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Background:α-[11C]methyl-L-tryptophan (α-MTrp) positron emission tomography (PET) is a promising tool in the localization of the epileptogenic area in selected group of focal epilepsy patients. Electrophysiological evidence suggests the involvement of the neocortex in periventricular nodular heterotopia (PVNH).
Purpose: To determine whether α-MTrp PET can detect neocortical changes in patients with PVNH.
Methods: Four patients (2 male, mean age 28, range 23–35 years) with PVNH and intractable seizures were studied. The functional image in each patient was compared with those from 21 healthy controls (mean age 34.6 ± 14.2 years) by using statistical parametric mapping (SPM). The location of increased α-MTrp uptake was compared with the location of the EEG focus. A significant cluster was defined as a cluster with a height p = 0.005 and an extent threshold 100.
Results:α-MTrp PET revealed increased cortical uptake in two of four patients. The area of increased α-MTrp uptake in one patient was widespread. In the other patient, the area of increased uptake did not include the region where most seizures were generated on EEG. α-MTrp PET did not show increased uptake in the heterotopic nodules in any of the patients.
Conclusions:α-MTrp PET suggests abnormal metabolism of tryptophan in the neocortex. The increased uptake may be diffuse and may not co-localize with the EEG focus. This preliminary study suggests that α-MTrp PET may be useful, in conjunction with other evaluations, in localizing epileptic focus in patients with PVNH and refractory seizures.
Periventricular nodular heterotopia (PVNH) is a commonly identified malformation of cortical development (Barkovich & Kuziecky, 2000). Although the association between PVNH and epilepsy is well known (Dubeau et al., 1995; Battaglia et al., 1997), there is still controversy concerning the localization and the extend of the epileptogenic area (Dubeau et al., 1995; Kothare et al., 1998; Aghakhani et al., 2005; Battaglia et al., 2005; Tassi et al., 2005). Some evidence suggests involvement of the neocortex (Dubeau et al., 1995; Aghakhani et al., 2005; Battaglia et al., 2005; Tassi et al., 2005).
α-[11C]methyl-L-tryptophan (α-MTrp) has been developed as a tracer for PET measurement of serotonin synthesis in vivo (Diksic et al., 1990). Chugani et al. and we recently demonstrated that α-MTrp with positron emission tomography (PET) is a useful tool in the localization of the epileptogenic area in partial epilepsy, especially in patients with tuberous sclerosis or cortical dysplasia (Chugani et al., 1998; Fedi et al., 2001; Juhasz et al., 2003). However, in pathological conditions this tracer probably accumulates locally via the kynurenine pathway (Saito et al., 1993; Chugani & Muzik, 2000), in which case its uptake and trapping would not be related to the serotonin synthesis.
To determine whether metabolism in the brain serotonergic system, including the kynurenine pathway, is involved in the epileptic process associated with PVNH, we performed α-MTrp PET studies in patients with PVNH.
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The results in all patients are summarized in Table 1. MRI showed PVNH in all patients, but no obvious cortical abnormalities except for left frontal encephalomalacia in patient 2 (Fig. 1B).
Figure 1. MRI findings of all patients. (A) Patient 1 had bilateral posterior PVNH (arrows). (B) Patient 2 had bilateral diffuse PVNH (arrows) and additional left frontal encephalomalacia (white arrow). (C) Patient 3 had bilateral frontal PVNH (arrows). This patient also had an additional left frontal focal subcortical heterotopia. (D) In Patient 4, PVNH was seen only in the body of the left lateral ventricle (arrow).
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FDG-PET was performed in two patients, and did not reveal cortical abnormalities. FDG uptake in PVNH was lower than that of cortex.
α-MTrp PET revealed focal increased uptake in the cortex of two patients as detailed below. No patient showed increased uptake within the PVNH.
Patient 1 had bilateral posterior PVNH (Fig. 1A). α-MTrp PET showed increased uptake in the right temporal and frontal neocortex that included the seizure onset region (Fig. 2). SPM analysis revealed increased uptake in the left fronto-polar areas and also the right fronto-temporal cortex (Fig. 3). This patient had electrodes implanted in both temporal lobes including posterior temporal structures and periventricular nodules in the temporal and occipital horns. The majority (9 of 10) of clinical and EEG seizures originated in the right posterior temporal neocortex with or without simultaneous involvement of the underlying gray matter heterotopia. One seizure originated in the contralateral homologous posterior temporal neocortical structures. The EEG findings showed a prominent zone of epileptogenicity in the right temporal region maximum in the posterior temporal neocortex, which was included in the areas of increased α-MTrp uptake. However, the areas of increased α-MTrp uptake were more widespread and covered the contralateral frontopolar area as well.
Figure 2. MRI and K*[μL/g/min] images of α-MTrp PET in patient 1. α-MTrp PET shows increased uptake in the right frontotemporal cortex (white arrowheads). There was no increased uptake of α-MTrp within the PVNH (black arrows).
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Figure 3. K*[μL/g/min] image of patient 1 compared with normal controls by SPM, using the threshold p = 0.005 and extend threshold set at 100 voxels. Significantly increased uptake of α-MTrp is observed in the right frontotemporal cortex, which includes the seizure onset region and also in the left frontopolar area.
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Patient 2 had bilateral diffuse PVNH and additional left frontal encephalomalacia (Fig. 1B). α-MTrp PET showed increased uptake in the right temporal and left occipital cortex by SPM analysis. The patient had electrodes implanted in both occipital, temporal and frontal lobe structures. The main seizure onset zone was found in the left frontal lobe (5 seizures recorded). Although seizures with left occipital onset were also recorded, the left occipital EEG findings were likely to be due to an acute lesion related to the implanted electrode. Increased α-MTrp uptake was not seen in the area corresponding to the left frontal focus.
Patient 3 had bilateral frontal PVNH and an additional left frontal focal subcortical heterotopia (Fig. 1C). On α-MTrp PET, we could not find increased uptake by SPM. He had electrodes implanted only in temporal lobe structures bilaterally. Of 34 seizures recorded, 25 had onset in both perihippocampal areas, 5 had onset in the right perihippocampal region, and 4 had onset in the right posterior temporal neocortex. No EEG–PET correlation could be made.
In Patient 4, three PVNH were seen only in the body of the left lateral ventricle (Fig. 1D) α-MTrp PET showed nonlocalized multiple areas of increased uptake in both hemispheres. This patient was not investigated with depth electrodes. No interictal or ictal abnormalities could be recorded during prolonged video-EEG monitoring.
Areas of decreased α-MTrp uptake in each patient were also determined by SPM analysis with the same criteria. In patient 1 and 3, areas of decreased α-MTrp were not detected. In patient 2, SPM showed decreased uptake in the left frontal lobes, but it corresponded to the defect in gray and white matter due to the encephalomalacia (Fig. 1B). In Patient 4, bilateral multiple small clusters were seen, but no specific areas of increased uptake were detected.
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This is the first study to use α-MTrp PET to evaluate possible abnormalities in tryptophan metabolism in the neocortex of patients with PVNH. We and others previously reported that α-MTrp PET is useful in detecting the epileptic focus in patients with partial epilepsy, in particular those related to tuberous sclerosis or focal cortical dysplasia (Chugani et al., 1998; Fedi et al., 2001; Juhasz et al., 2003). This is the first report focusing on α-MTrp PET findings in patients with PVNH.
α-MTrp PET revealed focal increased uptake in two out of four patients with PVNH. In Patient 1, the seizure onset was located in the neocortex overlying the PVNH. However, the area of abnormal α-MTrp PET was more widespread than that of the seizure onset. Interictal and ictal EEGs showed bilateral epileptic foci, although the majority of seizures originated on the right side. The widespread increase in α-MTrp uptake possibly indicated a more widespread epileptogenic zone with altered metabolism of tryptophan.
In Patient 2, α-MTrp PET showed increased uptake outside the main focus, but not in the left frontal region. It is possible that decreased α-MTrp uptake caused by encephalomalacia at the focus affected the result because of neuronal loss and partial volume effect.
In Patient 3, we could not find areas of increased α-MTrp uptake.
In Patient 4 with unilateral PVNH, areas of increased α-MTrp uptake were found bilaterally in several cortical regions. This patient had no seizures and no epileptiform discharges during the prolonged EEG monitoring. Therefore, it is possible that the lack of an active focus may have correlated with the nonlocalized PET finding. The significance of the multiple small clusters of increased or decreased α-MTrp uptake in this patient is not clear.
Seizure outcome after surgery has been reported to be unsatisfactory in patients with PVNH (Dubeau et al., 1995; Li et al., 1997), particularly in those with bilateral PVNH (Tassi et al., 2005). It is tempting to speculate that a widespread increase of α-MTrp uptake extending beyond the MRI-visible lesion and involving several neocortical areas may be an indicator for poor outcome after surgery. However, this hypothesis should be tested prospectively in future studies involving patients with PVNH undergoing surgical treatment for medically intractable seizures. At the present time, α-MTrp PET should be used only as one of several different modalities for localizing focus in patients with PVNH and refractory seizures. The main reason for this is the fact that the tracer uptake region did not always correlate with the EEG foci of the seizure onset.
The pathological abnormality underlying the widespread alteration of cortical tryptophan metabolism extending beyond the MRI-visible lesion remains unclear. Previous imaging studies indicate possible aberrant connectivity of the heterotopic nodules with distant cortical structures (Aghakhani et al., 2005). These abnormal networks may cause excitatory interactions with the overlying neocortex. A defect in cortical migration may also result in abnormal cortical organization of the overlying neocortex that causes abnormal cortical excitability and possibly increased serotoninergic innervation (Trottier et al., 1996). Therefore, the increased α-MTrp uptake observed in our patients may represent a serotonin-mediated compensatory mechanism with the purpose of decreased cortical excitability, and/or increased activity of the kynurenine pathway with formation of pro-convulsant products (Chugani & Muzik, 2000; Saito et al., 1993).
We did not find increased α-MTrp uptake within the heterotopiae themselves in the present group of patients. On the other hand, previous isolated reports demonstrated that at least in some patients, the main seizure generator is located within the heterotopic malformation (Dubeau et al., 1995; Kothare et al., 1998). Future studies combining α-MTrp PET with other imaging modalities and electrophysiological data are needed to fully explore the pattern of epileptogenic activity in PVNH.