Download Current Issues in HPV: Are you Up-To

4/25/2017
Current Issues in HPV:
Are you Up-To-Date?
Barbara Pahud MD MPH
Associate Professor of Pediatrics
©The Children's Mercy Hospital, 2015
© The Children’s Mercy Hospital, 2016
Disclosure
• None related to this talk
Objectives
HPV Infection & Disease
 Understand HPV infections in men and women
 Understand the burden of HPV disease in the US HPV Vaccines
 Define the importance of HPV vaccination for cancer prevention and the rationale for vaccinating at a young age  Provide useful and compelling information about HPV vaccine to parents to aid in making the decision to vaccinate.
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Understanding the Burden HPV INFECTION & DISEASE
HPV Types Differ in their Disease Associations
~40 Types
Mucosal
sites of infection
High risk (oncogenic)
HPV 16, 18 most common
Cervical Cancer
ancer
Anogenital Cancers
Oropharyngeal Cancer
Cancer Precursors
Low Grade Cervical Disease
Cutaneous
sites of infection
~ 80 Types
Low risk (non-oncogenic)
HPV 6, 11 most common
Genital Warts
Laryngeal Papillomas
Low Grade Cervical Disease
“Common”
Hand and Foot
Warts
HPV Infection
Almost all females and males will be infected with at least one type of HPV at some point in their lives
 Estimated 79 million Americans currently infected  14 million new infections/year in the US
 HPV infection is most common in people in their teens and early 20s
Most people will never know that they have been infected
Jemal A et al. J Natl Cancer Inst 2013;105:175‐201
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HPV Transmission
HPV exposure can occur with any type of intimate sexual contact
Intercourse is not necessary to become infected
Nearly 50% of high school students have already engaged in sexual (vaginal‐penile) intercourse
 1/3 of 9th graders and 2/3 of 12th graders have engaged in sexual intercourse  24% of high school seniors have had sexual intercourse with 4 or more partners
Jemal A et al. J Natl Cancer Inst 2013;105:175‐201
HPV is found in virgins
Study examined the frequency of vaginal HPV and the association with non‐coital sexual behavior in longitudinally followed cohort of adolescent women without prior vaginal intercourse
HPV was detected in 46% of women prior to first vaginal sex
70% of these women reported non‐coital behaviors that may in part explain genital transmission
Shew, J Infect Dis. 2012
Cervical Cancer
Cervical cancer is the most common HPV‐
associated cancer among women
 500,000+ new cases and 275,000 attributable deaths world‐wide in 2008
 11,000+ new cases and 4,000 attributable deaths in 2011 in the U.S.
37% cervical cancers occur in women who are between the ages of 20 and 44
 13% (or nearly 1 in 8) between 20 and 34  24% ( or nearly 1 in 4) between 35 and 44 CDC. HPV–associated cancers—US, 2004–2008. MMWR 2012;61(15):258–261.
Cervical Cancer Counts by Age. US Cancer Statistics data from 2010, CDC.gov.
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HPV Types That Cause Cervical Cancer: A Worldwide Survey
13%
HPV 16
9%
HPV 18
HPV 45
3%
4%
5%
HPV 31
53%
HPV 33
13%
HPV negative
All other HPV
types
Munoz et al, ‘03 n = 1918
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HPV‐Associated Cervical Cancer Rates by Race and Ethnicity, United States, 2004–2008
Jemal A et al. J Natl Cancer Inst 2013;105:175‐201
The Pap smear in the 21st Century
Sensitivity of pap smear is problematic
50% of women diagnosed with cervical cancer never had cytology screening
HPV testing is extremely sensitive, but less specific than Pap
All cervical cancers are due to HPV
But most HPV resolves without clinical disease
Combinations of tests may emphasize strengths and decrease weaknesses
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Without vaccination, annual burden of genital HPV‐related disease in U.S. females: 4,000 cervical cancer deaths
10,846 new cases of cervical cancer
330,000 new cases of HSIL: CIN2/3
(high grade cervical dysplasia)
1 million new cases of genital warts
1.4 million new cases of LSIL: CIN1
(low grade cervical dysplasia)
Nearly 3 million cases and $7 billion American Cancer Society. 2008; Schiffman Arch Pathol Lab Med. 2003; Koshiol
Sex Transm Dis. 2004; Insinga, Pharmacoeconomics, 2005
Annual Report to the Nation on the Status of Cancer: HPV‐Associated Cancers
From 2000 to 2009, oral cancer rates increased  4.9% for Native American men
 3.9% for white men
 1.7% for white women
 1% for Asian men
Anal cancer rates doubled from 1975 to 2009
Vulvar cancer rates rose for white and African‐
American women Penile cancer rates increased among Asian men Average Number of New HPV‐Associated Cancers by Sex, in the United States, 2015
See Pahud & Ault 2015 and Saraiya et al 2015
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HPV‐Associated Oropharyngeal Cancers
Prevalence increased from 16.3% (1984‐89) to 71.7% (2000‐04)
Population‐level incidence of HPV‐
positive cancers increased by 225%
while HPV‐negative cancers declined by 50%
If trends continue, the annual number of HPV‐positive oropharyngeal cancers is expected to surpass the annual number of cervical cancers by the year 2020
Chaturvedi, 2011, J Clin Oncol‐ data from SEER
George Papanicolaou
 Born in Greece 1883, came to USA 1913
 Initial interests were in cytological changes associated with ovulation
 Published initial article in 1941 with Dr. Traut in American Journal of Obstetrics and Gynecology
 Cytology atlas 1943
Sources – Michalas ‘00 photo from 1957 Life Magazine
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Cancer rates in Women – 20th Century
All uterine sites
i.e. cervical and
endometrial
Source: American Cancer Society
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Prevalence Update
Any HPV
During 2011–2014, prevalence of any oral
HPV was 7.3% among adults aged 18–69, 11.5% among men and 3.3% among women
Prevalence Update
 High‐risk HPV
During 2011–
2014, prevalence of high‐risk oral
HPV was 4% among adults aged 18–69, 6.8% among men and 1.2% among women
NCHS Data Brief‐No.280‐April 2017
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End of the World
During 2013–2014, prevalence of any and high‐risk genital HPV for adults aged 18–59 was 45.2% and 25.1% in men and 39.9% and 20.4% in women, respectively.
Nobel Prize, 2008
Harald zur Hausen
Images from Nobel Prize web site
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HPV Testing
HPV DNA test can find high‐risk HPV types
Indications:
Reflex testing: Determination for the need for colposcopy in women with an ASCUS cytology result (minor changes of unknown significance)
Cotesting : As an adjunct to cytology for cervical cancer screening in women 30‐65 and older
Primary cervical cancer screening in women 25 yrs and older*
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Evidence‐Based HPV Disease Prevention
HPV VACCINE
HPV Prophylactic Vaccines
Recombinant L1 capsid proteins that form “virus‐like” particles (VLP) Non‐infectious and non‐oncogenic
Produce higher levels of neutralizing antibody than natural infection
HPV Virus‐Like Particle
HPV Vaccine Comparison
These HPV Types Cause:
Genital warts ~66% of Cervical Cancers
~15% of Cervical Cancers
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HPV Vaccine Recommendation
Girls&BoyscanstartHPVvaccinationatage9
Preteens should finish HPV vaccine series by 13th birthday
Plusgirls13‐26yearsold
whohaven’tstartedor
finishedHPVvaccineseries
Plusboys13‐21yearsold
whohaven’tstartedor
finishedHPVvaccineseries
ACIP Recommendation and AAP Guidelines for HPV Vaccine
Routine HPV vaccination recommended for both males and females ages 11‐12 years
Catch‐up ages 13‐21 years for males; 13‐26 for females
Permissive use ages 9‐10 years for both males and females; 22‐26 for males
HPV Update
 CDC now recommends 11 to 12 year olds get two doses of HPV vaccine—rather than the previously recommended three
 Can start as early as 9 years of age (FDA approved)
 The second dose should be given 6‐12 months after the first dose.  Teens and young adults who start the series later, at ages 15 through 26 years, will continue to need three doses
 Immunocompromised patients will also need 3 doses
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HPV Vaccination Is Safe, Effective, and Provides Lasting Protection
HPV Vaccine is SAFE
 Benefits of HPV vaccination far outweigh any potential risks  Safety studies findings for HPV vaccination similar to safety reviews of MCV4 and Tdap vaccination
HPV Vaccine WORKS
 Population impact against early and mid outcomes have been reported in multiple countries
HPV Vaccine LASTS
 Studies suggest that vaccine protection is long‐lasting
 No evidence of waning protection
Garland et al, Prev Med 2011; Ali et al, BMJ 2013;
Markowitz JID 2013; Nsouli‐Maktabi MSMR 2013
HPV Vaccine Safety Data Sources
Over 57 million doses of HPV vaccine distributed in US since 2006
 Post‐licensure safety data (VAERS)1
 Post‐licensure observational comparative studies (VSD)2
 Ongoing monitoring by CDC and FDA
 Post‐licensure commitments from manufacturers
 Vaccine in pregnancy registries
 Long term follow‐up in Nordic countries
 Official reviews
 WHO’s Global Advisory Committee on Vaccine Safety 3
 Institute of Medicine’s report on adverse effects and vaccines, 20114
1Vaccine Adverse Events Reporting System, http://vaers.hhs.gov/index
2Vaccine Safety Datalink, http://www.cdc.gov/vaccinesafety/Activities/VSD.html
3http://www.who.int/vaccine_safety/Jun_2009/en/
4http://www.iom.edu/Reports/2011/Adverse‐Effects‐of‐Vaccines‐Evidence‐and‐Causality.aspx
9vHPV Vaccine Safety
Seven pre‐licensure studies including 15,000 males and females
Generally well tolerated Adverse event profile similar to that of 4vHPV across age, gender, race, and ethnicity
More injection‐site reactions expected among those who receive 9vHPV 12
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HPV Vaccine
Duration of Immunity
Studies suggest that vaccine protection is long‐lasting; no evidence of waning immunity
Available evidence indicates protection for at least 8‐10 years
Multiple cohort studies are in progress to monitor the duration of immunity
Monitoring Impact of HPV Vaccine Programs on HPV‐Associated Outcomes
HPV VACCINE IMPACT
HPV vaccine impact monitoring
 Post licensure evaluations are important to evaluate real world effectiveness of vaccines
 Population impact against early and mid outcomes have been reported:
Genital warts
Australia, New Zealand, Denmark, Sweden, Germany, Quebec, US
HPV prevalence
Australia, Norway, Denmark, Sweden, UK, US
Cervical lesions
Australia, British Columbia, Denmark, Sweden, US
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HPV Vaccine Impact:
High HPV Vaccine Coverage in Australia
80% of school‐age girls in Australia are fully vaccinated
High‐grade cervical lesions have declined in women less than 18 years of age
For vaccine‐eligible females, the proportion of genital warts cases declined dramatically by 93%
Genital warts have declined by 82% among males of the same age, indicating herd immunity
Garland et al, Prev Med 2011
Ali et al, BMJ 2013
Prevalence per 1000 Person‐years
Anogenital wart prevalence, female private insurance enrollees, U.S., 2003‐2010
20‐24
25‐29
30‐34
15‐19
35‐39
10‐14
Flagg, et al. AJPH 2013
Impact of HPV vaccination in Australia
Proportion of Australian born females and males diagnosed as having genital warts at first visit, by age group, 2004‐11
Females
Ali, et al. BMJ 2013
Males
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Systematic Review and Meta‐Analysis: Population‐Level Impact of HPV Vaccination
Review of 20 studies in 9 high income countries
In countries with >50% coverage, among 13‐19 yr olds
 HPV 16/18 prevalence decreased at least 68%
 Anogenital warts decreased by ~61%
Evidence of herd effects
Some evidence of cross protection against other types
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Drolet et al. Lancet Infect Dis 2015
International uptake of 3 doses HPV vaccine
Australia UK Canada Netherlands USA
Brotherton, Lancet 2011; Cuzick BJC 2010; Ogilvie et al., 2010; Marc et al., 2010, NIS‐Teen 2011 National Estimated Vaccination Coverage Levels among Adolescents 13‐17 Years, National Immunization Survey‐Teen, 2006‐2012
90
80
70
60
Tdap
50
MCV4
Percent Vaccinated
1 HPV girls
40
3 HPV girls
1HPV boys
30
3 HPV boys
20
10
0
2006
2007
2008
2009
2010
2011
2012
Survey Year
Tdap: tetanus, diphtheria, acellular pertussis vaccine.
MCV4: meningococcal conjugate vaccine
HPV: human papillomavirus vaccine
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Why We Need to Do Better in HPV Vaccination of 12 year olds
Currently 26 million girls <13 yo in the US; If none of these girls are vaccinated then:
168,400 will develop cervical cancer and
54,100 will die from it
 Vaccinating 30% would prevent 45,500 of these cases and 14,600 deaths
 Vaccinating 80% would prevent 98,800 cases and 31,700 deaths
For each year we stay at 30% coverage instead of achieving 80%, 4,400 future cervical cancer cases and 1400 cervical cancer deaths will occur.
Avoid Missed Opportunities
HPV vaccine can safely be given at the same time as the other recommended adolescent vaccines
Provide HPV vaccine during routine sports, or camp physicals
Review immunization record even at acute care visits
Systems interventions depend on clinician commitment‐ determine what would work best for YOUR practice
Actual and Achievable Vaccination Coverage if Missed Opportunities Were Eliminated: Adolescents 13‐17 Years, NIS‐Teen 2012
Among girls unvaccinated for HPV, 84% had a missed opportunity
Missed opportunity: Encounter when some, but not all ACIP‐recommended vaccines are given.
HPV‐1: Receipt of at least one dose of HPV.
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The Perfect Storm
Why is HPV vaccine different?  HPV vaccine issues sensationalized by popular media
 Different reasons for why some girls and boys don’t get the first shot and why some don’t finish all 3 shots
 Parents think sexuality instead of cancer prevention
 Some clinicians aren’t giving strong recommendations
 Parents have questions that are seen as hesitation by some doctors
 Phased girls‐then‐boys recommendations initially confusing to parents
 Systems interventions to improve coverage rates depend on clinician commitment
Talking about HPV vaccine
FRAMING THE CONVERSATION
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What’s in a recommendation?
Studies consistently show that a strong recommendation from you is the single best predictor of vaccination Give a Strong Recommendation to Receive HPV Vaccine at Ages 11 or 12
Not sexually active
Not recommended
Safety concern/Side effects
Not needed or necessary
Lack of knowledge
0
5
10
Percent
15
20
A strong recommendation from you is the main reason parents decide to vaccinate
 Many moms in focus groups stated that they trust their child’s doctor and would get the vaccine for their child as long as they received a recommendation from the doctor MMWR 2014; 63(29);625-633;
Unpublished CDC data, 2013.
Make an Effective Recommendation
Same way: Effective recommendations group all of the adolescent vaccines
Recommend HPV vaccination the same way you recommend Tdap & meningococcal vaccines.
Same day: Recommend HPV vaccine today
Recommend HPV vaccination the same day you recommend Tdap & meningococcal vaccines.
Unpublished CDC data, 2013.
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Some Parents Need Reassurance
Many parents simply accept of this bundled recommendation
Some parents may be interested in vaccinating, yet still have questions. Interpret a question as
they need additional reassurance from YOU, the clinician they trust with their child’s health care
Ask parents about their main concern (be sure you are addressing their real concern)
Unpublished CDC data, 2013.
An anti‐cancer vaccine
The “HPV vaccine is cancer prevention” message resonates strongly with parents
 In focus groups and online panels, mothers wanted more information on the types of HPV cancers
 In focus groups mothers stated they were influenced to vaccinate their child because HPV vaccine prevents cancer, they had a family history of cervical cancers, and/or because they had a personal experience with cervical cancer
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Tell me doctor, how bad is it?
Disease prevalence is not understood, and parents are unclear about what the vaccine actually protects against
Parents in focus groups knew HPV vaccine can prevent cervical cancers, however they lacked knowledge about indications for HPV vaccine other than cervical cancer for girls, all HPV vaccine indications for boys, and the recommended ages to receive HPV vaccine
Rationale for vaccinating early: Protection prior to exposure to HPV
82%
18 to 24
Markowitz MMWR 2007; Holl Henry J Kaiser Found 2003; Mosher Adv Data 2006 A green light for sexual activity?
Parents may be concerned that vaccinating may be perceived by the child as permission to have sex
 Kaiser Permanente Center for Health Research  1,398 girls who were 11 or 12 in 2006, 30% of whom were vaccinated, followed through 2010
 No difference in markers of sexual activity, including  Pregnancies
 Counseling on contraceptives
 Testing for, or diagnoses of, sexually transmitted infections
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Would you give it to your child?
Emphasizing your personal belief in the importance of HPV vaccine helps parents feel secure in their decision
 Some respondents in focus groups stated that they would feel more comfortable knowing that the doctor had vaccinated their own child or was planning to (if the child was <11)
 Respondents in an online survey stated that knowing that oncologists supported the recommendation made them more likely to get their child vaccinated
Scared of side effects
Understanding that the side effects are minor and emphasizing the extensive research that vaccines must undergo can help parents feel reassured
 Moms in focus groups stated concerns about both short term and long term vaccine safety as a reason that they would not vaccinate their child
 Respondents were not aware that HPV vaccine was tested in adolescents and adults and were concerned that their child’s fertility could be affected by the vaccine
When do we come back?
Many parents do not know that the full vaccine series requires 2 or 3 shots, depending on age
Your reminder will help them to complete the series
In focus groups, most respondents did not know the dosing schedule for HPV vaccine
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How Can Clinicians Help?
1. Give a STRONG recommendation
 Ask yourself, how often do you get a chance to prevent cancer? 2. Start conversation early and focus on cancer prevention
 Vaccination given well before sexual experimentation begins
 Better antibody response in preteens
3. Offer a personal story
 Own children/Grandchildren/Close friends’ children
 HPV‐related cancer case
4. Welcome questions from parents, especially about safety
 Remind parents that the HPV vaccine is safe and not associated with increased sexual activity
cdc.gov/vaccines/who/teens/infographic/hpv‐cancer‐prevention.html
www.cdc.gov/hpv
Free posters available for ordering in the following sizes: 8.5x11, 11x17, 18x24
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QUESTIONS?
[email protected]
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Tourette Syndrome
Overview, current research and treatment options
Keith A. Coffman, MD
Child Neurology/Neurodevelopmental Disabilities
Director, Children’s Mercy Tourette Syndrome Center of Excellence
Director, Movement Disorders Clinic
Children’s Mercy Kansas City
Division of Pediatric Neurology
Associate Professor of Pediatrics
UMKC School of Medicine
© The Children's Mercy Hospital, 2014. 03/14
Disclosure Statement
The content of this presentation does not relate to any product
of a commercial entity; therefore, I have no relationships to
report.
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© The Children's Mercy Hospital, 2014. 03/14
Disclosure Statement
•Most of the medications discussed in this presentation are
not FDA approved for the treatment of Tourette Syndrome.
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© The Children's Mercy Hospital, 2014. 03/14
Tic
• Definition
• A sudden, involuntary, rapid, recurrent, nonrhythmic, stereotyped motor movement or
vocalization.
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© The Children's Mercy Hospital, 2014. 03/14
Tic Disorders
DSM-V Criteria
•Provisional Tic Disorder
•For a person to be diagnosed with this disorder, he or she must:
•have one or more motor tics (for example, blinking or shrugging the
shoulders) or vocal tics (for example, humming, clearing the throat, or
yelling out a word or phrase).
•have been present for no longer than 12 months in a row.
•have tics that start before he or she is 18 years of age.
•have symptoms that are not due to taking medicine or other drugs, or
due to having a medical condition that can cause tics (for example,
Huntington disease or post-viral encephalitis).
•not have been diagnosed with TS or persistent motor or vocal tic
disorder.
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© The Children's Mercy Hospital, 2014. 03/14
Tic Disorders
DSM-V Criteria
•Persistent (Chronic) Motor or Vocal Tic Disorder
•For a person to be diagnosed with a persistent tic disorder, he or she must:
•have one or more motor tics (for example, blinking or shrugging the
shoulders) or vocal tics (for example, humming, clearing the throat, or
yelling out a word or phrase), but not both.
•have tics that occur many times a day nearly every day or on and off
throughout a period of more than a year.
•have tics that start before he or she is 18 years of age.
•have symptoms that are not due to taking medicine or other drugs, or due to
having a medical condition that can cause tics (for example, seizures,
Huntington disease, or postviral encephalitis).
•not have been diagnosed with TS.
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© The Children's Mercy Hospital, 2014. 03/14
Tourette Syndrome
DSM-V Criteria
•Tourette Syndrome (TS)
•For a person to be diagnosed with TS, he or she must:
•have both multiple motor tics (for example, blinking or shrugging the
shoulders) and vocal tics (for example, humming, clearing the throat, or
yelling out a word or phrase), although they might not always happen at
the same time.
•have had tics for at least a year. The tics can occur many times a day
(usually in bouts) nearly every day, or off and on.
•have tics that begin before he or she is 18 years of age.
•have symptoms that are not due to taking medicine or other drugs or
due to having another medical condition (for example, seizures,
Huntington disease, or postviral encephalitis).
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© The Children's Mercy Hospital, 2014. 03/14
Who develops tics?
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© The Children's Mercy Hospital, 2014. 03/14
Tourette Syndrome
Typical age at presentation
• Motor tics: 3-8 years of age
• Vocal: 8-15 years of age
• A small portion of patients develop
symptoms after 18 years of age
•Jankovic et al. Tourette Syndrome in Adults. Movement Disorders, 2010, 25: 2171-2175.
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© The Children's Mercy Hospital, 2014. 03/14
Tics
Epidemiology
• Prevalence
• All tic disorders: 20-60/1000 children and teens
• Tourette Syndrome/Chronic Tic disorder
• 1.2 % of the population (CDC update)
• Male to female ratio
• ~3-4:1
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© The Children's Mercy Hospital, 2014. 03/14
What do tics look and sound like?
• Just about anything!
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© The Children's Mercy Hospital, 2014. 03/14
Common Motor Tics
• Simple Motor
• Eye blink, face twitch, grimace, shoulder shrug, neck jerk,
abdomen tense
• Complex Motor
• Gesturing, jumping, touching, pressing, stomping, facial or
body contortions, licking, smelling, squatting, retracing
steps, twirling, “dystonic” tics (assuming and holding
unusual postures), blocking tics (all motor activity stops)
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© The Children's Mercy Hospital, 2014. 03/14
Common Vocal Tics
• Simple Vocal
• Sniffing, snorting, throat clearing, yipping, yelping, grunting,
humming, coughing, spitting, barking
• Complex Vocal
• Spontaneous expression of words or phrases
• Palilalia (repeating one's own sounds or words)
• Often in a decrescendo pattern
• Echolalia (repeating the last heard sound, word, or phrase)
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© The Children's Mercy Hospital, 2014. 03/14
Rare Motor Tics
• Copropraxia
• Spontaneous, involuntary, obscene, vulgar or sexual gestures
• Only 5.9 % of males and 4.9 % of females
• Freeman et al., Coprophenomena in Tourette syndrome. Developmental Medicine & Child
Neurology, 2009, 51: 218–227.
• Echopraxia
• Mirroring or mimicking another persons movements
• Paligraphia
• Repeating written letters, words and/or phrases
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© The Children's Mercy Hospital, 2014. 03/14
Rare Vocal Tics
• Coprolalia
• Spontaneous, non-intentional utterances of
profanity, ethnic, racial or religious slurs
• Only 19.3 % of males and 14.6 % of females
• Freeman et al., Coprophenomena in Tourette syndrome. Developmental Medicine & Child
Neurology, 2009, 51: 218–227.
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© The Children's Mercy Hospital, 2014. 03/14
Characteristics of tics
• Predictable
• But will vary throughout the day, week, month, etc.
• Can be temporarily voluntarily suppressed
• May be uncomfortable and costs attention
• Distractible
• Especially if engaged in an activity
• May disappear during sleep
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© The Children's Mercy Hospital, 2014. 03/14
Characteristics of tics
• Worsen with stress, excitement, fatigue, or illness
• Premonitory urge
• Physical feeling that often precedes tic
• Patients feel like they need to tic
• Similar to the feeling before a sneeze
• Typically “develops” between 8-11 years
• In truth, most patients realize that it is there by this point
in life.
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© The Children's Mercy Hospital, 2014. 03/14
Characteristics of tics
• Suggestible
• Patients will often do their tics after discussing them or seeing others
do them.
• Tics worsen when patients watch themselves tic
• Visual feedback of own tics increases tic frequency in patients with
Tourette’s syndrome
•
Brandt et al. Visual feedback of own tics increases tic frequency in patients with
Tourette's syndrome. Cognitive Neuroscience, 2015, 6:1-7.
• Obsessive-compulsive component
• Many feel the need to perform a tic in a specific way or a specific
number of times until it feels “just right.”
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© The Children's Mercy Hospital, 2014. 03/14
Characteristics of tics
Tics can be exhausting, both physically, and emotionally!
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© The Children's Mercy Hospital, 2014. 03/14
Tourette Syndrome
• Many neurologists say, "What's to worry about its
just tics!"
• If it were just tics, it might not be that bad.
• For most patients, however, tics have rather
miserable company.
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© The Children's Mercy Hospital, 2014. 03/14
Common Co-morbid Conditions
• Attention-Deficit/Hyperactivity Disorder (ADHD)
• Obsessive-Compulsive Disorder (OCD)
• Anxiety
• Intermittent explosive behavior
• 85.7% of patients with Tourette will have at least one comorbid disorder
• Hirschtritt et al., Lifetime prevalence, age of risk, and genetic relationships of
comorbid psychiatric disorders in Tourette syndrome. JAMA Psychiatry. 2015, 72:
325–333
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© The Children's Mercy Hospital, 2014. 03/14
Uncommon Associated Conditions
• Oppositional Defiant Disorder (ODD)
• Depression
• Learning disabilities
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© The Children's Mercy Hospital, 2014. 03/14
Associated Symptoms
• Sensitivity to stimulation
• Food and clothing textures
• Loud noises, bright lights
• Smelling of non-food objects
• Restless leg symptoms
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© The Children's Mercy Hospital, 2014. 03/14
Associated Symptoms
• Sleep disorders
• Restless leg syndrome, sleep walking and talking
• Executive function deficits
• Poor handwriting
• Does not improve with occupational therapy
• Compulsive buying/collecting of objects
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© The Children's Mercy Hospital, 2014. 03/14
Tourette Syndrome
Course of disorder
•Tics naturally wax and wane.
•The most predictable thing about tics is their unpredictability.
•Typically, the most severe time in life is between 9-15 years of age.
•Age of peak severity 12.3 (7.7-16-9 years)
•Shprecher et al., Temporal Course of the Tourette Syndrome Clinical Triad.
Tremor and other Hyperkinetic Disorders, 2014, 4:1-5.
‹#›
© The Children's Mercy Hospital, 2014. 03/14
Tourette Syndrome
Course of disorder
• After that, tics typically improve as age increases
• Late adolescence to adulthood
• 1/3 completely resolve
• In total, 75 % significantly improve
•Bloch and Leckman, Clinical course of Tourette syndrome. Journal of Psychosomatic
Research, 2009, 67: 497-501.
•Remission occurred at 17.4 years (13.6-21.1 years)
•Shprecher et al., Temporal Course of the Tourette Syndrome Clinical Triad. Tremor and other
Hyperkinetic Disorders, 2014, 4:1-5
‹#›
© The Children's Mercy Hospital, 2014. 03/14
What causes Tourette?
We don’t know
•Genetic
• Possible dominant pattern of inheritance
• For tics as well as associated features
• Heritability of 0.58 for Tourette and 0.37 for OCD
• Davis LK, et al. Partitioning the Heritability of Tourette Syndrome
and Obsessive Compulsive Disorder Reveals Differences in Genetic
Architecture. PLoS Genetics, 2013, 9: e1003864
‹#›
© The Children's Mercy Hospital, 2014. 03/14
What causes Tourette?
We don’t know
•Developmental
• Tics develop in early childhood and tend to remit by
late teens/early adulthood
‹#›
© The Children's Mercy Hospital, 2014. 03/14
What causes Tourette?
•Disturbance in one or more neurotransmitters
•Dopamine
•Serotonin
•GABA
•Acetylcholine (Central)
•Glutamate
•Norepinephrine
•Epinephrine
•Histamine
‹#›
© The Children's Mercy Hospital, 2014. 03/14
What causes Tourette?
•Neurosteroids?
•Tourette more common in males (4:1)
•Worsens with stress
•Explosive behavior and hypersexual behavior in some patients
•Presents in childhood around adrenarche
•Dramatically changes around puberty onset
•Improvement in adult males with TS when treated with
finasteride
• 5 α-reductase inhibitor that blocks androgen production
Muroni et al. A preliminary study of finasteride in Tourette Syndrome. Movement Disorders, 2011,
26:2146-7.
‹#›
© The Children's Mercy Hospital, 2014. 03/14
What causes Tourette?
•Neurosteroids in Tourette
•Rodent models of Tourette
•Improved sensorimotor gating with finasteride
•Reduction in tics with finasteride
•5 α-reductase modulates D1 and GABA receptors, both
implicated in the pathophysiology of Tourette.
Bortolato et al. The implication of neuroactive steroids in Tourette Syndrome pathogenesis: A
role for 5 α-reductase? J Neuroendocrinol. 2013, 25:1196-208.
Frau et al. The neurosteroidogenic enzyme 5 α-reductase modulates the role of D1 dopamine
receptors in rat sensorimotor gating. Psychoneuroendocrinology. 2016, 63:59-67.
‹#›
© The Children's Mercy Hospital, 2014. 03/14
Anatomic Neuroimaging Research
• Numerous studies have tried to use MRI
to delineate the anatomy of Tourette.
• There are a few key studies that
provide some significant insight.
‹#›
© The Children's Mercy Hospital, 2014. 03/14
Anatomic Neuroimaging Research
•Reduced cortical thickness in motor, premotor, prefrontal and
lateral orbitofrontal cortices
• Worbe et al. Distinct structural changes underpin clinical phenotypes in patients with
Gilles de la Tourette syndrome. Brain, 2010, 133: 3649-60.
•Relative grey matter volume reduction in orbitofrontal,
anterior cingulate and ventrolateral prefrontal cortices
• Draganski et al. Multispectral brain morphometry in Tourette syndrome persisting into
adulthood. Brain, 2010, 133:3661-75.
•Lower WM volume bilaterally in orbitofrontal and medial
prefrontal cortex, and greater GM volume in posterior
thalamus, hypothalamus and midbrain.
• Greene et al. Brain structure in pediatric Tourette syndrome. Mol Psychiatry, 2016,doi:
10.1038/mp.2016.194.
‹#›
© The Children's Mercy Hospital, 2014. 03/14
Anatomic Neuroimaging Research
• Cortical thinning in the sensory and motor cortices corresponding
to the face, mouth, tongue and throat representations
•Sowell et al. Thinning of sensorimotor cortices in children with Tourette syndrome.
Nature Neuroscience. 2008, 11: 637-639.
• Reduced caudate volume
•Peterson et al. Basal ganglia volumes in patients with Gilles de la Tourette
syndrome. Archives of General Psychiatry, 2003, 60: 415-424.
‹#›
© The Children's Mercy Hospital, 2014. 03/14
Neuropathology Research
•Autopsy studies
• There may be a developmental difference in the migration of
GABAergic inhibitory neurons in the basal ganglia in patients with TS.
• These changes were noted in the associative (cognitive) and
sensorimotor regions of the basal ganglia.
• This may lead to a dysfunction of both the input and output stages
of basal ganglia processing.
•Kalanithi et al. Altered parvalbumin-positive neuron distribution in basal ganglia of individuals with
Tourette syndrome. Proceedings of the National Academy of Sciences, 2005, 102:13307- 13312.
•Kataoka et al. Decreased Number of Parvalbumin and Cholinergic Interneurons in the Striatum of
Individuals with Tourette Syndrome. Journal of Comparative Neurology, 2010, 518:277–291.
‹#›
© The Children's Mercy Hospital, 2014. 03/14
What does it all mean?
• Tourette is a disorder of neural circuitry.
• There are both structural and functional
abnormalities in multiple nodes of
multiple neural circuits.
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© The Children's Mercy Hospital, 2014. 03/14
What do these data really mean?
•This is why is it is so complex.
•That is why it is so hard to treat.
•One cannot alter an isolated node within the brain.
•You always get upstream or downstream effects!
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© The Children's Mercy Hospital, 2014. 03/14
Functional Topography
‹#›
Motor
Sensory
Cognitive
Limbic
Caudate/
Putamen
Caudate/
Putamen
Caudate/
Putamen
Caudate/
Putamen
GPi/SNr
GPi/SNr
GPi/SNr
GPi/SNr
Thalamus
Thalamus
Thalamus
Thalamus
© The Children's Mercy Hospital, 2014. 03/14
Genetic Research
• Presently, there are no known genetic
causes for most patients with Tourette
Syndrome
• Twin Studies
• Identical twin concordance is 77-100%
• Fraternal twin concordance is 23%
•Price et al., A twin study of Tourette syndrome. Archives of General Psychiatry 1985,
42:815–20.
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© The Children's Mercy Hospital, 2014. 03/14
Genetic Research
• Most recent Tourette GWAS study
• 1,285 patient with Tourette
• 4,964 controls
• In a primary meta analysis of GWAS data, no
markers achieved a genome wide threshold of
significance.
• Linkage to Chromosome 9q32, gene COL27A1
• Scharf et al. 2013, Genome-wide association study of Tourette Syndrome.
Molecular Psychiatry, 2013, 18: 721–728.
‹#›
© The Children's Mercy Hospital, 2014. 03/14
Genetic Research
• Copy number variants and Tourette
• CNV are an abnormal number of copies sections of DNA
• Implicated in Autism, ADHD, schizophrenia
• Five exon-affecting rare CNVs identified in TS patients
• NRXN1, AADAC, CTNNA3, FSCB, (KCNE2, KCNE1 and RCAN1)
• Sundaram et al. Tourette syndrome is associated with recurrent exonic copy
number variants, Neurology, 2010, 74: 1583-1590.
• Two large rearrangement CNVs identified in TS patients
• NRXN1 and COL8A1
• Nag et al. CNV Analysis in Tourette Syndrome Implicates Large Genomic
Rearrangements in COL8A1 and NRXN1. PLoS ONE, 2013, 8: e59061
‹#›
© The Children's Mercy Hospital, 2014. 03/14
Genetic Research
• Copy number variants and Tourette
• 2435 subjects with Tourette and 4100 controls
• Duplications in CNTN6
• Deletions in NRXN1
• Present in 1% of those with Tourette
• First study with this level of prevalence of genetic abnormalities
• Huang et al. 2016, in press
‹#›
© The Children's Mercy Hospital, 2014. 03/14
Then how do we treat it?
‹#›
© The Children's Mercy Hospital, 2014. 03/14
We treat the symptoms.
‹#›
© The Children's Mercy Hospital, 2014. 03/14
To treat or not to treat?
•Pharmacological treatment
•Treatment does not affect outcome.
•Treatment does not decrease length of time patient will have
tics.
•Treatment does not prevent other tics from developing.
‹#›
© The Children's Mercy Hospital, 2014. 03/14
When to treat
•Tics that cause pain.
•Tics that bother the patient or interfere with desired
activities.
•Decline in academic performance
•Tics cause the patient to be bothered by others.
‹#›
© The Children's Mercy Hospital, 2014. 03/14
Goals of Treatment
•Tic treatment
•Patient dependent
•May be elimination of all tics (not-realistic), reduction in the
most severe tics, or elimination of the most bothersome tic
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© The Children's Mercy Hospital, 2014. 03/14
Goals of Treatment
•Must address other domains as well
•Anxiety, ADHD, OCD, Explosive Behavior
•School performance
•Social Functioning
•Sports
‹#›
© The Children's Mercy Hospital, 2014. 03/14
Goals of Treatment
•Family
•Immediate and extended family need to understand that tics are not
voluntary.
•Family must be on the same page with each other.
•Health care professionals need to counsel families about associated
conditions.
•Encourage parents to let the patient take an active role in his/her care.
•Siblings need to understand disease as well.
‹#›
© The Children's Mercy Hospital, 2014. 03/14
Goals of Treatment
•School
•Must address teacher and class comfort level
•Must ask about friends, bullying
•May need to consider an IEP, 504 agreement or RTII for school
accommodations
•Address common school stressors
•Tests, cafeteria, school bus, recess, and fire drills, assemblies,
delays and cancellations, substitute teachers, field trips
‹#›
© The Children's Mercy Hospital, 2014. 03/14
Psychological Treatment
• Comprehensive Behavioral Intervention for Tics (CBIT)
• Should be a part of the comprehensive treatment of patients with
Tourette syndrome
• Very effective and side-effect free.
• Many patients, especially teens, do not want to do it.
‹#›
© The Children's Mercy Hospital, 2014. 03/14
Psychological Treatment
• Principle is to train patients to replace tics with another
non-interfering behavior
• Components
• Motivation
• Become aware
• Self-monitoring
• Develop a competing response
• Relaxation techniques
‹#›
© The Children's Mercy Hospital, 2014. 03/14
Psychological Treatment
CBIT
• How effective is this?
• 52% of patients who engaged in this technique saw
improvement.
• This rate of improvement is comparable to trials of
medications for patients with TS!
• 87% of available responders to behavior therapy
exhibiting continued benefit 6 months following
treatment.
Piacentini et al., Behavior Therapy for Children with Tourette Disorder
A randomized controlled trial. JAMA, 2010; 303:1929-1937.
‹#›
© The Children's Mercy Hospital, 2014. 03/14
Psychological Treatment
CBIT
• How might CBIT work?
• Normalize aberrant cortico-striato-thalamo-cortical activation
• Functional MRI pre and post CBIT
• TS subjects had significant decrease in putaminal activation from preto post-treatment.
• Change in task-related activation from pre- to post-treatment in
Brodmann area 47 was negatively correlated with changes in tic
severity.
Deckersbach et al., Neural correlates of behavior therapy for Tourette's
disorder. Psychiatry Res. 2014, 224:269-74.
‹#›
© The Children's Mercy Hospital, 2014. 03/14
Psychological Treatment
CBIT
• If it is so great, why isn't everyone doing it?
• Many people are uninformed about the benefits of this approach.
• Many people have an irrational fear of anything to do with psychology
or psychiatry.
• This is hard work!! Teenagers hate the idea of working hard to make
themselves better.
‹#›
© The Children's Mercy Hospital, 2014. 03/14
Now it is time to discuss medications
‹#›
© The Children's Mercy Hospital, 2014. 03/14
Where do we treat?
‹#›
© The Children's Mercy Hospital, 2014. 03/14
Functional Topography
‹#›
Motor
Sensory
Cognitive
Limbic
Caudate/
Putamen
Caudate/
Putamen
Caudate/
Putamen
Caudate/
Putamen
GPi/SNr
GPi/SNr
GPi/SNr
GPi/SNr
Thalamus
Thalamus
Thalamus
Thalamus
© The Children's Mercy Hospital, 2014. 03/14
Medication Treatment
•FDA-Approved medications
•Haloperidol (Haldol)
•Pimozide (Orap)
•Aripiprazole (Abilify)
•Discussed in detail later
‹#›
© The Children's Mercy Hospital, 2014. 03/14
Medication Treatment
First Line
• α2 -adrenergic agonists
•Clonidine, Guanfacine
•Tablets or transdermal patch (clonidine)
•Effective in placebo controlled trials
•FDA-approved for ADHD
•May also be useful for aggression, insomnia
•Side effects:
•sedation, lightheadedness, dry mouth, hypotension, can
cause rebound hypertension if stopped abruptly
‹#›
© The Children's Mercy Hospital, 2014. 03/14
Medication Treatment
Second Line
•Topiramate
•Works on GABAA receptors, sodium channels, AMPA
receptors and carbonic anhydrase inhibitor
•FDA-approved for migraine and epilepsy
•Effective in a double-blind placebo trial
• Jankovic et al. A randomized, double-blind, placebo-controlled study of topiramate
in the treatment of Tourette syndrome, JNNP, 2010, 81:70-73.
•Side effects
•Decreased appetite, paresthesias, possible cognitive
slowing, sedation, risk of kidney stones, glaucoma
‹#›
© The Children's Mercy Hospital, 2014. 03/14
Medication Treatment
Second Line
•Baclofen
•GABAB receptor agonist
•Used for the treatment of spasticity
•Comes in tablets or liquid
•Sedation main side effect
•Singer et al., Baclofen treatment in Tourette syndrome: a double-blind, placebocontrolled, crossover trial, Neurology, 2001, 56:599-604.
•Botulinum toxin
•Blocks acetylcholine release
•Given via intramuscular injection
•Very effective for refractory neck or laryngeal tics, multiple citations
•Effective, three month relief
‹#›
© The Children's Mercy Hospital, 2014. 03/14
Medication Treatment
Second Line
•Clonazepam
•Benzodiazepine
•Acts on GABAA receptors to decrease neuronal activity
•Also decreases serotonin utilization
•Used for the treatment of epilepsy, anxiety, RLS
•Available as tablets and wafers
•Side effects
•Sedation, mood and behavioral change, tolerance,
withdrawal seizures
‹#›
© The Children's Mercy Hospital, 2014. 03/14
Medication Treatment
Third Line
•Antipsychotics
•Typical (dopamine antagonist)
•Haloperidol, Pimozide- FDA Approved for Tourette
•Fluphenazine- used but not FDA approved
•Atypical (dopamine and serotonin antagonists)
•Ziprasidone, Risperidone, Olanzapine
•Atypical (dopamine and serotonin agonist)
•Aripiprazole- FDA approved for Tourette
•Side effects
• sedation, weight gain, mood/behavioral changes, extrapyramidal side effects
(akathisia, tardive dyskinesia), prolonged QT interval, amenorrhea, oculogyric crisis,
seizures
‹#›
© The Children's Mercy Hospital, 2014. 03/14
Medication Treatment
Fourth Line
•Selective serotonin reuptake inhibitors
•For the anxiety or obsessive-compulsive disorders
•Fluoxetine, paroxetine, sertraline, escitalopram, citalopram,
fluvoxamine
•Very little data to show effectiveness for tics
•Side effects
•nausea, insomnia, drowsiness, decreased sexual interest,
tremors, increased sweating, suicidal behavior
•Ondansetron
•Serotonin receptor antagonist (5-HT3)
•Side effects: sedation, headache, dizziness
• Toren et al., Ondansetron treatment in Tourette's disorder: a 3-week, randomized, double-blind,
placebo-controlled study. J Clin Psychiatry, 2005, 66:499-503.
‹#›
© The Children's Mercy Hospital, 2014. 03/14
Medication Treatment
Fourth Line
•Delta 9-tetrahydrocannibinol
•Partial agonist of cannabinoid receptors
•FDA approved in U.S. for chemotherapy induced nausea as
dronabinol
• Small, placebo-controlled studies show effectiveness (oral capsules)
•No significant negative impact on neuropsychological testing
•Side effects: Euphoria, abnormal thinking, dizziness, paranoia,
somnolence
Muller-Vahl et al. Treatment of Tourette syndrome with delta-9-tetrahydrocannabinol (delta 9-THC): no
influence on neuropsychological performance. Neuropsychopharmacology. 2003, 28:384-8
Muller-Vahl et al. Delta 9-tetrahydrocannabinol (THC) is effective in the treatment of tics in Tourette
syndrome: a 6-week randomized trial. J Clin Psychiatry. 2003, 64:459-65
‹#›
© The Children's Mercy Hospital, 2014. 03/14
Surgical Treatment
•Deep brain stimulator therapy (DBS)
•Direct modulation of corticobasal ganglionic circuitry will reduce tics
•Multiple trials published to date
•Including placebo-controlled, crossover trials
•These studies indicate that there may be effectiveness for DBS in Tourette
•Controversy over target site, CM thalamus versus GPe versus GPi versus
ALIC
•Not FDA approved for Tourette
•Tourette Association of America has published guidelines for consideration
of surgical candidates
•Schrock et al., Tourette syndrome deep brain stimulation: A review and updated recommendations.
Movement Disorders, 2015, 30:448-471.
‹#›
© The Children's Mercy Hospital, 2014. 03/14
Tourette Association Center of Excellence
Children’s Mercy Hospital
STAFF
Keith A. Coffman, MD, Director
James R. Batterson, MD, Co-Director
J. Joshua Hall, PhD, Neuropsychology
Andrea Calvert, Pharm D, Clinical Pharmacist
Jayme Kagarice, RN, APRN, Child Neurology
Chandra Holliday Callow, LCSW, Family Therapy
Sandy Price, RN, MSN, Nurse Coordinator
Janelle Gerling, OTR/L
Meghan Turner, RN, CPN, Child Neurology
‹#›
© The Children's Mercy Hospital, 2014. 03/14
Tourette Association Center of Excellence
Children’s Mercy Hospital
Joining Soon- Summer 2017
Bridget Clark, MD
Triple Board graduate from Indiana University
Additional Child Neurology/Neurodevelopmental
Disabilities faculty- Two signed at this point
Additional Neurology Nurse Practitioner-Recruiting
‹#›
© The Children's Mercy Hospital, 2014. 03/14
Clinic Volumes
•Total patients seen in 2016–——————-1073
•New patients seen in 2016————————282
•DNKA in 2016———————55
•No show rate-5.1%
•Missouri, Kansas, Oklahoma, Iowa, Illinois,
Arkansas, California, Washington, Pennsylvania
‹#›
© The Children's Mercy Hospital, 2014. 03/14
Tourette Association Center of Excellence
Children’s Mercy Hospital
Care model
• Intake by Nurse Coordinator
• Triages patient to Child Neurologist, APRN, Child Psychiatrist, or
combo appointment with Neurology and Psychiatry
• Team meeting every Thursday morning
• Patient cases and issues discussed, research project updates
• Full-time family therapist for Tourette families
• Pediatric Neuropsychologist with expertise in Tourette
• Four providers certified and trained in CBIT
• Occupational therapist for CBIT and sensory therapy
• Close working relationship with community support group in KC
‹#›
© The Children's Mercy Hospital, 2014. 03/14
Any Questions?
Thank you
‹#›
© The Children's Mercy Hospital, 2014. 03/14
4/26/2017
Evidence Based
Medicine Lecture
ADHD In the Trenches
Chris D. Stone, MD
Section of General Pediatrics
Children’s Mercy Hospital and Clinics
DISCLOSURE STATEMENT
 I have no actual or potential conflict of interest in relation to this program.
Chris D. Stone, MD
 Graceland University BS Chemistry and Computer Science 1983
 University of Kansas School of Medicine MD 1987
 Combined Internal Medicine/Pediatrics Residency 1991
 Private Practice Freeport, Illinois 1991‐2001
 Academic Med/Peds Via Christi Family Medicine Residency Program 2001‐2008
 Academic Med/Peds Children’s Mercy Hospital 2008‐
present
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Learning Objectives
 Be able to diagnose ADHD and co morbid conditions
 Be familiar with medication titration strategies
 Be familiar with medication effects , side effects, insurance coverage and cost for long term use
Learning Objectives (cont.)
 List issues associated with both over and under diagnosis in children with ADHD.
 List two evidence‐based guidelines used in pharmacologic treatment of ADHD.
 Identify when to refer to specialist with ADHD.
Overview





What do we know about ADHD?
How to diagnose and treat ADHD?
What are consequences of treating or not treating?
How to diagnose and treat co‐morbidities?
What are consequences of treating or not treating co‐morbidities?
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Parents of 17 y/o adolescent w/ ADHD are concerned about the long‐term risk for mental health problems. The parents should be informed that which of the following co‐morbid mental health problems are common among adults with a history of childhood ADHD?





A. Alcohol abuse or dependence
B. Avoidant personality disorder
C. Bipolar disorder
D. Borderline personality disorder
E. Schizophrenia
Parents of 17 y/o adolescent w/ ADHD are concerned about the long‐term risk for mental health problems. The parents should be informed that which of the following co‐morbid mental health problems are common among adults with a history of childhood ADHD?
 A. Alcohol abuse or dependence
Barbaresi WJ, Colligan RC, Weaver AL, et al. Mortality, ADHD, and Psychosocial Adversity in Adults with Childhood ADHD: a prospective study. Pediatrics. 2014 Apr;131(4):637‐644.
A 12 y/o boy has ADHD and a co‐morbid anxiety disorder. Which of the following causes of death in early adulthood is most likely for this patient?





A. Accidental poisoning
B. Automobile accident
C. Gunshot wound
D. Suicide
E. Other medical condition
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A 12 y/o boy has ADHD and a co‐morbid anxiety disorder. Which of the following causes of death in early adulthood is most likely for this patient?
 D. Suicide
Barbaresi WJ, Colligan RC, Weaver AL, et al. Mortality, ADHD, and Psychosocial Adversity in aAdults with Childhood ADHD: a prospective study. Pediatrics. 2014 Apr;131(4):637‐644.
Approximately what percent of children with ADHD will be free from both ADHD and other psychiatric disorders in early adulthood?





A. 5%
B. 15%
C. 25%
D. 35%
E. 45%
Approximately what percent of children with ADHD will be free from both ADHD and other psychiatric disorders in early adulthood?
 D. 35%
Barbaresi WJ, Colligan RC, Weaver AL, et al. Mortality, ADHD, and Psychosocial Adversity in Adults with Childhood ADHD: a prospective study. Pediatrics. 2014 Apr;131(4):637‐644.
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What do we know about ADHD?
 Brief history overview
 Prevalence
 Associations
The history of attention‐deficit/hyperactivity disorder. Attention‐deficit/hyperactivity disorder (ADHD) ‘syndromes’ have been described in the medical literature since the eighteenth century, but the growth of systematic research required the development of operational diagnostic criteria in the late twentieth century. This schematic outlines selected important developments in the history of ADHD research. CBT, cognitive–
behavioural therapy; CDC, Centers for Disease Control and Prevention; DSM, Diagnostic and Statistical Manual of Mental Disorders. (2015). "ADHD." Nature Reviews Disease Primers 1: 15027.
Worldwide Prevalence of ADHD in Children
Ex USA
USA
N.Y., Mich., Wis.
North Carolina
Virginia
Missouri
Oregon
Minnesota
Tennessee
Iowa
Pittsburgh
New York City
Puerto Rico
Spain
New Zealand
Canada
Ireland
United Kingdom
Israel
Switzerland
Netherlands/Belgium
Germany
Ukraine
Brazil
Japan
New Zealand
Netherlands
China
India
Prevalence of ADHD (%)
Faraone SV et al. (2003), World Psychiatry 2(2):104‐113
Prevalence of ADHD (%)
www.mghcme.org
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Akinbami et al. NCHS Data Brief No. 70, August 2011
www.mghcme.org
Diagnosis of ADHD
• Diagnosis is based on clinical assessment of
symptoms, associated impairment and age of
onset
• No test is available
• Symptoms are subjective, as well as developmentally and context sensitive
www.mghcme.org
ADHD: Core Symptom Areas
www.mghcme.org
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ADHD: Course of the Disorder
Hyperactivity
Impulsivity
Inattention
Time
www.mghcme.org
Course of ADHD Symptoms Over Time by Sex: A Growth Curve Model
Age by Sex Interaction: NS
Biederman et al. 2009
www.mghcme.org
Developmental Course of ADHD in Persistent Cases
Faraone, S. V., et al. (2015). "ADHD." Nature Reviews Disease Primers 1: 15027
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Quality of life and ADHD, impairment as child, teen, and adult
Faraone, S. V., et al. (2015). "ADHD." Nature Reviews Disease Primers 1: 15027
Age‐Dependent Decline and Persistence of ADHD Throughout the Lifetime
(2015). "ADHD." Nature Reviews Disease Primers 1: 15027.
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Mortality, ADHD, and Psychosocial Adversity in Adults with Childhood ADHD: a prospective study
Barbaresi WJ, Colligan RC, Weaver AL, et al. Mortality, ADHD, and Psychosocial Adversity in Adults with Childhood ADHD: a prospective study. Pediatrics. 2014 Apr;131(4):637‐644.
ADHD has High Morbidity
• Early in life, ADHD is associated with:
– Learning problems
– Educational underachievement
– Peer problems
– Behavioral problems
– Accidents and Injuries
• Later in life, ADHD is associated with:
– Occupational under‐attainment
– Marital problems
www.mghcme.org
ADHD also Increases Risk for
• Psychiatric conditions including:
–
–
–
–
Antisocial and criminal behavior
Addiction
Mood and anxiety disorders
Posttraumatic Stress Disorder
• Medical conditions including:
–
–
–
–
Asthma
Obesity
Metabolic syndrome
Traumatic Brain Injury
www.mghcme.org
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Genetics and environmental Factors
ADHD
Schizophrenia
Panic Disorder
Height
Laarson 2004
Rietveld 2003
Martin 2002
Kuntsi 2001
Coolidge 2000
Thapar 2000
Willcutt 2000
Hudziak 2000
Nadder 1998
Levy 1997
Sherman1997
Silberg 1996
Gjone 1996
Thapar 1995
Schmitz 1995
Stevenson 1992
Edelbrock 1992
Gillis 1992
Goodman 1989
Willerman 1973
Matheny 1971
0
0.1
0.2
0.3
0.4
0.5
Heritability
Faraone et al. Biol Psychiatry. 2005;57:1313‐23.
0.6
0.7
0.8
0.9
1
Mean heritability of ADHD = 0.75
Environmental stressors increase the risk
of developing ADHD
 The timing of the stressor appears to be critical to confer risk; most associated stressors occur in utero or during the neonatal period.  Prenatal exposure to nicotine, alcohol, and recreational drugs is associated with ADHD or related behavioral traits.
 Nicotine, alcohol, and certain drugs can pass across the placenta, influencing fetal brain development.
 Prenatal exposure to excess glucocorticoids or maternal stress during pregnancy also contributes to the development of ADHD.
(Smith, Mick, & Faraone, 2009)
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Environmental stressors increase the risk
of developing ADHD (cont.)
 Environmental factors related to ADHD include perinatal stress and low birth weight
 Severe traumatic brain injury
 Maternal smoking during pregnancy
 Exposure to lead
 Very severe early social deprivation
 Gene environment interactions may be critical in the development of ADHD.
(Dopheide & Pliszka, 2009)
Instructions for Diagnosis
 What are the bare bones to make diagnosis? DSM V criteria, familiarity and knowledge of ADHD.
 What makes it easier? Primary care physician knows the patient and family, able to skip over many items.
 Guidelines and toolkits can make this easier.
Changes in DSM‐V ADHD
• Neurodevelopmental” ‐ not “disruptive”
• ≥ 6/9 inattentive or ≥ 6/9 impulsive/hyperactive symptoms over last six months (>5 for adults)
• Symptoms caused impairment by age 12 (no longer
7)
• ASDs no longer exclusionary
• No more “subtypes”; Inattentive / Hyperactive‐
impulsive / Combined are now “Presentations”
• Restricted inattentive subtype: In Appendix, worthy of further study
www.mghcme.org
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Threshold Too Low
•
•
•
•
DO NO HARM
Not everyone that is gifted with energy has ADHD
Symptoms with impairment before 7 years of age.
Impairment from the symptoms in 2 or more settings (school/occupation, home, in public). • Clear evidence of clinically significant impairment in social, academic, or occupational functioning (DSM IV)
Threshold Too Low
• Ask developmental and age appropriate threshold questions.
• Think of common situations for that child, family.
 School‐Grades and behavior
 Public‐friends, grocery store, movies, eat out
 Family‐behavior at home
Threshold Too High
•
•
•
•
•
DO NO HARM
ADHD does actually exist
Typically one child per class of 25 has ADHD
Missed diagnoses are just as bad as over diagnoses
Look at as relative risk‐similar to CD risk of illicit drug use without drug treatment
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Adherence in ADHD is Dismal
Only 13% of patients consistently take their
medication one year out
100%
Patients (%)
80%
 Within 2 to 3 months, a majority of patients with ADHD have stopped taking medication consistently
OROS MPH
MPH LA
MAS XR
Atomoxetine
60%
 Patients renewed their monthly prescriptions about 2 to 3 times per year1
40%
20%
0%
1
3
5
7
9
11
13
15
Month
Zuvekas al. Am J Psychiatry 2012; 169:160‐166
www.mghcme.org
www.mghcme.org
Published in Journal of Child and Adolescent Psychopharmacology. August 2016, 26(6):
520-526.
DOI: 10.1089/cap.2015.0228
© Mary Ann Liebert, Inc.
FIG. 1. Percentage of population with any stimulant prescriptions by sex and age, United States, 2008. IMS
LifeLink® Information Assets-LRx Longitudinal Prescription Database, 2008, IMS Health Incorporated.
Denominators for national estimates of any stimulant use by sex and single year of age based on 2008
National Medical Expenditure Survey data.
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Poor Adherence to Treatment in
ADHD
This is so despite the well documented morbidity of ADHD, the marked efficacy and safety of stimulants as well as the fact that ADHD symptoms return rapidly when the medication is not taken
www.mghcme.org
How to Diagnose co morbidities?
 ADHD AAP Toolkit 2011 new assessment items‐see Gen Peds Website for access.
 UW PAL for kids‐
http://www.seattlechildrens.org/pdf/PAL/WA/WA‐care‐
guide.pdf (works as of 4‐3‐17)
ADHD Comorbidities
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AAP ADHD Toolkit  2011 Initial Vanderbilt assessment form adds
tic and movement disorder questions
 New tools available to better diagnose co
morbidities-SCARED, PHQ-9, etc.
Early Intervention May Reduce
Later Disease Burden
• Detecting ADHD symptoms early can lead to
increased vigilance and monitoring
– School accommodations may reduce burden of disease on academic progress
– Parent education may reduce burden of disease
on family and social functioning
– Behavioral interventions may reduce degree of associated behavioral disturbances
www.mghcme.org
Long Delays in the Initiation of
Treatment (n=1498)
9
7.8
8
7
6
p < 0.001
5
4
3.3
3
2
1
0
Age of Onset of Diagnosis
Age of Onset of Treatment MGH Pediatric Psychopharmacology Clinic
www.mghcme.org
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Delay in Diagnosis
• There is often a significant delay from
symptom onset to diagnosis
• Symptoms most often begin in the preschool
years (ages 3‐6), but the majority of children
are diagnosed in grade school years (ages 6‐
10)
www.mghcme.org
Early Diagnosis Can Be Challenging
• Diagnosis in preschoolers (3‐5) can be
particularly challenging
– May not have an alternate setting
– May not be able to use the same rating scales
– Developmental differences
www.mghcme.org
Dealing with Diagnostic Uncertainty in Small Children
•
•
•
•
•
Careful developmental History
Referral for behavior therapy
Start school/structured day setting
Special education evaluation
Invest in rating scales validated for this age (Conners, ADHD‐RS‐IV‐Preschool Version)
• Close follow‐up
www.mghcme.org
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What is Comorbidity in ADHD?
• Most often used to refer to a co‐existing
psychiatric disorder
• Other types of comorbidity
– Subthreshold psychiatric symptoms
– Medical illness
– Psychosocial stress
www.mghcme.org
Comorbidity with ADHD is
Common
• By most estimates, about two‐thirds of individuals with ADHD have at least one comorbid condition
• Many more have “subthreshold” symptoms
www.mghcme.org
Comorbid Disruptive Behavior
Disorders and ADHD
• 40‐70% of children with ADHD have ODD or CD
• 40‐60% of children with ODD or CD have ADHD
Newcorn J et al, “ADHD and Oppositionality and Aggression” in ADHD and Comorbidities: Handbook for Complications in Children and Adults.
www.mghcme.org
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Comorbid Depression and ADHD
• 70% of referred children with depression had
comorbid ADHD
• 30% of referred children with ADHD had comorbid depression
Biederman J et al. Arch Gen Psychiatry. 1996;53:437‐446
Biederman J et al. J Am Acad Child Adolesc Psychiatry. 1995;34:579‐590.
www.mghcme.org
Comorbid Anxiety and ADHD
• About 30% of individuals with generalized
anxiety disorder also have ADHD
• About 25‐50% of children with ADHD have a co‐morbid anxiety disorder
.Spencer, T., Biederman, J., & Wilens, T. (1999). Pediatric Clinics of North America, 46, 915‐927.
www.mghcme.org
Comorbid PTSD and ADHD
• In our meta‐analysis, individuals with ADHD had nearly 4x the risk of developing PTSD compared to those without ADHD
• Individuals with PTSD had 2x the risk of ADHD compared to controls with similar trauma exposure
Spencer A et al, J Clin Psychiatry, 2015
www.mghcme.org
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Comorbid Substance Use
Disorders and ADHD
• Individuals with ADHD are twice as likely to develop a substance use disorder compared to those without ADHD
• Comorbidities increase the risk, especially conduct disorder
Zulauf et al, Curr Psychiatry Rep, 2014.
www.mghcme.org
Pediatricians are better able to identify
and treat ADHD than comorbidities
• Pediatricians were most confident about identifying ADHD (vs. other psychiatric disorders)
• Also reasonably confident about identifying:
– Depression
– Developmental Disorders
– Substance Use Disorders
www.mghcme.org
Children were most often referred for
ADHD with comorbidity
• 57.3% of evaluated children had ADHD, many with multiple co‐morbidities
32%
43%
25%
No ADHD
ADHD Simplex ADHD Complex
www.mghcme.org
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Approach to Assessing Comorbidities in Primary Care
• Have high clinical concern for comorbidities in
children with ADHD
• Consider screening children with ADHD for comorbidities using standardized tools
• Consider screening for ADHD to identify early
and prevent later complications
• Child Psychiatry Consultation can be helpful to
evaluate significant comorbidities
www.mghcme.org
Standardized Tools to Identify ADHD
and Comorbidities: Some Examples
• Narrow Band
– Vanderbilt Rating Scales
– ADHD Rating Scales
– SNAP‐IV Rating Scales
– Conners Rating scales
• Broad Band
– Pediatric Symptom Checklist (PSC)
– Strengths and Difficulties Questionnaire (SDQ)
– Child Behavior Checklist (CBCL)
www.mghcme.org
Comorbidity Complicates Treatment in Primary Care
• PCP’s are more comfortable treating ADHD
than other psychiatric conditions
• PCPs may be less likely to treat ADHD if they suspect comorbidities
• ADHD treatment may affect comorbid
symptoms
• Each single condition may be harder to treat
www.mghcme.org
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Approach to Treating Comorbid
ADHD in Primary Care
• Early detection of ADHD to minimize later
dysfunction
• Optimize ADHD treatment when possible
• Monitor identified comorbidities
• Monitor for development of new comorbid symptoms
• Refer for treatment of more severe
comorbidities
www.mghcme.org
Unique Ways to Improve Treatment for
Comorbid ADHD in Primary Care
• Short term parenting programs (e.g. Triple P,
Incredible Years, PCIT)
• Parent mental health history and referral
• Collaborative or Integrated Child Psychiatry Consultation
www.mghcme.org
Disparity in Identification
• Socioeconomically disadvantaged and underrepresented minority children with ADHD experience:
–
–
–
–
–
Under‐diagnosis
Medication underuse
Treatment attrition
Poor linkage to school services
Decreased utilization of subspecialty care
• They are also at high risk of poor outcomes associated with ADHD including educational underachievement and addiction
www.mghcme.org
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ADHD as a Brain Disorder:
Neuroimaging Findings
www.mghcme.org
MRI findings in Adult with ADHD
Seidman et al. Biol Psychiatry, 2006; 60: 1071‐1080
www.mghcme.org
Volume Reductions in Adult ADHD
Volumetric reductions
in light blue (frontal and
cerebellar regions)
Superior frontal gyrus
Anterior Cerebellar cingulate cortex
gyrus
Seidman et al. Biol Psychiatry, 2006; 60: 1071‐1080
www.mghcme.org
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Cortical Thickness Analysis in Adult with ADHD
Supramarginal Gyrus
(BA40)
Dorsolateral Frontal
Cortex (BA 8, 9)
Angular Gyrus
(BA39)
Middle Temporal Gyrus
(BA21)
Superior Temporal Gyrus
(BA22)
Makris et al. Cerebral Cortex June 2007; 17:1364‐1375
www.mghcme.org
Cortical Thickness Analysis in Adult with ADHD
Anterior Cingulate
Gyrus (BA24)
Orbital Frontal Cortex
((BA 11, 12, 13, 14)
Orbital Frontal Cortex
((BA 11, 12, 13, 14)
Makris et al. Cerebral Cortex June 2007; 17:1364‐1375
www.mghcme.org
A DTI‐MRI Study of Connections in ADHD
Makris et al. Cerebral Cortex 2008 May;18(5):1210‐20
www.mghcme.org
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Dorsal Anterior Cingulate Cortex (Cognitive
Division) Fails to Activate in ADHD
Normal Controls
y = +21 mm
ADHD
1 x 10‐2
y = +21 mm
1 x 10‐2
1 x 10‐3
1 x 10‐3
MGH‐NMR Center & Harvard‐ MIT CITP
Bush et al, Biological Psychiatry 1999
www.mghcme.org
Methylphenidate Activates Dorsal
Anterior Midcingulate Cortex
2.5
2
OROS MPH
Placebo
P = 0.02 vs PBO
1.5
1
0.5
0
Baseline
6 Weeks
• fMRI at baseline and again at week 6
• OROS MPH group showed higher daMCC activation at 6 weeks vs placebo
• N=21 adults with ADHD; dosing to 1.3 mg/kg/day OROS MPH or placebo
Bush et al. Arch Gen Psychiatry. 2008:65:102‐114.
www.mghcme.org
www.mghcme.org
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Nakao et al. Am J Psychiatry 2011
www.mghcme.org
www.mghcme.org
ANOVA Analysis for Cortical Thickness
ANOVA tests showed 10 areas of significant
thickness change in the left hemisphere and 2 areas
in the right hemisphere (p < 0.001, cluster size
50mm2) (see Fig 4). In the post-hoc test, we found
that the TDC group had 8 areas (left: middle frontal
gyrus, precentral gyrus, dorsal and middle postcentral
gyrus, middle temporal gyrus, temporal pole,
intraparietal sulcus; right: precentral gyrus and central
sulcus) that had the highest thickness value as
compared to other groups. In contrast, the ADHD-I
group had 3 areas (left: orbital gyri and fusiform
gyrus; right: superior frontal gyrus) with the highest
thickness value. However, none of the highest values
was found in any region within the ADHD-C group.
Qureshi, M. N. I., et al. (2016). "Multiclass Classification for the Differential Diagnosis on the ADHD Subtypes Using Recursive
Feature Elimination and Hierarchical Extreme Learning Machine: Structural MRI Study." PLoS ONE 11(8): e0160697.
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Twelve regions with significant differences as determined by ANOVA.
Qureshi MNI, Min B, Jo HJ, Lee B (2016) Multiclass Classification for the Differential Diagnosis on the ADHD Subtypes Using
Recursive Feature Elimination and Hierarchical Extreme Learning Machine: Structural MRI Study. PLOS ONE 11(8): e0160697.
doi:10.1371/journal.pone.0160697
But, accuracy has a long way to go, average prediction 49.5% correct
ADHD-200 MRI dataset, which is publicly available at http://fcon_1000.projects.nitrc.org/indi/adhd200 referenced in:
Qureshi, M. N. I., et al. (2016). "Multiclass Classification for the Differential Diagnosis on the ADHD Subtypes Using Recursive
Feature Elimination and Hierarchical Extreme Learning Machine: Structural MRI Study." PLoS ONE 11(8): e0160697.
Faraone et al. Nature Reviews Disease Primers 2015
www.mghcme.org
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The DLPC is linked to WM, the VMPFC to complex decision making and strategic planning, and the parietal cortex to
attention
Brain Mechanisms in ADHD
The VMPFC, OFC & ventral striatum are the brain network associated with anticipation and reward
The frontal and parietal cortices and the thalamus support attentional function
The executive control and cortico‐cerebellar networks coordinate EFs
Negative correlations between the DMN and the
frontoparietal control network are weaker in patients with ADHD
(Faraone, Asherson et al. 2015)
Resting‐State Functional Connectivity in a Longitudinal Sample of ADHD Children Grown Up
www.mghcme.org
Adult ADHD: Decreased Positive
Correlations Between PCC‐MPFC
• 20 ADHD participants (mean age = 34.9; 16 male)
– Ascertained retrospectively
• 20 Controls (mean age = 31.2; 14 male)
Castellanos et al., 2008
www.mghcme.org
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Reduced MPFC‐PCC Coupling Reflects
Current Diagnostic State of ADHD
Mattfeld et al. Brain: A Journal of Neurology 2014, epub: June 10, 2014
www.mghcme.org
From: Brain differences between persistent and remitted attention deficit hyperactivity disorder
Brain. 2014;137(9):2423-2428. doi:10.1093/brain/awu137
Figure Legend:
(A) One sample t-tests in each group showed positive functional connectivity between the posterior cingulate cortex (MNI
coordinates: x = 15, y = −56, z = 28) and regions of the medial prefrontal cortex (MPFC) in control and remitted ADHD groups,
but not in the persistent ADHD group. (B) Between-group comparisons revealed greater positive functional connectivity
between posterior cingulate cortex and medial prefrontal cortex for the control group than the persistent ADHD group. (C) The
remitted ADHD group also showed greater positive functional connectivity between the posterior cingulate cortex and medial
prefrontal cortex than the persistent ADHD group. Statistical height threshold P < 0.05, FWE cluster corrected P < 0.05.
Date of download: 4/2/2017
© The Author (2014). Published by Oxford University Press on behalf of the Guarantors of Brain. All
rights reserved. For Permissions, please email: [email protected]
Neural Basis of Persistent ADHD
• Persistent ADHD alters intrinsic functional
organization of the brain
• Findings supports the idea that adult ADHD diagnosis reflects a true brain difference (vs. controls & vs. remitting ADHD)
Mattfeld et al. Brain: A Journal of Neurology 2014, epub: June 10, 2014
www.mghcme.org
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Mattfeld et al. Brain: A Journal of Neurology 2014, epub: June 10, 2014
www.mghcme.org
www.mghcme.org
ADHD Imaging Studies Summary
• Neuroimaging studies confirm that brain abnormalities in fronto‐subcortical networks are associated with ADHD
• Neuroimaging techniques are not valid tools for ADHD diagnosis; imaging measures are not sensitive or specific enough to be used for diagnostic
purposes
• Treatment attenuate neural deficits
Spencer et al. J Clin Psychiatry 2013 Sep;74(9):902‐17.
www.mghcme.org
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ADHD Diagnostic Considerations
Inattention
Impulsivity/Hyperactivity
www.mghcme.org
Cumulative Morbidity Risks for Psychiatric Disorders in ADHD and Control Probands
Cumulative Morbidity Risk
1
0.9
0.8
Control
0.7
ADHD
P ≤ .009 for all categories
0.6
0.5
0.4
0.3
0.2
0.1
0
Biederman et al. Psychological Medicine, 2006, 36, 167–179.
(Biederman et al., 2012)
www.mghcme.org
www.mghcme.org
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Parental Support at the 16‐Year
Follow‐Up
Controls
ADHD
40%
35%
z=2.13 p=0.03
30%
z=2.45
p=0.01
38.0%
26.6%
25%
20%
15.9%
13.3%
15%
10%
5%
0%
Financially Dependent on Parents
Lives with Parents
Biederman et al. JCP 2012
College Graduate at the 16‐Year Follow‐Up
Controls
100%
90%
80%
70%
60%
50%
40%
30%
20%
10%
0%
ADHD
z=‐4.78
p<0.001
84.6%
37.9%
Biederman et al. JCP 2012
Overall SES at the 16‐Year Follow‐Up
Controls
5.0
ADHD
z=3.47 p=0.001
(Higher Score = Higher SES
Hollingshead Mean Score
4.0
3.0
2.0
2.5
1.9
1.0
0.0
Biederman et al. JCP 2012
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Educational and Occupational Level at the 16‐Year Follow‐Up
Controls
ADHD
Hollingshead Mean Score
(Higher Score = Higher SES
9.0
z=‐5.36
p<0.001
8.0
7.0
6.6
6.1
6.0
z=‐3.12
p=0.002
5.2
5.1
5.0
4.0
3.0
2.0
1.0
0.0
Educational Level (1 to 7)
Occupational Level (1 to 9)
Biederman et al. JCP 2012
Biederman et al.
Pediatrics 2009
Protective Effect of Stimulants on Comorbidity
2
2
(1) =19.7, p<0.001
2
(1) =17.8, p<0.001
(1) =3.5, p=0.063
Biederman et al.
Pediatrics 2009
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Protective Effect of Stimulants on Comorbidity
2
2
(1) =1.3, p=0.258
2
(1) =21.4, p<0.001
(1) =19.9, p<0.001
Biederman et al.
Pediatrics 2009
Protective Effect of Stimulants
2
(1) =18.4, p<0.001
Biederman et al. Pediatrics 2009
www.mghcme.org
ADHD and Substance Abuse
Risk for SUD (%)
Risk for Substance Use Disorder (SUD)
Onset in Adults With Untreated ADHD
100
90
80
70
60
50
40
30
20
10
0
ADHD
Control
P ≤0.05, ADHD vs
control at end point
Earlier onset
Higher risk
0
10
20
30
40
50
60
Age at onset (years)
73
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SUD in ADHD Youth Growing Up:
Overall Rate of Substance Use Disorder
35
Percent of Group
30
p < 0.001
25
20
15
10
5
0
Control (n=344)
Medicated (n=117)
Unmedicated (n = 45)
Biederman, Wilens, Mick et al., Pediatric 1999
Forest Plot of Studies Examining the
ORs of PTSD in ADHD
Citation
Age
•For each comparison, the
dot gives the relative risk
and the horizontal line
gives the 95% confidence
interval
Sample
NORMAL CONTROLS
Antshel 2013
Ruhl 2009
Kessler 2006
Bernardi 2012
Park 2010
Biederman 2012
Adult ADHD
Adult Population
Adult Population
Adult Population
Adult Population
Adult ADHD
Smalley 2007
Child ADHD
Child ADHD
Wozniak 1999
Child ADHD
Hurtig 2007
•The center of the
diamond at the bottom
gives the weighted relative
risk across all studies and
the width of the diamond
gives its 95% confidence
interval
Subtotal
PSYCHIATRIC CONTROLS
McLeer 1994 (PSY) Child Population
Ford 2000
Subtotal
Child ADHD
TRAUMA CONTROLS
Daud 2009 (non-TP) Child Population
Daud 2009 (TP) Child Population
McLeer 1994 (SA) Child Population
Husain 2008
Child Population
Subtotal
.01
.5
1
Relative Risk for PTSD
10
100
PSY=psychiatric sample. SA=Sexually abused sample. TP=Sample of refugee
children with tortured parents. Non-TP=Sample of refugee children with nontraumatized parents.
Spencer‐Kimchi et al. 2014 submitted
www.mghcme.org
Forest Plot of Studies Examining the ORs of
ADHD after mTBI
www.mghcme.org
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Man et al. Pediatrics. 2014 Dec 15.
www.mghcme.org
Mikolajczyk et al. JAMA Pediatr. 2015; doi: 10.1001/jamapediatrics.2014.3275
www.mgh
Percent of Subjects Involved in Collisions During Surprise Events
*
During the five surprise events, drivers in the medication group were 67% less likely to have a collision than drivers in the placebo group
LDX = lisdexamfetamine dimesylate
Biederman et al. 2011 submitted
www.mgh
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(Chang, Lichtenstein et al. 2014)
Accidents and Near Misses
P<0.05*
80%
70%
P<0.05*
ADHD
Probability of Accident
60%
50%
ADHD
40%
30%
20%
10%
0%
Accident
Accident and Near Misses
*Indicates P<0.05 after controlling for gender, age, time of day and the age*ADHD interaction
(Reimer et al., submitted)
www.mghcme.org
Functional Impairments
Results of A Survey of 1000 Subjects
with and without ADHD
www.mghcme.org
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Educational Impairment in High School
Percentage of Those Who Attended High School
*
"C" average or lower
52%
27%
37%
Had a tutor *
Had special classes
*
Had to repeat a grade
*
13%
37%
10%
ADHD (N=464)
30%
Non‐ADHD (N=487)
8%
* p ≤.001
Biederman et al. J Clin Psychiatry. 2006 Apr; 67(4):524‐40
www.mghcme.org
Current Employment Status
Percentage of Each Group
Currently employed
Employed full time
Not currently employed
Looking for work
52%
*
72%
34%
*
57%
48%
*
27%
ADHD (N=500)
14%
*
Non‐ADHD (N=501)
5%
* p ≤.001
Biederman et al. J Clin Psychiatry. 2006 Apr; 67(4):524-40
Average Household Income by
Education Level Attained
Control
$100,000
$90,000
$80,000
$70,000
$60,000
$50,000
$40,000
$30,000
$20,000
$10,000
$0
ADHD
$91,316
$66,683 $63,086
$52,404
$46,471 $38,733
$29,577
$23,859
Less than High
School
High School/Some College/Some Post‐
College
Grad
Post‐graduate Degree
Education (Highest Degree Obtained)
Biederman and Faraone. Medscape General Medicine 2006; 8:12.
www.mghcme.org
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How to treat ADHD?
 MTA Study
 Medication titration and long term treatment
 Behavioral management
Medication Treatment
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Judges’ Reference Table for the March
2016 Psychotropic Medication Utilization
Parameters for Foster Children
http://www.dfps.state.tx.us/Child_Protection/Medical_Services/guidepsychotropic.asp Accessed on 3/30/17
CMAP‐R 2006
In 2006 Plizka, et al revised
the CMAP to accommodate
medication and algorithm
changes due to
implementation studies
noted above.
(Pliszka et al., 2006)
TMAP Algorithm for ADHD
(Pliszka et al., 2006)
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TMAP Algorithm for ADHD and Depression
(Pliszka et al., 2006)
TMAP Algorithm for ADHD and Anxiety
(Pliszka et al., 2006)
TMAP Algrorithm for ADHD and Aggression
(Pliszka et al., 2006)
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ADHD with Inadequate Response to Stimulants: Approaches to Management
(Childress & Sallee, 2014)
Cardiac evaluation of children and adolescents receiving or being considered for stimulant medications.
©2008 by American Academy of Pediatrics
James M. Perrin et al. Pediatrics 2008;122:451-453
In ADHD
Stimulants Found to Improve
Core Symptoms
•
•
•
Inattention
Impulsivity
Hyperactivity
AND
•
•
•
•
•
Noncompliance
Impulsive aggression
Social interactions
Academic efficiency
Academic accuracy
ADHD Practice Parameters. JAACAP 1997;36:85S. Zametkin and Ernst. N Eng J Med 1999;340:40.
www.mghcme.org
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ADHD and Methylphenidate: Dose Effects
on Attention in Clinic and Classroom
65
CPT
Weekly T‐Score
55
ADHD Comprehensive Teachers Rating Score
45
% Academic Efficiency
35
% On Task
25
15
placebo
5
10
15
20
Methylphenidate Dose
Rapport, et al. 1987
www.mghcme.org
Methylphenidate (MPH) in ADHD:
Optimizing Dosing
M e d ica tio n
S ta rtin g D o s e
M a x i m u m D o s e * Usua l Dosing
Dura tion
Ritalin IR ®
5 m g QD/BID
2 mg/kg/day
4 hr / B I D
Focalin ®
2.5 m g QD/BID
1 mg/kg/day
4–5 hr / BID–TID
Focalin X R ®
5 m g QD
1 mg/kg/day
10–12 hr QD
Daytr an a®
10 m g
Concerta ®
18 m g QD
Metadate CD®
20 m g QD
Ritalin LA ®
20 m g QD
8 hr /once
Quilliv ant ®
< 10 m g QD
12 hr /once
Quillichew™
< 10 m g QD
8 hr /once
Aptensio X R
10 m g QD
12 hr /once
*May exceed FDA approved dose.
Wilens TE, et al. Postgrad Med. 2010;122(5):97‐109.www.drugs.com.
6–16 hr
2 mg/kg/day
12 hr / once
8 hr / once
www.mghcme.org
Long Acting MPH formulations
42
4/26/2017
Bioavailability from two MPH
extended‐release formulations
Gonzalez et al. Int J Clin Pharmacol Ther 40(4):175–184
MPH ER Individual PK Plots
Conc (ng/mL)
20
15
10
5
0
0
2
4
6
8
10
Time (hrs)
Amphetamine (AMPH) in ADHD:
Optimizing Dosing
Starting Dose
Maximum Dose*
Usual Dosing
Adderall®
2.5–5 mg QD
1.5 mg/kg/day
Adderall XR®
2.5–5 mg QD
12 hr / QD
30 mg QD
12–14 hr / QD
Medication
Vyvanse®
6 hr / BID
3–5 hr / BID–QID
Dexedrine Tablets®
2.5–5 mg BID
Evekeo®
2.5–5 mg BID
3–5 hr / BID–QID
5 mg QD
6 hr / QD–BID
Dexedrine Spansule®
Dyanavel XR™
(suspension)
Adzenys XR™
(disintegrating
tab)
1.5 mg/kg/day
Duration
2.5–5 mg QD
1.5 mg/kg/day
12 hr / QD
6.3–12.5 mg QD
Not established
12 hr / QD
*May exceed FDA approved dose (eg, > 20 to 30 mg/day).
Wilens TE, et al. CNS News. 2007. Wilens TE, et al. Postgrad Med. 2010;122(5):97‐109.www.drugs.com.
www.mghcme.org
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MAS XR Efficacy:
Academic Productivity
Randomized, Double‐Blind, Placebo‐Controlled Study
Number of Math Problems Completed Correctly
PERMP Number Correct
140
N = 49
120
Placebo MAS 10 mg
MAS XR 10 mg
MAS XR 20 mg
MAS XR 30 mg
100
80
60
40
0.0
1.5
3.0
4.5
6.0
7.5 9.0
Time Postdose (h)
10.5 12.0
www.mghcme.org
McCracken JT, et al. J Am Acad Child Adolesc Psychiatry. 2003;42(6):673‐683.
LDX Chemistry
O
CH 3
H2N
O
H2N
N
H
OH
CH3
H2 N
Site of cleavage
NH 2
LDX
NH 2
l-lysine
d‐amphetamine
www.mghcme.org
LDX Extraction, Pharmacokinetic and Abuse Liability Studies: Results
• Amphetamine is very difficult to extract from LDX prodrug
• Intravenous administration does not result in appreciable serum amphetamine levels in rat and human studies
• Intranasal administration does not result in appreciable serum
amphetamine levels in rat and human studies
• Apparent “saturation” of LDX in gut limits ultimateserum
amphetamine levels (e.g., overdose implications)
• Marginally less likeability in human studies
Jasinski D, et al. Posters presented at CPDD Meeting, June, 2006, Scottsdale, AZ.;
Biederman J, et al. Poster presented at Annual APA Meeting, May 24, 2006, Toronto, Ontario, Canada.
Boyle L, et al. Presented at NCDEU, June 12‐15, 2006, Boca Raton, FL.
www.mghcme.org
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LDX : Duration of Action
SKAMP Time Course
N=50
3.0
LS Mean SKAMP Score
LDX
Adderall XR
Placebo
2.5
2.0
1.5
1.0
0.5
*
*
*
*
2.0
3.0
4.5
6.0
*
*
**
*
**
**
**
**
**
**
0.0
1.0
8.0
10.0 12.0
1.0
2.0
3.0
4.5
6.0
8.0
10.0 12.0
Postdose (h)
*P < .0001, **P < .01, LDX and Adderall XR vs placebo;
LS = Least Square.
www.mghcme.org
Adderall to Vyvanse dose equivalent





Vyvanse = 2.5 X Adderall
Adderall
Vyvanse
20 mg
50 mg
30 mg
70 mg
40 mg
80 mg
Thomas Spencer, ADHD Through the Lifespan course, 3/17/17
Food Effects on Focalin XR
 Administration times relative to meals and meal composition
may need to be individually titrated.
 No food effect study was performed with Focalin XR. However,
the effect of food has been studied in adults with racemic
methylphenidate in the same type of extended-release
formulation. The findings of that study are considered applicable
to Focalin XR. After a high fat breakfast, there was a longer lag
time until absorption began and variable delays in the time until
the first peak concentration, the time until the interpeak
minimum, and the time until the second peak. The first peak
concentration and the extent of absorption were unchanged after
food relative to the fasting state, although the second peak was
approximately 25% lower.
https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/021802s033lbl.pdf Accessed 3/30/2017
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Food Effects on Concerta
 In patients, there were no differences in
either the pharmacokinetics or the
pharmacodynamic performance of
CONCERTA when administered after a highfat breakfast. There is no evidence of dose
dumping in the presence or absence of food.
https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/021121s038lbl.pdf Accessed 3/30/17
Food Effects on Ritalin LA
 Administration times relative to meals and meal composition
may need to be individually titrated.
 When Ritalin LA was administered with a high fat breakfast to
adults, Ritalin LA had a longer lag time until absorption began
and variable delays in the time until the first peak concentration,
the time until the interpeak minimum, and the time until the
second peak. The first peak concentration and the extent of
absorption were unchanged after food relative to the fasting
state, although the second peak was approximately 25% lower.
The effect of a high fat lunch was not examined.
 There were no differences in the pharmacokinetics of Ritalin LA
when administered with applesauce, compared to administration
in the fasting condition. There is no evidence of dose dumping in
the presence or absence of food.
https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/021284s034lbl.pdf
Accessed on 3/30/17
Food effect on Adderall XR
 Food does not affect the extent of absorption of d-amphetamine
and l-amphetamine, but prolongs Tmax by 2.5 hours (from 5.2
hrs at fasted state to 7.7 hrs after a high-fat meal) for damphetamine and 2.7 hours (from 5.6 hrs at fasted state to 8.3
hrs after a high fat meal) for l-amphetamine after administration
of ADDERALL XR 30 mg.
 Opening the capsule and sprinkling the contents on applesauce
results in comparable absorption to the intact capsule taken in
the fasted state. Equal doses of ADDERALL XR strengths are
bioequivalent.
https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/021303s032lbl.pdf Accessed
3/30/17
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Food Effects on Metadate CD
 In a study in adult volunteers to investigate the effects of a highfat meal on the bioavailability of a dose of 40 mg, the presence of
food delayed the early peak by approximately 1 hour (range -2 to
5 hours delay). The plasma levels rose rapidly following the
food-induced delay in absorption. Overall, a high-fat meal
increased the Cmax of METADATE CD by about 30% and AUC by
about 17%, on average (see DOSAGE and ADMINISTRATION).
 After a single dose, the bioavailability (Cmax and AUC) of
methylphenidate in 26 healthy adults was unaffected by
sprinkling the capsule contents on applesauce as compared to
the intact capsule. This finding demonstrates that a 20 mg
METADATE CD Capsule, when opened and sprinkled on one
tablespoon of applesauce, is bioequivalent to the intact capsule.
https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/021259s030lbl.
pdf Accessed 3/30/17
Food effect on Vyvanse
capsule formulation
 Neither food (a high fat meal or yogurt) nor orange juice affects
the observed AUC and Cmax of dextroamphetamine in healthy
adults after single-dose oral administration of 70 mg of
VYVANSE capsules.
 Food prolongs Tmax by approximately 1 hour (from 3.8 hour at
fasted state to 4.7 hour after a high fat meal or to 4.2 hour with
yogurt).
 After an 8-hour fast, the AUC for dextroamphetamine following
oral administration of lisdexamfetamine dimesylate in solution
and as intact capsules were equivalent.
https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/021977s044lbl
.pdf Accessed on 3/30/17
Adverse Effects of Stimulants
• Adverse effects (AEs) are similar for all stimulants
Decreased appetite
Insomnia
Headache
Stomachache
Irritability/rebound phenomena
• Rates of these “AEs” may be high prior to any medical intervention; thus, baseline levels should always be obtained
Wilens T, Spencer T. In: Child and Adolescent Psychiatric Clinics of North America. Philadelphia, Pa:
Saunders Press; 2000:573-604.
www.mghcme.org
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4/26/2017
Psychopharmacological Treatment for Very Young Children
There are additional
guidelines for Disruptive
Behavior Disorder, Major
Depressive Disorder,
Bipolar Disorder, Anxiety
Disorders, PTSD,
Obsessive Compulsive
Disorder, Pervasive
Developmental Disorder
and Primary Sleep
Disorders.
(Gleason et al., 2007)
Blood Pressure and Heart Rate
Over 10 Years in the MTA
No significant treatment‐by‐time effect was observed on systolic or diastolic blood pressure.
A significant treatment‐by‐time effect was observed on heart rate (p=0.02), with significantly higher mean heart rates in the groups receiving medication at 14 months, but not afterward.
Vitiello et al. JAMA 2012
Growth Velocity Z Scores
1
Growth Over Time in Children Treated With MPH
Boys (n = 68)
Girls (n = 16)
0
-1
-2
Year Prior to Tx
First Year Tx
Second Year Tx
Third Year Tx
Duration of Tx
Lisska MC, Rivkees SA. J Pediatr Endocrinol Metab. 2003;16:711‐718.
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Early ADHD Treatment Reduces Marijuana Use
15 year follow‐up study (N=40,358; 10% with
ADHD)
Population risk
Stimulant use started prior to
9 years of age
Stimulant use started between 10‐14
years of age
*
Stimulant use started after
15 years of age
*
20%
30%
40%
50%
60%
Past Year Use
* p<0.001 vs controls
McCabe, West, Dickinson, Wilens. J Am Acad Child Adoles Psych 2016: 55:479‐486
www.mghcme.org
Protective Effect of Stimulants on Comorbidity
2
(1) =
2
19.7, p < 0.001
2
(1) =
(1) =
17.8, p < 0.001
3.5, p = 0.063
Biederman et al. Pediatrics. 2009.
Psychostimulant Treatment and the Developing
Cortex in ADHD
Shaw et al 2009
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Pharmacotherapy for ADHD
•
•
•
•
•
•
•
Stimulants (FDA approved)
– Methylphenidate
– Amphetamine compounds
Atomoxetine (FDA‐approved)
Alpha agonists (FDA‐approved)
– Guanfacine extended‐release
– Clonidine extended‐release
Combined alpha agonists plus stimulants (FDA approved)
– Extended‐release guanfacine plus stimulants
– Extended‐release clonidine plus stimulants
Antidepressants (not FDA approved [+evidence])
– Bupropion
– Tricyclics
Modafinil (not FDA approved [+evidence])
Research
(Wilens & Spencer, Postgraduate Medicine, 2010; Adler, Spencer, Wilens 2015)www.mghcme.org
Atomoxetine Improved Attention in Youth with ADHD and Dyslexia in a 16 Week, Randomized, Double‐Blind Trial
www.mghcme.org
Atomoxetine for Youth with ADHD & Anxiety
ADHD RS
N
Baseline
Improvement
Mean Change from Baseline
0.0
55
58
33.9 (8.9) 34.2 (10.7)
-2.0
Anxiety (PARS)
55
58
17.5 (3.0) 17.0 (2.5)
-1.4
-3.2
-4.0
Atomoxetine
-6.0
-5.5
-8.0
* p<.001
-10.0
-12.0
Placebo
**
effect size = 0.5
-10.5
** p=.011
*
effect s ize = 1.0
Dose of ATMX = 1.26 mg/kg/day
(Geller et al. JAACAP 2007)
www.mghcme.org
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Atomoxetine
•
•
Dosing (Wilens’ method):
– Start at 0.5 mg/kg/day for two weeks, then increase to 1.2 mg/kg/day.
– Treat to 4 weeks, if no response, try another agent. If response,
maintain dose for 6‐10 weeks then reevaluate
– After 6‐10 weeks if partial response, increase to 1.8‐2 mg/kg/day
Adverse effects:
– Rare hepatic injury (2 cases): advise, LFTs NOT required
– Suicidality (0.37% vs 0%): black box
– Somnolence, appetite suppression, GI upset/dyspepsia, blood pressure/pulse (adults), sexual dysfunction (adults), irritability
– Potential drug interactions (lower dose if using with p448
inhibitor and vice versa)
www.mghcme.org
Atomoxetine: When to Use
•
•
•
•
•
•
Monotherapy (higher likelihood of response as first start)
Stimulant nonresponders
Stimulant partial responders (monotherapy, adjunctive therapy‐no drug interactions with stimulants)
Adverse effects to stimulants
Concerns of stimulant diversion
Comorbid ADHD plus
– Oppositional disorder
– Anxiety
– Tics
– Substance abuse
www.mghcme.org
Alpha Agonists: Clonidine & Guanfacine
•
•
•
•
Alpha agonist agents
– Mimics Norepinephrine at alpha and beta receptors
– Presynaptic Alpha 2a (guanfacine more specific)
– Post synaptic alpha 1, 2 a‐c (alpha 2a in PFC)
Effect on Prefrontal cortex (PFC)
– May be dose dependent effects on pre/post 2a
– Largely inhibitory
– Modulated by “stress” dependent release of Nepi
– Improves PFC blood flow and functioning in animal models
Effect on Locus Coerulus
Modulate of neurotransmission of other neuronal systems (glutamate, GABA,
cholinergic, opioid)
(Arnsten and Li, Biol Psych 2005; Wilens J Clin Psych 2006)
www.mghcme.org
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Extended Release Clonidine for ADHD
FIGURE 3 Mean Attention-Deficit/Hyperactivity Disorder Rating Scale—IV (ADHD-RS-IV) total score from
baseline to week 5 using a last observation carried forward (LOCF) method. Note: ADHD-RS-IV total score
was significantly improved at week 1 for the CLON-XR 0.2-mg/day group. Significant improvement was
achieved in both CLON-XR groups beginning at week 2 and continued through study termination. Error bars
represent standard deviations. CLON-XR= clonidine hydrochloride extended-release tablets; a p = .0219 for
CLON-XR 0.2 mg/day. b p < .0001 for both groups. c p < .0003 for both groups. d p = .0005 for both groups.
e p < .0054 for both groups. f p < .0074 for both groups. g p ≤.0288 for both groups.
N=236; 61% completion rate
Jain et al. JAACAP ewwpwu.mbgh2cm0e.1or1g
Preparations of Clonidine
Immediate release
– Tablets (0.1, 0.2, 0.3 mg)
– QD to Q.I.D. administration
Extended release
• BID Dosed preparation FDA approved for pediatric ADHD (Kapvay)
– Tablet (0.1 and 0.2 mg)
– Start at 0.1 mg qHS; increase 0.1 mg/week
• QD Dosed preparation FDA approved for adult hypertension (Nexiclon) but NOT ADHD
– Chewable tablet form (0.17 mg; 0.26 mg)
– Oral suspension (0.09 mg/cc)
• Patch (0.1, 0.2, 0.3 mg)
www.mghcme.org
Guanfacine Extended‐Release in ADHD
(N=324 [51 sites]; 6 weeks active*, Mean Age 11±3 yrs)
Effect size:
0.41-0.89
*3 weeks titration
3 weeks maintenance (endpoint) 3 weeks taper
Sallee et al. J AM Acad Child Adolesc Psychiatry, 48: 155-165; 2009
www.mghcme.org
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Guanfacine Extended‐Release in ADHD
(N=324 (51 sites); 6 weeks, mean age 11±3 yrs)
•
•
Adverse effects
– Discontinuation rate similar: med vs placebo
– Somnolence (27% vs 12%[placebo]) and fatigue (9% vs 3%)
• Improved after titration
– Headache (21% vs 11%)
Cardiovascular changes (dose related)
– Heart rate (‐9.5 bpm at 4 mg [average change vs baseline])
• 6‐7% of subjects at 3‐4 mg with HR<50
• 1 subject with dizziness with standing (HR =64)
– Systolic BP (‐7.4 mmHg at 4 mg)
– Diastolic BP (‐5.4 mmHg at 4mg)
Sallee et al. J AM Acad Child Adolesc Psychiatry, 48:2, Feb 2009
www.mgh
Extended‐Release Guanfacine Has Similar Efficacy
with AM or PM Administration
6‐12 years, dosing 1‐4 mg/day; Samples size of GXR AM (n = 107), GXR PM (n = 114), or
placebo (n = 112).
Newcorn JH, et al. J Am Acad Child Adolesc Psychiatry. 2013;52(9):921‐
930.
www.mghcme.org
Guanfacine XR in Adolescent ADHD
Percentage of responders (full analysis set). Response was defined as a percentage reduction from the
baseline visit in the ADHD RS IV total score of ≥30% and a Clinical Global Impressions–Improvement of
1 or 2
(Wilens et al. J Am Acad Child Adoles Psych 2015; 54 (11) 916–w9w25w.em2g) hcme.org
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Alpha Agonists: When to Use
•
•
•
•
•
•
Monotherapy
Stimulant or nonstimulant nonresponders
Medication partial responders (adjunctive therapy)
– Studied with stimulant coadministration (N=5 studies)
Adverse effects to stimulants or nonstimulants
Comorbid ADHD plus
– Oppositional disorder
– Anxiety
– Tics
– “Emotional dysregulation” (one presented study negative)
Potentially younger children (needs to be studied)
www.mghcme.org
Combined (COMB) stimulant and guanfacine
for ADHD: Comparative Study
8 week, RCT, 3‐arm trial in 207 participants of 7‐14 year olds treated with IR guanfacine (1‐3 mg/day), IR d‐MPH 5‐20 mg/day), or the combination (COMB) with fixed flexible dosing (e.g. using CGI to guide dosing).
Response rate (CGI‐I + ADHD RS IV): 62% (guan), 63% (D‐MPH), 75% (COMB)
(McCracken et al, JAACAP, 2016 doi 10.1016/j.jaac.2016.06.015)
www.mghcme.org
Guanfacine XR plus Stimulants in the Treatment Of (Wilens et al. J Am Acad Child Adoles Psych: 2012)
ADHD (N=455)
www.mghcme.org
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Combination of Guanfacine XR Plus Stimulants in the Treatment Of ADHD: Adverse Events
Serious adverse effects ‐all unrelated to medication: 1) syncope, 2) poison ivy, 3) emotional outbursts
Cardiovascular indices at endpoint Heart rate: ‐5.6 bpm
Systolic blood pressure: ‐2.2 mm HG
Diastolic BP: ‐1.2 mm Hg
No ECG abnl, no QT prolongation
Wilens et al. J Am Acad Chld Adoles Psych: 2012
www.mghcme.org
Combination of Clonidine XR plus Stimulants in the Treatment Of ADHD
•Study of clonidine XR coadministration to partial
responders on stimulants (>ADHD RS 26 score)
• N= 197
• Dosing to 0.4 mg daily (in 0.2 mg BID dosing)
• Duration: 5 weeks (then taper)
(N=197)
(Kollins et al. Pediatrics epub 20w1w1w.)mghcme.org
Bupropion
• Superior to placebo in children
–N= 3 studies (104 subjects)
–May be good for irritability/mood+ADHD
–Dosing not well established‐use of 150 mg
XL (children), 300 mg XL (adolescents)
• Effective in ADHD adults
–N= 4 controlled
www.mghcme.org
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Nortriptyline in Pediatric ADHD
40
Placebo
30
20
*
*
*
Nortriptyline
10
0
4
2
*
*
*
6
7
8
9
Week
www.mghcme.org
(Prince, et al., JCAP, 2000)
Modafinil Effects on Overall Clinical Response
% Responders, CGI-I
80
Modafinil FCT 340/425 mg
Placebo
60
*
*
*
40
20
0
*
*
*
1
2
3
5
Time (Weeks)
7
Final Treatment
Phase Visit†
Responders defined as patients rated as much improved or very much improved on CGI-I.
*P.001 vs placebo.
†Last observation carried forward analysis.
Biederman, Lopez, Wilens APA, 2005
www.mghcme.org
Refractory ADHD Prominent Executive Function Deficits
•
•
•
•
•
Organizational training/coaching (focus on specific dysfunction)
Use of Norepi agent ‐ ATMX, alpha agonist, TCA, bupropion (alone or combined with stimulant, modafinil)*
Memantine* (alone, in combination with donepezil)
Vortioxetine* (anecdotal only)
Investigational:
– Nicotinic/ cholinergic agents*
• Indirect: Donepezil, galantamine
– Systematic data negative
– Case reports positive
• Direct: Nicotinic agents/gum/patch*
– Triamine reuptake inhibitors*
*Not FDA approved for ADHD
(Adler, Spencer, Wilens (eds) ADHD Across Lifespan: Cambridge Press 2015)
www.mghcme.org
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Combination of Atomoxetine plus
Stimulants in the Treatment Of ADHD
•Qualitative analysis of existing studies
• N= 3 prospective (1RCT)+ 7 retrospective reports
•Predominately children/adolescent with inadequate response to stimulants
• Most often used stimulant = methylphenidate
• Conclusions
•Small sample sizes
•“Existing evidence suggests, but does not confirm, that this drug combination may benefit some, but not all, patients who have tried several ADHD medications without success”.
Truer et. al. J Child Adolesc Psychopharmacol. 2013 Apr; 23(3): 179–193
www.mghcme.org
Melatonin for Sleep Disturbances
•
•
•
Controlled study of melatonin (5 mg) vs placebo
N= 4 Week RCT Cross over of 62 youth (aged 6‐12); 40% with ADHD receiving stimulants
Findings:
– Improvement in sleep questionnaire (RAND‐GHRi)
– Improvement in time of sleep onset (57 minutes earlier), and decreased sleep latency by 17 minutes
– Well tolerated
Long term open follow‐up of 44 developmentally disabled youth for up to 3.8 years
– Age 9.9 yrs at followup
– Continued effectiveness for sleep, behavior & cognition
– No apparent adverse effects, or deleterious effects on puberty
• Study at JHMC‐developmental disorders with branded
melatonin
(Smits et al., JAACAP:42:1286‐1293; Carr et al. J Pineal Res 2007:43:351‐359 )
www.mghcme.org
Pharmacological Treatments Not Generally Demonstrated Efficacious for ADHD
-Buspirone (failed multisite study)
-St John’s Wort (Webber et al. JAMA 2008)
-Herbal remedies

Blue green algai, huperzine, ginko, pycnogenol,
- Dietary manipulations: variable response (Pediatrics, 2012)
Overall weak effect
Best outcomes for supplementation in deficient
individuals
-Antipsychotics and mood stabilizers: Studies largely
in mood disordered individuals: Mixed outcomes for
ADHD
www.mghcme.org
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Summary: Non‐Stimulant
Pharmacotherapy of ADHD
• A number of non‐stimulant medications for ADHD
• Often lower effect size than stimulants
• A variety of effective drugs
• Noradrenergic agents (ATMX) ‐(FDA Approved)
• Alpha agonists +/‐ stimulants – ( FDA approved)
• Antidepressants /arousal agents ‐second line
•Both FDA (alpha agonist) and nonFDA (ATX, TCA) stimulant
combinations that may be effective
• Useful in comorbidity
www.mghcme.org
Long‐term Management
 Follow-up for medication usually 3 months
 Assess weight/height to monitor side effects of
medication
 Assess blood pressure
 Follow-up for behavioral interventions weekly-monthly
 Follow-up with school regarding IEP, annually or as
needed
American Academy of Pediatrics. (2001). Clinical practice guidelines: Treatment of the school-aged child with
attention-deficit/hyperactivity disorder. J. of the Amer. Acad. of Pediatrics, 108 (4), 1033-1044.
174
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Long‐Term Management
 Preschool
 School-age
 Adolescence
 Considerations for peer interactions and development
 Post secondary academic planning
 Mood, adjustment, medical adherence
 Adulthood
 Considerations for post secondary education and career
placement
 Considerations for independent living
 Mood, adjustment, medical adherence
175
When to refer
 Children under 6 years of age
 Not responding to preparatory guidance or behavioral
recommendations
 Aggressive, destructive behaviors at home and/or
school
 Children over 6 years of age
 Failed on stimulant medications
 Failing grades for more than one academic year
 Concerns about parent behavior management
techniques
Where to refer
 Psychiatry
 Multidisciplinary clinic focused on combined medication
and behavioral therapy
 Psychology/Therapy
 Psychology clinic focused on behavioral interventions,
school interventions, assessment of learning disabilities
and assessment/treatment comorbid conditions
 Community Mental health Services
 Limited multidisciplinary services
 May offer case management for more severe cases
 May have shorter wait times
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Summary
ADHD is a neurobehavioral disorder with a:
Complex etiology
Neurobiologic basis
Strong genetic component
ADHD
Affects millions of people of both genders
Persists through adolescence and adulthood in a
high percentage of cases
Can have negative impact on multiple areas of functioning
• ADHD is a highly treatable disorder
www.mghcme.org
Questions?
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Why don’t some patients respond?
 After normal behavior and medication treatment some improvement but still irritable.
 Still fighting, oppositional and poorly functional
 It is not severe enough for Bipolar, but not ODD
Juvenile Mania
• The type of irritability observed in manic children is very severe, persistent, and often
violent.
• The outbursts often include threatening or attacking behavior towards others, including family members, other children, adults, and
teachers.
Biederman et al. J Am Acad Child Adolesc Psychiatry. 1996; 35(8): 997‐1008.
www.mghcme.org
Furious Mania
(von Krafft‐Ebing, Textbook of Insanity, 1905)
•
•
•
•
•
Angry excitement
Shouting and bawling
Angry howling and fury
Constant spitting
Obscene scolding of
nurses
• Irritable exaltation
• Destructive outbreaks
www.mghcme.org
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Heterogeneity of Irritability
• Labile mood/hot temper: ODD
• Severe irritability: MDD
• Explosive/violent irritability: BPD
www.mghcme.org
Mick et al. Biological Psychiatry. 2005; 58:576‐582.
Irritability of ODD vs. Furiosity of Mania
• The irritable ODD child is hypersensitive to provoking stimuli from authority figures and may or may not be able to self‐regulate
• The furious bipolar child is hypersensitive and experiences extremes of emotion that are impossible to self‐regulate
www.mghcme.org
Irritability and CD
Diagnostic Overlap Between CD and BPD
BPD
N=110
N=116
N=76
CD
Biederman et al. J Am Acad Child Adolesc Psychiatry 1999; 38: 468-476
Biederman et al. Biological Psychiatry 2003; 53:952-960
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Deficits in Emotional Regulation vs. Mood Disorder
• Deficits in emotional regulation do not necessarily lead to extreme moods but always leads to poor self‐regulation of mood
• Deficits in emotional regulation subside relatively rapidly and do not form a distinct protracted episode of the type that would qualify for a mood
disorder
www.mghcme.org
Deficits in Emotional Regulation vs.
Mood Disorders
• Thus, deficits in emotional regulation are phenomenologically distinct from mood disorders, which are characterized by the experience of strong emotions, not their self‐regulation (Rosen & Epstein, 2010)
• Unlike deficits in emotional regulation , mood disorders require the presence of non‐mood criteria including somatic and behavioral impairments
• Mood disorders show dysregulted mood throughout each episode, not only in response to provoking stimuli
www.mghcme.org
Deficits in Emotional Regulation vs. Mood Disorders
• In contrast to mood disorders, subjects with
deficits in emotional regulation do not have
distinct episodes of DESR
• Unlike mood episodes, deficits in emotional regulation subsides relatively rapidly and does not form a distinct protracted episode of the type that would qualify for a mood disorder
• Thus, subjects with deficits in emotional regulation have normal moods but can become easily frustrated or angry with unexpected emotional challenges
www.mghcme.org
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Deficits in Emotional Regulation vs. Mood
Disorders: Important Caveat
• Deficits in emotional regulation and Mood Disorders are not mutually exclusive and can
co‐exist
www.mghcme.org
CBCL Clinical Scales
(Biederman et al., JAACAP, 1995)
Bipolar
ADHD
Control
85
*
75
Mean
65
*
*
*
*
*
p<0.01 Bipolar vs. ADHD
*
55
45
Delinquent Aggressive Withdrawn Somatic
Anxious
Social
Thought
Behavior Behavior
Complaints Depressed Problems Problems
Significantly elevated in children of BPD parents (Wals et al., JAACAP,2001)
Attention
Problems
www.mghcme.org
CBCL Mood Dysregulation Profiles
• CBCL‐DESR was operationalized using an aggregate score ≥180 and <210 in the Anxious/Depressed, Attention, and Aggression scales (AAA profile) of the
CBCL
• CBCL‐Severe Dysregulation (BP) profile was
defined as ≥210 on the CBCL‐AAA scale
www.mghcme.org
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CBCL‐DESR Profile
• CBCL‐DESR profile was selected because of its conceptual congruence with the clinical concept of DESR
• Its extreme (>210) form had been previously associated with severe forms of mood and behavioral dysregulation in children with ADHD
www.mghcme.org
DESR and Lifetime Psychopathology
Controls
60
50
40
30
20
10
0
ADHD
ADHD+DESR
AB
AB
A
A
AB
Oppositional
defiant
disorder
Conduct
disorder
A
Major
depression
w/ severe
impairment
A
0
Bipolar A
disorder
Multiple Psychoactive
(≥2) anxiety substance
disorders
use
disorders
Smoking
A: p<0.05 vs. Controls; B: p<0.05 vs.ADHD
(Spencer et al., Postgrad Med 2012)
www.mghcme.org
Executive Function Deficit
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How do medications work?
The Dopamine
Story...
Presynaptic Neuron
Dopamine Transporter
(DAT)
Dopamine
Methylphenidate
(MPH)
Dopamine
Receptor
(DRD4)
www.mghcme.org
Mechanism of Action MPH: Insights
from PET Imaging Studies
• Because DA enhances task‐specific neuronal signaling and decreases noise, MPH‐induced increases in DA could improve attention and decrease
distractibility
• Since DA modulates motivation, the increases in DA would also enhance the saliency of the task facilitating the “interest it elicits” and thus improving performance
Volkow et al. J Att Dis. 2002;(suppl)1
www.mghcme.org
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Methylphenidate (Concerta) Increases dACC
& DLPFC fMRI Activation in ADHD during MSIT
DLPFC
Dorsal ACC
DLPFC
VLPFC
Superior Parietal Cortex
Concerta (N=11) vs Placebo (N=10)
Bush et al. AGP ‐ 2008
www.mghcme.org
Behavior Management
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Behavioral Management Techniques
• Based on operant behavioral principles
Antecedent
–
–
–
–
–
–
Consequence
Behavior
Positive/negative reinforcement
Punishment
Contingent reinforcement
Extinction
Identifying antecedents to behaviors
Modeling
Slides from Aude Henin, Ph.D., MGH ADHD Across the Lifespan, 2017 conference
Examples of PMT Approaches
• Defiant Children (Barkley, 1997)
• The Incredible Years (Webster‐Stratton, 1992)
• Parent‐Child Interaction Therapy (PCIT; Eyberg & Robinson, 1982)
• Triple P‐Positive Parenting Program (Sanders et al., 2000)
• New Forest Parenting Package (NFPP: Sonuga‐Barke et
al., 2006)
Slides from Aude Henin, Ph.D., MGH ADHD Across the Lifespan, 2017 conference
Efficacy of PMT in Preschool Children:
Changes in ADHD Symptoms
Parent Training
Parent Support
Waitlist Control
Standardized ADHD Index
0.8
0.6
0.4
0.2
Baseline
Week 8
Week 23
0
-0.2
-0.4
-0.6
-0.8
-1
-1.2
a: vs PS a,b
b: vs WLC
Sonuga‐Barke et al., 2001; J Am Acad Child Adolesc Psychiatry; 40: 402‐408
a,b
www.mghcme.org
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Integrated Psychosocial Treatment for ADHD‐
Inattentive Subtype
(Pfiffner et al., 2014; JCCP; 82(6): 1115‐1127)
•
•
•
•
Child Life and Attention Skills (CLAS)
3 components:
1) group‐based parent training
2) group‐based child training (including organizational
and social components)
• 3) teacher consultation including daily report card
• Adaptations of well‐established interventions, including positive reinforcement, social assertion, distraction management, parent training, use of common terminology
• Decreased emphasis on reducing impulsivity
Slides from Aude Henin, Ph.D., MGH ADHD Across the Lifespan, 2017 conference
Study Results: Effect Sizes Across
Conditions
0.8
CLAS‐PFT 0.7
CLAS‐TAU
0.6
PFT‐TAU
0.5
0.4
0.3
0.2
0.1
0
Inattentive sxI‐nPattentive sx‐TOrg. Skills‐P Org skills‐T Social skills‐PSocial skills‐T
Pfiffner et al., 2014; JCCP; 82(6): 1115‐1127
Conclusions
• Behavioral approaches are well‐established, evidence‐based treatments for preschool‐ and school‐aged children with ADHD
• Behavioral treatments are less efficacious than medications for core ADHD symptoms
• However, they promote other positive outcomes (e.g., improved parent‐child relationships, decreased noncompliance)
Slides from Aude Henin, Ph.D., MGH ADHD Across the Lifespan, 2017 conference
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• The combination of medication and behavioral treatment is the most efficacious, powerful intervention (and may decrease the dosing of each)
• Parent interventions may be enhanced by school‐
based interventions to enhance generalization
• More work is needed to extend behavioral
treatment to primary care and community
settings
• More work needed to individualize treatments
given known mediators/moderators of change
(e.g., parental ADHD).
Slides from Aude Henin, Ph.D., MGH ADHD Across the Lifespan, 2017 conference
Conclusions
• Cognitive retraining approaches appear to have some benefits for specific deficits (e.g., working memory)
• Impact on ADHD sx and academic
performance not demonstrated
• More research needed before recommending
this as an intervention for youth with ADHD
Slides from Aude Henin, Ph.D., MGH ADHD Across the Lifespan, 2017 conference
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Alternative Treatments for ADHD
Slides from Wozniak, MGH ADHD Across the Lifespan, 2017 conference
Why alternative treatments for ADHD?
• 30% nonresponders
• Many can not tolerate side effects including
decreased appetite, insomnia, motor tics, GI
upset, anxiety.
• Yet concerns remain about purity, reliability,
safety and toxicity of ‘natural’ treatments
Slides from Wozniak, MGH ADHD Across the Lifespan, 2017 conference
Ineffective?
• St John’s Wort
• Linoleic Acid, Alpha Linoleic Acid
• DHA
Slides from Wozniak, MGH ADHD Across the Lifespan, 2017 conference
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open label
• Gingko Baloba Tree unique to Asia
• Bacopa Indian plant
Slides from Wozniak, MGH ADHD Across the Lifespan, 2017 conference
Pycnogenol (pine bark)
• Modulates DA and NE release
• Double blind placebo controlled trial N=61 age 6‐14 1mg/kg/d for one month improved ADHD symptoms with return of symptoms after discontinuation
Slides from Wozniak, MGH ADHD Across the Lifespan, 2017 conference
Valerian
•
•
•
•
Plant with sedative properties
Used for insomnia, anxiety
Inhibits breakdown of GABA
TID for 3 weeks, RCT placebo N=30, positive trial
Slides from Wozniak, MGH ADHD Across the Lifespan, 2017 conference
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Ginseng
• Neuroprotective and anti‐oxidant
• Increase DA and NE
• 1000mg BID RCT placebo controlled N=70 8
weeks
• Did not outperform MPH
Slides from Wozniak, MGH ADHD Across the Lifespan, 2017 conference
Passion Flower (Passiflora)
• Traditional remedy for anxiety
• N=34 .04mg/kg/d RCT with MPH 8 weeks
• No difference except fewer side effects in
parent and teacher rating scales
Slides from Wozniak, MGH ADHD Across the Lifespan, 2017 conference
Vitamins and Minerals
• Magnesium 6mg/kg/d and Vit B6 0.6mg/kg/d
8weeks open label 6 months Affects serotonoin production
• Vit C + ALA, improved hyperactivity and attn
• 3 trials of Zinc 15mg‐150mg 12 week RCT N=400 helped hyperactivity not attention (but also a negative study vs AMP)
Slides from Wozniak, MGH ADHD Across the Lifespan, 2017 conference
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Iron
• Cofactor in DA and NE synthesis
• Anemic children have poor attention
• RCT placebo N=23 with low iron improved in
ADHD symptoms
Slides from Wozniak, MGH ADHD Across the Lifespan, 2017 conference
Amino Acids
• Direct and indirect effects on neurotransmitter production (increases Ach synthesis
• ALC (Acetyl L Carnitine) 500‐1500mg BID,
• One positive study RCT placebo, 12 months N=51
• One negative study RCT placebo 16 weeks N=112
Slides from Wozniak, MGH ADHD Across the Lifespan, 2017 conference
Others?
• Chinese herbal Yizhi 10 herbs with MPH
• Chinese herbal Jingling with MPG
• Chinese medicine Ningdong ?promise in
Tourette’s similar to MPH in RCT
Slides from Wozniak, MGH ADHD Across the Lifespan, 2017 conference
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Fatty Acids‐positive RCT placebo
controlled studies
• N=41 EPA 186mg/DHA 480mg/ALA 96mg
• N=50 EPA 80mg/DHA 480mg/AA 40mg/GLA 96mg attention and conduct improved
• N=132 EPA 93mg/DHA 29mg (15 week)
• N=162 EPA+DHA 120mg
• But, a negative meta‐analysis
• Vayarin, a medical food, phosphatidylserine
omega‐3, “90 days” EPA 21.5/DHA 8.5
Slides from Wozniak, MGH ADHD Across the Lifespan, 2017 conference
Treatments with Extensive Empirical Evidence
 Stimulant Medications
 Behavioral Treatment
 Combination Therapy
Educational Interventions





Section 504
IEP
Common accommodations
Qualifying for services through school
Other Considerations
 Grade Retention
 Inclusion
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Behavioral Interventions


Advantages
 Empirical support
 Long term, generalizable skills
 Practical skills
Disadvantages
 Time commitment
 Slower positive outcomes
 Oversimplification environmental
influences, cognition, emotion
Treatments with Little Empirical Evidence
(National Resource Center on ADHD. CHADD. 2008)
 Dietary Changes
 Vitamins/Supplements
 Play Therapy
 Traditional Talk Therapy
(psychoanalysis)
 Chiropractic therapy
 Sensory integration Therapy
 Biofeedback Therapy
Alternative Treatments


Elimination Diets
 Limited support for kids with allergies
 Reducing sugar/candy not associated with reduction in symptoms
Nutritional Supplements
 Glyconutritional supplements to increase omega‐3 and omega‐6 2 studies have found small improvements in inattention & hyperactivity, one study found no improvements
 Megavitamins may be more harmful than taking regular dosage of vitamins
 Correcting deficiencies always first line treatment but does not support improvements for all individuals with ADHD who do not have deficiency
 St. John’s Wort has no evidence for improving ADHD and can affect the rate which the body metabolizes other medications
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Alternative Treatments


Neurofeedback training
 EEG biofeedback
 Child completes tasks while monitoring brain waves in order to learn to control brain waves better
 Positive results, but limited studies
Vision Therapy
 Tasks used to help child improve visual skills and processing  Used to treat conditions ranging from visual deficits to autism spectrum disorders
 Research studies have provided inconclusive results
Beware of Treatments That…
(National Resource Center on ADHD. CHADD. 2008)

Claim to “cure” ADHD
 Works immediately, works for everyone with ADHD

No empirical evidence for a “cure” only treatments to improve associated symptoms

Lack clear instructions, ingredients, side effects
 All Natural, harmless, work immediately, work for everyone

Promotion techniques
 Books or infomercials

Supported financially by specific company with no disclosure of conflict of interest

Not supported by medical community
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What is Dyslexia?
• An unexpected difficulty in reading in children and adults who otherwise possess the intelligence, motivation, and schooling considered necessary for accurate and fluent reading (Shaywitz 1998)
• Most Common of all of the known LD: affecting 1 in 5 children
in the U.S. and accounting for 80% of those diagnosed with an
LD
• While some professionals may define reading disability to include children whose primary deficit is in reading comprehension, focus is on dyslexia
Ellen B. Braaten, PhD
Director of the Learning and Emotional Assessment Program
(LEAP), MGH ADHD Across the Lifespan 2017 Lecture
www.mghcme.org
Definition Adopted by Internal
Dyslexia Association
• Characterizes dyslexia as difficulty with accurate and and/or fluent word recognition and by poor spelling and decoding abilities
• Dyslexia is a disorder within the language system, specifically the
phonological processing system
• In order to read, child must learn the alphabetic principle: spoken words can be pulled apart into different units with the smallest unit being the phoneme – and that letters can represent these sounds
• Results of numerous studies have confirmed that a deficit in phonology is the most robust and specific correlate of dyslexia and forms the basis for the most successful, evidence‐based interventions
www.mghcme.org
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Comorbidity Between ADHD
and Dyslexia
• Co‐occur more frequently than expected by chance, with 25‐40% of children with one disorder meeting criteria for another (Willcutt & Pennington, 2000)
• Children with comorbid dyslexia and ADHD exhibit a more extensive and severe profile of neuropsychological weaknesses and stronger genetic loading (Willcutt, 2009)
• Multiple cognitive deficit hypothesis suggests that there is considerable overlap of neurocognitive deficits between these disorders (Moura et al. 2016)
www.mghcme.org
Diagnosis & Treatment:
Secondary Symptoms
• Resistance to schoolwork
• Disruptive in school
• “Lack of motivation” – particularly in bright, older students
• Emotional or physical complaints such as anxiety, depression, stomach aches, reluctance to go to school
www.mghcme.org
History
• Family history of dyslexia or problems
learning to read
• Problems learning the alphabet, letter names
• Trouble learning to read
• School assistance in reading
• Difficulty with spelling, written work
• Not working “up to potential”
www.mghcme.org
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Diagnosing Dyslexia: Assessing
Intelligence
• Must assess intelligence, although somewhat controversial
• Recent study found that there was significant difference in General Ability Index (GAI) on the WISC between children with dyslexia and typically developing children (Moura et al. 2014)
• Most commonly used IQ tests:
–
–
–
–
Wechsler Intelligence Scale for Children (WISC‐IV)
Wechsler Adult Intelligence Scale (WAIS‐IV)
Differential Abilities Scale (DAS‐II)
Stanford Binet
www.mghcme.org
Assessment of Reading Ability:
Decoding Skills
• How accurately can the child decode (i.e., read aloud) single words?
• Visual errors are common on these tests
(e.g., “car” for “cat”)
• These errors are reflective of a phonological coding or phonics problem because the child is using visual similarity rather than phonics to decode the word
www.mghcme.org
Assessment of Reading Ability:
Non‐word Reading
• Is the child able to read non‐words?
• Non‐word reading is a benchmark for phonological decoding because in order to read a non‐word (zoop, grep, untroikest), knowledge of phonological decoding alone must be relied upon as these letter strings have never been seen or heard before
www.mghcme.org
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Assessment of Reading Ability:
Reading Fluency
• Is the child’s reading fluent?
• Gray Oral Reading Test (GORT‐5) most often
used; performance is based on measures of
rate and accuracy
• WIAT Oral Reading Fluency is another common
measure of rate and accuracy
• Children with dyslexia are usually slow and halting in oral reading and will often make function word errors (interchanging “a” and “the”)
www.mghcme.org
Assessment of Reading Ability:
Reading Comprehension
• Can assess single‐word comprehension as well as passages
• Children with dyslexia often perform better on tests of comprehension than on other measures of reading because:
– They can rely on context to guess the meaning of a word they may not otherwise be able to decode
– Reading comprehension is correlated with intelligence
• Comprehension has been shown to use different cognitive resources than the ones generally impaired by dyslexia (Kasirer and Mashal 2016)
www.mghcme.org
Assessment of Reading Ability:
Spelling
• Problems with spelling are extremely typical
• Proportion of errors that are not phonetically
accurate
(especially errors in which consonants have been added, omitted, or substituted) is important
• Dysphonetic Errors:
– ‘bol’ for ‘boy’
– ‘kerock’ for ‘cook’
– ‘expilen’ for ‘explain’
www.mghcme.org
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Assessment of Reading Ability:
Writing
• Tests of writing include Test of Written Language (TOWL), where child has 15 minutes to generate a story about a picture
• Other tests of writing fluency:
– WIAT Essay/Sentence Composition
– Woodcock Johnson Writing Samples
– Oral and Written Language Scales (OWLS‐II)
www.mghcme.org
Neuropsychological Measures
• Full assessment not completely necessary but can provide important information regarding child’s cognitive strengths and weaknesses and role they may play in the child’s reading deficiency, as well as in the remediation process
• Problems can be seen in:
– Difficulties with other aspects of language such as semantics and syntax (grammar)
www.mghcme.org
Neuropsychological Measures
• Children with dyslexia tend to:
– Underperform on phonological tasks such as Digit Span
– Show relative weaknesses on all verbal subtests
– Obtain lower nonverbal IQ scores relative to peers (although effect size is
smaller than for verbal IQ)
– Show slower processing speed
Processing speed is the shared cognitive deficit that accounts for the comorbidity between dyslexia and ADHD (Willcutt et al, 2010)
PS is also shown to become more impaired when ADHD and dyslexia are
comorbid as compared to individuals with only ADHD or dyslexia (Moura
2016)
Comorbidity between reading difficulties and ADHD is primarily attributable to common genetic influences that are shared with PS
www.mghcme.org
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Measures of Executive Function in Dyslexia
• Executive function is generally measured in
multiple sub‐categories
• Four commonly measured sub‐categories:
– Processing Speed
– Shifting
– Planning
– Verbal Fluency
Processing Speed
• Measures how quickly an individual can process information and respond to simple intellectual tasks
• Has been shown to be impaired in children with
dyslexia (Moura et al. 2014; Thomson et al. 2003)
• Common measures of processing speed:
– WISC Coding and Symbol Search
– WIAT Math Fluencies
– Woodcock Johnson Reading/Math/Writing Fluencies
www.mgh
Shifting
• Measures the ability to move between different mental
tasks or strategies
• Research has shown variation in the shifting ability of children with dyslexia, with some seeing no difference from typical developing children (Bental et al. 2007)
• Others found impairment in dyslexic children as compared to typically developing controls (Horowitz‐
Kraus 2012)
• Common measures of Shifting:
– Wisconsin Card Sorting Test (WCST)
– D‐Kefs Trails Test Module 4
www.mgh
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Planning
• Measures the ability to identify the procedure or
steps necessary to complete a specific task
• Research has produced varying conclusions, with some suggesting that dyslexic individuals will be able to identify the appropriate steps but require longer to do so than TD individuals (Reiter et al. 2005)
• Common measures of Planning:
– Tower of London
– Tower of Hanoi
– D‐KEFS Tower Test
www.mgh
Verbal Fluency
• Measures memory and language ability, generally broken down into two sub‐types: phonemic (generating words starting with a specific letter) and semantic (specific category)
• Dyslexic children have reduced ability to generate
words from phonemic cues (Landrel et al. 2009)
• Semantic VF tasks have been shown to be useful to differentiate dysphonetic and dyseidetic dyslexia (Cohen et al. 1999)
• Common measures of Verbal Fluency:
– D‐KEFS Verbal Fluency
– NEPSY Word Generation
www.mgh
Treatments for Dyslexia:
Remediation
•
•
Special education services or private tutoring
Highly structured, multi‐sensory phonics‐based approaches are most successful
•
Programs make very concrete and clear the letter‐sound correspondences:
– Orton Gillingham
– Lindamood Bell
– Wilson
•
Tutoring in
– Reading comprehension
– Study skills
– Writing
www.mgh
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Treatments for Dyslexia:
Compensation
• Extra time to complete tests and written assignments
• Giving feedback orally, permitting oral book reports
• Assistance with note taking
•
•
•
•
Marking but not downgrading for spelling errors
Use of laptop or handheld personal spellers
Use of calculator when appropriate
Providing access to lecture notes or tape‐recording lectures
www.mgh
Unsubstantiated Treatments for Dyslexia
• Optometric training: eye exercises, colored lenses
• Medications or exercises to improve vestibular or cerebellar functioning
• Vitamins or dietary treatment
• Chiropractic manipulation
Assessment of Bright Young Adults
with Dyslexia
• Diagnostic issues are more subtle and referral question
is often depression, not “performing up to par,” inattention
• Typically these students have been performing at grade
level, so no referral is made
• Tests measuring single‐word accuracy may be inadequate
• Timed tests of reading are needed
• By high school, reading may be accurate but lack automaticity
• History is very important
www.mghcme.org
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Essential Facts about Dyslexia in Adults
• Phonological weakness persists; it never goes away
• In children, the phonological weakness primarily affect reading accuracy; over time, accomplished dyslexia adults learn to read a core of words accurately
• In bright young adults the phonological weakness affects the speed of reading
• Skilled adult readers read accurately and rapidly; while adult dyslexics read slowly and laboriously – they are not fluent
• Brain imaging studies indicate adult dyslexics never switch over to the automatic reading circuit necessary for fluency reading
• Reliance on secondary reading pathways results in accurate but
slow reading
www.mghcme.org
Outcome in Adolescence and
Adulthood
• Well‐designed follow‐up studies repeatedly show
that reading disabilities persist
• General intelligence and initial severity of the reading disorder are best predictors of early adult reading levels
• Most children can learn to read quite well, although
they may remain slow readers and poor spellers
• Cognitive linguistic weaknesses in verbal memory or phonological representations persist but need not be impairing
www.mghcme.org
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What are Executive Functions?
Orchestration of basic cognitive processes during
goal‐oriented problem‐solving:
the “CONDUCTOR”
Fried, R. (2017). Neuropsychology of ADHD [PowerPoint Slides]. Retrieved from Dr. Ronna Fried, Ed.D.
www.mghcme.org
Executive
Functions
Functions of the“Orchestra”
Functions of the“Conductor”
Perception
Attention
Language processes
Visual-spatial processes
Memory
Sensory Inputs
Motor Outputs
Knowledge& Skills
Social
Non-social
Inhibit
Shift Flexibly
Modulate Emotions
Initiate
Working Memory
Plan
Organize
www.mghcme.org
Development of Executive Functions
 Plan/Organize/Monitor
 Emotional Modulation
3‐32 yrs
3‐???
 Verbal Working Memory
2‐13yrs
 Nonverbal Working Memory
3‐24 mo
 Inhibit
0‐???
www.mghcme.org
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Assessment of EFDs
• Neuropsychological Testing
• Checklists
www.mghcme.org
Neuropsychological Testing
• A large meta‐analysis domains of executive
functioning deficits in ADHD
Domains of Executive
Functioning
Meta-analytic Effect Size
(d)
Set shifting
0.50
Working memory (verbal)
0.45
Working memory
(spatial)
1.00
Planning
0.55
Inhibition
0.60
Nigg, J.T. (2006). What causes ADHD?: Understanding what goes wrong and why. New York, NY: The Guilford Press.
www.mghcme.org
Neuropsychological Tests
Neuropsychological Test
Executive Function
Color Word (D-KEFS)
Inhibition
Trails Making (D-KEFS), IED
Set Shifting
(CANTAB), Letter-Number Test (WAIS)
Stockings of Cambridge (CANTAB)
Planning/Organizing
Symbol Search (WAIS/WISC)
Task Monitoring, Initiating
Digit Span, Arithmetic, Letter-Number
Test (WAIS/WISC)
Working Memory
Coding (WAIS)
Initiating
Matrix (WAIS)
Inhibition, Spatial Working
Memory
www.mghcme.org
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Inhibition
• Ability to control impulses and stop one’s own behavior at the appropriate time
• Test
– Color Word (D‐KEFS)
• BRIEF examples
–
–
–
–
Interrupts or disrupts group activities
Has trouble putting on the brakes
Says/does things impulsively without thinking
Makes decisions that get them into trouble
Roth, R.M., Isquith, P.K., & Gioia, G.A. (2005). Behavior rating inventory of executive function-adult version: Professional manual. Lutz, FL:
PAR Psychological Assessment Resources,Inc.
www.mghcme.org
Set Shifting
• Ability to move from one situation, activity, or part of a problem to another as the condition demands
• Test
– Trails Making (D‐KEFS)
– Intra‐Extra Dimensional Shift Set (CANTAB),
• BRIEF examples
– Tries the same approach even when it does not work
– Has trouble moving from activity to activity
– Resists accepting a different solution
– Experiences anxiety, or extreme anger when things change
Roth, R.M., Isquith, P.K., & Gioia, G.A. (2005). Behavior rating inventory of executive function-adult version: Professional manual. Lutz, FL: PAR
Psychological Assessment Resources, Inc.
www.mghcme.org
Planning/Organizing
• Ability to manage current and future oriented task demands within the situational context
• Test
– Stockings of Cambridge (CANTAB), TOWER tasks
• BRIEF examples
–
–
–
–
Starts tasks without the right materials
Has trouble prioritizing or organizing activities
Starts homework or chores at the last minute
Underestimates the time to finish tasks
Roth, R.M., Isquith, P.K., & Gioia, G.A. (2005). Behavior rating inventory of executive function-adult version: Professional manual. Lutz, FL: PAR
Psychological Assessment Resources, Inc.
www.mghcme.org
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Task Monitoring
• Ability to check work and assess performance during or after finishing a task to ensure a goal is finished
• Test
– Symbol Search (WAIS/WISC)
• BRIEF examples
–
–
–
–
Does not check work for mistakes
Makes careless errors
Fails to catch one’s errors while completing a task
Does not problem solve during a task
Roth, R.M., Isquith, P.K., & Gioia, G.A. (2005). Behavior rating inventory of executive function-adult version: Professional manual. Lutz, FL: PAR
Psychological Assessment Resources, Inc.
www.mghcme.org
Initiating
• Ability to begin a task and independently generate ideas, responses, or problem solving strategies
• Test
– Coding, Symbol Search, and Matrix (WAIS/WISC), Color Word and Trails Making (D‐KEFS)
• BRIEF examples
–
–
–
–
Lies around the house a lot (couch potato)
Has good ideas but does not get the job done
Needs extensive reminders to begin a task
Has trouble getting started on tasks
Roth, R.M., Isquith, P.K., & Gioia, G.A. (2005). Behavior rating inventory of executive function-adult version: Professional manual. Lutz, FL: PAR
Psychological Assessment Resources, Inc.
www.mghcme.org
Self Monitoring
• Ability to keep track of the effect of one’s behavior on others and attend to one’s behavior in a social context
• TEST examples: careless errors (process approach)
• BRIEF examples
– Does not notice when behavior causes negative reactions
– Becomes too wild or silly
– Does not notice when others get mad until it is too late
– Makes inappropriate sexual comments
Roth, R.M., Isquith, P.K., & Gioia, G.A. (2005). Behavior rating inventory of executive function-adult version: Professional manual. Lutz, FL: PAR
Psychological Assessment Resources, Inc.
www.mghcme.org
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Working Memory
• Ability to hold information in one’s mind for purpose of generating a response or completing a task
• Test
– Digit Span, Letter Number, and Arithmetic (WISC/WAIS)
• BRIEF examples
– When given three things, remembers only the first or last
– Forgets to hand in homework
– Forgets what they are doing in the middle of things
– Has trouble remembering things, even for a few minutes
Roth, R.M., Isquith, P.K., & Gioia, G.A. (2005). Behavior rating inventory of executive function-adult version: Professional manual. Lutz, FL: PAR
Psychological Assessment Resources, Inc.
www.mghcme.org
Definition of EFD
• In our previous work, individuals with >= 2 impaired measures (across any domain) have showed particularly poor functional outcome
– 2 or more tests has face validity in terms of what a
neuropsychologist would need to conclude that an
EF impairment exists
– Operationally defined EFD as impairments in 2 or more tests
www.mghcme.org
CLINICAL CORRELATES OF WORKING MEMORY DEFICITS IN YOUTH WITH AND WITHOUT ADHD: A CONTROLLED STUDY
(Fried et al., 2016)
www.mghcme.org
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Main Aim:
• To assess the clinical correlates of WM deficits in
ADHD
• Compared the functional outcomes of WM deficits using data from children with and without ADHD
• Hypothesis: WM deficits will be more prevalent in children with ADHD relative to controls, and individuals with WM deficits will have
more impairments in academic functioning than
individuals with ADHD without WM deficits
www.mgh
FFD Proxy
• The significant correlation of .72 between the Freedom of Distractibility Factor and the Working Memory Index of the WISC‐IV renders the use of FFD factor scores an appropriate proxy for WM index.
www.mgh
WM Deficit Classification
1. Subjects with FSIQ of 120 or less who had Freedom from Distractibility (FFD) score 1 SD (15 points) lower than FSIQ
2. Any subject with FFD < 85
3. Subjects with full IQ > 120 with a FFD 1.5 SDs
(22.5 points) below full IQ.
www.mghcme.org
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Results
• Significantly more youth with ADHD had WM deficits than controls (31.9% vs. 13.7%, P<0.05)
Within Group Comparisons:
ADHD
Controls
WM Deficits
No WM Deficits
WM Deficits
No WM Deficits
N=88
N=188
N= 33
N=208
www.mghcme.org
Conclusions
• WM deficits among ADHD children significantly
increased the risk for:
– Grade retention
– Placement in special classes
– Lower academic achievement in reading and math
Slides from Aude Henin, Ph.D., MGH ADHD Across the Lifespan, 2017 conference
• Academic dysfunction could not be accounted for by differences in the clinical features of ADHD or by patterns of comorbidity
• No statistical evidence that WM deficits affected any other functional outcomes
• Findings provide support for selectively detrimental effect of WM deficits on cognitive and academic functioning in youth with ADHD
www.mghcme.org
Additional Resources
 Website that evaluate different treatments and programs www.Quackwatch.com
 National Center for Complementary and Alternative Medicines: http://nccam.nih.gov/
 Federal trade Commission warnings regarding internet publicized vitamins and supplements: http://www.ftc.gov/opa/2001/06/cureall.shtm
 Find active clinical trials: www.clinicaltrials.gov
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 www.chadd.org/
 www.webmd.com/add-adhd/default.htm
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 www.mayoclinic.com/health/adhd/DS00275/
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Nafees, B., Setyawan, J., Lloyd, A., Ali, S., Hearn, S., Sasane, R., . . . Hodgkins, P. (2014). Parent preferences regarding stimulant therapies for ADHD: a comparison across six European countries. European Child and Adolescent Psychiatry, 23(12), 1189‐1200. doi:10.1007/s00787‐013‐0515‐6
Ninan, A., Stewart, S. L., Theall, L., King, G., Evans, R., Baiden, P., & Brown, A. (2014). Psychotropic Medication Monitoring Checklists: Use and Utility for Children in Residential Care. Journal of the Canadian Academy of Child and Adolescent Psychiatry, 23(1), 38‐47. Overmeyer, S., Bullmore, E., Suckling, J., Simmons, A., Williams, S., Santosh, P., & Taylor, E. (2001). Distributed grey and white matter deficits in hyperkinetic disorder: MRI evidence for anatomical abnormality in an attentional network. Psychological Medicine, 31, 1425 ‐ 1435. Partridge, B., Lucke, J., & Hall, W. (2014). Over‐diagnosed and over‐treated: a survey of Australian public attitudes towards the acceptability of drug treatment for depression and ADHD BMC Psychiatry (Vol. 14, pp. 74). England.
Pliszka, S. R., Carlson, C. L., & Swanson, J. M. (1999). ADHD with Comorbid Disorders. New York: Guilford Press.
Pliszka, S. R., Crismon, M. L., Hughes, C. W., Corners, C. K., Emslie, G. J., Jensen, P. S., . . . Lopez, M. (2006). The Texas Children's Medication Algorithm Project: revision of the algorithm for pharmacotherapy of attention‐
deficit/hyperactivity disorder. Journal of the American Academy of Child and Adolescent Psychiatry, 45(6), 642‐657. doi:10.1097/01.chi.0000215326.51175.eb
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Polanczyk, G., de Lima, M. S., Horta, B. L., Biederman, J., & Rohde, L. A. (2007). The Worldwide Prevalence of ADHD: A Systematic Review and Metaregression Analysis. American Journal of Psychiatry, 164(6), 942‐948. doi:10.1176/appi.ajp.164.6.942
Polanczyk, G. V., Polanczyk, G. V., Willcutt, E. G., Salum, G. A., & Kieling, C. ADHD prevalence estimates across three decades: an updated systematic review and meta‐regression analysis. International Journal of Epidemiology, 43(2), 434‐
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Shier, A. C., Reichenbacher, T., Ghuman, H. S., & Ghuman, J. K. (2012). Pharmacological Treatment of Attention Deficit Hyperactivity Disorder in Children and Adolescents: Clinical Strategies. Journal of Central Nervous System Disease, 5(3462‐JCNSD‐Pharmacological‐Treatment‐of‐Attention‐Deficit‐Hyperactivity‐Disorder‐.pdf), 1‐17. doi:10.4137/JCNSD.S6691
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 For additional resources or tools mentioned
in this presentation, please email Chris
Stone, MD ([email protected]) with your
specific request.
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Functional GI disorders
The ongoing challenge
Nadia Hijaz MD
Objectives:

1. Defines major functional GI disorders FGIDs
mainly IBS, FD and abdominal migraine.

2. Understand the pathophysiology of IBS, FD,
and abdominal migraine.

3. Recognize the symptoms and accurately
diagnose each FGID.

4. Understand the therapy of FGIDs focusing on
the management of constituent symptoms.

5. Compare the current evidence of available
treatments for FGIDs.
FGIDs definition:
Multifactorial combination of symptoms
that are chronic or recurrent that results
from a complex interaction between
psychosocial and physiologic factors and
not explained entirely with current
structural or biochemical investigations.
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Chronic Abdominal Pain?
Occurs in approximately (10-20%) of school age
children and adolescent.
 The majority of patients with mild complaints
improve with reassurance and time.


Greater than 50% will have symptoms that persist
into adulthood.

For a distinct subset of patients with more severe
and disabling illness, finding effective treatment for
these disorders remains a challenge.
Epidemiology


The most common ages of onset are 4-6 years
and early adolescence.
It is uncommon under the age of 4 years.

Gender differences manifest around puberty
with a slight female predominance of 1.4:1.

Single parent household, a parent with
gastrointestinal complaints, low parental
academic attainment, or a low socioeconomic
status, are more likely to develop FGIDs.
Functional Gastrointestinal
Disorders
Diagnosis based on specific symptoms
clusters, not explained by structural or
metabolic abnormalities:
•Irritable
Bowel Syndrome
Dyspepsia
•Abdominal Migraine
•Functional Abdominal Pain Syndrome
•Functional
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The frequencies of FGIDs by parent report of symptoms,
child report of symptoms, and clinician diagnosis
Irritable Bowel Syndrome
Abdominal Pain or Discomfort in 2
months duration plus two of
features:

1. Relieved with Defecation

2. Change in stool frequency

3. Change in stool form
No evidence of an inflammatory, anatomic, metabolic, or
neoplastic process that explains the child’s symptoms.
(ROME IV changing this term to after appropriate medical
evaluation, symptoms can not be attributed to another medical
condition)
It is estimated that 10%-15% of older children and adolescents
suffer from IBS
Chronic Abdominal Pain: Organic
or not?
Social
Psychological
Non-organic
Organic
Biological
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Red flags

Involuntary weight loss

Growth retardation

Significant vomiting or diarrhea

Blood in stool

Pain localized away from the umbilicus Pain
interrupting sleep at night

Extra-intestinal symptoms (fever, rash, joint pain,
aphthous ulcers, urinary symptoms)

Abnormal labs: anemia, elevated sedimentation rate
Family history of organic disease (e.g., peptic ulcer,
inflammatory bowel disease).
A Biopsychosocial Model
Inflammation
Motility
Visceral sensitivity, etc.
Biological Factors
Social Factors
Psychological factors
Parent interventions
School interactions
Peer relationships
Depression
Anxiety
Coping skills
Sleep disturbances

An enteric viral, bacterial or parasitic infection which
causes an altered interaction between gut flora and
the enteric nervous system such that despite
resolution of the infection, symptoms of IBS may
persist for months to years.

Alterations along the brain-gut pain axis are thought
to result in central nervous system (CNS) amplification
of incoming visceral afferent signals resulting in hyperresponsiveness to physiologic as well as noxious
stimuli.

Children with FGIDs including IBS tend to use less
effective coping strategies to handle stress compared
to healthy controls, which explains the association
between depressive symptoms and many FGID
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Irritable Bowel Syndrome:
There are at least three interrelated factors that
affect symptoms to varying degrees:
1.
Altered gut reactivity (motility, secretion) in
response to luminal (e.g. meals, gut distention,
inflammation, bacteria factors) or environmental
(e.g. psychological stress) stimuli, resulting in
symptoms of diarrhea and/or constipation.
2.
Motility Abnormalities – 25% – 75%.
3.
Visceral hypersensitivity 50-70%.
Visceral Hyperalgesia
Cumulative percentage of patients with FAP, those with
IBS, and HV( healthy volunteers) reaching the threshold for
pain and disturbed contractile response to a meal (P <
0.001)
IBS: Psychological Features
Psychological stress exacerbates GI
symptoms
 Psychologic or psychiatric comorbidity is common (40-90%)
 Psychologic factors affect health
status and clinical outcome
 Psychologic factors influence
primary provider.

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IBS: Predominant Symptom
Diarrhea (D-IBS) vs. Constipation (C-IBS)

C-IBS : slowed transit, vagal dysfunction,

D-IBS : accelerated transit,

P-IBS : increased HAPC, which are more likely to
be associated with pain

A-IBS – Alternating subtype: sympathetic
adrenergic dysfunction

HAPC high amplitude peristaltic contractions
Dietary intervention

There is a lack of high quality evidence on the effectiveness of
dietary interventions such as lactose free diet.

There is lack of strong evidence to support the
supplementation with fiber as a dietary manipulation for
treating children with FGIDs.

Fermentable oligo-, di-, mono-saccharides and polyols
(FODMAPs) may play a role in triggering gastrointestinal
symptoms in IBS patients.

The effect of low FODMAP diet was prospectively evaluated
using a symptom questionnaire amongst 90 children with IBS
with a mean follow up of 15.7 mo. Abdominal pain, bloating,
flatulence and diarrhea were significantly improved amongst
participants while on low FODMAP diet .
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IBS: Most Frequent Adult
Therapy
Aimed at predominant symptom:

Fiber and osmotic laxatives – constipation (not
pain)

Opioids (Loperamide) – diarrhea

Anti-spasmodic PRN for severe episodes of pain

Daily anti-depressants – low dose TCAs for D-IBS or
conventional dose SSRIs for C-IBS
IBS Treatment:
ACG Guideline recommendations
Grade A
Tegaserod (IBS-C; 5HT4 agonist)
Alosetron (IBS-D; 5HT3 antagonist)
Grade B Bulking agents
Antispasmodics
Antidepressants
Laxatives/anti-diarrheal
Behavioral therapy
IBS: Probiotics

14 Adult and 1 pediatric RCT (N=50)

Probiotics associated with decreased distension
and bloating

2 adult studies – improved pain (N=362 in one;
associated with dose effect)

Studies generally short (pediatric – 6 weeks)
decreased bloating and pain frequency.
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IBS Treatment: Pediatrics
Lactobacillus GG
DB-placebo RCT of 50 IBS patients
At six weeks – lactobacillus GG associated
with decreased bloating, pain frequency
but no effect on other GI symptoms
Initial Treatment of IBS
IBS
C-IBS
D-IBS
Laxative (e.g., Miralax)
+
Anti-spasmodic or SSRI
Antibiotic (e.g. metronidazole or rifaximin)
or
Low dose TCA + prn anti-spasmodic
(e.g., Elavil 0.3 mg per kg qhs)
Rifaximin in IBS-D
50
%
Favorable
Response
40
30
20
10
0
Rifaximin
Placebo
Pimintel; Am J Gastro, 2006
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IBS Treatment: Pediatrics
Enteric coated peppermint oil
Mechanism: relaxes intestinal smooth muscles by decreasing calcium
influx into the cells
DB-RCT of 42 IBS patients
Outcome: Better/much better – 71% vs 43% (p<.002)
Worse/much worse – 0% vs 19%
Kline; J Pediatr, 2001
IBS-C Treatment: Pediatrics
Tegaserod
Randomized trial of 42 IBS patients
Miralax vs. Miralax/Tegaserod
M – Increased stools, no effect on pain
M/T – Increased stools, decreased pain
Khoshoo; Alim Pharm Ther, 2006
IBS-C Amitizia

Lubiprostone, a chloride channel
activator,

has been studied in constipation
predominant IBS adult patients and has
demonstrated significant improvement in
gastrointestinal symptoms at 1, 2, and 3
months follow up.

Other stimulants: Senna, biscodyl.
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Pediatric evidence of
psychotropic medications in IBS
Citalopram, a SSRI was shown to
improve IBS symptoms pain in
children.
 Amitriptyline, a TCA which has
anticholinergic as well as analgesic
effects, significantly improved
symptoms and overall quality of life
in adolescents with diarrheapredominant IBS.

Anticholinergic agents/ peds

Dicyclomine and hyoscyamine
mechanism: block muscarinic effects of
acetylcholine on the gastrointestinal
tract, relaxing smooth muscles, slowing
intestinal motility and decreasing
diarrhea.

There are, however, no randomized,
double-blind, placebo controlled trials
conducted in the pediatric population
investigating their efficacy.
IBS Treatment: Behavioral
 Relaxation
Training
 Hypnotherapy
 Biofeedback
 Cognitive-Behavioral
Therapy
 Psychotherapy
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Functional Dyspepsia
Persistent or recurrent pain or discomfort


Centered in the upper abdomen;

Unrelated to a change in stool frequency or form; and,

Not exclusively relieved by defecation

Not explained by organic, inflammatory, anatomic,
metabolic, or neoplastic process

The pain should recur at least once a week for
at least 2 months for a diagnosis to be made
Associated symptoms:

vomiting, nausea, abdominal fullness, bloating or
early satiety.


A positive diagnosis of FD helps to shift
focus from further testing to treatment of
symptoms rather than dx of exclusion.

The majority of children with dyspepsia
do not have mucosal lesions on
endoscopy; hence, endoscopy is not
mandatory for the diagnosis of FD.
Rome III FD Subtypes in
Adults

Epigastric Pain Syndrome
Pain or burning localized exclusively to the
epigastrium

Post Prandial Pain Syndrome
Early satiety and/or postprandial bloating
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Functional Dyspepsia
mechanisms:
 Delayed
Gastric Emptying
20-50%
 Impaired accommodation
40%
 Visceral Hypersensitivity
35-70%
 Abnormal EGG
35-65%
Inflammatory Cells in Dyspepsia:
Potential Mechanisms of Pain Production
Stimulation of afferent nerves
Sensitization of afferent nerves
Altered motility
Electrical disturbances
CNS mediator effects
Psychological profiles among
children with recurrent abdominal
pain
Child report vs. parent report

Cluster 1

Cluster 2

Cluster 3
52% vs. 42%
No Significant problems
35% vs. 45%
Anxiety with Somatization
Distress
13% Vs. 13%
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Psychology and QOL

Psychological disorders such as anxiety and
depression are very common.

Children with FAP tend to have a lower quality of life
than healthy children but similar quality of life as
patients with demonstrable organic gastrointestinal
disease.

Siblings of children with FGIDs experience more
emotional/behavioral symptoms than their peers.

Children with FGIDs including IBS tend to use less
effective coping strategies to handle stress compared
to healthy controls, which explains the association
between depressive symptoms and many FGID
Anxiety, Microbes, Allergens
and Inflammation
CRH, Bacteria, Allergen
Nerve Sensitization
Mast Cells
Nerve Stimulation
Dysmotility
T Cells
Nerve Destruction
Nerve Sensitization
Eosinophils
Nerve Stimulation
Dysmotility
Mast Cell Degranulation
Janeway CA Jr, Travers P, Walport M, and Shlomchik MJ. Immunobiology. 2005. p403.
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Inflammatory Cells in Functional
Dyspepsia
Lymphocytes (T cells)
Mast Cells
Eosinophils
Mast Cells - Nociceptive Products
Histamine
Serotonin
Platelet Activating Factor
Prostaglandins
Leukotrienes
Cytokines
Eosinophil Products
Stimuli
Tissue Injury
Chemokines
Viral Infections
Eotaxin
Allergens
Ag Presentation
RANTES
MHC-II
MIP-1
B 7.2
Lipid Mediators
Leukotrienes
Platelet activating
factor
Cytotoxic Secretory
Products
EPO
Cytokines
MBP
IL-2, IL-3, IL-4, IL-5
ECP
IL-6, IL-8, TGF, GM-CSF,
EDN
TNF , IFN8, IL-12
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Duodenal Eosinophils in Adults with
Functional Dyspepsia
Mean
Cells/hpf
*Duodenal eosinophils correlated with duodenal mast cells (r=0.48, p<.001)
Talley, et al. Gastroenterology. 2007
Extent of Degranulation of Duodenal
Eosinophils in Pediatric Dyspepsia
% of
Patients
<20%
20 – 60%
>60%
15
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Double Blind Placebo-Controlled Cross-Over
Trial of Montelukast in Pediatric Dyspepsia
Response Rate
(% Patients)
All Patients
Eos Counts 20-29
Conditions Associated with
Mucosal Eosinophils and
Mast Cells

Anxiety/Stress

Allergy

Post-infection bacterial or viral

Helicobacter pylori
EVALUATION OF
FD
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Alarm Signs & Symptoms

Weight loss

Deceleration of linear growth

Evaluation: CBC, albumin, ESR, CRP, stool
calprotectin and celiac serology
Alarm Signs & Symptoms

Significant vomiting

RUQ pain/tenderness

Evaluation: LFTs, amylase, lipase, UA, and abdominal
ultrasound

Dysphagia

Evaluation: GI consult and Upper endoscopy
Alarm Signs & Symptoms

Hematemesis, GI blood loss

Chronic severe diarrhea

Unexplained fever

Family history of IBD

Evaluation: CBC, ESR, CRP, stool calprotectin,
celiac serology, and stool cultures, endoscopy
17
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MANAGMENT
DIETARY INTERVENTIONS AND
SUPPLEMENTS

Diet modifications such as the avoidance of fatty
foods which may delay gastric emptying or avoidance
of gas-producing foods or drinks to prevent bloating
may be helpful in some patients.

There is limited evidence to support minimizing fatty,
gaseous, and spicy food intake.

Ginger root and peppermint, and chamomile — have
been shown in adult studies to be effective for relief
of dyspepsia symptoms.

Heather tummy tamers( ginger, fennel and
peppermint oil combination) helps in IBS and FD.

Studies in adults suggest that proton pump inhibitors
may improve symptoms in some individuals with FD
even in the absence of gastroesophageal reflux.

In a double-blind, placebo controlled trial of 25
children, famotidine was superior to placebo (68% vs.
12%) in treating abdominal pain and dyspepsia.
Moayyedi ,et al. Gastroenterology 2004
See MC et al. Dig Dis Sci 2001

PPIs may be more efficacious and cost-effective than
H2 blockers according to adult data.

At 3 months following therapy, patients taking
omeprazole had fewer days on medication, fewer
clinic visits, and higher quality-of-life scores
compared to those taking placebo.
18
4/25/2017
Initial Treatment of FD
FD
Reflux-like
Non-reflux
PPI
H2 Antagonist
H. pylori and FD
Helicobacter pylori is an uncommon
cause of dyspepsia in children, and
test and treat strategy is
discouraged.
 There is inadequate evidence to
support a causal relation between H.
pylori gastritis and abdominal pain in
the absence of ulcer; therefore,
abdominal pain alone does not justify
testing for H. pylori.( FD and HP is
found in 9% in children vs 30% In
adults).

When to test for H pylori?

Diagnosis of H. pylori-associated
disease is suspected in patients
with:

1. persistent symptoms despite
the use of acid blockers

2. whose symptoms recur upon
stopping such medications.
19
4/25/2017
Electromechanical
Treatments

Prokinetics: There is no pediatric convincing
evidence of its efficacy.
Erythromycin, domperidone, metoclopramide

Accommodation Induction
sumatriptan, buspirone, cyproheptadine

Desensitizing
SSRIs, TCAs
Anti-inflammatory
Treatment

H1/H2 antagonists

Leukotriene antagonists

Corticosteroids

Mast cell stabilizers
hydroxyzine, ranitidine, famotidine
montelukast
prednisone, budesonide
cromolyn, ketotifen
TCA

In a MC RCT in children, low dose amitriptyline (10mg
for weight < 35 kg and 20 mg for weight > 35 kg) was
not superior to placebo; however, both amitriptyline
and placebo had excellent therapeutic responses in
pediatric functional GI disorders.

Based on this study, it seems reasonable to reserve
TCAs for anxious children with FD who fail non
pharmacological therapy or are associated
psychological disorders.
Saps M, Youssef N, Miranda A, et al. Multicenter, randomized, placebo-controlled trial of
amitriptyline in children with functional gastrointestinal disorders. Gastroenterology.
2009;137:1261-1269.
20
4/25/2017
AAP and NASPGHAN
statement in 2005

Despite the wide range of potential pharmacologic options,
the lack of good quality, well controlled, pediatric trials
prompted a recent Cochrane review 2008 to conclude that the
“true efficacy of drugs for FGIDs in children remains to be
elucidated”.

A technical review endorsed by the AAP and NASPGHAN
similarly found limited evidence to justify the use of drugs or
herbal preparations for chronic abdominal pain in children

The use of low dose antidepressants may be beneficial for a
select group of patients, especially those with anxiety or
other psychological comorbidities.
Psychological therapies

Cognitive behavior therapy CBT is
useful when there is history of anxiety.

Guided imagery and progressive
relaxation have been shown to be
effective in pain-related functional GI
disorders.

Biofeedback-assisted relaxation
training, or BART, is a effective
adjunctive tool to medications.
Prognosis of functional
dyspepsia

70% of children with FD were either
asymptomatic or much improved at
6 months to 2 years follow up with
85% of those children on no specific
therapy.
21
4/25/2017
Abdominal migraine

Paroxysmal episodes of intense, acute
periumbilical pain that lasts for 1 hour to days
separated by asymptomatic periods lasting
weeks to months.

Accompanied by nausea, vomiting, anorexia,
photophobia, pallor or headaches.

A history of two episodes occurring in the last
12 months is required to make the diagnosis.

Severe enough to awaken the child and
interfere with normal activities while the
vomiting can be intense
Abdominal Migraine

Episodes are usually triggered by psychological
or physical stress.

Abdominal migraine affects 1%-4% of children
and is more common in girls than boys, with a
mean

age of onset at 7 years and a peak at 10-12
years.

It has been suggested that abdominal migraine,
cyclic vomiting syndrome, and migraine
headaches make up a continuum of a single
disorder.
Evaluation of abdominal
migraine

A basic metabolic panel and an upper
gastrointestinal radiography to exclude
biochemical and anatomic abnormalities
be performed.

It is recommended that that an upper
gastrointestinal radiography along with
empiric migraine therapy is the most
cost-effective strategy to manage
abdominal migraine.
22
4/25/2017

Pharmacological therapy utilizes a dual
approach of abortive and preventive
therapy depending on the severity of the
symptoms.

Prophylactic therapy includes:
amitriptyline, cyproheptadine,
phenobarbital or propranolol. These
medications have been shown to reduce
the frequency as well as severity of
episodes in children.

Abortive therapy includes:

Sumatriptan, a serotonin (5HT1)
receptor agonist, which substantially
decreases frequency, duration, and
intensity of attacks in children and

Ondansetron, a serotonin (5HT3)
receptor antagonist, which has a 76%
efficacy rate in reducing the severity of
vomiting.
Functional abdominal
pain/syndrome

Functional abdominal pain (Rome III criteria) is :

characterized by episodic or continuous abdominal
pain at least once a week for a minimum of 2 months.

It is distinguished from FD by the location of the pain
and lack of association with food intake, and from IBS
by the absence of associated bowel symptoms.

FAP which interferes with daily functioning or is
accompanied by somatic symptoms including
headaches, limb pain or difficulty in sleeping is
labeled functional abdominal pain syndrome.
23
4/25/2017
Anxiety & Abdominal Pain:
A Historical View
Anxiety
Abdominal Pain
Anxiety & Abdominal Pain:
The Current View
Anxiety
Abdominal Pain
SMC+BART: Physician Perspectives
Global Response to Treatment
BART: biofeedback assisted relaxation training
Completely better 5
SMC: standard medical care
Minimal pain, no interference 4
SMC
BART
Better, but still interferes 3
Same
Worse
2
1
Baseline
2 weeks
6 weeks
24
4/25/2017
Results: Child Perspectives
PDA: Pain Intensity (Faces Pain Scale – Revised)
6
5
4
3
2
1
0
Worst
↑
↑
SMC
BART
↑
Baseline
Post-Treatment
Minimal
No pain today
Results: Child Perspectives
PDA: Pain Duration
> 2 hours
4
1-2 hours
6-60 minutes
3
SMC
BART
2
1
1-5 minutes
0
Baseline
Post-Treatment
No pain today
Traditional Treatment Approaches
 Childhood
abdominal pain has been
historically (and inappropriately) attributed
to purely psychological factors
 “Wait
and see” has been the standard
approach to care
 Reassurance,
 Viewed
repeated as often as needed
as benign
25
4/25/2017
What’s Wrong with “Wait and See”?
 As
children continue to experience
abdominal pain over time, negative
effects become intense and far reaching
 What
began as a circumscribed problem
with pain can become a problem across
many domains of functioning
Approach and goals of therapy in
FGIDs

The physician should adopt an ‘active listening approach’ for
any patients concerns and positive and encouraging attitude
towards treatment.

Provide reassurance that a positive diagnosis of FAP or IBS is not
a failure to identify an underlying illness.

Explaining the pathophysiology of visceral pain and associated
complaints in the context of a brain–gut axis.

Symptoms should be validated as being real.

It is also important to make clear that treatment response is
often gradual and to set realistic goals.

Improved coping with symptoms and maintenance of normal
daily living activities, rather than expectation of a prompt
complete cure.
Personal &
Societal Costs
in Adulthood
The Case for Early
Intervention
Mood
Problems
Missed Learning
Opportunities
Chronic
Abdominal
Pain
Missed Social
Opportunities
School Absence
NORMAL DEVELOPMENTAL TRAJECTORY
26
4/25/2017
Academic Consequences

Frequent absenteeism

Failure to secure core academic
skills

Decreased sense of academic
competence

Increased burden of make up work

School difficulty and/or failure
Social Consequences





Missed opportunities with peers and
classmates
Possible peer rejection and/or change
in social group identification
Decreased participation in
extracurriculars
Disrupted relationships with parents,
siblings, and teachers
Failure to develop core social skills
and achieve social milestones
Psychological Consequences

Decreased quality of life

Sleep disturbance

Helplessness/hopelessness

Change in self-concept

Identification with the sick role

Development of depressed mood
and anxiety
27
4/25/2017
Developmental Costs

Goal of early (and aggressive)
intervention is to minimize or prevent:
 Disruption
of social and
developmental trajectories
 Learning
problems due to school
absence
 Mood
and anxiety problems
Developmental Costs

The greater the deviation from a child’s
expected developmental trajectory, the
harder it is to correct course and
achieve full recovery.

Early (and aggressive) intervention may
have protective effects.
Other Costs of Waiting
 More
medical resources required
 More
time, patience, and tolerance
required by families
 Greater
challenge for providers.
28
4/25/2017
Summery

FGID is a multifactorial condition that
results from a complex psychosocial
and physiological interaction.

Rome III criteria is established to
provide helpful direct clinical diagnosis
based on symptoms and to avoid
unnecessary testing.

Successful treatment includes
modification of physical and
psychological stress factors, dietary
changes, and drug therapy.


The key in managing this challenging
disorder is to establish a trusting
relationship with the child and parents by
providing education, reassurance, setting
up realistic expectation and active
psychological support.

Early intervention is important to minimize
academic, psychosocial and developmental
negative consequences.
Thank you
29
4/25/2017
Pediatric Topics Below the
Belt:
Cystitis to Scrotal Pain,
Reflux to Retention…
Could there be a Relationship?
John Gatti, MD
Department of Surgery & Urology
Children’s Mercy Hospital
Objectives
• Consider the many presentations of voiding
dysfunction
• Discuss the pathophysiology of bladder
instability and detrusor sphincter dyssynergia
• Review the evaluation and treatment of this
syndrome
What is voiding dysfunction?
A “garbage bag” term
• Dysfunctional Elimination Syndrome
– Inappropriate bladder or sphincter function or
coordination resulting in incontinence, dysuria or
urinary tract infection.
– Includes bowel assessment for constipation
• LUT function/malfunction
– Standardization of Terminology ICCS
– J Urol, July 2006
1
4/25/2017
Dysuria
Leaking
Wetting (Day or Night)
Dribbling
Dripping
Enuresis
Hematuria
Incontinence
Retention
Constipation
Urgency
Frequency
Bladder Spasms
Pain with Urination
Overactive Bladder
Thickened Bladder
Meatal Stenosis
Epididymitis
Scrotal Pain
Penile Pain
UTI (true or Cx negative)
Voiding
Dysfunction
Presentation
Bladder/Sphincter Function:
Dual Role
• Storage
• Micturition
– Detrusor Relaxation
– Sphincter Contraction
– Detrusor Contraction
– Sphincter Relaxation
Urodynamics: Normal
Pressure
Volume
2
4/25/2017
Urodynamics:
Overactive Bladder
Pressure
Volume
Urodynamics:
Detrusor Sphincter Dyssynergia
Diminished
Flow-rate &
Incomplete
emptying
Pressure
Inappropriate
Sphincter
Activity
Volume
Manifestations of OAB
• Incontinence (Urge)
– Bladder pressures
overcome sphincter
resistance
• Dribbling or Dampness
– Same but small volume
• Nocturnal Enuresis
• Frequent Voiding
– Sensation of Contraction
• Infrequent Voiding or
Holding Pattern
– Learn to ignore natural
sensation of bladder
fullness
– Cannot guard against
spasms when asleep
3
4/25/2017
Manifestations of OAB & DSD
• Dysuria
• Meatal Stenosis
– Voiding as Sphincter Snaps
– Watch voiding
Shut
• Thickened Bladder
• Penile & Suprapubic Pain
– Contraction against
– Referred Pain
obstruction
• Urinary Retention
• Hematuria (terminal)
• Recurrent Epididymitis
– Turbulent Forceful flow
through urethra
– Chemical irritation of
urine entering ejaculatory
ducts with pressured void
Voiding Dysfunction and Scrotal Pain
Bladder Contracts
Sphincter Dyssynergia
Ejaculatory
Duct Reflux
Pain &
Inflammation
UTI & the “Milk Back”
Phenomenon
Zone of
Bacterial
Colonization
4
4/25/2017
Reflux and Dysfunctional Voiding
OAB
&
DSD
VUR
VUR Does not cause Infection
VUR is a risk factor for bladder infection ascension
OAB will delay spontaneous resolution of VUR
Dysfunctional Voiding
• Special Considerations
– Daytime Urinary Frequency Syndrome of
Childhood
– Post Micturitional Dribbling
– “Giggle Incontinence”
– Hypercalciuria
– Sexual Abuse
– Ectopic Ureter (Girls Only)
– Urethral Valves (Boys Only)
– Neurogenic Bladder (Tethered Cord)
Voiding Dysfunction Evaluation
• Voiding pattern
–
–
–
–
Interval
Urgency
1st Thing in the Morning
Incontinence (simple
terms)
• When does it occur?
• Bowel Pattern
–
–
–
–
–
Frequency
Consistency
Size
Encopresis
Objective Historian
• UTI
– Documentation
Diary is Essential if Unclear
5
4/25/2017
Voiding Dysfunction Evaluation
• Examination
– Abdominal Exam
• Bladder Distention
• Fecal Burden
– Genital Exam with Stress Maneuvers
– Lumbosacral Exam
– Neurological Exam
– Watch Void if considering Meatal Stenosis
Watch Void or Have Family Film
Voiding Dysfunction Evaluation
• Ancillary Studies
– Urinalysis, Culture, Ca/Cr ratio
– Post Void Residual Volume
– Renal Bladder US (In all boys)
• Hydronephrosis
• Thickened Bladder
– KUB for Fecal Burden
– VCUG if History of Documented UTI
– Uroflow Study
– Formal Urodynamics
6
4/25/2017
VCUG
• Spinning Top Urethra
– The bladder contracts
against a closed
external sphincter
– Proximal urethra
balloons giving
appearance of a
“spinning top”
– Thickened Bladder
with diverticula results
External
Sphincter
Treatment
Dietary Modification
• Elimination Diet
– Caffeine, high sugar drinks
– Citrus fruits and drinks
– Artificial coloring
– Excessive Dairy intake
– Chocolate
Treatment
Infrequent Voiding
• Timed Voiding
– Every 2-3 hours, by the clock
• May void more frequently
– Allow several minutes
– Sitting is good, feet supported
– Books or toys allowed
– Voiding diary
– Star chart
7
4/25/2017
Treatment
Bowel Management
• Control of Constipation
– Increase Dietary Fiber
• Fruits, popcorn, bran cereal, fiber bars
– Stool Softeners
• Miralax
• Benefiber
• Lactulose
– Attempt BM after dinner (10 minutes)
• Books or toys allowed
– Voiding Diary
Treatment
Pharmacotherapy
Never First Line Therapy
• Anticholinergics (Detrol, Ditropan)
– Long Acting Formulations
– All exacerbate constipation
• Beta Agonist – Mirabegron (Merobetriq)
• Alpha agonists (Flomax, Hytrin, Cardura)
– Hypotension in non-selectives
• Antibiotic Suppression
– Short term until some improvement
Treatment
Aggressive Therapy
•
•
•
•
•
•
•
Biofeedback
Clean Intermittent Catheterization
Enema Regimen
Urethral Dilation (Historically)
Continent Catheterizable Stoma
Antegrade Continence Enema Stoma
Bladder Augmentation
8
4/25/2017
One Day in Message Center
10 y/o F
S/S: increased night time accidents, new onset of daytime accidents.
Medications: miralax "when needed"
they tried a few medications (one was sulfamethoxazole) but no
improvements.
UTI: no
Voiding: "not very often" x3 between getting home from school and going to
bed.
Urgency/Frequency: no
Day/Night accidents: increase in nocturnal enuresis & new onset of daytime
accidents.
Leaking: no
BM unsure
Constipation/Encopresis: has hx constipation
encopresis: once c/ miralax.
14 y/o M
In August, pt went to urgent care, pt was placed on antibiotics. Day 6 of the 7 days of antibiotics pt
began having hematuria (visible to the naked eye). Went to the ED Mosaic Hospital in St. Joseph,
MO. did RBUS, scrotal U/S. Went to Local Urology. took some time off of football (rested). MRI
there & urethra scope. Still in alot of pain, still urinating blood. Pt will wake up in pain stating that "it
feels like someone is kicking him in the testicles all the time” Encopresis/Constipation 2002 ,
colonoscopy (-)
Closing Remarks
•
•
•
•
•
Anyone can treat voiding dysfunction
Expect Denial
Patient Satisfaction is high
Repetition is Common
May Wax and Wane
Objectives
• Consider the many presentations of voiding
dysfunction
• Discuss the pathophysiology of bladder
instability and detrusor sphincter dyssynergia
• Review the evaluation and treatment of this
syndrome
9
4/25/2017
Ultimate Outcome…
Another
Happy
Bladder!
10