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Cognitive impairment in tuberous sclerosis complex is a multifactorial condition

From the Rudolf Magnus Institute of Neuroscience, Departments of Child Neurology (F.E.J., O.v.N.), Neurology (F.E.J., A.A.), Neuropsychology (O.B., A.J.-S.), and Image Sciences Institute (K.L.V., P.A.), Department of Clinical Epidemiology (A.A.), Julius Centre for Health Sciences and Primary Care, Departments of Internal Medicine (B.A.Z.), TSC Clinic and Clinical Neurophysiology (A.C.v.H.), University Medical Centre, Utrecht, Department of Clinical Genetics (M.N., A.v.d.O., D.H.), Erasmus Medical Centre, Rotterdam, the Netherlands.

Address correspondence and reprint requests to Dr Jansen, Department of Neurology, C03236, University Medical Centre, P.O. Box 85500, 3508 GA Utrecht, the Netherlands f.e.jansen{at}umcutrecht.nl

Objective: In patients with tuberous sclerosis complex (TSC), associations between tuber number, infantile spasms, and cognitive impairment have been proposed. We hypothesized that the tuber/brain proportion (TBP), the proportion of the total brain volume occupied by tubers, would be a better determinant of seizures and cognitive function than the number of tubers. We investigated tuber load, seizures, and cognitive function and their relationships.

Methods: Tuber number and TBP were characterized on three-dimensional fluid-attenuated inversion recovery MRI with an automated tuber segmentation program. Seizure histories and EEG recordings were obtained. Intelligence equivalents were determined and an individual cognition index (a marker of cognition that incorporated multiple cognitive domains) was calculated.

Results: In our sample of 61 patients with TSC, TBP was inversely related to the age at seizure onset and to the intelligence equivalent and tended to be inversely related to the cognition index. Further, a younger age at seizure onset or a history of infantile spasms was related to lower intelligence and lower cognition index. In a multivariable analysis, only age at seizure onset and cognition index were related.

Conclusions: Our systematic analysis confirms proposed relationships between tuber load, epilepsy and cognitive function in tuberous sclerosis complex (TSC), but also indicates that tuber/brain proportion is a better predictor of cognitive function than tuber number and that age at seizure onset is the only independent determinant of cognitive function. Seizure control should be the principal neurointervention in patients with TSC.

Abbreviations: FLAIR = fluid attenuated inversion recovery; HR = hazard ratio; IE = intelligence equivalent; IS = infantile spasms; KNN = K nearest neighbor; TBP = tuber/brain proportion; TSC = tuberous sclerosis complex.

Supplemental data at www.neurology.org

Editorial, page 904

See also page 908

e-Pub ahead of print on November 21, 2007, at www.neurology.org.

Floor Jansen was supported by the Epilepsy Fund of the Netherlands (project no. 02-13). Floor Jansen and Olga Braams were supported by the EPOCH Foundation. Financial support for Mark Nellist was provided by the Stichting Michelle and the Nederlandse Organisatie voor Wetenschappelijk Onderzoek (NWO).

Disclosure: The authors have reported no conflicts of interest.

Received December 4, 2006. Accepted in final form July 5, 2007.

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