant role in predicting treatment response and prognosis of the patients; certain syndromes-such as West syndrome and Dravet syndrome- have a well-established association with drug resistance, cognitive impairment, and psychosocial outcomes [ 30]. Importantly, several clinical trials showed a syndrome-specific efficacy of traditional ASMs and hormonal therapy [ 33, 34].

Nearly 75% of patients were historically classified as having epilepsy of unknown etiology. However, with the advancement in gene-sequencing studies and neuroimaging, there was a paradigm shift in identifying epilepsy etiologies, and several genetic mutations were incorporated into the etiology of epilepsy [ 35]. A better understanding of the underlying etiology can open the gate for the clinical application of precision medicine in the epilepsy setting and the development of targeted therapies that tackle the neurobiological pathways for epilepsy [ 36]. Therefore, the 2017 ILAE classification emphasizes identifying the underlying etiology of epilepsy, whenever possible, to guide clinical judgment and management algorithms. Etiologies for epilepsy are broadly classified into six categories (see Figure 1), with overlapping causes in many patients.

Congenital or acquired structural damages are common causes of childhood epilepsy, and their identification is crucial in achieving seizure-free status through appropriate interventions, such as respective surgery. On the other hand, metabolic conditions-such as mitochondrial cytopathies- can lead to epilepsy and require specific metabolic therapy to optimize patients' outcomes. Autoimmune etiologies have also been implicated in epilepsy secondary to the development of autoantibodies leading to inflammatory changes and encephalitis; autoimmune epilepsy usually responds to immunomodulatory therapies. Infectious etiology was also identified in patients with epilepsy, such as tuberculosis and meningococcal meningitis. Epilepsy of unknown etiology implies no identified causes and is usually associated with normal imaging findings and a lack of relevant history.

Several epilepsy syndromes are classified under genetic etiology-such as generalized genetic epilepsy syndromes-; nonetheless, it should be noted that a genetic etiology is not synonymous with generalized epilepsy; many focal epilepsies have known monogenic or complex polygenic causes [ 35]. De novo mutagenesis is increasingly identified in cases with epilepsy, donating a clear distinction between "genetic" and "inherited" epilepsy, as well as explaining the limited familial liability of epilepsy [ 37]. Certain genetic mutations were also linked to developmental delay and poor prognosis in CWE.

Lastly, the 2017 ILAE classification identified comorbidities as integral components during the evaluation and management of epilepsy due to their profound impact on the patient's outcomes and quality of life. In the next section, we discuss the burden of comorbidities in CWE.

3. The Burden of Psychiatric Comorbidities in Epilepsy

The burden of comorbidities is high in patients with epilepsy; compared to the general population [ 11]. The burden of comorbidities in patients with epilepsy also demonstrates distinct disparities between high and low-income countries and between the adult and pediatric populations. For instance, the comorbidities in patients (including infants and adults) with epilepsy were: depression (13%), psychosis (10.4%), alcohol abuse (8.7%), and drug abuse (7.8%) in the United States [ 38]. Comparably, in a systematic review and meta-analysis that covered 39 low and middle-income countries, the distribution of comorbidities of patients (including children and adults) with epilepsy in the published reports was as follows: infectious diseases-such as neurocysticercosis and meningitis-(44%), somatic comorbidities -such as cranial trauma, malnutrition, stroke, and diabetes- (37%), psychosocial (11%), and psychiatric comorbidities (8%) [ 39]. In adults, approximately half of patients with active epilepsy have at least one comorbidity [ 11, 40]. Reported comorbidities include mental and behavioral disorders and diseases related to the endocrine system, nervous system, circulatory system, respiratory system, digestive system, genitourinary system, musculoskeletal system, connective tissues, etc. [ 11]. In the pediatric population, nationwide reports indicated that up to 80% of CWE suffer from at least one comorbidity, with a notably high burden even in cases with complicated epilepsies [ 41, 42]. In a population-based in the United Kingdom that included 12,720 patients with epilepsy, nearly 70% of patients had one or more comorbidities, and 30.3% had three or more comorbidities [ 43]. Several comorbidities were reported in patients with epilepsy, including infectious diseases, neurological disorders (such as stroke, cerebral palsy, and malformations), non-neurological malformations, peptic ulcers, osteoporosis, neurodevelopmental, and psychiatric comorbidities [ 44]. Comorbidities can negatively impact the long-term developmental, learning, and psychological outcomes of affected children, as well as the quality of life of the patients and their families [ 44, 45].

Psychiatric comorbidities are prevalent in CWE, and the association between epilepsy and a higher risk of psychiatric disorders is well-established [ 46]. Data from the United States (US) showed that 39.9% of CWEs had at least one psychiatric disorder [ 38]. Another nationwide study from the US on six million children showed that the risk of neurodevelopmental disorders was significantly higher in children with newly diagnosed epilepsy (60% versus 23%) [ 47]. Data from the UK also show that the prevalence of psychiatric comorbidities ranges from 20-30% [ 48]. In two reports from Norway, the prevalence of psychiatric comorbidities in CWE ranged from 37.7% to 42.9%, compared to 6.6% in children from the general population [ 42, 49]. In India, nearly one-third of CWE were found to have psychiatric comorbidities [ 50]. Notably, in the abovementioned registries, neurodevelopmental and behavioral disorders were found to take a considerable pole in CWE and psychiatric comorbidities. In the Norwegian registries, 21.3% of the children were found to have neurodevelopmental disorders [ 42]. Jason et al. collected data from the Swedish Registry of Epilepsy and found that 32% of children had neurodevelopmental comorbidities at diagnosis, which increased to 35% after two years [ 51]. In 2012, Russ et al. utilized the 2007 National Survey of Children's Health data and found that CWE were more likely to have neurodevelopmental disorders than the general population [ 52]. In CWE, the most common neurodevelopmental disorders include neurodevelopmental delay, behavioral and emotional disorders, autistic spectrum disorder, intellectual disability, and ADHD [ 44].

4. Evolving Concepts in ADHD

ADHD is a neurodevelopmental spectrum disorder affecting mainly preschool and younger children and is characterized by excessive activities and impaired attention and concentration. In return, children with ADHD usually exhibit disorganization, difficulty in completing tasks, learning disabilities, impaired decision-making, emotional dysregulation, and risk-taking behavior [ 12]. It is the most common behavioral disorder in children, with nearly 5-7% of the global pediatric population having ADHD. The distribution of ADHD shows a notable geographical disparity. Recent reports showed an increase in the number of children with clinically diagnosed ADHD in the past few decades [ 53]. A report from Sweden showed a fivefold increase in the number of children with a clinical diagnosis of ADHD from 2004 to 2014, which is mainly attributed to increased awareness of ADHD among general pediatricians and the public rather than an actual increase in the number of children with diagnostic-level of ADHD [ 54].

Although the precise pathogenic mechanisms underpinning the development of ADHD are unclear, however, ADHD exhibits functional and structural abnormalities. Previous reports suggested the involvement of dysregulated neurotransmitters, including dopamine and norepinephrine [ 55], reduced cerebral blood flow in the prefrontal region [ 56], reduced gray matter volume in the prefrontal, parietal, striatal, and cerebellar areas [ 57] and in the basal ganglia [ 58], and dysfunction in the right inferior frontal cortex, striatal-thalamic areas, anterior cingulate cortex, and supplementary motor area [ 59, 60, 61], in the pathogenesis of ADHD.

The current literature describes several environmental and genetic risk factors for the development of ADHD in children. Environmental factors related to maternal parts, such as advanced age, socioeconomic factors, and psychosocial deprivation [ 62], smoking [ 63], alcohol [ 64], lead [ 65], polychlorinated biphenyls and dioxins [ 66] and anemia; neonatal parts, such as September births, low birth weight, breech delivery, prematurity, hypoxic-ischemic encephalopathy, small head circumference, cocaine and alcohol exposure, and iodine and thyroid deficiency [ 67]; low levels of Mg, Fe, Zn, Cu and Se in the children with ADHD [ 68]; environmental factors: air pollution [ 69], and infection diseases, such as influenza, human immunodeficiency virus, Enterovirus 71, Varicella Zoster, Borrelia burgdorferi, streptococcus, acute otitis media [ 67], showed strong associations with ADHD. Genetic factors represent the most significant predictors of ADHD, according to genome-wide association studies (GWAS) and nationwide observational studies. According to a 2010 meta-analysis by Nikolas et al., it was estimated that the heritability of ADHD is as high as 70-80% after controlling for potential confounders, such as sex, age, and diagnostic approach [ 70]. Besides, twin studies demonstrated a strong correlation between genetic factors and clinical traits of ADHD, donating that genetic factors also influence symptom distribution of ADHD [ 71]. ADHD is primarily a polygenic disorder; recent GWAS identified 304 genetic variants in 12 independent loci associated with the risk of ADHD [ 72]. Single-nucleotide polymorphisms (SNPs)-based heritability can present in up to 34% of children with ADHD, with a significant impact of these SNPs on symptoms score, suggesting both a polygenic architecture of ADHD and genetically influenced phenotype [ 73].

Several changes were made in the DSM-V regarding the diagnosis of ADHD compared to previous editions. The age at onset increased from seven to 12 years old to account for the fact that significant ADHD-related impairments can persist in adolescents and younger adults [ 77]. Besides, ADHD no longer belongs to disruptive behavior disorders, allowing for a separate diagnosis of ADHD and autism. The DSM-V also changed the term "subtype" to "presentation" to reflect that ADHD manifestations are dynamic and can change in adulthood. According to the predominant symptomatology, the DSM-V classifies ADHD into three presentations: primarily inattentive, primarily hyperactive, and a combined type [ 76].

5. The Burden of ADHD in CWE

The association between ADHD and CWE is under-recognized in clinical practice [ 42, 43, 78]. Statistical data shows that the reported prevalence of ADHD in CWE ranges from 12-70%, which is primarily attributed to disparity in screening tools, diagnostic criteria, and studied age groups [ 13, 16, 42, 49, 52, 79, 80, 81, 82, 83, 84] ( Table 2). However, the prevalence of ADHD in healthy children without epilepsy is approximately 5-15% [ 42]. Obviously, CWE has a higher risk of ADHD than the general population.

Primarily inattentive presentation of ADHD appears to be more common than other presentations in CWE, which contradicts the distribution of ADHD presentations in the general population [ 85]. Previous reports showed that problems with attention were more common in ADHD patients with epilepsy than in children with ADHD alone [ 86]. However, other reports showed a similar distribution of ADHD presentations in children with ADHD and epilepsy and the general ADHD population [ 87].

Several risk factors were implicated in the co-presence of ADHD in CWE. Although ADHD is more common in boys than girls, reports on CWE showed equal sex distribution of ADHD [ 85]. Besides, case-control studies showed that the male gender was not predictive of ADHD in CWE [ 49, 88]. The literature also indicates conflicting results regarding the association between age at the onset of epilepsy and ADHD. Further evidence is required to establish the association between younger age at seizure onset and ADHD [ 89, 90]. Besides, environmental factors, such as prenatal exposure to ASMs, increased the risks of ADHD symptoms in CWE [ 91].

On the other hand, previous reports demonstrated a trend toward an association between seizure characteristics and the risk of ADHD in CWE. For example, two reports showed a positive correlation between impaired level of attention and temporal lobe epilepsy or childhood absence epilepsy (CAE) [ 92, 93]; however, it should be noted that the other reports showed no correlation between seizure type and ADHD, reflecting that the current evidence is controversial regarding the association between seizure type and ADHD [ 85, 88]. Single-center experience also reported a significant association between increased spike index or interictal spikes and impaired attention [ 89, 94, 95]. However, the ILAE consensus on ADHD in CWE concluded that the current evidence is still limited to support the association between EEG variables and the risk of ADHD [ 91]. Seizure frequency has also been linked with the risk of ADHD in CWE; prospective studies showed that, in children with drug-resistant epilepsy, higher seizure frequency was a significant predictor of the presence of ADHD symptoms [ 96, 97]. Limited evidence is available regarding the association between ASMs and the development of ADHD. ASMs, such as phenobarbital, phenytoin, and valproic acid, were found to increase the risk of cognitive impairments, including inattention and hyperactivity [ 98]. However, it is still unclear whether there is an association between polypharmacy and the risk of ADHD, which requires future studies to investigate whether the adverse effects of polypharmacy increase the risk of ADHD comorbidity in CWE syndromes. Family history can play a role in the development of ADHD in CWE. A Previous single-center report showed that CWE and comorbid ADHD had a significantly higher rate of maternal history of ADHD than CWE only [ 99]. Nevertheless, there is a strong link between ADHD and epilepsy. Moreover, the impact of comorbid ADHD in epileptic patients is heavily, often associated with academic and occupational underachievement, anxiety, and depression [ 100].

6. ADHD and Epilepsy: Mechanisms of Association

Although a myriad of evidence indicates the high burden of ADHD in CWE, the precise mechanisms underpinning the association between ADHD and epilepsy are unclear. Several models were proposed to explain the reasons for the association between epilepsy and comorbidities, which are usually interchangeable and can co-exist in the same individuals. In 2009, Kaufmann et al. [ 101] proposed three hypotheses for the possible mechanisms of association between epilepsy and comorbidities. In 2016, Keezer et al. [ 11] extended these hypotheses and incorporated several aspects of other theories to classify the potential mechanisms of associations into five main categories. In this review, we adopted this framework to highlight the possible association mechanisms between ADHD and epilepsy.

6.1. ADHD and Epilepsy: A Chance?

ADHD and epilepsy are common in children; thus, it is expected to observe the co-existence of both disorders in some children. However, mounting evidence as suggested by Chou et al. [ 102] that ADHD may significantly increase the risk of epilepsy developing and vice versa. The magnitude of the association between epilepsy and ADHD largely rules out the possibility of a chance in this association.

6.2. Causative Mechanisms

The relationship between epilepsy and ADHD can be divided into direct and indirect based on the causative mechanisms. For example, ADHD may directly be attributed to the temporal effects of epileptic discharges [ 103] or may indirectly be due to the side effects of ASMs [ 104].

6.3. Resultants Mechanisms

CWE and ADHD patients exhibited significant adrenergic system dysfunction, which can explain the association between both disorders [ 105]. Previous experiments demonstrated that rats with induced epilepsy and interictal spikes showed significant levels of ADHD-related symptoms, such as inattention and impulsivity, which were attributed to reduced noradrenergic transmission [ 106, 107]. Thus, it can be hypothesized that adrenergic system dysfunction in CWE acts as a resultant mechanism for comorbid ADHD.

On the other hand, the current body of evidence showed an association between comorbid ADHD and complicated epilepsy [ 92, 93], increased spike index [ 89, 94, 95], and higher seizure frequency [ 96, 97]. Thus, researchers have also suggested that neuronal damage in children with complex or uncontrolled seizures may contribute to the increased risk of ADHD in these patients.

6.4. Shared Genetics

In return, biological models were developed to explain the genetic overlap between epilepsy and ADHD. ADHD is a neurobiological disorder that encompasses several biological dimensions with multifactorial interactions. Thus, ADHD and epilepsy may share certain aspects of biological dimensions, despite the distinct clinical phenotypes [ 110]. Therefore, comprehensive omics data analysis is needed to investigate the biological overlap between ADHD and epilepsy. Another proposed explanation for the genetic overlap between epilepsy and ADHD is the fact that ADHD is a spectrum disorder, and epileptic seizures can be defined along a single spectrum.

6.5. Shared Risk Factors

As elaborated by Brikell et al., the genetic correlation explained only 40% of the phenotypic correlation between epilepsy and ADHD [ 112], which is lower than the findings of the correlation between ADHD and other neurodevelopment disorders [ 113]. Such results suggest that the genetic correlation between ADHD and epilepsy does not fully explain the high burden of comorbid ADHD in epilepsy and that environmental or other factors play a significant role in this association [ 114]. Environmental factors, such as toxins, low birth weight, advanced maternal age, socioeconomic factors, and psychosocial deprivation, showed strong associations with ADHD risk in well-controlled studies [ 62]. Recently, a study merging the daily air pollution data from the Environmental Protection Administration and the population data including children with ADHD from the Taiwan National Health Insurance Research Database concluded that exposure to higher levels of air pollutants in early life, the risk of developing ADHD was higher [ 69]. Consistently, these factors were also implicated in the development of epilepsy [ 115, 116, 117, 118, 119].

6.6. Bidirectional Connection

7. ADHD in Different Types of Epilepsy

The prevalence of ADHD is significantly higher in CWE than in normal controls ( Table 2). Because it is not clear whether the cause for the connection between ADHD and CWE is due to a global attention deficit or a specific network deficit, therefore, the connection between ADHD and CWE has been presumed to be attributed to interactions between ongoing seizures, underlying causes of symptomatic epilepsy or innate properties of epilepsy [ 122, 123, 124, 125]. There are several types of epilepsy associated with ADHD discussed in the following.

7.1. Generalized Epilepsy

Generalized seizures start when all brain areas are affected by an abnormal, widespread, excessive electrical impulse. Symptoms include losing muscle tone, clonic, jerking, or stiffening limbs, staring and blinking, and rhythmic, full-body jerking, typically provoked by sleep deprivation, fatigue, and alcohol drinking [ 126]. Antecedent and birth history, neurological examination, intelligence, and head size are typically normal. Most children with seizures were found to be in a generalized manner [ 127]. Attentional difficulties are more common among patients with generalized epilepsies than those with partial seizures [ 85, 128]. Some of them also show memory impairment, learning problems, and psychomotor impairments [ 129]. The neurological basis for such cognitive impairments in patients with generalized epilepsy is unclear. Impaired brain development in children with epilepsy has been linked to a range of cognitive and behavioral issues, including the development of ADHD.

7.2. Frontal Lobe Epilepsy (FLE)

The frontal lobes, which constitute almost one-third of the human brain, are the largest parts of the brain. Frontal lobes can incorporate with other parts of the brain and contribute to overall brain function. FLE is the second most common partial epilepsies in childhood [ 130]. Any epileptic discharges within the frontal regions may potentially affect frontal lobe-associated functions, such as motor functions, control of continence, and olfaction, voluntary eye movements, speech and language abilities, executive functions, motivational behaviors, and social competency. Impairments of those functions may lead to variable symptoms in patients with FLE [ 131]. The manifestations of FLE include nausea, vomiting, vertigo, motor and cognitive abnormalities, abnormal body posturing, tics, disinhibition, excessive excitement/irritability, inattention, and impulsivity [ 132]. The psychiatric manifestations of FLE may be difficult to differentiate from those with ADHD without epilepsy, and ADHD may mimic FLE with or without ADHD and vice versa [ 133]. As the underlying mechanisms for FLE are that frontal cortex abnormalities dysregulate the frontal lobe networks, leading to attention and hyperactivity at a crucial early stage of brain maturation [ 134], it may be easily confused with ADHD [ 132]. Nocturnal FLE, is defined by seizures that attack in sleep and originate in the orbitofrontal or mesial frontal areas, and has been reported to be associated with ADHD [ 135]. Patients with tuberous sclerosis involving frontal lobes were reported to present seizures with concomitant ADHD [ 136].

7.3. Childhood Absence Epilepsy (CAE)

CAE is one of the common forms of pediatric epilepsy. Approximately 10-17% of all childhood-onset seizures are determined to be typical CAE [ 137], which presents with a short duration (4 to 30 s), transient disturbance of consciousness, blinking, staring, and/or subtle or motionless activity without post-ictal symptoms, and less commonly, various types of automatisms, occurring numerous times per day and happen without being noticed for long. CAE is typically provoked by hyperventilation and sleep deprivation. EEG shows generalized 2.5 to 5 Herz spike wave activity [ 138]. A study reports that 25% of CAE children have subtle cognitive deficits and ADHD is significantly associated with CAE (26% of children with CAE vs. 6% of normal children) [ 139], suggesting cognitive or psychiatric comorbidities, especially ADHD are associated with CAE.

7.4. Benign Rolandic Epilepsy (BRE)

BRE, or benign epilepsy with centrotemporal spikes (BECTS), is a common idiopathic focal epilepsy in childhood. Approximately 9.6-10.3% of all epilepsy cases in children are determined to be BRE and typically onsets between 2-13 years of age without any neurological or intellectual deficit before onset. Seizure types of BRE are characterized by brief hemitonic or hemiclonic movements localized in the orofacial region, often preceded by unilateral parasthesia, and anarthria or speech arrest and drooling of saliva due to sialorrhoea and saliva pooling [ 140]. Seizures occur mainly during sleep or upon awakening with or without a secondary generalization and remit during adolescence. Seizure frequency is usually low. EEG shows a high voltage spike (greater than 100 mV) focus located in the centro-temporal (Rolandic) area with normal background activity and epileptiform discharges actively occurring during sleep, which are diagnostic. Postictal weakness in the involved areas may occur [ 141].

8. Do stimulants Increase the Risk of Epilepsy?

8.1. Stimulants Are Highly Efficacious in CWE with Comorbid ADHD

8.2. MPH in Pediatric Subjects and AMP in Adults Are the First-Line ADHD Therapy

Two double-blind trials show that MPH achieved a response rate of 60-70% in CWE and comorbid ADHD [ 148, 149] ( Table 3); MPH was found to improve attention and memory, executive function, cognition, and the overall health-related quality of life [ 150]. The effect of MPH on cognition and memory was found to be dose-dependent [ 151]. The efficacy of stimulants was also evident in patients with refractory epilepsy. In two controlled trials, MPH had a response rate of 63-73% in children with severe epilepsy three months after treatment, regardless of the degree of learning disability [ 152, 153]. Although AMP achieved a response rate of 48-58% in adults with ADHD [ 154, 155], however, the evidence for AMP in CWE is less established, with a single-center retrospective study showing that the response to AMP was only 24% [ 156]. Cortese et al. compared the effectiveness and side effects of medications for the treatment of ADHD, including AMP and MPH through conducting a network meta-analysis and systematic review, and concluded that MPH in children and adolescents and AMP in adults are preferred first choice for short-term ADHD treatment [ 142].

8.3. Evaluating the Risk of Increasing Seizures in CWE and Comorbid ADHD Receiving Stimulants Is Crucial

Based on the findings of case reports [ 157, 158, 159] and a study pointing out possible seizure attacks in MPH overdose [ 160], stimulants were hypothesized to reduce the seizure threshold and, hence, increase the seizure frequency or even induce new seizures in patients with a long-standing seizure-free status [ 158, 161]. An open-label trial studied 30 ADHD children with epilepsy receiving a single or two ASMs for an 8-week observation, and a single dose of MPH was given to all patients for the following 8 weeks. Although none of the 25 children with seizure-free status, however, there was a trend of increased seizure numbers in children with an active seizure at enrolment [ 162]. The same findings were reported by controlled trials and retrospective chart reviews [ 149, 163]. The risk of seizure was also reported to be dose-dependent [ 156]. A population-based study retrieved the data of 29,604 ADHD children on MPH from the Hong Kong Clinical Data Analysis and Reporting System. Although the incidence of new-onset seizures in this report was only 0.2% (4.4 per 10,000 patient-years), seizure risk increased during the first month after treatment but not after three months when compared to pre-MPH [ 164]. Therefore, regulatory agencies indeed issued a caution for the use of stimulants in CWE and comorbid ADHD (i.e., www.fda.gov (https:// www.accessdata.fda.gov/drugsatfda_docs/label/2013/010187s077lbl.pdf, accessed on 2 March 2023), "Prescriber's Digital Reference", www.pdr.net (https:// www.pdr.net/drug-summary/Ritalin-LA-methylphenidate-hydrochloride-1003, accessed on 2 March 2023)). Despite the high efficacy of stimulants in ADHD, even in CWE, and in refractory epilepsy, many treating clinicians are reluctant to prescribe stimulants in CWE with comorbid ADHD due to the concern of the increased risk of seizure. Therefore, evaluating the risk of increasing seizure attacks in children with ADHD receiving stimulants, especially in CWE with refractory seizures, is crucial, because these patients have the highest risk of comorbid ADHD.

8.4. The False Myth of Increased Risk of Seizures with Stimulants

Subsequent evidence with larger samples and a more controlled design showed no increase in the risk of seizure in CWE and comorbid ADHD ( Table 3). In a retrospective study, the comparisons between the seizure frequencies in the 3 months before, during, and after MPH treatment in 30 children and adults with active post-traumatic seizures showed a trend toward lesser seizure attacks during MPH treatment [ 165]. Additionally, several published literature consistently showed no increase in the risk of seizures in patients with or without poorly-controlled epilepsy [ 144, 148, 150, 153, 156, 164, 166, 167, 168, 169, 170]. In a previous report, only two children reported an increased seizure frequency out of the included 22 patients with poorly controlled epilepsy [ 153]. Liu et al. conducted a retrospective chart review on 18,166 stimulant users and 54,197 non-users in CWE. The results indicated no difference in the risk of seizure-related hospitalization between users and non-users [ 171]. As these results were consistent in patients with complex epilepsy, concerns regarding increased seizure frequency in children with complex or uncontrolled seizures and combined ADHD [ 149, 162] can be relieved based on these data. In addition, a review of seven prospective studies concluded that MPH does not increase the seizure frequency or incidence of new-onset seizures [ 172]. Although the review was limited by the small number of pooled patients, short follow-up duration, and lack of a control group, studies with a larger sample size and longer duration follow-up were deemed necessary. While the evidence supports the safety of stimulants in CWE, it is still limited by the small sample size and uncontrolled design. Thus, safety data should be further studied in randomized, double-blinded, placebo-controlled trials.

Author

Year

Design

Patients

Stimulants/ADHD Improved the Rate

No.

Follow-Up

Main Findings

9. ADHD and Epilepsy: Challenges and Opportunities

9.1. ADHD Is A Spectrum Disorder

ADHD is a neurobiological spectrum disorder with underlying multiple, complex, pathophysiological mechanisms. As previously mentioned, several genetic, environmental, and anatomic factors contribute to the liability of ADHD; children with ADHD also show smaller cerebellum, cortical, and other brain structures than healthy children, which is involved in reduced white matter tract connectivity. Emerging evidence also suggested the involvement of several neurotransmitters in the pathogenesis of ADHD, with an established dysregulation in the dopaminergic and adrenergic pathways [ 173]. In return, CWE and comorbid ADHD can show substantial variations in their phenotypes, and there is a need to view ADHD not as a unitary disorder but rather as a "dimensional marker that points to a spectrum of related disorders" [ 151]. This concept is supported by the growing evidence that ADHD presentations are qualitatively different to the extent that they should be considered distinct disorders due to the overlap in both executive and non-executive function deficits that can hardly distinguish ADHD traits [ 174, 175]. The "dimensional" nature of ADHD can be challenging during the diagnosis and management; the difficulties in identifying the specific disorder of the ADHD spectrum can result in under or over-prescribing the pharmacological options. The challenge is expected to be even higher in patients with other disorders, such as CWE [ 151].

9.2. Challenges in the Early Diagnosis of ADHD in CWE

Early identification and interventions are crucial to optimize the developmental outcomes of children with ADHD. Previous reports showed that early treatment is associated with better ADHD-related symptoms, developmental outcomes, and quality of life. Additionally, early treatment demonstrated cost-effectiveness and reduced direct and indirect healthcare resource utilization [ 176]. Despite ADHD being a common comorbidity in CWE, however, there is lacking a guideline regarding screening, specific diagnostic methods, and proper treatment. The current guidelines state that a multidisciplinary team should diagnose ADHD after excluding other causes; the ADHD symptoms should be assessed through a validated rating scale filled by the parents and teachers [ 177, 178]. Several rating scales are currently available that evaluate various aspects of the child's activities; nonetheless, many of them still lack standardization in clinical practice. In the 2017 ILAE consensus, the authors concluded that limited evidence is available regarding the diagnostic yield of the ADHD rating scale in the setting of CWE. The currently available scales suffer from low sensitivity in identifying inattentive presentation of ADHD-a common presentation in CWE- and low specificity, which donates that these tools can be used for screening purposes only and should be complemented by a detailed psychiatric assessment [ 91]. The scales also exhibited limited utility and were not validated in some racial groups and patients with intellectual disabilities [ 179, 180]. To provide a practical and evidence-based guide in the managing of CWE, a working team under the ILAE Pediatric Commission targeting screening, diagnosis, and management of ADHD in CWE through a multi-trait, computerized, multi-method approach yielded a high positive predictive value in children with ADHD. Still, these approaches have neither been validated in larger multicenter studies nor in CWE [ 91].

9.3. Treatment Strategy for ADHD in Epilepsy

The treatment strategy for ADHD in epilepsy involves pharmacological management and behavioral therapy.

9.3.1. Pharmacological management

Choosing Proper ASMs

Pharmacological Management for ADHD in Epilepsy

Stimulants

Non-Stimulants

Non-Pharmacological Management: Behavioral Therapies

9.3.2. Drug Interactions

Atomoxetine has been shown to have no interactions with any AEDs [ 209], while MPH can increase serum phenytoin concentrations [ 210]. Additionally, concurrent administration of carbamazepine may reduce MPH serum concentrations, resulting in reduced efficacy [ 192].

9.4. Novel ASMs against Both Epilepsy and ADHD

Lamotrigine (6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine; molecular formula: C9H7N5Cl2; molecular weight: 256.09), developed by the GlaxoSmithKline, is a new generation broad-spectrum ASM for epilepsy and bipolar disorder. Lamotrigine was first approved by the US Food and Drug Administration (FDA) in 1994. Over the years, lamotrigine has been approved for the treatment of epilepsy and bipolar disorder [ 211]. Guidelines have recommended this medication as first-line monotherapy or polytherapy for focal and generalized seizures in children and adults [ 212, 213, 214, 215, 216]. Mechanisms of the antiepileptic effect of lamotrigine include blocking voltage-gated sodium channels and voltage-gated calcium channels, regulating the release of the inhibitory and excitatory neurotransmitters, stabilizing membrane potential of neurons, abolishing the repetitive firing of neurons [ 217, 218, 219].

Several studies show that lamotrigine can improve epilepsy without worsening ADHD symptoms [ 220, 221, 222, 223]. It is not clear how lamotrigine can exert favorable effects on ADHD symptoms in CWE. The anti-epileptic effect of this medication may mainly contribute to this positive effect in improving ADHD in CWE.

9.5. ASMs in CWE and Comorbid ADHD

Comorbid ADHD is usually present in children with complex epilepsy who tend to be on long-term treatment. Few studies have examined the impact of ASMs on behavioral and cognitive outcomes in CWE and comorbid ADHD. Phenobarbital, valproic acid, and ethosuximide increased ADHD symptoms, particularly attention deficit. On the other hand, published reports showed inconsistent results regarding the impact of other ASMs on cognitive functions and ADHD symptoms, with some small studies showing a beneficial role of lacosamide and carbamazepine on behavior [ 104]. It is still also unclear how polypharmacy, with multiple pharmacokinetic interactions, can affect the behavioral outcomes in CWE and comorbid ADHD. In the ILAE consensus, it was concluded that valproate and polypharmacy are associated with worsening inattentive symptoms in CWE. However, these findings should be cautiously interpreted as polytherapy may indicate complicated epilepsy rather than a cause of deteriorating ADHD symptoms [ 91].

9.6. Recent Medications Development for ADHD

Stimulants are the first-line treatment for ADHD. However, numerous clinicians, care providers, patients' families, and teachers notice that some patients may have a good initial response to stimulants, but the effects are lessened [ 224]. Due to the development of tolerance, variability in patient response to specific pharmaceutics agents, and unwanted side effects related to stimulants, the need for relief of ADHD drives research for new treatments targeting the core symptoms of ADHD and fewer side effects. New medications such as lisdexamfetamine, viloxazine, serdexmethylphenidate/d-MPH, and mazindol have been approved for ADHD. Centanafadine, dasotraline, vortioxetine, droxidopa, and baicalin have not been approved by FDA and are under investigation.

9.6.1. Lisdexamfetamine (LDX)

LDX is a long-acting amfetamine prodrug [ 225]. Catabolic products of LDX are d-amphetamine and L-lysine. LDX is safe and well-tolerated. LDX is approved for children, adolescences, and adults with ADHD because the efficacy of LDX in ADHD has been successfully investigated in several large-scale, double-blind, randomized clinical trials [ 226, 227, 228, 229, 230, 231]. Adverse effects include decreased appetite, headache, insomnia, irritability, and weight reduction [ 232].

9.6.2. Viloxazine

Viloxazine is a selective norepinephrine reuptake inhibitor with activity in the noradrenergic and serotonergic pathways [ 233], is approved to be used in the treatment of ADHD children and adolescents and is administered orally in once-daily oral doses [ 234]. One possible action mechanism for viloxazine against ADHD is through increased efflux of norepinephrine and dopamine in the prefrontal cortex [ 235]. Viloxazine has no drug interactions with LDX or MPH [ 233, 236]. Adverse effects include somnolence, sedation, headache, fatigue, decreased appetite, abdominal pain, upper respiratory infection, nausea and vomiting, cardiovascular effects and suicidal ideation.

9.6.3. Serdexmethylphenidate (SDX)

Serdexmethylphenidate (SDX) structurally consists of d-methylphenidate connected to a nicotinoyl-L-serine molecule via a carboxymethylene linker. SDX has no affinity for DATs, NETs or serotonin transporters (SERTs). Although SDX is a novel prodrug of d-methylphenidate (d-MPH) and is pharmacologically inactive until gradually converted to active d-MPH in the lower intestinal tract, FDA has not approved it as a single entity for any indication [ 237]. As the immediate-release d-MPH component accounts for the rapid increase in plasma MPH concentrations, while the SDX component increases the MPH concentration through the evening hours, a multicenter, randomized, double-blind, placebo-controlled laboratory classroom study, SDX/d-MPH was shown to be efficacious and well tolerated in children aged 6-12 years with ADHD [ 238]. Therefore, SDX/d-MPH has been approved by FDA. Adverse effects include decreased appetite, nausea, vomiting, dyspepsia, abdominal pain, decreased weight, anxiety, dizziness, irritability, tachycardia, and increased blood pressure.

9.6.4. Mazindol

Mazindol, originally designed as an appetite suppressant, displays unique pharmacologic activities that include NET, DAT, and SERT inhibition [ 239], and modulation of serotonin (5-HT 1A, 5-HT ₇), muscarinic, histamine H ₁, μ-opioid, and orexin-2 receptors [ 240]. Since mazindol's potency as a NET inhibitor is similar to atomoxetine, mazindol is presumed to be effective in the treatment of ADHD. A study concluded that the effect of mazindol was similar to d-amphetamine and nicotine by PET imaging in human subjects [ 241]. Mazindol has been shown to be effective in ADHD with good safety in children [ 242] and adults [ 240]. Adverse effects include fatigue, decreased appetite, weight loss, drowsiness, dry mouth, nausea, constipation, intestinal distension and upper abdominal pain, and increases in blood pressure and heart rate.

9.6.5. Centanafadine

Centanafadine (EB-1020), a norepinephrine and dopamine reuptake inhibitor, is not a stimulant like MPH. Centanafadine can increase striatal dopaminergic neurotransmission, differentiating it from the noradrenergic ADHD drugs, atomoxetine and viloxazine [ 194]. Since this medication was found to increase dopamine and norepinephrine in the prefrontal cortex and striatum of animals [ 194], and it was also effective in preventing hyperactivity in the neonatal 6-hydroxydopamine brain lesion model of ADHD [ 194], centanafadine was therefore presumed to be a potential medication for the treatment of ADHD. Two Phase II clinical trials of centanafadine treatment significantly improve adults with ADHD [ 243]. Adverse effects include decreased appetite, nausea, insomnia, fatigue and dry mouth.

9.6.6. Dasotraline

Dasotraline [(1R, 4S)-4-(3, 4-Dichlorophenyl)-1, 2, 3, 4-tetrahydronaphthalen-1-amine] is a dual dopamine and norepinephrine reuptake inhibitor (DNRI). However, human PET studies demonstrated its preferential inhibition of dopamine transporters (DAT) and NET and weaker inhibition of serotonin transporters [ 244, 245]. Several studies have shown a good effect of dasotraline in improving ADHD symptoms and the safety of this medication in the general population [ 246, 247, 248]. Adverse effects include insomnia, irritability, appetite suppression, decreased weight, dry mouth, anxiety, panic attack, hallucinations, and delusions were reported [ 246].

9.6.7. Vortioxetine (VTX)

VTX (1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine) is approved as an antidepressive medication with multiple mechanisms of action: serotonin reuptake inhibitor, 5-HT7, 5-HT3 and 5-HT1D receptor antagonist, 5-HT1B receptor partial agonist, and 5-HT1A receptor agonist, leading to modulation of histamine, norepinephrine, acetylcholine, glutamate, and γ-aminobutyric acid (GABA) [ 249, 250]. An animal study shows that VTX significantly increased the extracellular concentration of 5-HT in the prefrontal cortex with mild increases in norepinephrine and dopamine [ 250]. VTX can reverse phencyclidine-induced deficits in attentional set-shifting [ 251]. There are two cases with ADHD comorbid learning difficulties in major academic domains, and wider symptoms of sickness behavior reported to be responsive to MPH in combination with Vortioxetine [ 252]. However, a phase II random control trial did not detect a better effect of VTX than placebo in improving ADHD symptoms [ 253]

9.6.8. Droxidopa

Droxidopa (L-threo-dihydroxyphenylserine), is chemically analogous to levodopa. Droxidopa is a CNS-penetrant norepinephrine prodrug that is metabolized by DOPA decarboxylase to increase extracellular concentrations of norepinephrine in the brain [ 254]. The efficacy of droxidopa is predicted to be similar to the α 2A-adrenoceptor agonists. Droxidopa is approved for adults with neurogenic orthostatic hypotension associated with primary autonomic failure (such as Parkinson's disease, multiple system atrophy or pure autonomic failure), dopamine β-hydroxylase deficiency or nondiabetic autonomic neuropathy) and is administered orally [ 255]. Droxidopa is reported to significantly decrease the ADHD-RS-Total score [ 256]. Adverse events include abnormal dreams, depressed mood, headache, insomnia, somnolence, sedation, suicidal ideation, musculoskeletal stiffness and myalgia, hyperhidrosis, nausea, and cough [ 256].

9.6.9. Baicalin

Scutellaria baicalensis Georgi (SBG), a Chinese traditional medicine is used to treat fever, hepatitis, hypertension, inflammation, and jaundice [ 257]. Baicalin (or baicalein), a flavonoid purified from SBG, can protect against several neurotoxins, which employ DAT [ 258, 259]. Baicalin is found to decrease hyperactivity in the spontaneously hypertensive rat model and increase markers of striatal dopamine function. Therefore, it is proposed to be a potential medication for the treatment of ADHD [ 260].

9.7. Impact of Comorbid ADHD on Developmental Outcomes

Previous reports showed that CWE, particularly complex types, suffer from impaired sustained attention, working memory, processing speed, and neuroanatomical derangements [ 78]. Imaging studies demonstrated that children with focal epilepsy had significantly thinner cortical thickness beyond the focal seizure area and slower white matter expansion; both abnormalities were significantly correlated with lower performance and verbal intelligence quotient (IQ), alongside lower executive functions than normal control [ 261, 262]. On the other hand, ADHD patients showed relative cortical thinning compared to normal control, which correlated with worse outcomes in the global assessment scales and remission [ 263]. Thus, it can be hypothesized that CWE and comorbid ADHD may exhibit neuroanatomical abnormalities, leading to worse cognitive and intellectual outcomes.

9.8. Potential Role of Precision Medicine

Precision medicine is an emerging field that aims to tailor the treatment of disorders with genetic backgrounds according to the detected genetic mutation and functional alteration. The concept of precision medicine stems from the fact that genetic mutations affect the eligibility and response to treatment, as well as the safety outcomes [ 264]. In the setting of epilepsy, some genetic epilepsies were found to be associated with an increased risk of recurrence and sudden death [ 265]. As the growing body of evidence shows a shared genetic background between epilepsy and ADHD, precision medicine can play a role in tailoring more effective treatments that optimize long-term developmental and behavioral outcomes.

10. Conclusions

The association between CWE and comorbid ADHD is still under-recognized in clinical practice, even though the well-established bidirectional connection and shared genetic/non-genetic factors between epilepsy and comorbid ADHD largely rule out the possibility of a chance in this association. Stimulants are effective in children with comorbid ADHD, and the current body of evidence supports their safety in CWE within the approved dose. Early identification and proper management of comorbid ADHD are crucial to optimize the prognosis and reduce the risk of adverse long-term neurodevelopmental outcomes.

Author Contributions

Conceptualization, H.-C.F., C.-M.C. and J.-D.T.; methodology, K.-L.C. and K.-H.C.; validation, H.-C.F., K.-L.C. and K.-H.C.; formal analysis and investigation, C.-M.C., K.-L.C. and K.-H.C.; resources and data curation, C.-M.C., K.-L.C. and K.-H.C.; writing-original draft preparation, H.-C.F., C.-M.C. and J.-D.T.; writing-review and editing, H.-C.F., C.-M.C., K.-L.C. and J.-D.T.; supervision, C.-M.C. and J.-D.T. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by the Tungs' Taichung Metroharbor hospital research grant number TTMHH-R1120001.

Institutional Review Board Statement

Not applicable for studies not involving humans or animals.

Informed Consent Statement

Not applicable for studies not involving humans or animals.

Data Availability Statement

Not applicable because this review did not report any new data.

Acknowledgments

We would like to express our sincere gratitude to Ping-Yi Hou (Department of Psychiatrics, Tungs' Taichung metro harbor hospital, Taichung, Taiwan) and I-Ching Chou (Department of Pediatrics, Children's medical center, China Medical University Hospital, Taichung, Taiwan), Shyi-Jou Chen (Department of Pediatrics, Tri-Service general hospital, Taipei, Taiwan), Wang-Tso Lee (Department of Pediatric Neurology, National Taiwan University Children's Hospital), Kuang-Lin Lin and Huei-Shyong Wang (Division of Pediatric Neurology, Chang Gung Children's Hospital at Linkou, Taoyuan, Taiwan; College of Medicine, Chang Gung University, Taoyuan, Taiwan) for helpful suggestions and comments on the MS.

Conflicts of Interest

The authors declare no conflict of interest.

Abbreviations

ADHD

attention deficit hyperactivity disorder

AMP

amphetamine

ASC

amphetamine salt combination

ASMs

antiseizure medications

BECTS

benign epilepsy with centrotemporal spikes

BRE

benign rolandic epilepsy

CAE

childhood absence epilepsy

CWE

children with epilepsy

DAS

dextroamphetamine sulfate

DAT

dopamine transporters

D-MPH

dexmethylphenidate hydrochloride

DNRI

dopamine and norepinephrine reuptake inhibitor

DSM

Diagnostic and Statistical Manual of Mental Disorders

EEG

electroencephalogram

FDA

Food and Drug Administration

FLE

frontal lobe epilepsy

GABA

γ-aminobutyric acid

GWAS

genome-wide association studies

ILAE

International League Against Epilepsy

IQ

intelligence quotient

LDX

lisdexamfetamine dimesylate

MAH

methamphetamine hydrochloride

MECP2

methyl-CpG binding protein 2

MEF2C

myocyte enhancer factor 2

MPH

methylphenidate

MPHH

methylphenidate hydrochloride

NET

norepineph- rine transporter

SBG

Scutellaria baicalensis Georgi

SDX

Serdexmethylphenidate

SEEG

stereo electroencephalogram

SERT

serotonin transporter

SNP

single nucleotide polymorphism

VMAT2

vesicular monoamine transporter 2

VTX

Vortioxetine

References

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6. Taylor, F.B. Comparing guanfacine and dextroamphetamine for adult ADHD: Efficacy and implications. In Proceedings of the 153rd Annual Meeting of the American Psychiatric Association, Chicago, IL, USA, 13-18 May 2000; p. NR 658. [Google Scholar]

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Figure 1. Etiology of epilepsies.

Table 1. Key symptoms of ADHD.

Inattentive Symptoms

Hyperactivity/Impulsivity Symptoms

Pays no attention to details and makes reckless actions

❖ Excessive fidgets.

Inability to maintain attention in school, exercise, and work

Failure to remain in the seat when required.

When addressed, he does not appear to listen.

Frequently runs around or climbs in inappropriate settings.

Inability to follow directions, failure to complete work

Often unable to quietly participate in play when needed.

Demonstrate a significant level of disorganization during the execution of tasks and activities

Always "on the move" and appears "powered by a motor."

Tendency to avoid tasks that require attention, such as reading long papers.

Talks excessively.

Items required for tasks and activities are misplaced.

Answers impatiently before the inquiry is finished.

Extraneous stimuli such as irrelevant ideas cause distraction.

Frequently unable to await their turn.

Inattention to regular tasks such as paying bills and making appointments

Frequently interrupts or interferes with others

Table 2. Prevalence of ADHD in CWE.

Country

Published Year

ADHD/CWE%

References

China

2012, 2018

24.7-42

[ 81, 84]

Norway

2011, 2016

12.1-31.7

[ 42, 49]

UK

2014, 2003

12-33

[ 78, 80]

AMA Style

Fan H-C, Chiang K-L, Chang K-H, Chen C-M, Tsai J-D. Epilepsy and Attention Deficit Hyperactivity Disorder: Connection, Chance, and Challenges. International Journal of Molecular Sciences. 2023; 24(6):5270. https://doi.org/10.3390/ijms24065270

Chicago/Turabian Style

Fan, Hueng-Chuen, Kuo-Liang Chiang, Kuang-Hsi Chang, Chuan-Mu Chen, and Jeng-Dau Tsai. 2023. "Epilepsy and Attention Deficit Hyperactivity Disorder: Connection, Chance, and Challenges" International Journal of Molecular Sciences 24, no. 6: 5270. https://doi.org/10.3390/ijms24065270

APA Style

Fan, H.-C., Chiang, K.-L., Chang, K.-H., Chen, C.-M., & Tsai, J.-D. (2023). Epilepsy and Attention Deficit Hyperactivity Disorder: Connection, Chance, and Challenges. International Journal of Molecular Sciences, 24(6), 5270. https://doi.org/10.3390/ijms24065270

# data[].attributes.attachment_link.title
Epilepsy and Attention Deficit Hyperactivity Disorder: Connection, Chance, and Challenges

# data[].attributes.attachment_link.description
Comorbidities are common in children with epilepsy, with nearly half of the patients having at least one comorbidity. Attention deficit hyperactivity disorder (ADHD) is a psychiatric disorder characterized by hyperactivity and inattentiveness level disproportional to the child's developmental stage.

# data[].attributes.headline
Guidance for identification and treatment of individuals with attention deficit/hyperactivity disorder and autism spectrum disorder based upon expert consensus

# data[].attributes.subject
Guidance for identification and treatment of individuals with attention deficit/hyperactivity disorder and autism spectrum disorder based upon expert consensus

# data[].attributes.attachment_link.title
Guidance for identification and treatment of individuals with attention deficit/hyperactivity disorder and autism spectrum disorder based upon expert consensus - BMC Medicine

# data[].attributes.attachment_link.description
Background Individuals with co-occurring hyperactivity disorder/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) can have complex presentations that may complicate diagnosis and treatment. There are established guidelines with regard to the identification and treatment of ADHD and ASD as independent conditions. However, ADHD and ASD were not formally recognised diagnostically as co-occurring conditions until the Diagnostic and Statistical Manual of Mental Disorders 5 (DSM-5) was published in 2013. Hence, awareness and understanding of both conditions when they co-occur is less established and there is little guidance in the clinical literature. This has led to uncertainty among healthcare practitioners when working with children, young people and adults who present with co-existing ADHD and ASD. The United Kingdom ADHD Partnership (UKAP) therefore convened a meeting of professional experts that aimed to address this gap and reach expert consensus on the topic that will aid healthcare practitioners and allied professionals when working with this complex and vulnerable population. Method UK experts from multiple disciplines in the fields of ADHD and ASD convened in London in December 2017. The meeting provided the opportunity to address the complexities of ADHD and ASD as a co-occurring presentation from different perspectives and included presentations, discussion and group work. The authors considered the clinical challenges of working with this complex group of individuals, producing a consensus for a unified approach when working with male and female, children, adolescents and adults with co-occurring ADHD and ASD. This was written up, circulated and endorsed by all authors. Results The authors reached a consensus of practical recommendations for working across the lifespan with males and females with ADHD and ASD. Consensus was reached on topics of (1) identification and assessment using rating scales, clinical diagnostic interviews and objective supporting assessments; outcomes of assessment, including standards of clinical reporting; (2) non-pharmacological interventions and care management, including psychoeducation, carer interventions/carer training, behavioural/environmental and Cognitive Behavioural Therapy (CBT) approaches; and multi-agency liaison, including educational interventions, career advice, occupational skills and training, and (3) pharmacological treatments. Conclusions The guidance and practice recommendations (Tables 1, 4, 5, 7, 8 and 10) will support healthcare practitioners and allied professionals to meet the needs of this complex group from a multidisciplinary perspective. Further research is needed to enhance our understanding of the diagnosis, treatment and management of individuals presenting with comorbid ADHD and ASD.

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Interventions for ADHD in Children & Adolescents with Epilepsy: A Review and Decision Tree to Guide Clinicians, 2022

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Interventions for ADHD in Children & Adolescents with Epilepsy: A Review and Decision Tree to Guide Clinicians, 2022

# data[].attributes.attachment_link.readable_text
Eating disorders are characterised by preoccupation with weight, shape and calorie balance. Purging, overexercise and preoccupation with body image cause psychosocial and physical harm. Eating disorders typically begin in early to mid-adolescence, but can emerge at any age. The lifetime prevalence of anorexia nervosa in the general population in Western countries is about 1% in women and 0.5% in men. With treatment, around 50% of people with anorexia nervosa achieve full functional recovery. Adolescents have higher rates of full recovery and lower mortality than adults.

Remit and target users

This guideline provides recommendations based on current evidence for best practice in the management of people with eating disorders of all ages and gender groups, in any health or social care setting. Eating disorders covered are:

anorexia nervosa

bulimia nervosa

binge eating disorder

eating-disordered psychopathology occurring in the context of type 1 diabetes mellitus.

This guideline will be of interest to primary, secondary and tertiary healthcare professionals, education and social care professionals involved in the care of people with eating disorders, as well as patients and their families and carers.

How this guideline was developed

This guideline was developed using a standard methodology based on a systematic review of the evidence. Further details can be found in SIGN 50: A Guideline Developer's Handbook.

Keeping up to date

This guideline was published in 2022 and will be considered for review in three years. The review history, and any updates to the guideline in the interim period, are noted in the update report.

# data[].attributes.attachment_link.description
This guideline provides recommendations based on current evidence for best practice in the management of people with anorexia nervosa, bulimia nervosa, binge eating disorders and eating-disordered psychopathology occurring in the context of type 1 diabetes mellitus. It covers all ages and gender groups, in any health or social care setting.

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2022 European clinical guidelines for Tourette syndrome and other tic disorders 

# data[].attributes.subject
2022 European clinical guidelines for Tourette syndrome and other tic disorders 

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Tourettes Action is a support and research charity working to improve the lives of people living with Tourette Syndrome. Our services include online live-chat and email support, a befriender network, information, webinars, events and resources.

# data[].attributes.headline
SIGN 156 - Children and young people exposed prenatally to alcohol: A national clinical guideline, Jan 2019

# data[].attributes.subject
SIGN 156 - Children and young people exposed prenatally to alcohol: A national clinical guideline, Jan 2019

# data[].attributes.headline
Fetal alcohol spectrum disorder - Quality standard, QS204, 16 March 2022

# data[].attributes.subject
Fetal alcohol spectrum disorder - Quality standard, QS204, 16 March 2022

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This quality standard covers assessing and diagnosing fetal alcohol spectrum disorder (FASD) in children and young people. It also covers support during pregnancy to prevent FASD. It describes high-quality care in priority areas for improvement.

The quality standard uses the terms 'woman' or 'mother' throughout. These should be taken to include people who do not identify as women but who are pregnant.

How to use NICE quality standards and how we develop them

Quality standards help you improve the quality of care you provide or commission. They apply in England and Wales (see the UK government website and Welsh government website). Decisions on how they apply in Scotland and Northern Ireland are made by ministers in the Scottish government and Northern Ireland Executive.

Find out how to use quality standards and how we develop them. We check our quality standards every August to make sure they are up to date.

Your responsibility

Service providers and healthcare professionals should satisfy themselves that they are complying with their legal and professional regulatory duties. When exercising their judgement, professionals and practitioners are expected to take this quality standard into account, alongside the individual needs, preferences and values of their patients or the people using their service. It is not mandatory and does not override the responsibility to make decisions appropriate to the circumstances of the individual, in consultation with them and their families and carers or guardian.

When supporting people to make decisions, service providers and healthcare professionals should ensure that people have the information they need to make decisions and to give consent in line with General Medical Council (GMC) guidance and the Nursing and Midwifery Council (NMC) Code.

# data[].attributes.attachment_link.description
This quality standard covers assessing and diagnosing fetal alcohol spectrum disorder (FASD) in children and young people. It also covers support during pregnancy to prevent FASD. It describes high-quality care in priority areas for improvement. The quality standard uses the terms 'woman' or 'mother' throughout.

# data[].attributes.headline
Fetal alcohol spectrum disorder: a guideline for diagnosis across the lifespan, 2016

# data[].attributes.subject
Fetal alcohol spectrum disorder: a guideline for diagnosis across the lifespan, 2016

# data[].attributes.headline
First Evidence-Based Guideline for Interventions in FASD, 2025

# data[].attributes.subject
First Evidence-Based Guideline for Interventions in FASD, 2025