Transcript Tuberous Sclerosis and Behavior

Tuberous Sclerosis
and Behavior
Neuroscience Case Conference
August 11, 2006
The Case of JJ
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ID: 20 year old Caucasian female, single,
lives with her mother, High School
graduate, unemployed
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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 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.
Past Psychiatric Hx: No inpatient
admissions or outpatient psychiatric
treatment. School testing suggested mild
MR. No prior suicide attempts
 Past Medical Hx:
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– 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
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– 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
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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
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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
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 sclerosis—TSC1 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
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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
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
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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.
Cognitive and Behavioral
Involvement
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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
Cognitive and Behavioral
Involvement
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In studies examining individuals with
tuberous sclerosis and normal intelligence
– 50% met criteria for a hyperkinetic syndromeexcessive 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
Cognitive and Behavioral
Involvement
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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
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.
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
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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
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
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(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)
Cognitive and Behavioral
Involvement
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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%).
Summary
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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.
Discussion