**3. Nuclear imaging (PET, SPECT)**

Positron emission tomography (PET) and single photon emission computed tomography (SPECT) utilizes radiotracers, and are performed primarily to identify or confirm the ictal focus in preparation for surgery. PET and SPECT help to investigate the pathophysiology of partial and generalized seizure disorders. Occasionally, PET is performed to identify eloquent cortical regions to be spared during epilepsy surgery.

Radiotracer studies using PET or SPECT allow for in vivo assessment of physiologic function of the brain. Such studies include glucose consumption ([18F]fluoro-2-deoxyglucose; [18F]FDG), cerebral blood flow ([15O]water), neurotransmitter synthesis (dopamine and serotonin), receptor ligand binding (agonists or antagonists to benzodiazepine, opiate, serotonin, and N-methyl-d-aspartate [NMDA] receptors), transporter proteins, and microglia. PET has a practical resolution of 2–3 mm, which is superior to that of SPECT, and can be quantitated. Compound half-lives help decide the use and application of PET ligands: 18F-tagged compounds have a 110-minute half-life, 11C a 20-minute half-life, and 15O a 2-minute half-life. The long half-life of [18F]FDG makes it not a good candidate for assessing short-lived physiologic phenomena such as ictal states, whereas the very short half-life of [15O]water allows it to capture the brief activity of cognitive processes. Given the relatively short half-life of PET ligands, data acquisition must occur shortly or immediately after injection.

#### **3.1 PET**

The most clinical experience for evaluating patients with partial epilepsy is with [18F]FDG-PET. Studies have demonstrated interictal regional decreases in glucose consumption ipsilateral to the seizure focus that is most pronounced in the temporal lobe [103–105]. This figure is close to 90% on recent generation scanners [106–109]. The area of decreased glucose utilization is often more extensive than the epileptogenic zone, may extend into adjacent inferior frontal or parietal lobe neocortex [105, 110] and occasionally into ipsilateral thalamus [111] and contralateral cerebellum [105].

The reason for regional hypometabolism is incompletely understood. Cell loss resulting in synaptic loss and altered remote projections, or hippocampal atrophy in mesial temporal sclerosis, may account for a portion of regional hypometabolism in TLE [112–114]. Hypometabolism does not correlate with lifetime generalized tonicclonic (GTC) seizures or complex partial seizure (CPS) frequency [115]. Dysplastic tissue with aberrant synaptic connectivity can have either decreased or normal glucose consumption [116]. In focal cortical dysplasia, mitochondrial complex IV function may be decreased in areas of hypometabolism [117]. The abnormalities in some circumstances appear to be functional, as some patients have profound decreases in glucose uptake and no discernible pathology. In patients with mesial temporal sclerosis, the predominant regions that may manifest decreased glucose consumption are the lateral neocortex and, to a lesser extent, the frontal cortex. This may reflect the distant projection of functional loss in mesial structures. Frontal hypometabolism and contralateral hypometabolism appears to be reversible with successful temporal lobectomy [118]. Patterns of hypometabolism may reflect seizure characteristics and seizure propagation. Nevertheless, there is sufficient variability that individual predictions of seizure focus within the temporal lobe cannot be made based on [18F] FDG-PET alone [119], whereas a combination of MRI and PET findings predicted outcome—those with persistent abnormalities fared less well [120].

Metabolic abnormalities are less common in patients with recent-onset, nonrefractory, or well-controlled partial epilepsy [121]. Regional hypometabolism was also found to be changed in relation to seizure frequency in children with worsening seizures [122]. Similar to adults, 70% of children with chronic partial epilepsy (duration 10 years) have focal metabolic abnormalities. There is evidence that adult patients with a greater duration of epilepsy are more likely to have focal [18F]FDG-PET abnormalities [105, 123, 124]. Partial seizures of greater duration are also associated with a greater dissociation between metabolism and blood flow. These [18F]FDG and cerebral blood flow studies, along with cross-sectional studies using volumetric MRI, may be taken as evidence that TLE in some patients is associated with chronic and continued neuronal injury [106, 125].

Although glucose consumption in temporal cortex is decreased, perfusion is often maintained, especially in lateral neocortex [106, 123]. Interictal studies of cerebral blood flow using [15O]water find a decrease in perfusion in only 50% of patients [106]. These data suggest that vascular tone may be impaired in TLE and that there is dissociation between metabolism and perfusion, rendering interictal blood flow studies unreliable markers of the epileptogenic zone and surgical outcome [126].

Focal interictal regional hypometabolism can predict good surgical outcome [107, 127–129]. Additionally, extent of resection of PET abnormalities is found to correlate with post operative outcome [130]. Bilateral temporal hypometabolism is associated with a less optimistic surgical outcome and in 50% of patients reflects bilateral foci [131]. Patients with focal temporal abnormalities have more than 90% likelihood of good surgical outcome, and in those without, this figure is reduced to about 63% [128, 129]. The ability to confirm the focus and predict surgical outcome is better when quantitative means are used, typically when asymmetry indexes [AI; e.g., AI = 2(left − right)/ (left + right)] are greater than two standard deviations from normative data. Cortical segmentation may also improve yield for FDG-PET but not SPECT [132]. Focal abnormalities on [18F]FDG-PET may reduce the need for or extent of, invasive monitoring [104, 128, 129]. Nonetheless, questions of frontal versus temporal focus may not always reliably be resolved by interictal [18F]FDG-PET studies, and invasive studies or other PET ligand studies may be needed. Conflicting localizing or lateralization data nearly always merit invasive monitoring. False lateralization by PET has been demonstrated after surgery [103], specifically when interpretation relied upon non-quantitative analysis, or occurred during subclinical seizures [103, 133, 134].

[18F]FDG-PET is less efficacious in identifying the epileptogenic zone in extratemporal lobe epilepsy [135]. Most extratemporal lobe epilepsy series include patients with structural lesions that show concordant hypometabolism. When patients with abnormal MRI findings are excluded, 11–50% of the relatively small patient populations remaining show regional decreases in glucose consumption [109, 126]. FDG-PET abnormalities remote from the lesion lessen prospects of good surgical outcome. Abnormal focal PET (or SPECT) findings should be followed by review of "normal" MRI, as focal MRI findings often ensue and will positively affect yield of epilepsy surgery [136–138].

In absence seizures, glucose consumption and perfusion are globally increased [139]. [15O]Water studies performed during electroencephalographic (EEG) bursts of spike and wave demonstrate not only an increase in global perfusion but also a preferential increase in the thalamic regions, supporting the notion of the thalamus as the facilitator of absence events [140]. Interestingly, there is some evidence that valproate decreases cerebral blood flow in the thalamus, which may explain the effect of valproate in controlling generalized epilepsies. In Juvenile myoclonic epilepsy, [(11)C]PE2I, a marker of dopamine transporter (DAT) activity is reduced in midbrain and the high-affinity dopamine (D2/D3) receptor ligand [18F]Fallypride ([(18) F]FP) is reduced in putamen [141].

Some children with a generalized EEG and normal MRI can exhibit regional metabolic abnormalities [142]. "Interictal" FDG-PET will show hypermetabolic areas in

2–6% of pediatric studies. Regional uptake is associated with frequent spike activity and originates from focal cortical dysplasia. Intracranial EEG finds these regions are effectively in status and, when resected, are associated with good outcome [143, 144]. In some children, however, the metabolic abnormalities seen at onset of infantile spasms may resolve or shift with time and thus may represent a functional state that is potentially reversible with successful medical therapy [145, 146]. In children with Rasmussen's encephalitis and hemimegalencephaly, widespread hemispheric hypometabolism is typically seen. PET has been advocated in some circumstances to assess the integrity of the good hemisphere before extensive cortical resection [116, 147]. Isolated hemispheric abnormalities are associated with excellent outcomes for hemispherectomy (90%) but contralateral abnormalities may also be associated with good outcomes (75%) [148]. In tuberous sclerosis, tubers are often hypometabolic, whereas there is some evidence that the more epileptogenic tubers have increased serotonin or kynurenic acid synthesis, reflected by increased [11C]AMT uptake [149, 150]. [11C]AMT uptake is also increased in focal cortical dysplasia when MRI (especially in children <2 years) and [18F]FDG-PET may be normal [149–151]. In hypothalamic hamartoma, remote frontal and parietal cortical hypometabolism appears to be associated with cognitive impairment [152].

#### **3.2 SPECT**

SPECT ligands used in epilepsy are primarily markers of perfusion, though some receptor ligands are also available, such as [123I]iomazenil ([123I]IMZ) for benzodiazepine receptor studies. The compounds that mark blood flow, HMPAO and ECD, have a distribution in the brain that is proportional to cerebral blood flow. Both ligands are lipophilic; they readily cross the blood-brain barrier on their first pass through brain tissue, become trapped, and exhibit little subsequent redistribution. A potential limitation is that neither ligand has linear uptake at high cerebral blood flow rates, and thus, cerebral blood flow is underestimated under certain circumstances [153]. The efficacy of HMPAO and ECD in epilepsy studies is comparable.

For an ictal SPECT study to be useful, injection of the ligand must occur no later than 30 seconds after cessation of the seizure. The earlier the injection (<20 seconds from seizure onset), the more reliable are the study results [154, 155]; injections after 20 seconds will result in image propagation from the seizure onset zone and lessen localization value [156, 157]. SPECT ligands have a longer half-life compared to PET. 99mTc-Hexamethyl-propyleneamine oxime (99mTc-HMPAO) or 99mTc-ethyl cysteinate dimer (99mTc-ECD) for cerebral perfusion has replaced 123I-based ligands such as [123I]iodoamphetamine and [123I]trimethyl-hydroxymethyl-iodobenzylpropane diamine, because these ligands have a rapid first-pass uptake and long half-life. The long half-life permits bedside injection at ictus and offers a longer window of injectability (from 30 minutes to 4 hours after composition) as well as time to arrange for data acquisition scanning within 4–6 hours after injection. During ictus, there is focal increase in cerebral blood flow to involved cortex, often with decreased perfusion in adjacent areas. After the seizure, there is postictal hypoperfusion, which may return to an interictal state rapidly [158]. Postictal hypoperfusion abnormalities are more reliable than interictal hypoperfusion (60–70% vs. 40–50%, respectively). After ligand injection, lorazepam is sometimes administered to diminish the likelihood of subsequent seizures. It is important to recall that if a patient has multiple seizure types, each type must be captured. Automated systems may be helpful to improve

*Neuroimaging for Epilepsy Diagnosis and Management DOI: http://dx.doi.org/10.5772/intechopen.112356*

timing (approximately 8 seconds) and reliability of ligand delivery; video-EEG monitoring is critical for interpretation of SPECT studies [159, 160].

The usefulness of SPECT ictal studies approaches that of [18F]FDG-PET in patients with TLE, and ictal studies are probably superior for extratemporal focus localization [161–163]. Partial seizures often show more reliable results than secondarily generalized seizures [164]. False localization is reported in 3–4% of studies, presumably because of seizure propagation, and is more likely to occur with later injection times [107]. Subtraction techniques with MRI co-registration provide enhanced comparison and semiquantitation of perfusion changes between the interictal and ictal states compared with visual comparison alone. Focal ictal SPECT can also predict whether surgical outcome will be good. SPECT is considered most useful in evaluating patients with nonlesional partial epilepsy, especially extra-temporal partial epilepsy. Ictal subtraction SPECT may also be useful in evaluating patients who have failed initial surgery.

Interictal SPECT studies demonstrate regional hypoperfusion in 40–50% of patients with partial epilepsy of temporal lobe origin. However, approximately 5–10% of studies are falsely lateralizing [106, 107, 109, 165, 166].

## **4. Neuroimaging and brain connectome**

To date, structural connectivity analyses have been able to demonstrate abnormal networks in patients with epilepsy. There is decreased fiber density of connections in the limbic system among patients with medial TLE [130], which is paradoxically associated with increased nodal clustering and efficiency in the thalamus, insula, and superior temporal regions [131]. Other studies have further revealed atypically strong thalamic–limbic connections with aberrant linkages beyond the medial temporal lobes [167]. These atypical patterns of simultaneous brain activity appear to translate to a reorganization of the functional connectome [168–176]. Reorganization of the functional connectome in epilepsy also appears to be confounded by age [177], age of seizure onset [173, 178], and disease duration [179], reflecting the importance of understanding how disease burden can affect atypical functional patterns.

Identifying these deviant connectome patterns is important because it helps us understand the abnormal plasticity associated with epilepsy and what architectural changes to the brain network provide the substrate for hyperexcitable states. In addition, there is a potential role for identification of specific aberrant connections that may help phenotype different subgroups according to brain imaging parameters and clinical features. For instance, language difficulties in epilepsy have been associated with altered patterns in functional connectivity involving language areas [180], especially when hippocampal sclerosis occurs in the dominant hemisphere [119].

Connectome-based lesion-symptom mapping (CLSM) is a novel approach to lesion mapping that establishes relationships between behavioral measures and specific white matter tracts in the connectome using statistical methods [151]. At the individual level this has the potential to predict clinical outcomes and guide tailored treatments on a case-by-case basis [106, 149]. With approximately one-third of patients with seizures refractory to multiple antiseizure medications [181], and with epilepsy surgery now considered an effective treatment for drug-resistant focal epilepsy [182], it is paramount to identify the factors that may affect postoperative seizure control. Clinical variables alone, however, have been insufficient to predict postoperative outcome. This points to the direction that epilepsy is more of a network disorder than a purely lesional one. It is in this context that network imaging may help to more accurately predict which patients are likely to benefit from epilepsy surgery.

Nowadays computational algorithm based on machine learning is capable of classifying patients who become seizure free postsurgically by analyzing fiber density values with an accuracy of 70% [144]. White matter tracts including the fimbria-fornix, the uncinate fasciculus, and the parahippocampal white matter bundle, have been suggested to contribute to seizure propagation. Reorganization of structural networks after surgery can affect seizure control outcomes [138]. Each patient exhibits different network patterns at the individual level. Features located in the contralateral hemisphere can contribute to prediction accuracy. Deep learning has been shown to be able to sieve through connectivity information derived from presurgical MRI of patients to identify biomarkers which can predict surgical outcome [183]. For example, in TLE patients with persistent postoperative seizures, circumscribed alterations in two regions were found in those with poor postoperative seizure control: the dorsal segment of the ipsilateral fornix and the contralateral parahippocampal white matter bundle [141].

In addition to predicting outcome, network imaging may prove useful in planning surgical targets. Utilization of diffusion measures to study white matter tracts can yield information on laterality of the lesion [184]. While promising, it is important to note that the aforesaid findings were all yielded from retrospective analyses and must therefore be validated in prospective studies.
