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

2. The Case of JJ ID: 20 year old Caucasian female, single, lives with her mother, High School graduate, unemployed ID: 20 year old Caucasian female, single, lives with her mother, High School graduate, unemployed CC: “anger problems” CC: “anger problems”

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

4. Past Psychiatric Hx: No inpatient admissions or outpatient psychiatric treatment. School testing suggested mild MR. No prior suicide attempts Past Psychiatric Hx: No inpatient admissions or outpatient psychiatric treatment. School testing suggested mild MR. No prior suicide attempts Past Medical Hx: Past Medical Hx: –Ages 4 and 5 had seizure episodes. –Age 7 craniotomy – 6/9/06 – Neurology started on Dilantin for suspected sz d/o although normal EEG Medications: Dilantin 100 mg QHS Medications: Dilantin 100 mg QHS Allergies: NKDA Allergies: NKDA

5. Family History: no clear psychiatric history Family History: no clear psychiatric history –Father died s/p seizure episode Developmental History: normal pregnancy, delivery, met all developmental milestones Developmental History: normal pregnancy, delivery, met all developmental milestones Social History Social History –No substance abuse –Special Education; H.S. graduate, full diploma –Unemployed, no job history –19 yo brother, 10 yo ½ brother –Lives with mother –Attends church regularly –Hobbies revolve around church activities

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

7. Diagnosis: Diagnosis: –A1: Dysthymia r/o MDD recurrent, Mood d/o due to a GMC with depressive features, Bipolar –A2: defer –A3: tuberous sclerosis, seizure d/o –A4: good family support, financial stressors –A5: 60-65 Treatment Plan Treatment Plan –Cymbalta 60mg QAM –Discuss with Neurology change of seizure medication for improved mood stabilization

8. Follow up 7/1/06 Follow up 7/1/06 –Patient mood described as “happy” with a congruent affect –Patient seen with Dr. Kumar: Dilantin switched to Topomax, repeat MRI, EEG ordered Follow up 7/20/06 Follow up 7/20/06 –Pt states she felt worse, stopped taking Cymbalta states she was “confused about her medications” –Instructed patient to restart Cymbalta

9. What is Tuberous Sclerosis? Tuberous sclerosis complex is a genetic condition characterized by lesions of the skin and central nervous system, tumor growth and seizures Tuberous sclerosis complex is a genetic condition characterized by lesions of the skin and central nervous system, tumor growth and seizures The disease affects some people severely, while others are so mildly affected that it often goes undiagnosed The disease affects some people severely, while others are so mildly affected that it often goes undiagnosed

10. Prevelance Estimates place tuberous sclerosis affected births at one in 6,000 to 9,000 Estimates place tuberous sclerosis affected births at one in 6,000 to 9,000 Nearly 1 million people worldwide are known to have tuberous sclerosis, Nearly 1 million people worldwide are known to have tuberous sclerosis, 50,000 in the United States 50,000 in the United States

11. Genetics Two genes have been identified that can cause tuberous sclerosis—TSC1 or TSC2 Two genes have been identified that can cause tuberous sclerosis—TSC1 or TSC2 Tuberous sclerosis is transmitted either through genetic inheritance or as a spontaneous genetic mutation Tuberous sclerosis is transmitted either through genetic inheritance or as a spontaneous genetic mutation Since it is autosomal dominantly inherited, children have a 50 percent chance of inheriting TSC if one of their parents has this condition Since it is autosomal dominantly inherited, children have a 50 percent chance of inheriting TSC if one of their parents has this condition Only one-third of TSC cases are known to be inherited Only one-third of TSC cases are known to be inherited

12. Genetics The TSC1 and TSC2 genes are believed to suppress tumor growth in the body. The TSC1 and TSC2 genes are believed to suppress tumor growth in the body. The genes also play a role in the early fetal development of the brain and skin. The genes also play a role in the early fetal development of the brain and skin.

13. CLINICAL MANIFESTATIONS TSC can cause tumors in the skin, kidneys, brain, heart, eyes, lungs, teeth as well as other organ systems. TSC can cause tumors in the skin, kidneys, brain, heart, eyes, lungs, teeth as well as other organ systems. In most individuals, the disease affects only some of these organs In most individuals, the disease affects only some of these organs

14. CLINICAL MANIFESTATIONS Epilepsy is the most common presenting symptom in tuberous sclerosis, with estimates as high as 80 to 90% Epilepsy is the most common presenting symptom in tuberous sclerosis, with estimates as high as 80 to 90% Seizures typically develop in childhood, many in the first year of life Seizures typically develop in childhood, many in the first year of life Manifests as infantile spasms in one-third of individuals Manifests as infantile spasms in one-third of individuals

15. Diagnostic Criteria for Tuberous Sclerosis Complex Major Features Major 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

16. Diagnostic Criteria for Tuberous Sclerosis Complex Minor Features Minor Features Multiple randomly distributed pits in dental enamel Multiple randomly distributed pits in dental enamel Hamartomatous rectal polyps Hamartomatous 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 cysts Multiple renal cysts

17. Diagnostic Criteria for Tuberous Sclerosis Complex Definite TSC: Either 2 major features or 1 major feature with 2 minor features Definite TSC: Either 2 major features or 1 major feature with 2 minor features Probable TSC: One major feature and one minor feature Probable TSC: One major feature and one minor feature Possible TSC: Either 1 major feature or 2 or more minor features Possible TSC: Either 1 major feature or 2 or more minor features

19. Brain Involvement Cortical tubers are small areas in the cortex that do not develop normally. It is thought this is what causes seizures in individuals with TSC. Cortical tubers are small areas in the cortex that do not develop normally. It is thought this is what causes seizures in individuals with TSC. Subependymal nodules develop near the walls of the cerebral ventricles. Typically, these nodules accumulate calcium within the first few months or years of life and are not though to be directly responsible for neurological problems. Subependymal nodules develop near the walls of the cerebral ventricles. Typically, these nodules accumulate calcium within the first few months or years of life and are not though to be directly responsible for neurological problems. Subependymal giant cell astrocytomas (SEGAs). This type of tumor develops in approximately 15 percent of individuals with tuberous sclerosis, the chance for their growth decreases after age 20. Subependymal giant cell astrocytomas (SEGAs). This type of tumor develops in approximately 15 percent of individuals with tuberous sclerosis, the chance for their growth decreases after age 20.

20. Cognitive and Behavioral Involvement Assessment in a sample of 108 individuals and their nonaffected siblings (C. Joinson, F.J. O’Callaghan, J.P. Osborne, et al. Learning disability and epilepsy in an epidemiological sample of individuals with tuberous sclerosis complex, Psychol Med 33 (2003), pp. 335–344 ) Assessment in a sample of 108 individuals and their nonaffected siblings (C. Joinson, F.J. O’Callaghan, J.P. Osborne, et al. Learning disability and epilepsy in an epidemiological sample of individuals with tuberous sclerosis complex, Psychol Med 33 (2003), pp. 335–344 ) –Approximately 55% of individuals scored within the normal range and 44% had an IQ below 70 –Even in those with normal intellectual skills, scores were skewed toward the lower end of the average range and were significantly lower than those of unaffected siblings

21. Cognitive and Behavioral Involvement In studies examining individuals with tuberous sclerosis and normal intelligence In studies examining individuals with tuberous sclerosis and normal intelligence –50% met criteria for a hyperkinetic syndrome- excessive activity, emotional instability, significantly reduced attention span, and an absence of shyness and fear –dyspraxia, speech delay, visuospatial disturbance, memory impairment, and dyscalculia have been reported

22. Cognitive and Behavioral Involvement Epilepsy is a risk factor for cognitive impairment in tuberous sclerosis Epilepsy is a risk factor for cognitive impairment in tuberous sclerosis –Early onset of seizures, in particular infantile spasms, is associated with poor developmental outcome –a significant relationship between infantile spasms and low IQ was observed, even after controlling for tuber count –Reduction of infantile spasms with vigabatrin has been shown to improve development –a lack of seizure control is associated with a lack of developmental progression

23. A. Humphrey, J. Williams, E. Pinto and P.F. Bolton, A prospective longitudinal study of early cognitive development in tuberous sclerosis: a clinic based study, Eur Child Adolesc Psychiatry 13 (2004), 159–165) –assessed children between the ages of 11 and 37 months at 6-month intervals –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 mean onset of 4 months –While raw scores increased over time, representing absolute development, the group declined relative to age-appropriate normative data –The average composite score for the group as a whole fell in the mentally retarded range of functioning at all intervals –At 12 months, an 5-month lag in development was noted compared with normative means, which increased to 13 months at 36 months –The only child in the average range of intelligence for more than 6 months did not have seizures and had a normal EEG –the developmental quotients of those with infantile spasms were similar to those with partial seizures –two children had a decline of more than 20 points in developmental quotient following a worsening/onset of seizures –The one child with an increase of 20 points or more exhibited this after a period of seizure control.

24. Cognitive and Behavioral Involvement Cognitive status in tuberous sclerosis has also been correlated with tuber number, size, and location, designated tuber burden Cognitive status in tuberous sclerosis has also been correlated with tuber number, size, and location, designated tuber burden Genetic contributions to developmental outcome in tuberous sclerosis are now recognized with lower rates of mental retardation in TSC1 cases Genetic contributions to developmental outcome in tuberous sclerosis are now recognized with lower rates of mental retardation in TSC1 cases medication effects may contribute to the cognitive profile in tuberous sclerosis medication effects may contribute to the cognitive profile in tuberous sclerosis

25. Cognitive and Behavioral Involvement Tuberous sclerosis provides the clearest link of any medical disorder to autism Tuberous sclerosis provides the clearest link of any medical disorder to autism –Rates of prevalence of autism in tuberous sclerosis vary from 50% to 60% –Tuberous sclerosis with autism is not associated with the male preponderance observed in idiopathic cases –In general, the greater the degree of neurological impairment, the higher the rate of autism –The risk for autism in tuberous sclerosis is higher in those with epilepsy than in those without, particularly when seizures arise early in life and infantile spasms are observed –Several studies have pointed to temporal lobe pathology as a possible mechanism for autism in tuberous sclerosis

26. Cognitive and Behavioral Involvement Other problem behaviors are common in tuberous sclerosis, including but not limited to inattention, hyperactivity, anxiety, and depression Other problem behaviors are common in tuberous sclerosis, including but not limited to inattention, hyperactivity, anxiety, and depression Anxiety disorder was observed in 20 of 36 adults able to complete a questionnaire, and depression was observed in 7 of 56 (J.C.Lewis, H.V. Thomas, K.C. Murphy and J.R. Sampson, Genotype and psychological phenotype in tuberous sclerosis, J Med Genet 41 (2004), pp. 203–207) Anxiety disorder was observed in 20 of 36 adults able to complete a questionnaire, and depression was observed in 7 of 56 (J.C.Lewis, H.V. Thomas, K.C. Murphy and J.R. Sampson, Genotype and psychological phenotype in tuberous sclerosis, J Med Genet 41 (2004), pp. 203–207)

27. Cognitive and Behavioral Involvement In a comparison of individuals with fetal alcohol syndrome, Prader–Willi syndrome, fragile X syndrome, and tuberous sclerosis had less severe psychopathology (H.C. Steinhausen, A. Von Gontard and H.L. Spohr et al., Behavioral phenotypes in four mental retardation syndromes: fetal alcohol syndrome, Prader–Willi syndrome, fragile X syndrome, and tuberosis sclerosis, Am J Med Genet 111 (2002), pp. 381–387) In a comparison of individuals with fetal alcohol syndrome, Prader–Willi syndrome, fragile X syndrome, and tuberous sclerosis had less severe psychopathology (H.C. Steinhausen, A. Von Gontard and H.L. Spohr et al., Behavioral phenotypes in four mental retardation syndromes: fetal alcohol syndrome, Prader–Willi syndrome, fragile X syndrome, and tuberosis sclerosis, Am J Med Genet 111 (2002), pp. 381–387) –at least half of the tuberous sclerosis sample was rated as impulsive, overly attention seeking, overactive, and distracted –Attention-deficit/hyperactivity disorder (ADHD) was the most common comorbid diagnosis (44%), followed by oppositional defiant disorder (25%) and separation anxiety disorder (19%).

28. Summary Tuberous sclerosis complex (TSC) is a genetic disorder that causes tumors to form in many different organs, primarily in the brain, eyes, heart, kidney, skin and lungs. Pathology in the brain affects IQ, behavior and the severity of epilepsy. Tuberous sclerosis complex (TSC) is a genetic disorder that causes tumors to form in many different organs, primarily in the brain, eyes, heart, kidney, skin and lungs. Pathology in the brain affects IQ, behavior and the severity of epilepsy.

29. Discussion