Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
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. 1 4/25/2017 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 2 4/25/2017 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. 3 4/25/2017 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 •10 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 •12 4 4/25/2017 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 15 5 4/25/2017 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 17 Cancer rates in Women – 20th Century All uterine sites i.e. cervical and endometrial Source: American Cancer Society 18 6 4/25/2017 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 7 4/25/2017 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 8 4/25/2017 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* 9 4/25/2017 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 10 4/25/2017 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 33 11 4/25/2017 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 4/25/2017 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 39 13 4/25/2017 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 42 14 4/25/2017 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 43 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 15 4/25/2017 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. 16 4/25/2017 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 17 4/25/2017 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. 18 4/25/2017 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 19 4/25/2017 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 20 4/25/2017 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 21 4/25/2017 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 22 4/25/2017 QUESTIONS? [email protected] 23 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. ‹#› © 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. ‹#› © The Children's Mercy Hospital, 2014. 03/14 Tic • Definition • A sudden, involuntary, rapid, recurrent, nonrhythmic, stereotyped motor movement or vocalization. ‹#› © 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. ‹#› © 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. ‹#› © 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). ‹#› © The Children's Mercy Hospital, 2014. 03/14 Who develops tics? ‹#› © 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. ‹#› © 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 ‹#› © The Children's Mercy Hospital, 2014. 03/14 What do tics look and sound like? • Just about anything! ‹#› © 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) ‹#› © 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) ‹#› © 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 ‹#› © 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. ‹#› © 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 ‹#› © 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. ‹#› © 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.” ‹#› © The Children's Mercy Hospital, 2014. 03/14 Characteristics of tics Tics can be exhausting, both physically, and emotionally! ‹#› © 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. ‹#› © 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 ‹#› © The Children's Mercy Hospital, 2014. 03/14 Uncommon Associated Conditions • Oppositional Defiant Disorder (ODD) • Depression • Learning disabilities ‹#› © 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 ‹#› © 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 ‹#› © 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. ‹#› © 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! ‹#› © 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. ‹#› © 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 ‹#› © 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 1 4/26/2017 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? 2 4/26/2017 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 3 4/26/2017 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. 4 4/26/2017 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 5 4/26/2017 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 6 4/26/2017 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 7 4/26/2017 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. 8 4/26/2017 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 9 4/26/2017 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) 10 4/26/2017 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 11 4/26/2017 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 12 4/26/2017 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. 13 4/26/2017 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 14 4/26/2017 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 15 4/26/2017 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 16 4/26/2017 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 17 4/26/2017 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 18 4/26/2017 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 19 4/26/2017 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 20 4/26/2017 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 21 4/26/2017 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 22 4/26/2017 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 23 4/26/2017 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 24 4/26/2017 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. 25 4/26/2017 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 26 4/26/2017 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 27 4/26/2017 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 28 4/26/2017 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 29 4/26/2017 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 30 4/26/2017 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 31 4/26/2017 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 32 4/26/2017 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 33 4/26/2017 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 34 4/26/2017 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 35 4/26/2017 (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 36 4/26/2017 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 37 4/26/2017 How to treat ADHD? MTA Study Medication titration and long term treatment Behavioral management Medication Treatment 38 4/26/2017 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) 39 4/26/2017 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) 40 4/26/2017 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 41 4/26/2017 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 43 4/26/2017 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 44 4/26/2017 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 45 4/26/2017 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 46 4/26/2017 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 47 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. 48 4/26/2017 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 49 4/26/2017 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 50 4/26/2017 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 51 4/26/2017 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 52 4/26/2017 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 53 4/26/2017 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 54 4/26/2017 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 55 4/26/2017 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 56 4/26/2017 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 57 4/26/2017 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 58 4/26/2017 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 59 4/26/2017 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? 60 4/26/2017 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 61 4/26/2017 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 62 4/26/2017 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 63 4/26/2017 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 64 4/26/2017 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 65 4/26/2017 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 66 4/26/2017 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 67 4/26/2017 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 68 4/26/2017 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 69 4/26/2017 • 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 70 4/26/2017 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 71 4/26/2017 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 72 4/26/2017 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 73 4/26/2017 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 74 4/26/2017 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 75 4/26/2017 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 76 4/26/2017 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 77 4/26/2017 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 78 4/26/2017 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 79 4/26/2017 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 80 4/26/2017 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 81 4/26/2017 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 82 4/26/2017 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 83 4/26/2017 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 84 4/26/2017 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 85 4/26/2017 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 86 4/26/2017 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 87 4/26/2017 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 88 4/26/2017 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 89 4/26/2017 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 90 4/26/2017 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 91 4/26/2017 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 92 4/26/2017 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 93 4/26/2017 References 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. Attention deficit hyperactivity disorder. University of Maryland Medical Center http://umm.edu/health/medical/reports/articles/attentiondeficit-hyperactivity-disorder#ixzz2ZExmwQAA Litman, T. (2012). Evaluating Research Quality: Guidelines for Scholarship. International Electronic Symposium on Knowledge Communication & Peer Reviewing, International Institute of Informatics and Systematics. http://www.vtpi.org/resqual.pdf Martin, B. (2007). Treatment for Attention Deficit Disorder (ADHD). Psych Central. Retrieved on July 22, 2013, from http://psychcentral.com/lib/treatment-for-attention-deficit -disorder-adhd/0001204. MTA Cooperative Group. (1999). A 14-month randomized clinical trial of treatment strategies for attentiondeficit/hyperactivity disorder. Archives of General Psychiatry, 56, 1073:1086. Rabiner, D. (2012). New Review of Neurofeedback Treatment for ADHD-Current State of the Science. Resources Other ADHD sites: www.cmeonadhd.com www.nimh.nih.gov/health/publications/attention-deficithyperactivity-disorder/ www.chadd.org/ www.webmd.com/add-adhd/default.htm www.cdc.gov/ncbddd/ADHD/ www.mayoclinic.com/health/adhd/DS00275/ References Abou‐Khadra, M. K., Amin, O. R., Shaker, O. G., & Rabah, T. M. (2013). Parent‐reported sleep problems, symptom ratings, and serum ferritin levels in children with attention‐deficit/hyperactivity disorder: a case control study BMC Pediatr (Vol. 13, pp. 217). England. Attention‐Deficit Disorders and Comorbidities in Children, Adolescents, and Adults (2nd Edition). (2008). Arlington, VA, USA: American Psychiatric Publishing. Barbaresi, W. J., Colligan, R. C., Weaver, A. L., Voigt, R. G., Killian, J. M., & Katusic, S. K. (2013). Mortality, ADHD, and Psychosocial Adversity in Adults With Childhood ADHD: A Prospective Study. Pediatrics, 131(4), 637‐644. doi:10.1542/peds.2012‐2354 Baumann, P., Hiemke, C., Ulrich, S., Eckermann, G., Gaertner, I., & Gerlach, M. (2004). The AGNP‐TDM expert group consensus guidelines: therapeutic drug monitoring in psychiatry. Pharmacopsychiatry, 37. doi:10.1055/s‐2004‐832687 Baweja, R., Mayes, S. D., Hameed, U., & Waxmonsky, J. G. (2016). Disruptive mood dysregulation disorder: current insights. Neuropsychiatr Dis Treat, 12, 2115‐2124. doi:10.2147/ndt.s100312 Beck, O., Stephanson, N., Sandqvist, S., & Franck, J. (2014). Determination of amphetamine and methylphenidate in exhaled breath of patients undergoing attention‐deficit/hyperactivity disorder treatment. Therapeutic Drug Monitoring, 36(4), 528‐534. doi:http://dx.doi.org/10.1097/FTD.0000000000000046 Benedetto Vitiello, Glen R. Elliott, James M. Swanson, L. Eugene Arnold, Lily Hechtman, Howard Abikoff, . . . Robert Gibbons. (2012). Blood Pressure and Heart Rate Over 10 Years in the Multimodal Treatment Study of Children With ADHD. American Journal of Psychiatry, 169(2), 167‐177. doi:10.1176/appi.ajp.2011.10111705 Biederman, J., Spencer, T., Lomedico, A., Day, H., Petty, C. R., & Faraone, S. V. (2012). Deficient emotional self‐ regulation and pediatric attention deficit hyperactivity disorder: A family risk analysis. Psychological Medicine, 42(3), 639‐646. doi:10.1017/s0033291711001644 94 4/26/2017 References Brinkman, W. B., Sherman, S. N., Zmitrovich, A. R., Visscher, M. O., Crosby, L. E., Phelan, K. J., & Donovan, E. F. (2012). In Their Own Words: Adolescent Views on ADHD and Their Evolving Role Managing Medication. Acad Pediatr, 12(1), 53‐61. doi:http://dx.doi.org/10.1016/j.acap.2011.10.003 Bush, G., Spencer, T. J., Holmes, J., & et al. (2008). Functional magnetic resonance imaging of methylphenidate and placebo in attention‐ deficit/hyperactivity disorder during the multi‐source interference task. Archives of General Psychiatry, 65(1), 102‐114. doi:10.1001/archgenpsychiatry.2007.16 Camfield, C. S., Chaplin, S., Doyle, A. B., Shapiro, S. H., Cummings, C., & Camfield, P. R. (1979). Side effects of phenobarbital in toddlers: behavioral and cognitive aspects. Journal of Pediatrics, 95. doi:10.1016/s0022‐3476(79)80507‐7 Cardiovascular safety of methylphenidate among children and young people with attention‐deficit/hyperactivity disorder (ADHD): nationwide self controlled case series study. (2016). BMJ, 353, i3123. Chang, Z., Lichtenstein, P., D’Onofrio, B. M., Sjölander, A., & Larsson, H. (2014). Serious transport accidents in adults with attention‐ deficit/hyperactivity disorder and the effect of medication: A population‐based study. JAMA Psychiatry, 71(3), 319‐325. doi:10.1001/jamapsychiatry.2013.4174 Charach, A., Yeung, E., Volpe, T., Goodale, T., & Dosreis, S. (2014). Exploring stimulant treatment in ADHD: narratives of young adolescents and their parents BMC Psychiatry (Vol. 14, pp. 110). England. Childress, A. C., & Sallee, F. R. (2014). Attention‐Deficit/Hyperactivity Disorder with Inadequate Response to Stimulants: Approaches to Management. CNS Drugs, 28(2), 121‐129. doi:10.1007/s40263‐013‐0130‐6 Choi, J., Jeong, B., Lee, S. W., & Go, H. J. (2013). Aberrant development of functional connectivity among resting state‐related functional networks in medication‐naive ADHD children PLoS ONE (Vol. 8, pp. e83516). United States. Cooper, W. O., Habel, L. A., Sox, C. M., Chan, K. A., Arbogast, P. G., Cheetham, T. C., . . . Ray, W. A. (2011). ADHD Drugs and Serious Cardiovascular Events in Children and Young Adults. New England Journal of Medicine, 365(20), 1896‐1904. doi:doi:10.1056/NEJMoa1110212Abou‐Khadra, M. K., Amin, O. R., Shaker, O. G., & Rabah, T. M. (2013). Parent‐reported sleep problems, symptom ratings, and serum ferritin levels in children with attention‐deficit/hyperactivity disorder: a case control study BMC Pediatr (Vol. 13 pp 217) England References Correll, C. U. (2008). Antipsychotic use in children and adolescents: minimizing adverse effects to maximize outcomes. Journal of the American Academy of Child and Adolescent Psychiatry, 47. doi:10.1097/chi.0b013e31815b5cb1 Correll, C. U., & Carlson, H. E. (2006). Endocrine and metabolic adverse effects of psychotropic medications in children and adolescents. Journal of the American Academy of Child and Adolescent Psychiatry, 45. doi:10.1097/01.chi.0000220851.94392.30 Cortese, S., Brown, T. E., Corkum, P., Gruber, R., O’Brien, L. M., Stein, M., . . . Owens, J. (2013). Assessment and Management of Sleep Problems in Youths With Attention‐Deficit/Hyperactivity Disorder. Journal of the American Academy of Child and Adolescent Psychiatry, 52(8), 784‐796. doi:http://dx.doi.org/10.1016/j.jaac.2013.06.001 Couluris, M. D. O., Mayer, J. L. R. M. D., Freyer, D. R. D. O. M. S., Sandler, E. M. D., Xu, P. M. P. H., & Krischer, J. P. P. (2008). The Effect of Cyproheptadine Hydrochloride (Periactin) and Megestrol Acetate (Megace) on Weight in Children With Cancer/Treatment‐related Cachexia. Journal of Pediatric Hematology/Oncology, 30(11), 791‐797. Drozda, K., Muller, D. J., & Bishop, J. R. (2014). Pharmacogenomic testing for neuropsychiatric drugs: current status of drug labeling, guidelines for using genetic information, and test options. Pharmacotherapy, 34(2), 166‐184. doi:10.1002/phar.1398 Emslie, G. J., Rush, A. J., & Weinberg, W. A. (1997). A double‐blind, randomized placebo‐controlled trial of fluoxetine in children and adolescents with depression. Archives of General Psychiatry, 54. doi:10.1001/archpsyc.1997.01830230069010 Epstein, R. A., Fonnesbeck, C., Potter, S., Rizzone, K. H., & McPheeters, M. (2015). Psychosocial Interventions for Child Disruptive Behaviors: A Meta‐analysis. Pediatrics. doi:10.1542/peds.2015‐2577 References Evans, S. W., Owens, J. S., & Bunford, N. (2014). Evidence‐Based Psychosocial Treatments for Children and Adolescents with Attention‐Deficit/Hyperactivity Disorder. Journal of Clinical Child & Adolescent Psychology, 43(4), 527‐551. doi:10.1080/15374416.2013.850700 Fabiano, G. A., Pelham, J. W. E., Waschbusch, D. A., Gnagy, E. M., Lahey, B. B., Chronis, A. M., . . . Burrows‐MacLean, L. (2006). A Practical Measure of Impairment: Psychometric Properties of the Impairment Rating Scale in Samples of Children With Attention Deficit Hyperactivity Disorder and Two School‐Based Samples. Journal of Clinical Child & Adolescent Psychology, 35(3), 369‐385. doi:10.1207/s15374424jccp3503_3 Faraone, S. V., Asherson, P., Banaschewski, T., Biederman, J., & Buitelaar, J. (2015). ADHD. Nature Reviews Disease Primers, 1, 15027. doi:10.1038/nrdp.2015.27 Faraone, S. V., Perlis, R. H., Doyle, A. E., Smoller, J. W., Goralnick, J. J., Holmgren, M. A., & Sklar, P. (2005). Molecular Genetics of Attention‐Deficit/Hyperactivity Disorder. Biological Psychiatry, 57(11), 1313‐1323. doi:http://dx.doi.org/10.1016/j.biopsych.2004.11.024 Faraone, S. V., Sergeant, J. A., Gillberg, C., Biederman, J., Sahlgrenska, a., Sahlgrenska, A., . . . Göteborgs, u. (2003). The Worldwide prevalence of ADHD: is it an American condition? World Psychiatry, 2(2), 104‐113. Fiks, A. G., Mayne, S., DeBartolo, E., Power, T. J., & Guevara, J. P. (2013). Parental Preferences and Goals Regarding ADHD Treatment. Pediatrics, 132(4), 692‐702. doi:10.1542/peds.2013‐0152 Findling, R. L., & Dinh, S. (2014). Transdermal therapy for attention‐deficit hyperactivity disorder with the methylphenidate patch (MTS). CNS Drugs, 28(3), 217‐228. doi:10.1007/s40263‐014‐0141‐y Fleischhaker, C., Heiser, P., Hennighausen, K., Herpertz‐Dahlmann, B., Holtkamp, K., & Mehler‐Wex, C. (2006). Clinical drug monitoring in child and adolescent psychiatry: side effects of atypical neuroleptics. Journal of Child and Adolescent Psychopharmacology, 16. doi:10.1089/cap.2006.16.308 95 4/26/2017 References Fost, N. (2001). Ethical issues in research and innovative therapy in children with mood disorders. Biological Psychiatry, 49. doi:10.1016/s0006‐3223(01)01181‐7 Froehlich, T. E., Antonini, T. N., Brinkman, W. B., Langberg, J. M., Simon, J. O., Adams, R., . . . Epstein, J. N. (2014). Mediators of methylphenidate effects on math performance in children with attention‐deficit hyperactivity disorder Journal of Developmental and Behavioral Pediatrics (Vol. 35, pp. 100‐107). United States. Garland, E. J. (2004). Facing the evidence: antidepressant treatment in children and adolescents (Commentary). Canadian Medical Association Journal, 170. doi:10.1503/cmaj.1040687 Getahun, D., Jacobsen, S. J., Fassett, M. J., Chen, W., Demissie, K., & Rhoads, G. G. (2013). Recent trends in childhood attention‐deficit/hyperactivity disorder. JAMA Pediatr, 167(3), 282‐288. doi:10.1001/2013.jamapediatrics.401 Gleason, M. M., Egger, H. L., Emslie, G. J., Greenhill, L. L., Kowatch, R. A., Lieberman, A. F., . . . Zeanah, C. H. (2007). Psychopharmacological Treatment for Very Young Children: Contexts and Guidelines. J. Am. Acad. Child Adolesc. Psychiatry,. Gold, M. S., Blum, K., Oscar‐Berman, M., & Braverman, E. R. (2014). Low dopamine function in attention deficit/hyperactivity disorder: should genotyping signify early diagnosis in children? Postgraduate Medicine, 126(1), 153‐177. doi:10.3810/pgm.2014.01.2735 Gold, M. S., & Frost‐Pineda, K. (2006). Regarding “Is Cigarette Smoking a Gateway to Alcohol and Illicit Drug Use Disorders? A Study of Youths with and without Attention Deficit Hyperactivity Disorder”. Biological Psychiatry, 60(10), 1166. doi:http://dx.doi.org/10.1016/j.biopsych.2006.04.016 Golubchik, P., Sever, J., & Weizman, A. (2014). Methylphenidate treatment in children with attention deficit hyperactivity disorder and comorbid social phobia. International Clinical Psychopharmacology, 29(4), 212‐215. doi:10.1097/yic.0000000000000029 References Gracious, B. L., Findling, R. L., Seman, C., Youngstrom, E. A., Demeter, C. A., & Calabrese, J. R. (2004). Elevated thyrotropin in bipolar youths prescribed both lithium and divalproex sodium. Journal of the American Academy of Child and Adolescent Psychiatry, 43. doi:10.1097/00004583‐200402000‐00018 Greenhill, L. L., Vitiello, B., Abikoff, H., Levine, J., March, J. S., & Riddle, M. A. (2001). Improving the methods for evaluating the safety of psychotropic medications in children and adolescents. Current Therapeutic Research, Clinical and Experimental, 62. doi:10.1016/s0011‐393x(01)80092‐8 Gruber, R., Grizenko, N., Schwartz, G., Bellingham, J., Guzman, R., & Joober, R. (2007). Performance on the continuous performance test in children with ADHD is associated with sleep efficiency. Sleep, 30(8), 1003‐1009. Hammerness, P., Doyle, R., Kotarski, M., Georgiopoulos, A., Joshi, G., Zeitlin, S., & Biederman, J. Atomoxetine in children with attention‐deficit hyperactivity disorder with prior stimulant therapy: a prospective open‐label study. Harstad, E., Levy, S., Levy, S., Ammerman, S. D., Gonzalez, P. K., Ryan, S. A., . . . Smith, V. C. (2014). Attention‐ Deficit/Hyperactivity Disorder and Substance Abuse. Pediatrics, 134(1), e293‐e301. doi:10.1542/peds.2014‐0992 Harstad, E. B., Weaver, A. L., Katusic, S. K., Colligan, R. C., Kumar, S., Chan, E., . . . Barbaresi, W. J. (2014). ADHD, Stimulant Treatment, and Growth: A Longitudinal Study. Pediatrics. doi:10.1542/peds.2014‐0428 Hinshaw, S. P., Hinshaw, S. P., & Arnold, L. E. Attention‐deficit hyperactivity disorder, multimodal treatment, and longitudinal outcome: evidence, paradox, and challenge. Wiley interdisciplinary reviews. Cognitive science, 6(1), 39‐52. doi:10.1002/wcs.1324 Jain, R., Babcock, T., Burtea, T., Dirks, B., Adeyi, B., Scheckner, B., & Lasser, R. (2011). Efficacy of lisdexamfetamine dimesylate in children with attention‐deficit/hyperactivity disorder previously treated with methylphenidate: a post hoc analysis. Child and Adolescent Psychiatry and Mental Health, 5, 35‐35. doi:10.1186/1753‐2000‐5‐35 References Jensen, P. S., Hinshaw, S. P., Swanson, J. M., Greenhill, L. L., Conners, C. K., Arnold, L. E., . . . Wigal, T. (2001). Findings from the NIMH Multimodal Treatment Study of ADHD (MTA): implications and applications for primary care providers. Journal of Developmental and Behavioral Pediatrics, 22(1), 60‐73. King, R. A., Riddle, M. A., Chappell, P. B., Hardin, M. T., Anderson, G. M., & Lombroso, P. (1991). Emergence of self‐ destructive phenomena in children and adolescents during fluoxetine treatment. Journal of the American Academy of Child and Adolescent Psychiatry, 30. doi:10.1097/00004583‐199103000‐00003 Klein, D. F. (2006). The flawed basis for FDA post‐marketing safety decisions: the example of antidepressants and children. Neuropsychopharmacology, 31. doi:10.1038/sj.npp.1300996 Koro, C. E., Fedder, D. O., L'Italien, G. J., Weiss, S. S., Magder, L. S., & Kreyenbuhl, J. (2002). Assessment of independent effect of olanzapine and risperidone on risk of diabetes among patients with schizophrenia: population based nested case‐control study. BMJ, 325. doi:10.1136/bmj.325.7358.243 Lam, Y. W. F., Gaedigk, A., Ereshefsky, L., Alfaro, C. L., & Simpson, J. CYP2D6 Inhibition by Selective Serotonin Reuptake Inhibitors: Analysis of Achievable Steady‐State Plasma Concentrations and the Effect of Ultrarapid Metabolism at CYP2D6. Law, E. C., Sideridis, G. D., Prock, L. A., & Sheridan, M. A. (2014). Attention‐Deficit/Hyperactivity Disorder in Young Children: Predictors of Diagnostic Stability. Pediatrics, 133(4), 659‐667. doi:10.1542/peds.2013‐3433 96 4/26/2017 References Levy, S., Katusic, S. K., Colligan, R. C., Weaver, A. L., Killian, J. M., Voigt, R. G., & Barbaresi, W. J. (2014). Childhood ADHD and risk for substance dependence in adulthood: a longitudinal, population‐based study. PLoS ONE [Electronic Resource], 9(8), e105640. doi:http://dx.doi.org/10.1371/journal.pone.0105640 Lichtenstein , P., Halldner , L., Zetterqvist , J., Sjölander , A., Serlachius , E., Fazel , S., . . . Larsson , H. (2012). Medication for Attention Deficit–Hyperactivity Disorder and Criminality. New England Journal of Medicine, 367(21), 2006‐2014. doi:doi:10.1056/NEJMoa1203241 Man, K. K. C., Chan, E. W., Coghill, D., Douglas, I., Ip, P., Leung, L.‐p., . . . Wong, I. C. K. (2015). Methylphenidate and the Risk of Trauma. Pediatrics, 135(1), 40‐48. doi:10.1542/peds.2014‐1738 March, J., Silva, S., Petrycki, S., Curry, J., Wells, K., & Fairbank, J. (2004). Fluoxetine, cognitive‐behavioral therapy, and their combination for adolescents with depression: Treatment for Adolescents With Depression Study (TADS) randomized controlled trial. JAMA, 292. doi:10.1001/jama.292.7.807 March, J. S., Karayal, O., & Crisman, A. (2007). CAPTN: The pediatric adverse event rating scale Proceedings of the 54th Annual Meeting of the American Academy of Child and Adolescent Psychiatry. Martin, P. T., Corcoran, M., Zhang, P., & Katic, A. (2014). Randomized, double‐blind, placebo‐controlled, crossover study of the effects of lisdexamfetamine dimesylate and mixed amphetamine salts on cognition throughout the day in adults with attention‐deficit/hyperactivity disorder. Clin Drug Investig, 34(2), 147‐157. doi:10.1007/s40261‐013‐0156‐z Mattfeld, A. T. A. T. (2014). Brain differences between persistent and remitted attention deficit hyperactivity disorder. Brain (London, England : 1878), 137, 2423‐2428. doi:10.1093/brain/awu137 McCann, D. C., Thompson, M., Daley, D., Barton, J., Laver‐Bradbury, C., Hutchings, J., . . . Sonuga‐Barke, E. (2014). Study protocol for a randomized controlled trial comparing the efficacy of a specialist and a generic parenting programme for the treatment of preschool ADHD Trials (Vol. 15, pp. 142). England. References McTate, E. A., & Leffler, J. M. Diagnosing disruptive mood dysregulation disorder: Integrating semi‐structured and unstructured interviews. Clinical Child Psychology and Psychiatry, 0(0), 1359104516658190. doi:doi:10.1177/1359104516658190 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 00004583‐200606000‐00005 [pii] References Pliszka, S. R., Greenhill, L. L., Crismon, M. L., Sedillo, A., Carlson, C., Conners, C. K., . . . Toprac, M. G. (2000). The Texas Children's Medication Algorithm Project: Report of the Texas Consensus Conference Panel on Medication Treatment of Childhood Attention‐Deficit/Hyperactivity Disorder. Part II: Tactics. Journal of the American Academy of Child and Adolescent Psychiatry, 39(7), 920‐927. doi:http://dx.doi.org/10.1097/00004583‐200007000‐00022 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‐ 442. doi:10.1093/ije/dyt261 Posner, M., & Peterson, S. (1990). The attention system of the human brain. Annual Review of Neuroscience, 13, 25 ‐ 42. Qureshi, M. N. I., Min, B., Jo, H. J., & 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 Ramtvedt, B. E., Aabech, H. S., & Sundet, K. (2014). Minimizing adverse events while maintaining clinical improvement in a pediatric attention‐deficit/hyperactivity disorder crossover trial with dextroamphetamine and methylphenidate. Journal of Child and Adolescent Psychopharmacology, 24(3), 130‐139. doi:10.1089/cap.2013.0114 Rapport, M., Alderson, R. M., Kofler, M., Sarver, D., Bolden, J., & Sims, V. Working Memory Deficits in Boys with Attention‐deficit/Hyperactivity Disorder (ADHD): The Contribution of Central Executive and Subsystem Processes. Roberts, R., Rodriguez, W., Murphy, D., & Crescenzi, T. (2003). Pediatric drug labeling. JAMA, 290. doi:10.1001/jama.290.7.905 97 4/26/2017 References Rubia, K., Alegria, A. A., Cubillo, A. I., Smith, A. B., Brammer, M. J., & Radua, J. Effects of Stimulants on Brain Function in Attention‐Deficit/Hyperactivity Disorder: A Systematic Review and Meta‐Analysis. Biological Psychiatry. Safer, D. J. (2004). A comparison of risperidone‐induced weight gain across the age span. Journal of Clinical Psychopharmacology, 24. doi:10.1097/01.jcp.0000130558.86125.5b Safer, D. J., Zito, J. M., & Gardner, J. F. (2001). Pemoline hepatotoxicity and post‐marketing surveillance. Journal of the American Academy of Child and Adolescent Psychiatry, 40. doi:10.1097/00004583‐200106000‐00006 Shalev, R., & Gross‐Tsur, V. (2001). Developmental dyscalculia. Pediatric Neurology, 24, 337 ‐ 342. Shaw, P., Stringaris, A., Nigg, J., & Leibenluft, E. (2014). Emotion dysregulation in attention deficit hyperactivity disorder American Journal of Psychiatry (Vol. 171, pp. 276‐293). United States. 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 Sikirica, V., Fridman, M., Bruno, A., Hodgkins, P., & Erder, M. H. (2013). Concomitant pharmacotherapy of psychotropic medications in EU children and adolescents with attention‐deficit/hyperactivity disorder. Drugs R D, 13(4), 271‐280. doi:10.1007/s40268‐013‐0034‐4 Sjowall, D., & Thorell, L. B. (2014). Functional impairments in attention deficit hyperactivity disorder: the mediating role of neuropsychological functioning. Dev Neuropsychol, 39(3), 187‐204. doi:10.1080/87565641.2014.886691 Sleath, B., Sulzer, S. H., Carpenter, D. M., Slota, C., Gillette, C., Sayner, R., . . . Sandler, A. (2014). Communication about ADHD and its treatment during pediatric asthma visits. Community Mental Health Journal, 50(2), 185‐192. doi:10.1007/s10597‐013‐9678‐3 References Spencer, R. C., Klein, R. M., & Berridge, C. W. (2012). Psychostimulants Act Within the Prefrontal Cortex to Improve Cognitive Function. Biological Psychiatry, 72(3), 221‐227. doi:10.1016/j.biopsych.2011.12.002 Srinivas, N. R. Drug disposition of chiral and achiral drug substrates metabolized by cytochrome P450 2D6 isozyme: case studies, analytical perspectives and developmental implications. Strom, B. L. (2000). Pharmacoepidemiology. New York: John Wiley and Sons, Ltd. Swanson, J. M., Arnold, L. E., Molina, B. S. G., Sibley, M. H., Hechtman, L. T., Hinshaw, S. P., . . . Kraemer, H. C. (2017). Young adult outcomes in the follow‐up of the multimodal treatment study of attention‐deficit/hyperactivity disorder: symptom persistence, source discrepancy, and height suppression. Journal of Child Psychology and Psychiatry. doi:10.1111/jcpp.12684 Tan‐Kam, T., Suthisisang, C., Pavasuthipaisit, C., Limsila, P., Puangpetch, A., & Sukasem, C. (2013). Importance of pharmacogenetics in the treatment of children with attention deficit hyperactive disorder: a case report. Pharmgenomics Pers Med, 6, 3‐7. doi:10.2147/PGPM.S36782 Teicher, M. H., Glod, C., & Cole, J. O. (1990). Emergence of intense suicidal preoccupation during fluoxetine treatment. American Journal of Psychiatry, 147. doi:10.1176/ajp.147.2.207 Tovo‐Rodrigues, L., Rohde, L. A., Menezes, A. M., Polanczyk, G. V., Kieling, C., Genro, J. P., . . . Hutz, M. H. (2013). DRD4 rare variants in Attention‐Deficit/Hyperactivity Disorder (ADHD): further evidence from a birth cohort study PLoS ONE (Vol. 8, pp. e85164). United States. Turner, S., Nunn, A. J., & Choonara, I. (2004). Unlicensed drug use in children in the UK The International Journal of Pharmacy. Vining, E. P. G., Mellits, E. D., Dorsen, M. M., Cataldo, M. F., Quaskey, S. A., & Spielberg, S. P. (1987). Psychologic and behavioral effects of antiepileptic drugs in children: a double‐blind comparison between phenobarbital and valproic acid. Pediatrics, 80. References Volkow, N., Wang, G., Newcorn, J., Telang, F., Solanto, M., Fowler, J., . . . Swanson, J. (2007). Depressed dopamine activity in caudate and preliminary evidence of limbic involvement in adults with attention‐deficit/hyperactivity disorder. Archives of General Psychiatry, 64, 932 ‐ 940. Wigal, S. B., Childress, A. C., Belden, H. W., & Berry, S. A. (2013). NWP06, an extended‐release oral suspension of methylphenidate, improved attention‐deficit/hyperactivity disorder symptoms compared with placebo in a laboratory classroom study. Journal of Child and Adolescent Psychopharmacology, 23(1), 3–10. doi:10.1089/cap.2012.0073 Wilens, T. E., Biederman, J., Kwon, A., Chase, R., Greenberg, L., & Mick, E. (2003). A systematic chart review of the nature of psychiatric adverse events in children and adolescents treated with selective serotonin reuptake inhibitors. Journal of Child and Adolescent Psychopharmacology, 13. doi:10.1089/104454603322163862 Wilens, T. E., & Spencer, T. J. Understanding attention‐deficit/hyperactivity disorder from childhood to adulthood. Postgraduate Medicine, 122(5), 97. Williams, N. M., Zaharieva, I., Martin, A., Langley, K., Mantripragada, K., Fossdal, R., . . . Thapar, A. (2010). Rare chromosomal deletions and duplications in attention‐deficit hyperactivity disorder: a genome‐wide analysis. The Lancet, 376(9750), 1401‐1408. Woo, H. D., Kim, D. W., Hong, Y. S., Kim, Y. M., Seo, J. H., Choe, B. M., . . . Kim, J. (2014). Dietary patterns in children with attention deficit/hyperactivity disorder (ADHD) Nutrients (Vol. 6, pp. 1539‐1553). Switzerland. Zito, J. M., Derivan, A. T., Kratochvil, C. J., Safer, D. J., Fegert, J. M., & Greenhill, L. L. (2008). Off‐label psychopharmacologic prescribing for children: History supports close clinical monitoring. Child and Adolescent Psychiatry and Mental Health, 2(1), 24. doi:10.1186/1753‐2000‐2‐24 Zito, J. M., & Safer, D. J. (2007). The efficacy and safety of selective serotonin reuptake inhibitors for the treatment of depression in children and adolescents. In R. Mann & E. B. Andrews (Eds.), Pharmacovigilance. 98 4/26/2017 For additional resources or tools mentioned in this presentation, please email Chris Stone, MD ([email protected]) with your specific request. 99 4/25/2017 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. 1 4/25/2017 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 2 4/25/2017 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 3 4/25/2017 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 4 4/25/2017 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. 5 4/25/2017 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 . 6 4/25/2017 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. 7 4/25/2017 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 8 4/25/2017 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. 9 4/25/2017 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 10 4/25/2017 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 11 4/25/2017 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% 12 4/25/2017 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. 13 4/25/2017 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 14 4/25/2017 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 4/25/2017 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 16 4/25/2017 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 4/25/2017 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