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