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Tuberous Sclerosis Tuberous Sclerosis and Behavior and Behavior Neuroscience Case Neuroscience Case Conference Conference August 11, 2006 August 11, 2006
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Tuberous Sclerosis and Behavior

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Tuberous Sclerosis and Behavior. Neuroscience Case Conference August 11, 2006. The Case of JJ. ID: 20 year old Caucasian female, single, lives with her mother, High School graduate, unemployed CC: “anger problems”. - PowerPoint PPT Presentation
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Page 1: Tuberous Sclerosis and Behavior

Tuberous SclerosisTuberous Sclerosisand Behaviorand Behavior

Neuroscience Case Neuroscience Case ConferenceConference

August 11, 2006August 11, 2006

Page 2: Tuberous Sclerosis and Behavior

The Case of JJThe Case of JJ ID: 20 year old Caucasian female, ID: 20 year old Caucasian female,

single, lives with her mother, High single, lives with her mother, High School graduate, unemployedSchool graduate, unemployed

CC: “anger problems”CC: “anger problems”

Page 3: Tuberous Sclerosis and Behavior

HPI: 20 yo CF with Tuberous Sclerosis referred by HPI: 20 yo CF with Tuberous Sclerosis referred by Family Practice for mood swings and depression. Family Practice for mood swings and depression. According to her mother the patient has anger According to her mother the patient has anger episodes lasting anywhere from 3 minutes to 3 days episodes lasting anywhere from 3 minutes to 3 days caused by minor triggers. Furthermore, she has had caused by minor triggers. Furthermore, she has had “behavioral changes” since childhood but mother has “behavioral changes” since childhood but mother has had increasing difficulty controlling them. Per the had increasing difficulty controlling them. Per the patient her anger comes on slowly and is relieved by patient her anger comes on slowly and is relieved by going to her room and listening to music sometimes going to her room and listening to music sometimes prayer. Patient states at times she wishes she wasn’t prayer. Patient states at times she wishes she wasn’t here but denies suicidal ideation. Admits she feels here but denies suicidal ideation. Admits she feels depressed but doesn’t feel it is severe and has depressed but doesn’t feel it is severe and has always had a “low” mood—more than 2 years. She always had a “low” mood—more than 2 years. She has decreased concentration, increased frustration, has decreased concentration, increased frustration, possible hopelessness, no weight changes or crying possible hopelessness, no weight changes or crying spells. Although she says she gets “hyper” at times spells. Although she says she gets “hyper” at times no history of expansive mood, sleeplessness, racing no history of expansive mood, sleeplessness, racing thoughts or pressured speech. No hx of psychotic sx.thoughts or pressured speech. No hx of psychotic sx.

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Past Psychiatric Hx: No inpatient Past Psychiatric Hx: No inpatient admissions or outpatient psychiatric admissions or outpatient psychiatric treatment. School testing suggested treatment. School testing suggested mild MR. No prior suicide attemptsmild MR. No prior suicide attempts

Past Medical Hx: Past Medical Hx: – Ages 4 and 5 had seizure episodes. Ages 4 and 5 had seizure episodes. – Age 7 craniotomyAge 7 craniotomy– 6/9/06 – Neurology started on Dilantin for 6/9/06 – Neurology started on Dilantin for

suspected sz d/o although normal EEGsuspected sz d/o although normal EEG Medications: Dilantin 100 mg QHSMedications: Dilantin 100 mg QHS Allergies: NKDAAllergies: NKDA

Page 5: Tuberous Sclerosis and Behavior

Family History: no clear psychiatric historyFamily History: no clear psychiatric history– Father died s/p seizure episodeFather died s/p seizure episode

Developmental History: normal pregnancy, Developmental History: normal pregnancy, delivery, met all developmental delivery, met all developmental milestonesmilestones

Social HistorySocial History– No substance abuseNo substance abuse– Special Education; H.S. graduate, full diplomaSpecial Education; H.S. graduate, full diploma– Unemployed, no job historyUnemployed, no job history– 19 yo brother, 10 yo ½ brother19 yo brother, 10 yo ½ brother– Lives with motherLives with mother– Attends church regularlyAttends church regularly– Hobbies revolve around church activitiesHobbies revolve around church activities

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MSE: MSE: – The patient came into the office with her The patient came into the office with her

mother, dressed casually, lethargic but mother, dressed casually, lethargic but calm and friendly. She was quiet, exhibiting calm and friendly. She was quiet, exhibiting poor eye contact leaning on the desk with poor eye contact leaning on the desk with her elbow, speech had a regular rate and her elbow, speech had a regular rate and rhythm with a normal prosody. She rhythm with a normal prosody. She described her mood as “OK” with a described her mood as “OK” with a restricted affect. Her thoughts were restricted affect. Her thoughts were organized and goal directed without organized and goal directed without hallucinations or delusions. Did not express hallucinations or delusions. Did not express suicidal or homicidal ideations. Her three suicidal or homicidal ideations. Her three wishes were to be a teacher, get married, wishes were to be a teacher, get married, and music ministry. Insight was limited but and music ministry. Insight was limited but judgment appeared intact.judgment appeared intact. MMSE: 30/30MMSE: 30/30

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Diagnosis:Diagnosis:– A1: Dysthymia r/o MDD recurrent, Mood d/o A1: Dysthymia r/o MDD recurrent, Mood d/o

due to a GMC with depressive features, due to a GMC with depressive features, BipolarBipolar

– A2: deferA2: defer– A3: tuberous sclerosis, seizure d/oA3: tuberous sclerosis, seizure d/o– A4: good family support, financial stressorsA4: good family support, financial stressors– A5: 60-65A5: 60-65

Treatment PlanTreatment Plan– Cymbalta 60mg QAMCymbalta 60mg QAM– Discuss with Neurology change of seizure Discuss with Neurology change of seizure

medication for improved mood stabilizationmedication for improved mood stabilization

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Follow up 7/1/06Follow up 7/1/06– Patient mood described as “happy” with Patient mood described as “happy” with

a congruent affecta congruent affect– Patient seen with Dr. Kumar: Dilantin Patient seen with Dr. Kumar: Dilantin

switched to Topomax, repeat MRI, EEG switched to Topomax, repeat MRI, EEG orderedordered

Follow up 7/20/06Follow up 7/20/06– Pt states she felt worse, stopped taking Pt states she felt worse, stopped taking

Cymbalta states she was “confused Cymbalta states she was “confused about her medications”about her medications”

– Instructed patient to restart Cymbalta Instructed patient to restart Cymbalta

Page 9: Tuberous Sclerosis and Behavior

What is Tuberous Sclerosis?What is Tuberous Sclerosis? Tuberous sclerosis complex is a Tuberous sclerosis complex is a

genetic condition characterized by genetic condition characterized by lesions of the skin and central nervous lesions of the skin and central nervous system, tumor growth and seizures system, tumor growth and seizures

The disease affects some people The disease affects some people severely, while others are so mildly severely, while others are so mildly affected that it often goes affected that it often goes undiagnosed undiagnosed

Page 10: Tuberous Sclerosis and Behavior

PrevelancePrevelance Estimates place tuberous sclerosis Estimates place tuberous sclerosis

affected births at one in 6,000 to affected births at one in 6,000 to 9,0009,000

Nearly 1 million people worldwide are Nearly 1 million people worldwide are known to have tuberous sclerosis, known to have tuberous sclerosis,

50,000 in the United States 50,000 in the United States

Page 11: Tuberous Sclerosis and Behavior

GeneticsGenetics Two genes have been identified that can Two genes have been identified that can

cause tuberous sclerosis—TSC1 or TSC2cause tuberous sclerosis—TSC1 or TSC2 Tuberous sclerosis is transmitted either Tuberous sclerosis is transmitted either

through genetic inheritance or as a through genetic inheritance or as a spontaneous genetic mutationspontaneous genetic mutation

Since it is autosomal dominantly inherited, Since it is autosomal dominantly inherited, children have a 50 percent chance of children have a 50 percent chance of inheriting TSC if one of their parents has inheriting TSC if one of their parents has this condition this condition

Only one-third of TSC cases are known to Only one-third of TSC cases are known to be inherited be inherited

Page 12: Tuberous Sclerosis and Behavior

GeneticsGenetics The TSC1 and TSC2 genes are The TSC1 and TSC2 genes are

believed to suppress tumor growth in believed to suppress tumor growth in the body. the body.

The genes also play a role in the The genes also play a role in the early fetal development of the brain early fetal development of the brain and skin. and skin.

Page 13: Tuberous Sclerosis and Behavior

CLINICAL MANIFESTATIONSCLINICAL MANIFESTATIONS TSC can cause tumors in the skin, TSC can cause tumors in the skin,

kidneys, brain, heart, eyes, lungs, kidneys, brain, heart, eyes, lungs, teeth as well as other organ systems. teeth as well as other organ systems.

In most individuals, the disease In most individuals, the disease affects only some of these organs affects only some of these organs

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CLINICAL MANIFESTATIONSCLINICAL MANIFESTATIONS Epilepsy is the most common Epilepsy is the most common

presenting symptom in tuberous presenting symptom in tuberous sclerosis, with estimates as high as 80 sclerosis, with estimates as high as 80 to 90%to 90%

Seizures typically develop in Seizures typically develop in childhood, many in the first year of lifechildhood, many in the first year of life

Manifests as infantile spasms in one-Manifests as infantile spasms in one-third of individuals third of individuals

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Diagnostic Criteria for Diagnostic Criteria for Tuberous Sclerosis Complex Tuberous Sclerosis Complex

Major FeaturesMajor Features Facial angiofibromas or forehead plaque Facial angiofibromas or forehead plaque Non-traumatic ungual or periungual fibroma Non-traumatic ungual or periungual fibroma Hypomelanotic macules (more than three) Hypomelanotic macules (more than three) Shagreen patch (connective tissue nevus) Shagreen patch (connective tissue nevus) Multiple retinal nodular hamartomas Multiple retinal nodular hamartomas Cortical tubera Cortical tubera Subependymal nodule Subependymal nodule Subependymal giant cell astrocytoma Subependymal giant cell astrocytoma Cardiac rhabdomyoma, single or multiple Cardiac rhabdomyoma, single or multiple Lymphangiomyomatosisb Lymphangiomyomatosisb Renal angiomyolipomab Renal angiomyolipomab

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Diagnostic Criteria for Diagnostic Criteria for Tuberous Sclerosis ComplexTuberous Sclerosis Complex

Minor FeaturesMinor Features Multiple randomly distributed pits in dental Multiple randomly distributed pits in dental

enamel enamel Hamartomatous rectal polypsHamartomatous rectal polyps Bone cysts Bone cysts Cerebral white matter migration lines Cerebral white matter migration lines Gingival fibromas Gingival fibromas Non-renal hamartomac Non-renal hamartomac Retinal achromic patch Retinal achromic patch "Confetti" skin lesions "Confetti" skin lesions Multiple renal cystsMultiple renal cysts

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Diagnostic Criteria for Diagnostic Criteria for Tuberous Sclerosis ComplexTuberous Sclerosis Complex

Definite TSC: Either 2 major features Definite TSC: Either 2 major features or 1 major feature with 2 minor or 1 major feature with 2 minor featuresfeatures

Probable TSC: One major feature and Probable TSC: One major feature and one minor featureone minor feature

Possible TSC: Either 1 major feature Possible TSC: Either 1 major feature or 2 or more minor featuresor 2 or more minor features

Page 18: Tuberous Sclerosis and Behavior
Page 19: Tuberous Sclerosis and Behavior

Brain InvolvementBrain Involvement Cortical tubers are small areas in the cortex that Cortical tubers are small areas in the cortex that

do not develop normally. It is thought this is what do not develop normally. It is thought this is what causes seizures in individuals with TSC. causes seizures in individuals with TSC.

Subependymal nodules develop near the walls of Subependymal nodules develop near the walls of the cerebral ventricles. Typically, these nodules the cerebral ventricles. Typically, these nodules accumulate calcium within the first few months or accumulate calcium within the first few months or years of life and are not though to be directly years of life and are not though to be directly responsible for neurological problems.responsible for neurological problems.

Subependymal giant cell astrocytomas (SEGAs). Subependymal giant cell astrocytomas (SEGAs). This type of tumor develops in approximately 15 This type of tumor develops in approximately 15 percent of individuals with tuberous sclerosis, the percent of individuals with tuberous sclerosis, the chance for their growth decreases after age 20. chance for their growth decreases after age 20.

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Cognitive and Behavioral Cognitive and Behavioral InvolvementInvolvement

Assessment in a sample of 108 individuals Assessment in a sample of 108 individuals and their nonaffected siblings and their nonaffected siblings (C. Joinson, F.J. (C. Joinson, F.J. O’Callaghan, J.P. Osborne, et al. Learning disability and epilepsy in an O’Callaghan, J.P. Osborne, et al. Learning disability and epilepsy in an epidemiological sample of individuals with tuberous sclerosis complex, epidemiological sample of individuals with tuberous sclerosis complex, Psychol MedPsychol Med 3333 (2003), pp. 335–344 ) (2003), pp. 335–344 )– Approximately 55% of individuals scored within Approximately 55% of individuals scored within

the normal range and 44% had an IQ below 70 the normal range and 44% had an IQ below 70 – Even in those with normal intellectual skills, Even in those with normal intellectual skills,

scores were skewed toward the lower end of scores were skewed toward the lower end of the average range and were significantly lower the average range and were significantly lower than those of unaffected siblings than those of unaffected siblings

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Cognitive and Behavioral Cognitive and Behavioral InvolvementInvolvement

In studies examining individuals with In studies examining individuals with tuberous sclerosis and normal tuberous sclerosis and normal intelligence intelligence – 50% met criteria for a hyperkinetic 50% met criteria for a hyperkinetic

syndrome-excessive activity, emotional syndrome-excessive activity, emotional instability, significantly reduced attention instability, significantly reduced attention span, and an absence of shyness and fearspan, and an absence of shyness and fear

– dyspraxia, speech delay, visuospatial dyspraxia, speech delay, visuospatial disturbance, memory impairment, and disturbance, memory impairment, and dyscalculia have been reported dyscalculia have been reported

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Cognitive and Behavioral Cognitive and Behavioral InvolvementInvolvement

Epilepsy is a risk factor for cognitive Epilepsy is a risk factor for cognitive impairment in tuberous sclerosis impairment in tuberous sclerosis – Early onset of seizures, in particular infantile Early onset of seizures, in particular infantile

spasms, is associated with poor developmental spasms, is associated with poor developmental outcome outcome

– a significant relationship between infantile a significant relationship between infantile spasms and low IQ was observed, even after spasms and low IQ was observed, even after controlling for tuber count controlling for tuber count

– Reduction of infantile spasms with vigabatrin Reduction of infantile spasms with vigabatrin has been shown to improve developmenthas been shown to improve development

– a lack of seizure control is associated with a a lack of seizure control is associated with a lack of developmental progression lack of developmental progression

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A. Humphrey, J. Williams, E. Pinto and P.F. Bolton, A A. Humphrey, J. Williams, E. Pinto and P.F. Bolton, A prospective longitudinal study of early cognitive development prospective longitudinal study of early cognitive development in tuberous sclerosis: a clinic based study, in tuberous sclerosis: a clinic based study, Eur Child Adolesc Eur Child Adolesc

PsychiatryPsychiatry 1313 (2004), 159–165) (2004), 159–165)– assessed children between the ages of 11 and 37 months at 6-month assessed children between the ages of 11 and 37 months at 6-month

intervals intervals – All but one subject had a diagnosis of epilepsy and/or an abnormal All but one subject had a diagnosis of epilepsy and/or an abnormal

EEG. Age at onset of epilepsy ranged from 1 to 21 months, with a EEG. Age at onset of epilepsy ranged from 1 to 21 months, with a mean onset of 4 monthsmean onset of 4 months

– While raw scores increased over time, representing absolute While raw scores increased over time, representing absolute development, the group declined relative to age-appropriate normative development, the group declined relative to age-appropriate normative data data

– The average composite score for the group as a whole fell in the The average composite score for the group as a whole fell in the mentally retarded range of functioning at all intervals mentally retarded range of functioning at all intervals

– At 12 months, an 5-month lag in development was noted compared At 12 months, an 5-month lag in development was noted compared with normative means, which increased to 13 months at 36 months with normative means, which increased to 13 months at 36 months

– The only child in the average range of intelligence for more than 6 The only child in the average range of intelligence for more than 6 months did not have seizures and had a normal EEG months did not have seizures and had a normal EEG

– the developmental quotients of those with infantile spasms were the developmental quotients of those with infantile spasms were similar to those with partial seizures similar to those with partial seizures

– two children had a decline of more than 20 points in developmental two children had a decline of more than 20 points in developmental quotient following a worsening/onset of seizures quotient following a worsening/onset of seizures

– The one child with an increase of 20 points or more exhibited this after The one child with an increase of 20 points or more exhibited this after a period of seizure control. a period of seizure control.

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Cognitive and Behavioral Cognitive and Behavioral InvolvementInvolvement

Cognitive status in tuberous sclerosis has Cognitive status in tuberous sclerosis has also been correlated with tuber number, also been correlated with tuber number, size, and location, designated size, and location, designated tuber burdentuber burden

Genetic contributions to developmental Genetic contributions to developmental outcome in tuberous sclerosis are now outcome in tuberous sclerosis are now recognized with lower rates of mental recognized with lower rates of mental retardation in retardation in TSC1TSC1 cases cases

medication effects may contribute to the medication effects may contribute to the cognitive profile in tuberous sclerosis cognitive profile in tuberous sclerosis

Page 25: Tuberous Sclerosis and Behavior

Cognitive and Behavioral Cognitive and Behavioral InvolvementInvolvement

Tuberous sclerosis provides the clearest link of Tuberous sclerosis provides the clearest link of any medical disorder to autism any medical disorder to autism – Rates of prevalence of autism in tuberous sclerosis vary Rates of prevalence of autism in tuberous sclerosis vary

from 50% to 60% from 50% to 60% – Tuberous sclerosis with autism is not associated with the Tuberous sclerosis with autism is not associated with the

male preponderance observed in idiopathic cases male preponderance observed in idiopathic cases – In general, the greater the degree of neurological In general, the greater the degree of neurological

impairment, the higher the rate of autism impairment, the higher the rate of autism – The risk for autism in tuberous sclerosis is higher in The risk for autism in tuberous sclerosis is higher in

those with epilepsy than in those without, particularly those with epilepsy than in those without, particularly when seizures arise early in life and infantile spasms are when seizures arise early in life and infantile spasms are observed observed

– Several studies have pointed to temporal lobe pathology Several studies have pointed to temporal lobe pathology as a possible mechanism for autism in tuberous sclerosis as a possible mechanism for autism in tuberous sclerosis

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Cognitive and Behavioral Cognitive and Behavioral InvolvementInvolvement

Other problem behaviors are common Other problem behaviors are common in tuberous sclerosis, including but not in tuberous sclerosis, including but not limited to inattention, hyperactivity, limited to inattention, hyperactivity, anxiety, and depressionanxiety, and depression

Anxiety disorder was observed in 20 of Anxiety disorder was observed in 20 of 36 adults able to complete a 36 adults able to complete a questionnaire, and depression was questionnaire, and depression was observed in 7 of 56 observed in 7 of 56 (J.C.Lewis, H.V. Thomas, K.C. (J.C.Lewis, H.V. Thomas, K.C. Murphy and J.R. Sampson, Genotype and psychological phenotype in Murphy and J.R. Sampson, Genotype and psychological phenotype in tuberous sclerosis, tuberous sclerosis, J Med GenetJ Med Genet 4141 (2004), pp. 203–207) (2004), pp. 203–207)

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Cognitive and Behavioral Cognitive and Behavioral InvolvementInvolvement

In a comparison of individuals with fetal In a comparison of individuals with fetal alcohol syndrome, Prader–Willi syndrome, alcohol syndrome, Prader–Willi syndrome, fragile X syndrome, and tuberous sclerosis fragile X syndrome, and tuberous sclerosis had less severe psychopathology had less severe psychopathology (H.C. Steinhausen, (H.C. Steinhausen, A. Von Gontard and H.L. Spohr A. Von Gontard and H.L. Spohr et al.et al., Behavioral phenotypes in four mental , Behavioral phenotypes in four mental retardation syndromes: fetal alcohol syndrome, Prader–Willi syndrome, fragile X retardation syndromes: fetal alcohol syndrome, Prader–Willi syndrome, fragile X syndrome, and tuberosis sclerosis, syndrome, and tuberosis sclerosis, Am J Med GenetAm J Med Genet 111111 (2002), pp. 381–387) (2002), pp. 381–387)– at least half of the tuberous sclerosis sample at least half of the tuberous sclerosis sample

was rated as impulsive, overly attention was rated as impulsive, overly attention seeking, overactive, and distractedseeking, overactive, and distracted

– Attention-deficit/hyperactivity disorder (ADHD) Attention-deficit/hyperactivity disorder (ADHD) was the most common comorbid diagnosis was the most common comorbid diagnosis (44%), followed by oppositional defiant (44%), followed by oppositional defiant disorder (25%) and separation anxiety disorder disorder (25%) and separation anxiety disorder (19%). (19%).

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SummarySummary Tuberous sclerosis complex (TSC) is Tuberous sclerosis complex (TSC) is

a genetic disorder that causes a genetic disorder that causes tumors to form in many different tumors to form in many different organs, primarily in the brain, eyes, organs, primarily in the brain, eyes, heart, kidney, skin and lungs. heart, kidney, skin and lungs. Pathology in the brain affects IQ, Pathology in the brain affects IQ, behavior and the severity of behavior and the severity of epilepsy.epilepsy.

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DiscussionDiscussion