Skip to main content

Advertisement

SpringerLink
Log in

Tuberous sclerosis complex: a review of the management of epilepsy with emphasis on surgical aspects

  • Special Annual Issue
  • Published:
Child's Nervous System Aims and scope Submit manuscript

Abstract

Objective

To review the management of epilepsy in patients with tuberous sclerosis complex (TSC) with an emphasis on surgical aspects, neuropathology, and pathogenesis.

Methods

Review of the literature and presentation of the authors’ experience of surgery for refractory epilepsy in patients with TSC.

Results

TSC is a multisystem genetic disorder with variable phenotypic expression. TSC results from a mutation in the TSC1 gene on chromosome 9, which codes for hamartin, or in the TSC 2 gene on chromosome 16 which codes for tuberin. The majority of the patients have TSC as a result of spontaneous genetic mutations while in one-third of the patients, the disorder is inherited in an autosomal dominant manner. Epilepsy is the most common neurological complication, and up to 80–90% of individuals with TSC develop epilepsy at some point in their lifetime. The onset of epilepsy is typically in early childhood. Infantile spasms are a very common early seizure type although partial seizures may occur. Developmental delay, intellectual impairment, autism, behavioral problems, and neuropsychiatric disorders occur commonly in individuals with TSC and may be associated with poorly controlled epilepsy. Antiepileptic drugs are the first-line management for epilepsy but the ketogenic diet, resection of one or more tubers, corpus callosotomy, and vagus nerve stimulation are other therapeutic options for individuals with poorly controlled epilepsy.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Aicardi J, Mumford JP, Dumas C, Wood S (1996) Vigabatrin as initial therapy for infantile spasms: a European retrospective survey. Sabril IS Investigator and Peer Review Groups. Epilepsia 37:638–642

    Article  PubMed  CAS  Google Scholar 

  2. Anonymous (1993) Identification and characterization of the tuberous sclerosis gene on chromosome 16. The European Chromosome 16 Tuberous Sclerosis Consortium. Cell 75:1305–1315

    Google Scholar 

  3. Asano E, Chugani DC, Muzik O et al (2000) Multimodality imaging for improved detection of epileptogenic foci in tuberous sclerosis complex. Neurology 54:1976–1984

    PubMed  CAS  Google Scholar 

  4. Asano E, Chugani DC, Muzik O et al (2001) Autism in tuberous sclerosis complex is related to both cortical and subcortical dysfunction. Neurology 57:1269–1277

    PubMed  CAS  Google Scholar 

  5. Avellino AM, Berger MS, Rostomily RC, Shaw CM, Ojemann GA (1997) Surgical management and seizure outcome in patients with tuberous sclerosis. J Neurosurg 87:391–396

    PubMed  CAS  Google Scholar 

  6. Bebin EM, Kelly PJ, Gomez MR (1993) Surgical treatment for epilepsy in cerebral tuberous sclerosis. Epilepsia 34:651–657

    Article  PubMed  CAS  Google Scholar 

  7. Bolton PF, Park RJ, Higgins JN, Griffiths PD, Pickles A (2002) Neuro-epileptic determinants of autism spectrum disorders in tuberous sclerosis complex. Brain 125:1247–1255

    Article  PubMed  Google Scholar 

  8. Bonnin JM, Rubinstein LJ, Papasozomenos SC, Marangos PJ (1984) Subependymal giant cell astrocytoma. Significance and possible cytogenetic implications of an immunohistochemical study. Acta Neuropathol (Berl) 62:185–193

    Article  CAS  Google Scholar 

  9. Burger PC, Scheithauer BW (1994) Tumors of the central nervous system. In: Anonymous (ed) Atlas of tumor pathology, series 3. Armed Forces Institute of Pathology, Washington, DC

    Google Scholar 

  10. Carbonara C, Longa L, Grosso E et al (1996) Apparent preferential loss of heterozygosity at TSC2 over TSC1 chromosomal region in tuberous sclerosis hamartomas. Genes Chromosomes Cancer 15:18–25

    Article  PubMed  CAS  Google Scholar 

  11. Chiron C, Dumas C, Jambaque I, Mumford J, Dulac O (1997) Randomized trial comparing vigabatrin and hydrocortisone in infantile spasms due to tuberous sclerosis. Epilepsy Res 26:389–395

    Article  PubMed  CAS  Google Scholar 

  12. Chou TM, Chou SM (1989) Tuberous sclerosis in the premature infant: a report of a case with immunohistochemistry on the CNS. Clin Neuropathol 8:45–52

    PubMed  CAS  Google Scholar 

  13. Chugani DC, Chugani HT, Muzik O et al (1998) Imaging epileptogenic tubers in children with tuberous sclerosis complex using alpha-[11C]methyl-L-tryptophan positron emission tomography. Ann Neurol 44:858–866

    Article  PubMed  CAS  Google Scholar 

  14. Curatolo P, Brinchi V (1993) Antenatal diagnosis of tuberous sclerosis. Lancet 341:176–177

    PubMed  CAS  Google Scholar 

  15. Curatolo P, Cusmai R, Cortesi F, Chiron C, Jambaque I, Dulac O (1991) Neuropsychiatric aspects of tuberous sclerosis. Ann NY Acad Sci 615:8–16

    Article  PubMed  CAS  Google Scholar 

  16. Cusmai R, Chiron C, Curatolo P, Dulac O, Tran-Dinh S (1990) Topographic comparative study of magnetic resonance imaging and electroencephalography in 34 children with tuberous sclerosis. Epilepsia 31:747–755

    Article  PubMed  CAS  Google Scholar 

  17. Ferrer I, Fabregues I, Coll J, Ribalta T, Rives A (1984) Tuberous sclerosis: a Golgi study of cortical tuber. Clin Neuropathol 3:47–51

    PubMed  CAS  Google Scholar 

  18. Franz DN, Tudor C, Leonard J et al (2001) Lamotrigine therapy of epilepsy in tuberous sclerosis. Epilepsia 42:935–940

    Article  PubMed  CAS  Google Scholar 

  19. Fukushima K, Inoue Y, Fujiwara T, Yagi K (2001) Long-term follow-up study of West syndrome associated with tuberous sclerosis. Brain Dev 23:698–704

    Article  PubMed  CAS  Google Scholar 

  20. Ganji S, Hellman CD (1985) Tuberous sclerosis: long-term follow-up and longitudinal electroencephalographic study. Clin Electroencephalogr 16:219–224

    PubMed  CAS  Google Scholar 

  21. Goh S, Butler W, Thiele EA (2004) Subependymal giant cell tumors in tuberous sclerosis complex. Neurology 63:1457–1461

    PubMed  Google Scholar 

  22. Gomez MR (1999) Natural history of cerebral tuberous sclerosis. In: Gomez MR, Sampson JR, Whittemore VH (eds) Tuberous sclerosis complex (Developmental perspectives in psychiatry), 3rd edn. Oxford University Press, New York, pp 29–46

    Google Scholar 

  23. Goodman M, Lamm SH, Engel A, Shepherd CW, Houser OW, Gomez MR (1997) Cortical tuber count: a biomarker indicating neurologic severity of tuberous sclerosis complex. J Child Neurol 12:85–90

    PubMed  CAS  Google Scholar 

  24. Green AJ, Smith M, Yates JR (1994) Loss of heterozygosity on chromosome 16p13.3 in hamartomas from tuberous sclerosis patients. Nat Genet 6:193–196

    Article  PubMed  CAS  Google Scholar 

  25. Guerreiro MM, Andermann F, Andermann E et al (1998) Surgical treatment of epilepsy in tuberous sclerosis: strategies and results in 18 patients. Neurology 51:1263–1269

    PubMed  CAS  Google Scholar 

  26. Hamano S, Tanaka M, Mochizuki M, Sugiyama N, Eto Y (2003) Long-term follow-up study of West syndrome: differences of outcome among symptomatic etiologies. J Pediatr 143:231–235

    Article  PubMed  Google Scholar 

  27. Hancock E, Osborne JP (1999) Vigabatrin in the treatment of infantile spasms in tuberous sclerosis: literature review. J Child Neurol 14:71–74

    Article  PubMed  CAS  Google Scholar 

  28. Harding GF, Wild JM, Robertson KA et al (2000) Electro-oculography, electroretinography, visual evoked potentials, and multifocal electroretinography in patients with vigabatrin-attributed visual field constriction. Epilepsia 41:1420–1431

    Article  PubMed  CAS  Google Scholar 

  29. Harding GF, Wild JM, Robertson KA, Rietbrock S, Martinez C (2000) Separating the retinal electrophysiologic effects of vigabatrin: treatment versus field loss. Neurology 55:347–352

    Article  PubMed  CAS  Google Scholar 

  30. Hirano A, Tuazon R, Zimmerman HM (1968) Neurofibrillary changes, granulovacuolar bodies and argentophilic globules observed in tuberous sclerosis. Acta Neuropathol (Berl) 11:257–261

    CAS  Google Scholar 

  31. Hirose T, Scheithauer BW, Lopes MB et al (1995) Tuber and subependymal giant cell astrocytoma associated with tuberous sclerosis: an immunohistochemical, ultrastructural, and immunoelectron and microscopic study. Acta Neuropathol (Berl) 90:387–399

    Article  CAS  Google Scholar 

  32. Hunt A (1993) Development, behaviour and seizures in 300 cases of tuberous sclerosis. J Intellect Disabil Res 37(Pt 1):41–51

    PubMed  Google Scholar 

  33. Huttenlocher PR, Heydemann PT (1984) Fine structure of cortical tubers in tuberous sclerosis: a Golgi study. Ann Neurol 16:595–602

    Article  PubMed  CAS  Google Scholar 

  34. Jambaque I, Cusmai R, Curatolo P, Cortesi F, Perrot C, Dulac O (1991) Neuropsychological aspects of tuberous sclerosis in relation to epilepsy and MRI findings. Dev Med Child Neurol 33:698–705

    Article  PubMed  CAS  Google Scholar 

  35. Jansen FE, Braun KP, van Nieuwenhuizen O et al (2003) Diffusion-weighted magnetic resonance imaging and identification of the epileptogenic tuber in patients with tuberous sclerosis. Arch Neurol 60:1580–1584

    Article  PubMed  Google Scholar 

  36. Jarrar RG, Buchhalter JR, Raffel C (2004) Long-term outcome of epilepsy surgery in patients with tuberous sclerosis. Neurology 62:479–481

    PubMed  CAS  Google Scholar 

  37. Johnson MW, Kerfoot C, Bushnell T, Li M, Vinters HV (2001) Hamartin and tuberin expression in human tissues. Mod Pathol 14:202–210

    Article  PubMed  CAS  Google Scholar 

  38. Joinson C, O’Callaghan FJ, Osborne JP, Martyn C, Harris T, Bolton PF (2003) Learning disability and epilepsy in an epidemiological sample of individuals with tuberous sclerosis complex. Psychol Med 33:335–344

    Article  PubMed  CAS  Google Scholar 

  39. Jozwiak S, Goodman M, Lamm SH (1998) Poor mental development in patients with tuberous sclerosis complex: clinical risk factors. Arch Neurol 55:379–384

    Article  PubMed  CAS  Google Scholar 

  40. Kagawa K, Chugani DC, Asano E et al (2005) Epilepsy surgery outcome in children with tuberous sclerosis complex evaluated with alpha-[11C]methyl-L-tryptophan positron emission tomography (PET). J Child Neurol 20:429–438

    Article  PubMed  Google Scholar 

  41. Kawai K, Shimizu H, Yagishita A, Maehara T, Tamagawa K (2004) Clinical outcomes after corpus callosotomy in patients with bihemispheric malformations of cortical development. J Neurosurg 101:7–15

    PubMed  Google Scholar 

  42. Koh S, Jayakar P, Resnick T, Alvarez L, Liit RE, Duchowny M (1999) The localizing value of ictal SPECT in children with tuberous sclerosis complex and refractory partial epilepsy. Epileptic Disord 1:41–46

    PubMed  CAS  Google Scholar 

  43. Koh S, Jayakar P, Dunoyer C et al (2000) Epilepsy surgery in children with tuberous sclerosis complex: presurgical evaluation and outcome. Epilepsia 41:1206–1213

    Article  PubMed  CAS  Google Scholar 

  44. Lachhwani DK, Pestana E, Gupta A, Kotagal P, Bingaman W, Wyllie E (2005) Identification of candidates for epilepsy surgery in patients with tuberous sclerosis. Neurology 64:1651–1654

    Article  PubMed  CAS  Google Scholar 

  45. Lamb RF, Roy C, Diefenbach TJ et al (2000) The TSC1 tumour suppressor hamartin regulates cell adhesion through ERM proteins and the GTPase Rho. Nat Cell Biol 2:281–287

    Article  PubMed  CAS  Google Scholar 

  46. Lazarowski A, Lubieniecki F, Camarero S et al (2004) Multidrug resistance proteins in tuberous sclerosis and refractory epilepsy. Pediatr Neurol 30:102–106

    Article  PubMed  Google Scholar 

  47. Miloloza A, Rosner M, Nellist M, Halley D, Bernaschek G, Hengstschlager M (2000) The TSC1 gene product, hamartin, negatively regulates cell proliferation. Hum Mol Genet 9:1721–1727

    Article  PubMed  CAS  Google Scholar 

  48. Mizuguchi M, Ikeda K, Takashima S (2000) Simultaneous loss of hamartin and tuberin from the cerebrum, kidney and heart with tuberous sclerosis. Acta Neuropathol (Berl) 99:503–510

    Article  CAS  Google Scholar 

  49. Morimoto K, Mogami H (1986) Sequential CT study of subependymal giant-cell astrocytoma associated with tuberous sclerosis. Case report. J Neurosurg 65:874–877

    PubMed  CAS  Google Scholar 

  50. `Nellist M, van Slegtenhorst MA, Goedbloed M, van den Ouweland AM, Halley DJ, van der Sluijs P (1999) Characterization of the cytosolic tuberin–hamartin complex. Tuberin is a cytosolic chaperone for hamartin. J Biol Chem 274:35647–35652

    Article  PubMed  CAS  Google Scholar 

  51. Nixon JR, Houser OW, Gomez MR, Okazaki H (1989) Cerebral tuberous sclerosis: MR imaging. Radiology 170:869–873

    PubMed  CAS  Google Scholar 

  52. Ohtsuka Y, Ohmori I, Oka E (1998) Long-term follow-up of childhood epilepsy associated with tuberous sclerosis. Epilepsia 39:1158–1163

    Article  PubMed  CAS  Google Scholar 

  53. Osborne JP, Fryer A, Webb D (1991) Epidemiology of tuberous sclerosis. Ann NY Acad Sci 615:125–127

    Article  PubMed  CAS  Google Scholar 

  54. Parain D, Penniello MJ, Berquen P, Delangre T, Billard C, Murphy JV (2001) Vagal nerve stimulation in tuberous sclerosis complex patients. Pediatr Neurol 25:213–216

    Article  PubMed  CAS  Google Scholar 

  55. Plank TL, Logginidou H, Klein-Szanto A, Henske EP (1999) The expression of hamartin, the product of the TSC1 gene, in normal human tissues and in TSC1- and TSC2-linked angiomyolipomas. Mod Pathol 12:539–545

    PubMed  CAS  Google Scholar 

  56. Richardson EP Jr (1991) Pathology of tuberous sclerosis. Neuropathologic aspects. Ann NY Acad Sci 615:128–139

    Article  PubMed  Google Scholar 

  57. Rintahaka PJ, Chugani HT (1997) Clinical role of positron emission tomography in children with tuberous sclerosis complex. J Child Neurol 12:42–52

    Article  PubMed  CAS  Google Scholar 

  58. Roach ES, Williams DP, Laster DW (1987) Magnetic resonance imaging in tuberous sclerosis. Arch Neurol 44:301–303

    PubMed  CAS  Google Scholar 

  59. Romanelli P, Verdecchia M, Rodas R, Seri S, Curatolo P (2004) Epilepsy surgery for tuberous sclerosis. Pediatr Neurol 31:239–247

    Article  PubMed  Google Scholar 

  60. Sharp D, Robertson DM (1983) Tuberous sclerosis in an infant of 28 weeks gestational age. Can J Neurol Sci 10:59–62

    PubMed  CAS  Google Scholar 

  61. Soucek T, Pusch O, Wienecke R, DeClue JE, Hengstschlager M (1997) Role of the tuberous sclerosis gene-2 product in cell cycle control. Loss of the tuberous sclerosis gene-2 induces quiescent cells to enter S phase. J Biol Chem 272:29301–29308

    Article  PubMed  CAS  Google Scholar 

  62. Szelies B, Herholz K, Heiss WD et al (1983) Hypometabolic cortical lesions in tuberous sclerosis with epilepsy: demonstration by positron emission tomography. J Comput Assist Tomogr 7:946–953

    Article  PubMed  CAS  Google Scholar 

  63. Takanashi J, Sugita K, Fujii K, Niimi H (1995) MR evaluation of tuberous sclerosis: increased sensitivity with fluid-attenuated inversion recovery and relation to severity of seizures and mental retardation. AJNR Am J Neuroradiol 16:1923–1928

    PubMed  CAS  Google Scholar 

  64. Thiele EA (2004) Managing epilepsy in tuberous sclerosis complex. J Child Neurol 19:680–686

    PubMed  Google Scholar 

  65. Van Bogaert L, Paillas JE, Berard-Badier, Payan H (1958) Etude sur la sclerose tubereuse de Bourneville a forme cerebelleuse. Rev Neurol (Paris) 98:673–689

    Google Scholar 

  66. van Slegtenhorst M, de Hoogt R, Hermans C et al (1997) Identification of the tuberous sclerosis gene TSC1 on chromosome 9q34. Science 277:805–808

    Article  PubMed  Google Scholar 

  67. van Slegtenhorst M, Nellist M, Nagelkerken B et al (1998) Interaction between hamartin and tuberin, the TSC1 and TSC2 gene products. Hum Mol Genet 7:1053–1057

    Article  PubMed  Google Scholar 

  68. Weiner HL (2004) Tuberous sclerosis and multiple tubers: localizing the epileptogenic zone. Epilepsia 45(Suppl 4):41–42

    Article  PubMed  Google Scholar 

  69. Westmoreland B (1999) The electroencephalogram in tuberous sclerosis. In: Gomez MR, Sampson JR, Whittemore VH (eds) Tuberous sclerosis complex: developmental perspectives in psychiatry, 3rd edn. Oxford University Press, New York, pp 63–74

    Google Scholar 

  70. White R, Hua Y, Scheithauer B, Lynch DR, Henske EP, Crino PB (2001) Selective alterations in glutamate and GABA receptor subunit mRNA expression in dysplastic neurons and giant cells of cortical tubers. Ann Neurol 49:67–78

    Article  PubMed  CAS  Google Scholar 

  71. Wong M, Ess KC, Uhlmann EJ et al (2003) Impaired glial glutamate transport in a mouse tuberous sclerosis epilepsy model. Ann Neurol 54:251–256

    Article  PubMed  CAS  Google Scholar 

  72. Yamanouchi H, Jay V, Rutka JT, Takashima S, Becker LE (1997) Evidence of abnormal differentiation in giant cells of tuberous sclerosis. Pediatr Neurol 17:49–53

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Pediatric Neurology, Department of Pediatrics, University of British Columbia and British Columbia’s Children’s Hospital, Vancouver, British Columbia, Canada

    Mary B. Connolly

  2. Division of Anatomic Pathology, Department of Pathology, University of British Columbia and British Columbia’s Children’s Hospital, Vancouver, British Columbia, Canada

    Glenda Hendson

  3. Division of Pediatric Neurosurgery, Department of Surgery, University of British Columbia and British Columbia’s Children’s Hospital, Vancouver, British Columbia, Canada

    Paul Steinbok

  4. Division of Neurology, BC Children’s Hospital, 4480 Oak Street, Vancouver, BC, V6H 3V4, Canada

    Mary B. Connolly

Authors
  1. Mary B. Connolly
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Glenda Hendson
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Paul Steinbok
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Mary B. Connolly.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Connolly, M.B., Hendson, G. & Steinbok, P. Tuberous sclerosis complex: a review of the management of epilepsy with emphasis on surgical aspects. Childs Nerv Syst 22, 896–908 (2006). https://doi.org/10.1007/s00381-006-0130-7

Download citation

  • Received:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00381-006-0130-7

Keywords

Search

Navigation