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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