20
Epilepsy
Nicolaas I. Bohnen and James M. Mountz
PET for Functional and Neurochemical Imaging
Positron emission tomography (PET) can be used to perform neuro- chemical and functional brain imaging studies. First, neurochemical imaging studies allow assessment of the regional distribution and quan- titative measurement of neurotransmitters, enzymes, or receptors in the living brain. Benzodiazepine receptor binding scans are an example of neurochemical receptor studies that are used in the evaluation of chil- dren with epilepsy. Second, functional brain imaging studies can measure regional cerebral blood flow (rCBF) or glucose metabolism.
These studies may be performed in the resting state when the child is not having seizures (interictal) or at the time of a seizure (ictal study).
Seizure activation of the brain is accompanied by increases in rCBF and glucose consumption. Interictal fluorodeoxyglucose (FDG)-PET studies are most commonly performed in the clinical PET imaging evaluation of children with epilepsy at the present time. Although technically more challenging, ictal FDG- or rCBF-PET studies may be performed when children have frequent or predictable seizures.
Imaging for Presurgical Workup
Epileptic syndromes are classified as generalized and partial types of seizures. Primary generalized epilepsy is associated with diffuse and bilateral epileptiform discharges on an electroencephalogram (EEG) without evidence of focal brain lesions. In contrast, partial epilepsy is thought to arise from a focal gray matter lesion (localization-related epilepsy). Partial-onset seizures may remain partial or may secondar- ily generalize. Medically refractory epilepsy is defined by seizure syn- dromes that are not effectively controlled by antiepileptic drugs. The management of medically refractory partial epilepsy has been revolu- tionized by neurosurgical techniques aimed at the resection of the epileptogenic brain focus. Therefore, precise seizure localization is the primary objective of the presurgical workup. Electroencephalogram
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monitoring and structural brain imaging using magnetic resonance imaging (MRI) are part of the standard workup of epilepsy patients undergoing presurgical evaluation. Functional imaging studies, such as FDG-PET, can provide additional localizing information in patients with nonlocalizing surface ictal EEG and can reduce the number of patients requiring intracranial EEG studies (1). Even when intracranial EEG is required, FDG-PET can be helpful in guiding placement of sub- dural grids or depth electrodes prior to surgical ablative therapy.
Obtaining a FDG-PET scan is strongly recommended before perform- ing intracranial EEG because prior depth electrode insertion can cause small hypometabolic regions that may lead to false-positive PET inter- pretations (2). The FDG-PET scan in the routine clinical setting is usually interpreted in a qualitative analysis by physicians experienced in the normal cerebral distribution of the tracer in the brain.
Figure 20.1 shows a normal FDG-PET brain scan of a 16-year-old girl.
It was performed on the Siemens (CTI PET Systems, Knoxville, TN)
A
Figure 20.1. Normal FDG-PET scan in 16–year-old girl. The normal mild asymmetry in metabolism typically seen in the temporal lobe is illustrated, as well as the normal degree of apparent reduction in metabolism in the anterior and mesial temporal lobe regions. A: Normal MRI scan. B: Normal FDG- PET scan.
B
Figure 20.1. Continued.
HR+ dedicated brain PET scanner. After the intravenous injection of
7.2 mCi of fluorine-18 (
18F)-FDG, the patient waited on a comfortable
recliner in a dimly lit, quiet room for approximately 30 minutes to allow
for tracer incorporation into the brain. The figure illustrates the typical
pattern of FDG uptake in the brain of a child. It has been previously
reported that there is increased metabolic activity in the anterior cin-
gulate cortex and thalamus in children (3). Figure 20.1 also illustrates
the importance of using symmetry or other semiqualitative methods
to establish the presence of abnormally reduced metabolism in the
temporal lobes, because there is a variability of symmetrical uptake of
approximately 15% in this location (4). The PET scan should be inter-
preted as being abnormal if there is a definite focal area of reduced FDG
uptake identified during the interictal state. It is also highly recom-
mended that the FDG-PET scan be reviewed with full information
available including the current MRI scan, clinical history, neurologic
examination, seizure semiology, and EEG results.
Regional Glucose Hypometabolism and Epileptogenic Focus
The use of FDG-PET in clinical epilepsy emerged from early observa- tions of regionally reduced cortical glucose metabolism at the site of the epileptogenic focus (5). It should be noted that FDG-PET may show more widespread hypometabolism than suspected on the basis of the scalp-recorded EEG (1). The pathophysiology of interictal cortical hypometabolism in partial epilepsy is incompletely understood. Areas of interictal hypometabolism in epileptogenic cortex appear to be par- tially uncoupled from blood flow with metabolic reductions being greater relative to flow (6). Although there are significant correlations between hippocampal volume and inferior mesial and lateral tempo- ral lobe cerebral metabolic rates in patients with temporal lobe epilepsy (7), hippocampal neuronal loss cannot fully account for the regional interictal hypometabolism of temporal lobe epilepsy (8). Children with new onset of seizures are less likely to have hypometabolism (9). There- fore, it is uncertain whether hypometabolism reflects the effects of repeated seizures on the brain, the underlying pathologic process, or an initial insult such as early status epilepticus (9). It is possible that synaptic mechanisms rather than cell loss may contribute to the observed hypometabolism (10).
Ictal SPECT Combined with Interictal FDG
Single photon emission computed tomography (SPECT) is a nuclear medicine imaging method that facilitates the measurement of rCBF (11).
Its utility is based on the fact that partial seizures are associated with an increase in rCBF (12). In ictal SPECT, a photon-emitting radio- tracer [usually technetium-99m (
99mTc)-hexamethylproleneamine- oxime (HMPAO) or
99mTc-ethylcysteinate dimer (ECD)] is injected intravenously at the onset of a seizure and the subject is scanned when stable using a rotating gamma camera to obtain SPECT images. This provides a three-dimensional image of the distribution of the radio- tracer during the seizure, for the radiotracer accumulates and remains
“fixed” in different areas of the brain proportional to the cerebral per- fusion to those regions at the time of injection. In partial seizures, the increased blood flow closely corresponds with the site of seizure origin.
The interpretation of ictal rCBF-SPECT has several potential limitations.
Extratemporal seizures are often associated with multiple areas of increased rCBF that may be due to seizure propagation or to individual variability in the baseline rCBF patterns of tracer uptake (13–15). Also, if the epileptogenic zone is hypoperfused at baseline (interictal), the ictal increase in tracer uptake may be obscured despite relative hyper- perfusion (15,16). These factors have led to the widespread but not uni- versal practice of combining an ictal with an interictal study (13,15,16).
Typically, qualitative comparison of the ictal and interictal studies is
undertaken when both are available; otherwise, qualitative or semi-
quantitative side-to-side comparison of the ictal study alone is per- formed. More recently it has been shown that the accuracy of this method may be enhanced by subtraction of the interictal from the ictal SPECT and then co-registration of the resulting images onto MRI (15).
Ictal SPECT can corroborate the findings on interictal FDG, as shown in Figure 20.2. However, due to late propagation and cross-hemispheric electrocortical activation, the findings on ictal SPECT must be carefully interpreted. This difficulty with ictal SPECT is illustrated in a 9-year- old, right-handed boy with history of intractable partial epilepsy.
Seizure onset was in the first few months of life. The EEG showed left temporal slowing as well as left sharp waves. An MRI scan showed left
A B
C D
Figure 20.2. A 9–year-old, right-handed boy with history of intractable partial epilepsy. A: MRI coronal sections through the mesial temporal lobe region show left mesial temporal lobe sclerosis with villous atrophy. B: Transverse sections from a FDG-PET scan show left temporal lobe hypometabolism with greatest reduction in the left mesial temporal lobe. C: Transverse interictal regional cerebral blood flow (rCBF)-SPECT (top two rows) compared with ictal rCBF-SPECT (bottom two rows) shows increased blood flow to the lateral temporal lobe region during ictus. D: Coronal interictal rCBF-SPECT of the same scan as shown in C (top two rows) compared with ictal rCBF-SPECT (bottom two rows) shows increased blood flow to the lateral temporal lobe region during ictus.
R L R L R L
MRI F-18 FDG PET MRI-FDG PET Fusion
Figure 20.3. Right mesial temporal lobe sclerosis in a 16–year-old boy. The MRI-PET fusion image illus- trates that the reduction in FDG corresponds to the region of MRI increase in signal intensity in the right mesial temporal lobe (hippocampal region).
medial temporal sclerosis with villous atrophy. The FDG-PET scan showed left medial temporal hypometabolism. However, the ictal SPECT showed an increase in left lateral temporal lobe perfusion. Thus, although ictal SPECT correctly lateralized the epileptogenic focus to the correct lobe of the brain, only interictal FDG-PET localized the true epileptogenic focus to the left mesial temporal lobe.
Interictal FDG-PET Studies in Temporal Lobe Epilepsy (TLE)
Mesial temporal lobe epilepsy is commonly associated with hip- pocampal sclerosis. Fluorodeoxyglucose-PET has high sensitivity in detecting temporal hypometabolic foci and can be visualized as a region of reduced metabolism that, when compared to the normal tem- poral lobe, may show a significant asymmetry in FDG uptake (4).
Figure 20.3 illustrates concordance between abnormalities on MRI and FDG-PET in a 16-year-old boy with temporal lobe epilepsy. The MRI shows abnormal high signal intensity in the right hippocampal region.
The FDG-PET shows a corresponding area of focal reduction of FDG uptake in the right hippocampal region.
Fluorodeoxyglucose-PET is most useful for those patients with TLE
who have equivocal or no structural MRI abnormalities to provide the
necessary lateralization information (7,17). Although most patients
with TLE will have the findings of hippocampal sclerosis on a high res-
olution MRI, a significant minority of patients with electroclinically
well-lateralized temporal lobe seizures have no evidence of sclerosis on
MRI (18). Figure 20.4 illustrates a normal MRI scan and an abnormal FDG-PET scan in a 15-year-old boy with intractable complex partial seizures. He averaged about one to two complex partial seizures a month and two to three simple partial seizures per day. His surface EEG showed ictal discharges from the right frontotemporal region. The MRI and interictal rCBF-SPECT studies were normal. An interictal FDG-PET showed right temporal hypometabolism involving medial and anterior aspects of the right temporal lobe.
It should be noted that false lateralization is rare but may occur in FDG-PET studies of temporal lobe epilepsy. For example, unrecognized epileptic activity can make the contralateral temporal lobe appear spuriously depressed (2). Furthermore, normal right-to-left asym- metry between temporal lobes should not be interpreted as pathologic hypometabolism. Although FDG-PET images can be analyzed visually, additional information can be obtained by semiquantitative analysis, such as left-to-right asymmetry indices. Semiquantitative analysis using the asymmetry index is generally considered significant when a difference of 15% or greater exists between the affected and contralat- eral sides (19). Quantitative asymmetry indices should reduce poten- tial error due to misinterpreting these normal left-to-right variations (20). Registration programs can be used to align structural MRI and PET for more precise anatomic localization of the hypometabolic area.
Although regional hypometabolism is typically present in the tempo- ral lobe ipsilateral to EEG seizure onset, other brain regions may also show patterns of glucose hypometabolism. For example, an FDG-PET study of patients with temporal lobe epilepsy demonstrated hypometa- bolic regions ipsilateral to seizure onset that included lateral temporal (in 78% of patients), mesial temporal (70%), thalamic (63%), basal ganglia (41%), frontal (30%), parietal (26%), and occipital (4%) regions (21). In pure TLE, however, the extratemporal hypometabolic regions rarely show epileptiform activity on EEG but may be affected by rapid seizure propagation (21).
Cerebellar hypometabolism may be ipsilateral, contralateral, or bilateral, depending on the distribution and spread of ictal activity and possible effects of phenytoin therapy (2,22). Bilateral cerebellar hypometabolism, which often is present, cannot be fully explained by the effects of phenytoin (22). Unilateral temporal hypometabolism pre- dicts good surgical outcome from temporal lobectomy. The greater the metabolic asymmetry, the greater the chance of becoming seizure-free (2). Bilateral temporal hypometabolism may represent a relative con- traindication for surgery (2). Similarly, thalamic asymmetry on FDG- PET is a strong predictor of surgical outcome; hypometabolism in the thalamus contralateral to the presumed EEG focus almost invariably predicts poor surgical outcome (23).
FDG-PET Imaging in Extratemporal Epilepsy
The localization of epileptic foci in patients who have intractable
extratemporal epilepsy remains a major diagnostic challenge in the
presurgical evaluation of children with epilepsy. The most common underlying pathology in extratemporal neocortical epilepsy is micro- scopic focal cortical dysplasia, which cannot be readily detected by current MRI techniques (24). Fluorodeoxyglucose-PET may not be as valuable in the evaluation of patients with extratemporal seizures, such as frontal lobe epilepsy, because of limited sensitivity (20,25). Areas of hypometabolism in frontal lobe epilepsy have been found to be focal, regional, or hemispheric (26). Interictal hypometabolism may be uncom- mon in the absence of co-localized structural imaging abnormality in frontal lobe epilepsy (27). Furthermore, large zones of extrafrontal, par- ticularly temporal, hypometabolism are commonly observed ipsilateral to frontal hypometabolism in frontal lobe epilepsies (27). Figure 20.5 illustrates this limitation on the localization capability of interictal FDG- PET in extratemporal lobe epilepsy in a 14-year-old girl with intractable epilepsy. The patient had one to two brief seizures per day. Video-EEG monitoring was nonlocalizing. The MRI scan was normal. Ictal
99mTc- HMPAO showed focal intense right frontal lobe hyperperfusion. Inter- ictal FDG-PET was nonlocalizing, but in retrospect, after review of the
AFigure 20.4. A 15–year-old boy with intractable complex partial seizures. A: Normal MRI scan. B: Inter- ictal FDG-PET shows right temporal hypometabolism in the hippocampal region.
ictal rCBF study, showed subtle right frontal hypometabolism. In this case interictal FDG was confirmatory but by itself was not localizing.
Recent data show that observer-independent automatic statistical brain mapping techniques may increase the usefulness of FDG-PET in patients with extratemporal lobe epilepsy (28). For example, a study using an automated brain mapping method found significantly higher sensitivity in detecting the epileptogenic focus (67%) than visual analysis (19% to 38%) in patients with extratemporal epilepsy (29). Hypometabolic regions in partial epilepsies of neocortical origin have been usually associated with structural imaging abnor- malities (25). Therefore, PET data should always be interpreted in the context of high-quality anatomic MRI, providing a structural- functional correlation. The importance of precise localization using an an automated registration mapping method is illustrated in Figure 20.6,
B
Figure 20.4. Continued.
9 10 11 12 13 14
15 16 17 18 19 20
21 22 23 24 25 26
27 28 29 30 31 32
F-18 FDG INTER-ICTAL A.R.
15 Y/O F
A.R.
14 Y/O F
TC-99m HHPAO ICTAL
F-18 FDG
Figure 20.5. A 14–year-old girl with a history of intractable epilepsy with seizure frequency as one to two seizures per day. MRI coronal sections are normal (left upper quadrant). FDG-PET shows normal variability in metabolic uptake with no convincing areas of metabolic reduction that are diagnostic for the epileptogenic focus (right upper quadrant). Ictal technetium-99m (99mTc)-hexamethylproleneamine- oxime (HMPAO) SPECT in coronal section (top) demonstrates a region of focal intense blood flow in the right medial frontal lobe compared with co-registered coronal sections from the interictal FDG-PET scan. In retrospect, a region of hypometabolism is detectable (left lower quadrant). Co-registered MRI, ictal SPECT, and FDG-PET images show the MRI is normal in the location of intense hyperemia on ictal SPECT, in the same area retrospectively showing hypometabolism on PET (right upper quadrant).
Figure 20.6. A 15–year-old boy with generalized tonic-clonic seizures from a right parieto-occipital cavernous venous angioma. A: MRI shows right parieto- occipital cavernous venous angioma. B: FDG-PET scan shows reduced metab- olism in the area of the cavernous venous angioma. C: Ictal SPECT transverse section (bottom) shows increased blood flow to the right parietal lobe in the location of the angioma. Interictal SPECT (top) shows reduced blood flow cor- responding to the location of the angioma. D: Ictal SPECT sagittal section (bottom) shows increased blood flow to the right parietal lobe in the location anterior to the angioma. Interictal SPECT (top) shows reduced blood flow cor- responding to the location of the angioma. E: Statistical pixel analysis map in transverse section of significant ictal rCBF greater than interictal rCBF (yellow) or less that interictal rCBF (blue). Map shows significant ictal associated hyper- emia in the region of the angioma. F: Statistical pixel analysis map in sagittal section of significant ictal rCBF greater than interictal rCBF (yellow) or less that interictal rCBF (blue). Map shows significant ictal associate hyperemia anterior to the angioma. (See color insert, parts E and F only.)
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A
R
A
R A
B
(Continued)
C
D
Figure 20.6. Continued.
E
F
Figure 20.6. Continued.
see color insert, by the example of a 15-year-old, right-handed boy undergoing evaluation for a generalized tonic-clonic seizure disorder caused by a right parietooccipital cavernous venous angioma. The EEG showed right parieto-occipital focal slow and sharp waves. The MRI showed right parieto-occipital cavernous venous angioma with evi- dence of bleeding. The FDG-PET scan showed reduced metabolism in the area of the cavernous venous angioma. An ictal SPECT showed increased uptake in the right parietal lobe, anterior and medial to the area of reduction of blood flow in right parietal lobe caused by the angioma. The patient underwent electrocorticography and mapping of the lesion for subsequent resection of the lesion and surrounding epileptogenic area. On electrocorticography and intraoperative mapping, the area of increased epileptogenesis was found to correlate with the findings of ictal SPECT.
Interictal FDG-PET studies have limited usefulness in the presence of multiple hypometabolic regions in patients with multifocal brain syndromes, such as in children with tuberous sclerosis. Such children with multifocal lesions represent a special challenge during pre- surgical evaluation. The goal of functional imaging in these cases is to identify the epileptogenic lesions and differentiate them from nonepileptogenic ones. In this context, ictal rCBF-SPECT may have useful clinical applications but may be technically challenging when seizures are short, as is particularly common in frontal lobe epilepsy and in children who have infantile spasms that are associated with multifocal cortical dysplasia (30). Figure 20.7 shows such a case in a 1-year-old boy with tuberous sclerosis. Several lesions appeared anatomically abnormal on the CT portion of the PET-CT scan. These areas also showed reduced FDG uptake on PET. Ictal SPECT was able to identify the dominant area of presumed epileptogenesis associated with a large tuber in the right frontal lobe.
Figure 20.7. A 1–year-old boy with tuberous sclerosis underwent a PET–
computed tomography (CT) scan as well as ictal and interictal rCBF-SPECT. A:
CT portion of PET-CT scan showing the tubers. B: FDG-PET portion of PET- CT scan showing reduced metabolism in the multiple areas of the tubers. C:
PET-CT fusion image showing that the areas of decreased metabolism corre- spond to the numerous tuber abnormalities identified on the CT scan. D: FDG- PET scan coronal sections showing reduced metabolism in multiple areas of the tubers. E: Ictal rCBF-SPECT coronal section (bottom) showing intense hyperemia corresponding to the large tuber in the right frontal lobe. Interictal rCBF-SPECT does not show blood flow reduction to the degree of metabolic reduction identified on interictal PET.
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A
B
C
D
Figure 20.7. Continued.
FDG-PET Studies of Children with Infantile Spasms (West Syndrome)
An infantile spasm is an epileptic syndrome that begins in early infancy in which children have tonic and myoclonic seizures, arrhythmia on EEG, and development arrest. Among patients with infantile spasms, FDG-PET studies suggest that the spasms are the result of secondary generalization from cortical foci and that maturational factors result in the recruitment of basal ganglia and brainstem serotonin mechanisms that lead to secondary generalization and the unique semiology of the spasms (31,32). Most infants who are diagnosed with “cryptogenic”
spasms have focal or multifocal cortical regions of decreased (or occa- sionally increased) glucose metabolic activity on PET that are often con- sistent with areas of cortical dysplasia missed by MRI (31,33). When a single region of abnormal glucose hypometabolism is apparent on PET and corresponds to the EEG focus, and the seizures are intractable, sur- gical removal of the PET focus results in seizure control and in com- plete or partial reversal of the associated developmental delay (30).
When the pattern of glucose hypometabolism is generalized and sym- metric, a lesional cause is not likely, and neurometabolic or neuroge- netic disorders should be considered when further evaluating the child
E
Interictal
Ictal
Figure 20.7. Continued.
(30). Results of serial FDG-PET imaging have shown that when PET after the initial treatment shows no abnormalities, even though the first PET shows hypometabolism, infants with cryptogenic West syndrome may have a favorable developmental or seizure outcome (34).
FDG-PET Studies in Lennox-Gastaut Syndrome
Lennox-Gastaut syndrome is a childhood epileptic encephalopathy characterized by an electroclinical triad of generalized slow spike wave activity in the EEG, multiple types of epileptic seizures, and slow mental development. It is usually subdivided into symptomatic and crypto- genic types, the latter accounting for at least one fourth of all patients.
Symptomatic cases are due to diverse cerebral conditions, which are usually bilateral, diffuse, or multifocal, involving cerebral gray matter (35). Fluorodeoxyglucose-PET studies have shown that Lennox-Gastaut syndrome can be classified into four predominant subtypes, each with a distinct metabolic pattern: unilateral focal hypometabolism, unilateral diffuse hypometabolism, bilateral diffuse hypometabolism, and normal (36). Patients who have the unilateral focal and unilateral diffuse pat- terns may be considered for cortical resection provided that there is con- cordance between FDG-PET and ictal EEG findings (30).
Interictal and Ictal PET Studies
Interictal 15O-H2O rCBF-PET Studies
It should be noted that interictal oxygen-15 (
15O)-H
2O rCBF-PET studies, when compared to FDG-PET studies, have reduced sensitivity in localizing epileptogenic zones and sometimes may be false lateral- izing (37). Furthermore, rCBF-PET scans are noisier than FDG-PET, which may increase partial volume effects and make detection of a hypoperfused area more difficult. Therefore, interictal rCBF-PET studies are unreliable markers for epileptic foci and should not be used in the presurgical evaluation of patients with epilepsy (6).
Ictal PET
Although not always practical, FDG-PET can also be used for ictal studies in patients who have frequent seizures (38). It should be noted that FDG-PET may be less accurate for ictal compared to interictal glucose metabolic measurements because seizures may alter the
“lumped constant,” which describes the relationship between FDG and
its physiologic substrate glucose (2). Furthermore, a typical seizure is
much shorter than the average 30-minute FDG uptake period. There-
fore, an “ictal” scan may include interictal, ictal, and postictal meta-
bolic changes with combinations of hypermetabolic and hypometabolic
regions (2).
15O-H
2O PET imaging has been used to study quantitative
alterations in rCBF accompanying seizures induced by pentylenetetra-
zole (39). Patients with generalized tonic-clonic seizures demonstrated
asymmetric flow increases. One patient with a complex partial seizure
demonstrated 70% to 80% increases in bitemporal flow. Thalamic flow increased during both complex partial and generalized seizures, indicating the importance of this subcortical structure during ictal activation (39).
Factors That May Affect Interpretation of Interictal and Ictal FDG-PET Studies
A number of other factors need to be considered when interpreting brain PET images of children with epilepsy. It should be realized that brain glucose metabolic or blood flow PET images are functional in nature. For example, when a child is moving or talking around the time of injection, increased activity in specific brain regions, like the basal ganglia, motor cortex, or language centers, may be present. Metabolic activity in the visual cortex was increased in subjects studied with their eyes open when compared to a baseline of subjects studied with their eyes closed (40). Therefore, knowledge of the clinical or behavioral state of the patient at the time of the injection and study is critical for proper image interpretation.
Positron emission tomography in children often requires sedation.
An FDG-PET study of propofol sedation in children found significant hypometabolism in the medial parieto-occipital cortex bilaterally, including the lingual gyrus, cuneus, and middle occipital gyrus (41).
The bilateral parieto-occipital hypometabolism is likely to be a seda- tion-specific effect and should be taken into account when evaluating cerebral FDG-PET scans in sedated children. Diazepam sedation has been found to reduce cerebral glucose metabolism globally by about 20% (42). A study by Wang et al. (43) found that lorazepam significantly decreased whole-brain metabolism over 10%. However, regional effects of lorazepam were largest in the thalamus and occipital cortex (about 20% reduction). Similarly, antiepileptic drugs have been found to reduce glucose metabolism and rCBF. Studies on valproate have shown global FDG (about 9% to 10%) and global CBF (about 15%) reductions with greatest regional reductions in the thalamus (44). Phenytoin has been found to cause an average reduction of cerebral glucose metabo- lism by 13% (45). Cerebellar metabolism may also be reduced by phenytoin, although the effect of the drug is probably less than that due to early onset of uncontrolled epilepsy (22,46). Studies on the bar- biturate phenobarbital and cerebral glucose metabolism have shown very prominent global reductions of about 37% (47).
Emerging Clinical Applications of Neurochemical PET Imaging
The inhibitory neurotransmitter g-aminobutyric acid (GABA) has anti-
convulsant properties. Benzodiazepine receptor ligands, such as
carbon-11 (
11C)-flumazenil (FMZ), have been used to study the regional
cerebral distribution of benzodiazepine receptor binding sites that are
related to GABA
Areceptors. The high density of GABA
Areceptors in
the normal hippocampus accounts for the high sensitivity of FMZ-PET
to detect even mild decreases in binding that are consistent with hippocampal sclerosis in TLE. Where available, FMZ-PET provides a useful alternative for FDG-PET in the evaluation of children with epilepsy. A regional decrease in benzodiazepine receptor binding has been associated with the presence of a possible epileptogenic focus.
Unilaterally decreased temporal FMZ binding can also help to lateral- ize the epileptic focus in patients who have TLE that is associated with bilateral temporal hypometabolism on FDG-PET (30). When compared to FDG studies, FMZ-PET studies have been reported to demonstrate less extensive cortical involvement. For example, a study comparing FDG and FMZ-PET imaging in patients with temporal lobe epilepsy found a wide range of mesial temporal, lateral temporal, and thalamic glucose hypometabolism ipsilateral to ictal EEG changes as well as extratemporal hypometabolism. In contrast, each patient demonstrated decreased benzodiazepine-receptor binding in the ipsilateral anterior mesial temporal region, without neocortical changes. Thus, interictal metabolic dysfunction can be variable and usually is extensive in temporal lobe epilepsy, whereas decreased central benzodiazepine- receptor density appears to be more restricted to mesial temporal areas (48). Similar benzodiazepine receptor findings have been reported for patients with extratemporal lobe seizures caused by focal cortical dys- plasia (49). Unlike the more widespread glucose hypometabolic pat- terns, benzodiazepine receptor changes may reflect localized neuronal loss that is more specific to the epileptogenic zone (48). Therefore, FMZ imaging may be useful in the presurgical evaluation of children with epilepsy. However, focal increases of benzodiazepine receptor binding have also been reported in the temporal lobe as well as extratemporal sites in patients with temporal lobe epilepsy when statistical brain mapping analysis is performed (50). This may lead to false-localizing information when attention is paid only to areas of decreased uptake.
The development of radioligands that are specific for excitatory amino acid and selected opioid receptor subtypes, such as
11C- carfentanil for mu-opiate receptors, may help to better explore the pathophysiology of epileptic syndromes. Another promising direction in the development of new PET tracers for epilepsy is to target sero- tonergic neurotransmission. A novel tracer, a-
11C-methyl-L-tryptophan (AMT), which accumulates in epileptic foci in the interictal state, can be a useful approach to identify epileptogenic sites in children with multifocal brain lesions (30,51). This radiotracer may also be useful in identifying nonresected epileptic cortex in young patients with a pre- viously failed neocortical epilepsy surgery (52).
Conclusion
The use of FDG-PET in clinical epilepsy emerged from early observa-
tions of regionally reduced cortical glucose metabolism at the site of
the epileptogenic focus. Fluorodeoxyglucose is the most commonly
used PET radiotracer in the diagnostic and presurgical evaluation of
children with epilepsy at the present time. Measurement of receptors or neurotransmitter metabolism is a unique ability of PET that has not achieved its full potential in the study of pediatric epilepsy. For example, PET measures of central benzodiazepine receptor binding and serotonin synthesis may have increasing clinical applications in the presurgical evaluation of children with localization-related epilepsy.
It is anticipated that the use of such tracers will further enhance the clinical yield of PET in the diagnostic workup and presurgical evalua- tion of children with medically intractable epilepsy and will further improve our understanding of the pathophysiology of pediatric epilepsy.
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![A Firenze messe le basi per una Piattaforma internazionale per una corretta gestione delle risorse idriche sotterranee
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