α-[¹¹C]-methyl-L-tryptophan PET for tracer localization of epileptogenic brain regions: clinical studies

Abstract

Of several molecular probes used in PET, only α-[(11)C]-methyl-L-tryptophan (AMT) is able to pinpoint the epileptic focus itself in the interictal state, by revealing a focus of increased AMT uptake, even when an MRI or glucose metabolism PET demonstrates normal findings. AMT PET appears to be particularly useful in patients with tuberous sclerosis complex and in patients with cortical developmental malformations. Although the sensitivity of AMT PET in finding the epileptic focus is about 70%, its specificity is almost 100%, indicating that if AMT PET identifies an area of increased uptake, it likely represents the epileptic focus which needs to be resected for better surgical outcome. In nontuberous sclerosis complex patients with cortical dysplasia, increased AMT uptake is usually associated with cortical dysplasia type IIB and a very good surgical outcome. Previously, no imaging modality has been able to predict the exact pathology subtype or differentiate between epileptogenic and nonepileptogenic lesions interictally. The neuropathological similarities between tubers and type IIB cortical dysplasia suggest a common mechanism of epilepsy, for which AMT PET is a biomarker. Due to the limited access to AMT PET, as presently it is labeled with (11)C, which has a half-life of only 20 min and therefore has to be synthesized on site using a cyclotron, most of the AMT experience has originated primarily from only two centers. Therefore, there is a need for more clinical studies from other centers and this can be greatly facilitated if AMT can be labeled with (18)F, a PET radionuclide widely available with a half-life of 110 min.

Figure 1. Usefulness of α-methyl-l-tryptophan PET in tuberous sclerosis patients with nonlateralizing EEG

(A) Fluid attenuated inversion recovery MRI showing a large tuber in the right sensorimotor cortex near midline (purple arrow), in a 5-year-old male child with tuberous sclerosis, intractable seizures and bilateral epileptiform activity on scalp EEG. Also seen are multiple small tubers, bilaterally (small red arrows). (B) α-methyl-l-tryptophan (AMT) PET scan showing increased AMT uptake only in the large right tuber, which was hypometabolic on 2-¹⁸F-fluoro-2-deoxy-d-glucose PET scan (C). All other small tubers are showing decreased AMT and 2-¹⁸F-fluoro-2-deoxy-d-glucose uptake (small red arrows). (D) Coregistration of AMT PET and intracranial electrodes (red circles: seizure onset; white circles: no seizure activity) on a 3D rendered brain MRI showing seizure onset (E) from the region of this large right tuber with increased AMT uptake (purple arrow). Close proximity to the midline was the likely reason for bilateral synchrony on scalp EEG. The patient underwent resective surgery, including this epileptogenic tuber, with a good surgical outcome. Lt: Left; Rt: Right.

Figure 2. Localization of epileptic focus in a tuberous sclerosis complex patient with lateralizing but nonlocalizing EEG

(A) Fluid attenuated inversion recovery MRI, (B) 2-¹⁸F-fluoro-2-deoxy-d-glucose PET and (C) α-methyl-l-tryptophan PET in a 3-year-old female child with tuberous sclerosis and intractable seizures. MRI and 2-¹⁸F-fluoro-2-deoxy-d-glucose PET showed multiple tubers, scattered throughout the brain, with diffuse nonfocal EEG changes over the left hemisphere on scalp EEG. α-methyl-l-tryptophan PET scan revealed increased α-methyl-l-tryptophan uptake in the left inferior frontal region at the periphery of a large left inferior frontal tuber (arrows), adjacent (lateral) to the left caudate nucleus and buried inside the left sylvian fissure. Lt: Left; Rt: Right.

Figure 3. α-methyl-l-tryptophan PET predicts histopathology in a child with molecular coincidence detection of epileptogenic focus by α-methyl-l-tryptophan PET in patients with cortical dysplasia and intractable seizures

(A) α-methyl-l-tryptophan PET scan showing increased tracer uptake in left parietal lobe in an 8-year-old girl with intractable seizures and (B) normal MRI. (C) Postsurgical histopathology revealed cortical dysplasia type IIB with balloon cells (magnification 25×, hematoxylin and eosin stain). The child remained seizure free for 7 years after surgery.

Figure 4. Role of α-methyl-l-tryptophan PET in patients with failed epilepsy surgery

(A) α-methyl-l-tryptophan PET scan showing a focal area of increased α-methyl-l-tryptophan uptake posterior to the surgical margin in the right frontal area in a 3.5-year-old boy with failed epilepsy surgery. All other imaging investigations, including (B) spoiled gradient echo MRI and 2-¹⁸F-fluoro-2-deoxy-d-glucose PET (not shown here) were noncontributory. Lt: Left; Rt: Right.