Tb Sl iTuberous Sclerosis - UK HealthCare CECentral Sclerosis...Neurology 2008;70; 9042008;70; 904-...
Transcript of Tb Sl iTuberous Sclerosis - UK HealthCare CECentral Sclerosis...Neurology 2008;70; 9042008;70; 904-...
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T b S l iT b S l iTuberous SclerosisTuberous SclerosisA Neurologist’s Point of ViewA Neurologist’s Point of View
DonitaDonita LightnerLightner, MD, MDPediatric Neurology ResidentPediatric Neurology ResidentPediatric Neurology ResidentPediatric Neurology Resident
University University of of Kentucky Department of Kentucky Department of NeurologyNeurology
ObjectivesObjectives
Learn neurological manifestations of Learn neurological manifestations of dididiseasedisease
Educate how these patients presentEducate how these patients present
Inform audience of treatment options, Inform audience of treatment options, medical and surgicalmedical and surgical
Educate regarding widely variableEducate regarding widely variableEducate regarding widely variable Educate regarding widely variable prognosisprognosis
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IntroductionIntroduction
First fully described by Bourneville around 1880First fully described by Bourneville around 1880
TSC 1TSC 1 (H ti )(H ti ) TSC 2TSC 2 (T b i )(T b i )TSC 1TSC 1 (Hamartin) vs (Hamartin) vs TSC 2TSC 2 (Tuberin)(Tuberin)
About 15% of patients with TS show no About 15% of patients with TS show no identifiable mutation and are milder forms of identifiable mutation and are milder forms of diseasedisease
Accounts for 0.66% of mentally retarded patients Accounts for 0.66% of mentally retarded patients d 0 32% f ti t ff i f ild 0 32% f ti t ff i f iland 0.32% of patients suffering from epilepsyand 0.32% of patients suffering from epilepsy
Defects in tumor suppressor genes, resulting in Defects in tumor suppressor genes, resulting in numerous numerous benignbenign lesionslesions
Manifestations of DiseaseManifestations of Disease
Cognitive delay may or may not be Cognitive delay may or may not be ttpresentpresent
Cortical tubersCortical tubers
Subependymal giant cell astrocytomasSubependymal giant cell astrocytomas
Cutaneous malformationsCutaneous malformations
EpilepsyEpilepsy
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Cortical TubersCortical Tubers
Neurons can become Neurons can become up to 3up to 3 4 times their4 times theirup to 3up to 3--4 times their 4 times their normal sizenormal size
Surgically resected Surgically resected tubers show tubers show activation of a cellactivation of a cell--size control pathwaysize control pathwaysize control pathway size control pathway (mTOR)(mTOR)
Possible foci of Possible foci of epileptogenicityepileptogenicity
mTOR PathwaymTOR Pathway
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Subependymal Giant Cell Subependymal Giant Cell Astrocytomas (SEGAs)Astrocytomas (SEGAs)
Occur in 5Occur in 5--15% of TS patients15% of TS patientsUsually present in first or Usually present in first or second decade of life second decade of life Benign intraventricular massBenign intraventricular massUsually occur near the Usually occur near the Foramen of MonroeForamen of MonroeCan result in obstructive Can result in obstructive hydrocephalus, but hydrocephalus, but unpredictable what lesions unpredictable what lesions should be removed vs.should be removed vs.should be removed vs. should be removed vs. observedobservedImage every 1Image every 1--3 years, if 3 years, if patient develops symptoms, or patient develops symptoms, or for any change in clinical for any change in clinical statusstatus
Cutaneous ManifestationsCutaneous Manifestations
Shagreen patchShagreen patch
H l tiH l tiHypomelanotic Hypomelanotic maculesmacules
Adenoma sebaceumAdenoma sebaceum
Ungular and Ungular and subungual fibromassubungual fibromas
Dental enamel pitsDental enamel pits
Gingival fibromasGingival fibromas
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EpilepsyEpilepsy
Infantile spasmsInfantile spasms
Partial seizures which may or may not Partial seizures which may or may not secondarily generalizesecondarily generalize
May require multiple antiepileptic May require multiple antiepileptic medicationsmedications
Patient 1Patient 1
5mo female presented for evaluation of spells5mo female presented for evaluation of spellsSpells lasted for seconds and occurred inSpells lasted for seconds and occurred inSpells lasted for seconds and occurred in Spells lasted for seconds and occurred in clusters usually upon awakeningclusters usually upon awakeningPatient would become extremely fussy during Patient would become extremely fussy during the eventsthe eventsMom had previously been told episodes were Mom had previously been told episodes were due to refluxdue to refluxNormal developmentNormal developmentNormal developmentNormal developmentExam revealed brisk reflexesExam revealed brisk reflexeshttp://www.youtube.com/watch?v=l5xhttp://www.youtube.com/watch?v=l5x--Eh8wEh8w--tI&feature=relatedtI&feature=related
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Patient 2Patient 2
14yo male with known history of global 14yo male with known history of global developmental delay and intractable epilepsy ondevelopmental delay and intractable epilepsy ondevelopmental delay and intractable epilepsy on developmental delay and intractable epilepsy on multiple medications and VNS placement multiple medications and VNS placement presented with respiratory distress, fever, and presented with respiratory distress, fever, and increased seizuresincreased seizures
He was later diagnosed with pneumoniaHe was later diagnosed with pneumonia
On exam he was nonverbal (baseline) didn’tOn exam he was nonverbal (baseline) didn’tOn exam, he was nonverbal (baseline), didn t On exam, he was nonverbal (baseline), didn t follow commands (baseline), had a shagreen follow commands (baseline), had a shagreen patch, multiple adenoma sebacea, subungual patch, multiple adenoma sebacea, subungual fibromas, hyperreflexia with clonusfibromas, hyperreflexia with clonus
ImagingImaging
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ImagingImaging
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Medical TreatmentMedical Treatment
ACTHACTH
Vi b t iVi b t i
LamotrigineLamotrigine
R fi idR fi idVigabatrinVigabatrin
OxcarbazepineOxcarbazepine
LevetiracetamLevetiracetam
TopiramateTopiramate
Valproic AcidValproic Acid
RufinamideRufinamide
DiastatDiastat
Ketogenic dietKetogenic diet
?Rapamycin?Rapamycin
pp
Surgical TreatmentSurgical Treatment
Vagal Nerve StimulatorVagal Nerve Stimulator
Corpus callosotomyCorpus callosotomy
Tuber resectionTuber resection
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Evaluation for SurgeryEvaluation for Surgery
Video EEGVideo EEG
MRIMRI
AlphaAlpha--Methyltryptophan PET (Methyltryptophan PET (AMTAMT--PET)PET)
Ictal SPECTIctal SPECT
PrognosisPrognosis
Widely variable Widely variable
TSC1 vs TSC2 mutationTSC1 vs TSC2 mutation
Age of seizure onsetAge of seizure onset
Presence or absence of Infantile spasmsPresence or absence of Infantile spasms
Tuber burdenTuber burden
Controlled vs. Intractable EpilepsyControlled vs. Intractable Epilepsy
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Text SourcesText SourcesAdams & VictorAdams & VictorBissler, J.J. et al. Bissler, J.J. et al. Sirolimus for angiomyolipoma in Tuberous Sclerosis Complex or LymphangioleiomyomatosisSirolimus for angiomyolipoma in Tuberous Sclerosis Complex or Lymphangioleiomyomatosis. . NEJM NEJM 2008;358:1402008;358:140--151.151.Curatolo, P. et al. Curatolo, P. et al. Vigabatrin for tuberous sclerosis Vigabatrin for tuberous sclerosis complex. complex. Brain & Development Brain & Development 23 (2001) 64923 (2001) 649--653.653.,, gg pp pp ( )( )Elliott, R.E. et al. Elliott, R.E. et al. Refractory epilepsy in tuberous sclerosis: Vagus nerve stimulation with or without subsequent Refractory epilepsy in tuberous sclerosis: Vagus nerve stimulation with or without subsequent resective surgeryresective surgery. . Epilepsy and Behavior Epilepsy and Behavior 16(2009) 45416(2009) 454--460.460.Heide, Avd et al. Heide, Avd et al. Identification of the epileptogenic zone in patients with tuberous sclerosis: Concordance of Identification of the epileptogenic zone in patients with tuberous sclerosis: Concordance of interictal and ictal epileptiform activity.interictal and ictal epileptiform activity. Clinical Neurophysiology (Clinical Neurophysiology (2010), doi 10.1016/j.clinph.2010.01.010.2010), doi 10.1016/j.clinph.2010.01.010.Jambaque, I. et al. Jambaque, I. et al. Mental and behavioural outcome of infantile epilepsy treated by vigabatrin in tuberous sclerosis Mental and behavioural outcome of infantile epilepsy treated by vigabatrin in tuberous sclerosis patientspatients. . Epilepsy Research Epilepsy Research 38 (2000) 15138 (2000) 151--160.160.Kagawa, K. et al. Kagawa, K. et al. Epilepsy surgery outcome in children with Tuberous Sclerosis Complex evaluated with alphaEpilepsy surgery outcome in children with Tuberous Sclerosis Complex evaluated with alpha--Methyltryptophan Positron Emission Tomography.Methyltryptophan Positron Emission Tomography. Journal of Child NeurologyJournal of Child Neurology 2005: 20(5): 4292005: 20(5): 429--438.438.Krueger, D.A. & D.N. Franz. Krueger, D.A. & D.N. Franz. Current management of Tuberous Sclerosis ComplexCurrent management of Tuberous Sclerosis Complex. . Pediatric DrugsPediatric Drugs 2008: 10(5): 2008: 10(5): 299299--313.313.Napolioni, V. et al. Napolioni, V. et al. Recent advances in neurobiology of Tuberous Sclerosis Complex.Recent advances in neurobiology of Tuberous Sclerosis Complex. Brain & DevelopmentBrain & Development 31 31 (2009) 104(2009) 104--113.113.Nass, R, & Peter B. Crino. Nass, R, & Peter B. Crino. Tuberous sclerosis complex: A tale of two genesTuberous sclerosis complex: A tale of two genes. . Neurology Neurology 2008;70; 9042008;70; 904--905.905.O’Callaghan F J K et alO’Callaghan F J K et al Subependymal nodules giant cell astrocytomas and the tuberous sclerosis complex: aSubependymal nodules giant cell astrocytomas and the tuberous sclerosis complex: aO Callaghan, F.J.K. et al. O Callaghan, F.J.K. et al. Subependymal nodules, giant cell astrocytomas and the tuberous sclerosis complex: a Subependymal nodules, giant cell astrocytomas and the tuberous sclerosis complex: a population based study. population based study. Arch. Dis. Child. Arch. Dis. Child. www.adc.bmj.comwww.adc.bmj.com..Osborne, JP, J. Merrefield, F.J.K. O’Callaghan. Osborne, JP, J. Merrefield, F.J.K. O’Callaghan. Tuberous sclerosis: what’s new?Tuberous sclerosis: what’s new? Arch. Dis. Child.Arch. Dis. Child.www.adc.bmj.comwww.adc.bmj.com..Zaroff, C.M. et al. Zaroff, C.M. et al. Mental retardation and relation to seizure and tuber burden in tuberous sclerosis complex.Mental retardation and relation to seizure and tuber burden in tuberous sclerosis complex.Seizure Seizure (2006)15, 558(2006)15, 558--562.562.
Sources for FiguresSources for FiguresCortical tubers figure courtesy of Cortical tubers figure courtesy of http://www2.massgeneral.org/livingwithtsc/images/affects/popup/i_affects_br_anatomy_tuber.jpghttp://www2.massgeneral.org/livingwithtsc/images/affects/popup/i_affects_br_anatomy_tuber.jpgCutaneous Manifestations figure courtesy of Cutaneous Manifestations figure courtesy of http://images google com/imgres?imgurl=http://img medscape com/fullsize/migrated/495/642/jcn4http://images google com/imgres?imgurl=http://img medscape com/fullsize/migrated/495/642/jcn4http://images.google.com/imgres?imgurl=http://img.medscape.com/fullsize/migrated/495/642/jcn4http://images.google.com/imgres?imgurl=http://img.medscape.com/fullsize/migrated/495/642/jcn495642.fig1.jpg&imgrefurl=http://www.medscape.com/viewarticle/495642_2&usg=__9dktuX2mSPS95642.fig1.jpg&imgrefurl=http://www.medscape.com/viewarticle/495642_2&usg=__9dktuX2mSPS0ENO9qzPiQ_Q_4z4=&h=475&w=400&sz=34&hl=en&start=19&um=1&itbs=1&tbnid=kbpPfr8wn0ENO9qzPiQ_Q_4z4=&h=475&w=400&sz=34&hl=en&start=19&um=1&itbs=1&tbnid=kbpPfr8wnwT_8M:&tbnh=129&tbnw=109&prev=/images%3Fq%3Dshagreen%2Bpatch%26um%3D1%26hlwT_8M:&tbnh=129&tbnw=109&prev=/images%3Fq%3Dshagreen%2Bpatch%26um%3D1%26hl%3Den%26rlz%3D1R2GGLJ_en%3Den%26rlz%3D1R2GGLJ_en--GBUS349%26tbs%3Disch:1GBUS349%26tbs%3Disch:1mTOR Pathway Figure courtesy of mTOR Pathway Figure courtesy of http://www.biochemsoctrans.org/bst/034/0012/bst0340012a02.gifhttp://www.biochemsoctrans.org/bst/034/0012/bst0340012a02.gifSubependymal Giant Cell Astrocytoma histology courtesy of Subependymal Giant Cell Astrocytoma histology courtesy of http://www.pathconsultddx.com/images/S1559867506705435/gr2http://www.pathconsultddx.com/images/S1559867506705435/gr2--sml.jpgsml.jpgSubependymal Giant Cell Astrocytoma MRI courtesy of Subependymal Giant Cell Astrocytoma MRI courtesy of http://images.google.com/imgres?imgurl=http://www.pathconsultddx.com/images/S155986750670http://images.google.com/imgres?imgurl=http://www.pathconsultddx.com/images/S1559867506705435/gr15435/gr1--sml.jpg&imgrefurl=http://www.pathconsultddx.com/pathCon/diagnosis%3Fpii%3DS1559sml.jpg&imgrefurl=http://www.pathconsultddx.com/pathCon/diagnosis%3Fpii%3DS1559--8675(06)705438675(06)70543--5&usg=__q1HX8UHmvdTDHWS_KGeC425&usg=__q1HX8UHmvdTDHWS_KGeC42--33--k8 &h 210& 225& 7&hl & t t 12& 1&itb 1&tb id kYk5F1D i l M &tb h 101&tbk8 &h 210& 225& 7&hl & t t 12& 1&itb 1&tb id kYk5F1D i l M &tb h 101&tbk8=&h=210&w=225&sz=7&hl=en&start=12&um=1&itbs=1&tbnid=kYk5F1DsiglzeM:&tbnh=101&tbk8=&h=210&w=225&sz=7&hl=en&start=12&um=1&itbs=1&tbnid=kYk5F1DsiglzeM:&tbnh=101&tbnw=108&prev=/images%3Fq%3Dsubependymal%2Bgiant%2Bcell%2Bastrocytoma%26um%3D1nw=108&prev=/images%3Fq%3Dsubependymal%2Bgiant%2Bcell%2Bastrocytoma%26um%3D1%26hl%3Den%26sa%3DG%26rlz%3D1R2GGLJ_en%26hl%3Den%26sa%3DG%26rlz%3D1R2GGLJ_en--GBUS349%26tbs%3Disch:1GBUS349%26tbs%3Disch:1