Tuberous Sclerosis and Behavior

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Tuberous Sclerosisand Behavior

• Neuroscience Case Conference
• August 11, 2006

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The Case of JJ

• ID 20 year old Caucasian female, single, lives
  with her mother, High School graduate, unemployed
• CC anger problems

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• 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 wasnt here but
  denies suicidal ideation. Admits she feels
  depressed but doesnt feel it is severe and has
  always had a low moodmore 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.

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• Past Psychiatric Hx No inpatient admissions or
  outpatient psychiatric treatment. School testing
  suggested mild MR. No prior suicide attempts
• 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
• Allergies NKDA

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• Family History no clear psychiatric history
• Father died s/p seizure episode
• Developmental History normal pregnancy,
  delivery, met all developmental milestones
• 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

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• 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

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• 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
• Cymbalta 60mg QAM
• Discuss with Neurology change of seizure
  medication for improved mood stabilization

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• 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
• Pt states she felt worse, stopped taking Cymbalta
  states she was confused about her medications
• Instructed patient to restart Cymbalta

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

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Prevelance

• 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,
• 50,000 in the United States

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Genetics

• Two genes have been identified that can cause
  tuberous sclerosisTSC1 or TSC2
• 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
• Only one-third of TSC cases are known to be
  inherited

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Genetics

• 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.

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CLINICAL MANIFESTATIONS

• 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

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CLINICAL MANIFESTATIONS

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

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Diagnostic Criteria for Tuberous Sclerosis
Complex

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

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Diagnostic Criteria for Tuberous Sclerosis Complex

• Minor Features
• Multiple randomly distributed pits in dental
  enamel
• Hamartomatous rectal polyps
• Bone cysts
• Cerebral white matter migration lines
• Gingival fibromas
• Non-renal hamartomac
• Retinal achromic patch
• "Confetti" skin lesions
• Multiple renal cysts

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Diagnostic Criteria for Tuberous Sclerosis Complex

• Definite TSC Either 2 major features or 1 major
  feature with 2 minor features
• Probable TSC One major feature and one minor
  feature
• Possible TSC Either 1 major feature or 2 or more
  minor features

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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.
• 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.

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Cognitive and Behavioral Involvement

• Assessment in a sample of 108 individuals and
  their nonaffected siblings (C. Joinson, F.J.
  OCallaghan, J.P. Osborne, et al. Learning
  disability and epilepsy in an epidemiological
  sample of individuals with tuberous sclerosis
  complex, Psychol Med 33 (2003), pp. 335344 )
• 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

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Cognitive and Behavioral Involvement

• 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

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Cognitive and Behavioral Involvement

• 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

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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), 159165)

• 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.

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Cognitive and Behavioral Involvement

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

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Cognitive and Behavioral Involvement

• 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

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Cognitive and Behavioral Involvement

• 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. 203207)

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Cognitive and Behavioral Involvement

• In a comparison of individuals with fetal alcohol
  syndrome, PraderWilli 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, PraderWilli syndrome, fragile X
  syndrome, and tuberosis sclerosis, Am J Med Genet
  111 (2002), pp. 381387)
• 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).

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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.

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Discussion