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1 2 ADHD & Behavioral Challenges in Tuberous Sclerosis Complex Candida M. Brown, MD Diablo Valley Child Neurology An affiliate of Stanford Children’s Health Alliance June 27th, 2015 3 Objectives • To review the genetics of TSC • To review the neurologic presentation of TSC • To discuss the cognitive and behavioral challenges of • TSC To discuss potential treatments of behavioral disorders of TSC 4 Tuberous Sclerosis Complex • A genetic condition with multisystem involvement • Development of tumors and other abnormalities in multiple organs • Incidence: 1:6000 5 Tuberous Sclerosis Genes • 70% are new mutations • 30% are familial and inherited in an Autosomal Dominant fashion 6 Tuberous Sclerosis Complex Genes TSC1: hamartin TSC2: tuberin 7 Tuberous Sclerosis Complex Genes 8 Tuberous Sclerosis Presentation Cardiac Renal Cerebral Skin Lungs 0 20 40 60 80 Courtesy of Dr. Stephen Ashwal, Loma Linda University School of Medicine Tuberous Sclerosis Presentation • Causes hamartomas in various organs: brain, skin, kidneys and heart • Harmartoma= group of abnormally formed, disorganized cells within an organ with some growth potential 10 TSC Neurologic Manifestations • CNS involvement is a hallmark of the disease, and is seen in 95% of affected individuals – – – – – – Infantile spasms Partial seizures, often multifocal, independent (80%) Cognitive Delay/Learning Problems (50%) Autistic Spectrum Disorder Behavior/Psychiatric Comorbidities (anxiety, depression) Sleep disturbances 11 TSC Neurologic Manifestations • • • • • • • • Intelligence correlated with seizure frequency & type Outcome poorer with infantile spasms Greater numbers of tubers associated with lower IQ Brain Malformations (hemimegancephaly) Cortical tuber Subependymal nodule (88-95%) Giant cell astrocytoma (5-15%) White matter radial migration lines 12 Cortical tubers 1. Subependymal nodules 2. Cortical tubers http://www.socialstyrelsen.se/rarediseases/tuberoussclerosis 13 Cortical tubers Diagnosis, Screening & Clinical Care of Individuals with TSC, published by the Tuberous Sclerosis Alliance. 14 Subependymal Nodues Diagnosis, Screening & Clinical Care of Individuals with TSC, published by the Tuberous Sclerosis Alliance. Subependymal Giant Cell Astrocytoma (SEGA) Courtesy of David Franz, MD, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA 16 White Matter Radial Migrational Lines http://www.biomedsearch.com/attachments/00/19/88/10/19881070/IJRI-19-135-g018.jpg 17 Hemimegancephaly Role of MRI in Epilepsy in Radiology Assistant, Neuroradiology Laurens De Cocker, Felice D'Arco and Philippe Demaerel and Robin Smithuis 18 Pathology of tubers and SEGAs Hum. Mol. Genet. (15 October 2005) 14 (suppl 2): R251-R258. doi: 10.1093/hmg/ddi260 19 Cognitive and Behavioral Difficulties in TSC November 2011 | Vol. 23 No. 4 | Annals of Clinical 268 Psychiatry 20 Cognitive and Behavioral Difficulties in TSC • • • • • • • • • ADHD Autistic spectrum disorder Aggression, rage outbursts and temper tantrums Negativity (temporary resistance to change) Emotional lability Depression Anxiety and OCD Sleep disorders Epilepsy-related psychotic disorders 21 Cognitive and Behavioral Difficulties in TSC • • • • Global cognitive deficits: intellectual delay and learning disabilities Receptive and expression language delays Social-communication deficits Attentional deficits: selective attention, sustained attention and attention switching • Executive deficits: planning, poor sequencing, perseveration • Memory deficits: working memory and episodic memory • Motor deficits: Fine motor, gross motor and movement disorders 22 Cognitive and Behavioral Difficulties in TSC • Correlation between seizures and neuropsychiatric • • comorbidities, including ADHD and ASD Cortical tubers in temporal and insular areas play a significant role in TSC patients with ASD Higher prevalence of cystic-like tumors in patients with TSC and ASD Huang C-H, et al., The relationship of neuroimaging findings and neuropsychiatric comorbidities in children with tuberous sclerosis complex, Journal of the Formosan Medical Association (2014), http://dx.doi.org/10.1016/ j.jfma.2014.02.008 23 • Temporal lobe associated with: – Social perception – Language • Insular cortex associated with: – Interoceptive processes – Affective processes – Empathy • Clear association between ASD and TSC2 missense mutations • Tuber count: controversial: – History of infantile spasms – Higher tuber burden – Early age of onset of seizures 24 Cognitive and Behavioral Difficulties in TSC • • • • ADHD Autistic Spectrum Disorder Mood disorder: anxiety, OCD and aggressive behaviors Sleep disruption 25 Attention Deficit Hyperactivity Disorder • ADHD-Inattentive Type • ADHD-Hyperactive Type • ADHD-Combined Type 26 Attention Deficit Hyperactivity Disorder • Inattention • Hyperactivity • Impulsivity 27 • Inattention – – – – – – – – – Be easily distracted, miss details, forget things, and frequently switch from one activity to another Have difficulty focusing on one thing Become bored with a task after only a few minutes, unless they are doing something enjoyable Have difficulty focusing attention on organizing and completing a task or learning something new Have trouble completing or turning in homework assignments, often losing things (e.g., pencils, toys, assignments) needed to complete tasks or activities not seem to listen when spoken to Daydream, become easily confused, and move slowly Have difficulty processing information as quickly and accurately as others Struggle to follow instructions. 28 Attention Deficit Hyperactivity Disorder • Hyperactivity – fidget and squirm in their seats – talk nonstop – Dash around, touching or playing with anything and everything in sight – Have trouble sitting still during dinner, school, and story time – Be constantly in motion – Have difficulty doing quiet tasks or activities. 29 Attention Deficit Hyperactivity Disorder • Impulsivity – Be very impatient – Blurt out inappropriate comments, show their emotions without restraint, act without regard for consequences – Have difficulty waiting for things they want or waiting their turns in games – often interrupt conversations or others’ activities. 30 Attention Deficit Hyperactivity Disorder • Incidence in TSC patients: 30-60% • Causes hypothesized: – Localization of CNS lesions in associative areas – Comorbidity with epilepsy – Comorbidity with ASD and intellectual disabilities (60%) 31 • Diagnosis – Based on history provided by the patient, parents and teachers – Several different tools available • Vanderbilt ADHD Diagnostic Rating Scales • Connor Questionnaire 32 Attention Deficit Hyperactivity Disorder • Treatment – Behavioral • Schedule – • Organize everyday items – • • • Have a place for everything, and keep everything in its place. This includes clothing, backpacks, and toys. Use homework and notebook organizers Stress to your child the importance of writing down assignments and bringing home the necessary books. Be clear and consistent – • Keep the same routine every day, from wake-up time to bedtime. Include time for homework, outdoor play, and indoor activities. Keep the schedule on the refrigerator or on a bulletin board in the kitchen. Write changes on the schedule as far in advance as possible. Children with ADHD need consistent rules they can understand and follow. Give praise or rewards – Children with ADHD often receive and expect criticism. Look for good behavior, and praise it. 33 Attention Deficit Hyperactivity Disorder • Medications: – Derivatives of Ritalin an Dexedrine • • • Ritalin (amphetamines: Concerta, Focalin) Dexedrine (methylphenidates: Adderall, Vyvanse) Common side effects: – – – – Non-stimulants (Strattera) • Common side effects: – – GI distress Alpha adrenergic agonists • • – Decreased appetite Sleep difficulties Mood lability Clonidine, guanfascine (Intuniv, Kapvay) Sleepiness Other therapies • • • Buproprion Imipramine Nortriptyline 34 Autistic spectrum disorder • Diagnostic criteria: – Impairment in social communication function – Presence of restricted, repetitive patterns of behaviors or interests 35 Autistic Spectrum Disorder • Impairment in social communication function – Deficits in social-emotional reciprocity – Deficits in non-verbal communication – Deficits in developing, maintaining and understanding relationships 36 Autistic Spectrum Disorder • Restricted, repetitive patterns of behavior, interests or activities, as manifested by at least two of the following: – Stereotyped or repetitive motor movements – Insistence on sameness, inflexible adherence to routine or ritualized patterns of verbal or non-verbal behaviors – Highly restricted, fixated interests that are abnormal in intensity or focus – Hyperactivity or hypo-activity to sensory input or unusual interest in sensory aspects of the environment 37 Autistic Spectrum Disorder • Treatment: – Behavioral: Applied Behavioral Analysis (ABA) – Medications: • Only FDA-approved medications for ASD are the atypical antipsycholitcs – Respiridone (Respirdal) and ariprazole (Abilify) – Approved for the treatment of irritability: physical aggression and tantrum behaviors 38 Mood disorders • Anxiety and OCD without or with depression (16%) – Anxiety: a feeling of worry, nervousness, or unease, typically about an imminent event or something with an uncertain outcome – Obsessive Compulsive Behaviors: repetitive thoughts or the need to do behaviors that help to alleviate anxiety • Aggressive behaviors due to mood regulation issues (37%) – Aggression toward others: hitting, biting, kicking – Self-injurious behaviors: hitting self, head banging – Fight risk: bolting 39 Mood disorders • Applied Behavioral Analysis • Cognitive Behavioral therapy – Anxiety – Depression – OCD • Medications 40 Sleep disruption • • Most common sleep problem in children with ASD is insomnia, or lack of sufficient sleep Typical patterns: – – • Delayed sleep onset Maintenance of sleep Prevalence in ASD: 53-78% – Look for causes: GI (reflux) and pulmonary (apnea) – Behavioral interventions • • • – Keeping a bedtime routine and schedule Quieting activities prior to bedtime Limiting daytime naps Medication interventions • • • • Melatonin Benadryl Clonidine Trazadone 41 Medications commonly used to treat patients with TSC: • Based on the study of “Psychiatric Comorbidity and Treatment Response in Patients with TSC” (Annals of Clinical Psychiatry: Vol 23, No 4, November 2011, pp. 263-69) 42 Medications commonly used to treat patients with TSC: • Antipsychotics: – – – – – – – – Risperidone (30/46, 65.2%) Quetiapine (10/32, 59.4%) Ariprazole (7/10, 70%) Haloperidol (0/1, 0%) Olanzapine (2/3, 66.7%) Perphanazine (1/1, 100% ) Metirosine (0/1, 0%) Pimozide (1/2, 50%) 43 Medications commonly used to treat patients with TSC: • Antidepressants: – – – – – – – – – Escitalopram (16/38: 42.1%) Buproprion (8/10, 80%) Citalopram (2/2, 100%) Fluoxetine (3/5, 60%) Venlafexine (0/2, 0%) Amitriptyline (7/10, 70%) Trazodone (0/1, 0%) Doxepin (0/1, 0%) Impipramine 1/1, 100%) 44 Medications commonly used to treat patients with TSC: • Mood stabilizers: – Lithium (2/2, 100%) – Lamotrigine (14/18, 77.8%) – Oxcarbazepine (11/14, 78.6%) – Valproic Acid (16/23, 69.3%) 45 Medications commonly used to treat patients with TSC: • Alpha-adrenergic agonists: – Guanfacine (2/5, 40%) – Clonidine (1/5. 20%) 46 Medications commonly used to treat patients with TSC: • Anxiolytics: – Lorazepam 10/14 (71.4%) – Clonazepam 0/2 (0/2, 0%) – Chordiazepoxide (0/1, 0%) 47 Medications commonly used to treat patients with TSC: • Other: – Naltrexone (2/2, 100%) – Sirolimus (1/1, 100%) – Everolimus (2/2, 100%) 48 Medications commonly used to treat patients with TSC: • Total: – 73/113 (64.6%) 49 Summary • Tuberous Sclerosis Complex is: – AD inherited disorder – Due to mutations in the TSC1 or TSC2 genes – Affects the inhibition of cell growth resulting in hamartomas of various organs 50 Summary • The most common behavioral presentations in the order of severity are: – – – – Behavioral disorders (37%) Autistic spectrum disorders (24%) Anxiety disorders (16%) ADHD (13%) 51 Summary • Treatment may include: – Behavioral therapy • • • Applied Behavioral Analysis Behavioral techniques for ADHD Cognitive Behavioral Therapy (CBT) for anxiety, OCD and depression – Medications • • • • • • • Antipsychotics Antidepressants Mood stabilizers Stimulants Alpha-adrenergic agonists Anxiolytics Other medications 52 The End 53