Elsevier

Epilepsy Research

Volume 52, Issue 3, January 2003, Pages 203-213
Epilepsy Research

α-[11C]-Methyl-l-tryptophan PET identifies the epileptogenic tuber and correlates with interictal spike frequency

https://doi.org/10.1016/S0920-1211(02)00216-4Get rights and content

Abstract

Epilepsy surgery has been successfully performed in patients with tuberous sclerosis complex (TSC) and seizures arising from a restricted epileptogenic area. The outcome of cortical excision depends on accurate pre-surgical identification of the epileptogenic tuber. [11C] α-methyl-l-tryptophan (α-MTrp) was originally developed to measure serotonin synthesis in vivo with positron emission tomography (PET). However in pathologic conditions its uptake may also depend on the synthesis of quinolinic or kynurenic acid via the kynurenine pathway. Increased levels of serotonin and quinolinic acid have been observed in epileptogenic lesions, raising the possibility that α-MTrp PET may localize the epileptogenic area. The aim of this study was to correlate α-MTrp PET uptake with the localization of the epileptogenic area and with interictal spike frequency in patients with TSC. α-MTrp uptake was measured in 8 patients (2 males, mean age 29.6±14.9 years, range 3–50 years) with intractable partial epilepsy due to TSC. All patients underwent scalp EEG monitoring during the PET scan. In four (50%), increased uptake of α-MTrp occurred in the epileptogenic area alone. Two (25%) patients showed multifocal abnormalities and the remaining two (25%) did not show focal changes. PET localization was mostly seen in patients with frequent interictal abnormalities on the EEG. Furthermore, there was a significant correlation between α-MTrp uptake and the frequency of interictal spikes (r=0.6; P<0.05). α-MTrp PET is a promising diagnostic tool in the localization of the epileptogenic area in patients with TSC.

Introduction

Tuberous sclerosis complex (TSC) is an autosomal dominant disorder that affects the skin, the central nervous system and a number of other organs (Roach, 1992). The most prominent and characteristic clinical findings are caused by lesions in the brain, and include seizures in about 92% of cases (Gomez, 1988). Although cortical lesions are usually multiple, seizures often originate from a restricted region of abnormal cortex, making surgery a valid therapeutic option for some (Guerreiro et al., 1998, Avellino et al., 1997, Bebin et al., 1993). Neuroimaging methods capable of differentiating epileptogenic from non-epileptogenic tubers in patients with TSC are likely to improve the surgical outcome. Magnetic resonance imaging (MRI), especially fluid-attenuated inversion recovery (FLAIR) imaging detects cortical tubers and subcortical lesions with high sensitivity (Takanashi et al., 1995), but does not identify the epileptogenic tuber. Positron emission tomography (PET) imaging employing [11C] α-methyl-l-tryptophan (α-MTrp) has been used successfully to identify the epileptogenic area not only in patients with single (cortical dysplasia) or multiple (TSC) cortical dysplastic lesions but also in those where other techniques have failed to detect any abnormality (Fedi et al., 2001, Asano et al., 2000). α-MTrp, an analogue of l-tryptophan, was initially developed to study the serotonergic system in vivo (Diksic et al., 1990, Okazawa and Diksic, 1998, Muzik et al., 1997). However, it has been shown that in pathologic conditions such as TSC, α-MTrp uptake may also relate to metabolism in the kynurenine pathway (Chugani and Muzik, 2000). Since increased levels of serotonin and quinolinic acid in regions of seizure onset have been described in TSC (Huttenlocher and Heydemann, 1984, Chugani et al., 1997, Louw et al., 1989, Pintor et al., 1990, Trottier et al., 1996) in the present study we addressed two issues. First, we evaluated the clinical value of α-MTrp PET in the pre-surgical evaluation of patients with intractable seizures and TSC, comparing the patterns of α-MTrp uptake and the localization of the epileptogenic area defined on the basis of clinical semiology, EEG and MRI findings. Second, we examined the correlation between α-MTrp uptake in the presumed seizure focus and interictal EEG activity.

Section snippets

Methods

Eight patients (2 males; age range 3–50 years; mean 29.6±14.9 years) with intractable partial epilepsy due to definite TSC, according to published criteria (Gomez, 1991), seen at the Epilepsy Service of the Montreal Neurological Hospital participated in the study. Eleven neurologically normal subjects (6 males; mean age 24.4±4 years; range 16–31 years) were also studied. The control subjects were not taking any medication and had no history of neurologic or psychiatric disorders. Although the

Results

The plasma levels of CBZ, CLZ, PHT and VPA were in the therapeutic range (mean CBZ 29.1±11.6 μmol/l; CLZ 12 ng/ml; PHT 18.7 μg/ml; VPA 98.3±16.4 μg/ml). Free tryptophan levels were not significantly different between patients and healthy controls (patients 5.2±2.5 pmol/ml; controls 4.5±1.7 pmol/ml; P=0.6).

Discussion

This study suggests that α-MTrp PET is of value in identifying the epileptogenic area in patients with TSC. These data corroborate and extend the observations by other authors of increased α-MTrp uptake in relation to the site of seizure onset in children with TSC (Asano et al., 2000, Chugani et al., 1997). Seizures in patients with TSC are often severe and medically intractable, thus leading to a poor prognosis for cognitive and social functioning. Recently, surgical removal of the

Acknowledgements

Supported by the MRC of Canada (MT-13368), US Public Service (RO1-NS29629). We wish to thank Richard Fukasawa and Gary Sauchuk for their assistance during data acquisition and processing.

References (46)

  • K Watanabe et al.

    The effect of the acute administration of various selective antagonists on focal hippocampal seizures in freely-moving rats

    Euro. J. Pharmacol.

    (2000)
  • K Watanabe et al.

    Effect of acute administration of various 5-HT receptor agonists on focal hippocampal seizures in freely moving rats

    Eur. J. Pharmacol.

    (1998)
  • R.J Wurtman et al.

    Control of brain neurotransmitter synthesis by precursor availability and nutritional state

    Biochem. Pharmacol.

    (1976)
  • R Andrade et al.

    Pharmacologically distinct action of serotonin on single pyramidal neurons of the rat hippocampus recorded in vivo

    J. Physiol.

    (1987)
  • V.I Arvanov et al.

    Pre- and post-synaptic actions of hallucinogens on NMDA neurotransmission in the rat medial frontal cortical cells

    Soc. Neurosci.

    (1996)
  • E Asano et al.

    Multimodality imaging for improved detection of epileptogenic foci in tuberous sclerosis complex

    Neurology

    (2000)
  • A.M Avellino et al.

    Surgical management and seizure outcome in patients with tuberous sclerosis

    J. Neurosurg.

    (1997)
  • E.M Bebin et al.

    Surgical treatment for epilepsy in cerebral tuberous sclerosis

    Epilepsia

    (1993)
  • D.C Chugani et al.

    Imaging epileptogenic tubers in children with tuberous sclerosis complex using α-[11C] methyl-l-tryptophan positron emission tomography

    Ann. Neurol.

    (1998)
  • D.C Chugani et al.

    Abnormal serotonin synthesis in epileptic foci of children: an in vivo study with α-methyl-tryptophan positron emission tomography

    Epilepsia

    (1997)
  • D.C Chugani et al.

    Alpha [C-11]methyl-l-tryptophan PET maps brain serotonin synthesis and kynurenine pathway metabolism

    J. Cereb. Blood Flow Metab.

    (2000)
  • D.L Collins et al.

    Automatic 3D intersubject registration of MR volumetric data in standardized Talaraich space

    J. Comput. Assist. Tomogr.

    (1994)
  • M.J Croucher et al.

    Anticonvulsant action of excitatory amino acid antagonists

    Science

    (1982)
  • Cited by (0)

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