Transcript ADHD and Behavioral Challenges in TSC

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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
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Objectives
• To review the genetics of TSC
• To review the neurologic presentation of TSC
• To discuss the cognitive and behavioral challenges of
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TSC
To discuss potential treatments of behavioral disorders of
TSC
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Tuberous Sclerosis Complex
• A genetic condition with multisystem involvement
• Development of tumors and other abnormalities in
multiple organs
• Incidence: 1:6000
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Tuberous Sclerosis Genes
• 70% are new mutations
• 30% are familial and inherited
in an Autosomal Dominant
fashion
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Tuberous Sclerosis Complex
Genes
TSC1: hamartin
TSC2: tuberin
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Tuberous Sclerosis Complex
Genes
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Tuberous Sclerosis Presentation
Cardiac
Renal
Cerebral
Skin
Lungs
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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
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TSC Neurologic Manifestations
• CNS involvement is a hallmark of the disease, and is
seen in 95% of affected individuals
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Infantile spasms
Partial seizures, often multifocal, independent (80%)
Cognitive Delay/Learning Problems (50%)
Autistic Spectrum Disorder
Behavior/Psychiatric Comorbidities (anxiety, depression)
Sleep disturbances
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TSC Neurologic Manifestations
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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
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Cortical tubers
1. Subependymal nodules 2. Cortical tubers
http://www.socialstyrelsen.se/rarediseases/tuberoussclerosis
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Cortical tubers
Diagnosis, Screening & Clinical Care of Individuals with TSC, published by the Tuberous Sclerosis Alliance.
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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
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White Matter Radial Migrational
Lines
http://www.biomedsearch.com/attachments/00/19/88/10/19881070/IJRI-19-135-g018.jpg
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Hemimegancephaly
Role of MRI in Epilepsy in Radiology Assistant, Neuroradiology
Laurens De Cocker, Felice D'Arco and Philippe Demaerel and Robin Smithuis
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Pathology of tubers and SEGAs
Hum. Mol. Genet. (15 October 2005) 14 (suppl 2): R251-R258.
doi: 10.1093/hmg/ddi260
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Cognitive and Behavioral Difficulties in TSC
November 2011 | Vol. 23 No. 4 | Annals of Clinical 268 Psychiatry
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Cognitive and Behavioral Difficulties in TSC
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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
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Cognitive and Behavioral Difficulties in TSC
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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
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Cognitive and Behavioral Difficulties in TSC
• Correlation between seizures and neuropsychiatric
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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
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• 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
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Cognitive and Behavioral Difficulties in TSC
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ADHD
Autistic Spectrum Disorder
Mood disorder: anxiety, OCD and aggressive behaviors
Sleep disruption
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Attention Deficit Hyperactivity
Disorder
• ADHD-Inattentive Type
• ADHD-Hyperactive Type
• ADHD-Combined Type
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Attention Deficit Hyperactivity Disorder
• Inattention
• Hyperactivity
• Impulsivity
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Inattention
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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.
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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.
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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.
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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%)
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• Diagnosis
– Based on history provided by the patient,
parents and teachers
– Several different tools available
• Vanderbilt ADHD Diagnostic Rating Scales
• Connor Questionnaire
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Attention Deficit Hyperactivity Disorder
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Treatment
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Behavioral
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Schedule
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Organize everyday items
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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
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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
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Children with ADHD often receive and expect criticism. Look for good behavior, and praise it.
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Attention Deficit Hyperactivity Disorder
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Derivatives of Ritalin an Dexedrine
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Ritalin (amphetamines: Concerta, Focalin)
Dexedrine (methylphenidates: Adderall, Vyvanse)
Common side effects:
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Non-stimulants (Strattera)
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Common side effects:
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GI distress
Alpha adrenergic agonists
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Decreased appetite
Sleep difficulties
Mood lability
Clonidine, guanfascine (Intuniv, Kapvay)
Sleepiness
Other therapies
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Buproprion
Imipramine
Nortriptyline
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Autistic spectrum disorder
• Diagnostic criteria:
– Impairment in social communication function
– Presence of restricted, repetitive patterns of
behaviors or interests
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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
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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
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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
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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
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Mood disorders
• Applied Behavioral Analysis
• Cognitive Behavioral therapy
– Anxiety
– Depression
– OCD
• Medications
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Sleep disruption
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Most common sleep problem in children with ASD is insomnia, or lack of sufficient sleep
Typical patterns:
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Delayed sleep onset
Maintenance of sleep
Prevalence in ASD: 53-78%
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Look for causes: GI (reflux) and pulmonary (apnea)
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Behavioral interventions
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Keeping a bedtime routine and schedule
Quieting activities prior to bedtime
Limiting daytime naps
Medication interventions
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Melatonin
Benadryl
Clonidine
Trazadone
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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)
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Medications commonly used to treat patients with TSC:
• Antipsychotics:
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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%)
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Medications commonly used to treat patients with TSC:
• Antidepressants:
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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%)
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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%)
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Medications commonly used to treat patients with TSC:
• Alpha-adrenergic agonists:
– Guanfacine (2/5, 40%)
– Clonidine (1/5. 20%)
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Medications commonly used to treat patients with TSC:
• Anxiolytics:
– Lorazepam 10/14 (71.4%)
– Clonazepam 0/2 (0/2, 0%)
– Chordiazepoxide (0/1, 0%)
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Medications commonly used to treat patients with TSC:
• Other:
– Naltrexone (2/2, 100%)
– Sirolimus (1/1, 100%)
– Everolimus (2/2, 100%)
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Medications commonly used to treat patients with TSC:
• Total:
– 73/113 (64.6%)
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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
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Summary
• The most common behavioral
presentations in the order of severity are:
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Behavioral disorders (37%)
Autistic spectrum disorders (24%)
Anxiety disorders (16%)
ADHD (13%)
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Summary
• Treatment may include:
– Behavioral therapy
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Applied Behavioral Analysis
Behavioral techniques for ADHD
Cognitive Behavioral Therapy (CBT) for anxiety, OCD and depression
– Medications
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Antipsychotics
Antidepressants
Mood stabilizers
Stimulants
Alpha-adrenergic agonists
Anxiolytics
Other medications
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The End
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