PET

PET is an imaging technique used to noninvasively image and measure the function of various organs. In PET, positronemitting radionuclides, such as ¹⁸F, ¹¹C, ¹⁵O, and ¹³N, are used to label various natural biological substrates and drugs or pharmaceuticals. These all contain hydrogen, carbon, oxygen, or nitrogen, which can be replaced with their radioactive positronemitting counterpart. The resulting radioactive substance, also known as a radiotracer or PET tracer, will have similar behavior and will follow the same physiological pathways by emitting paired high-energy (511 Kev) photons. These photons can be detected by external detectors, and the whole process can be traced or imaged. Any physiological or metabolic process, such as glucose metabolism, protein synthesis, enzymatic processes, or receptor–ligand interaction, can be studied using an appropriate radiotracer and various kinetic models.1

The most commonly used PET tracer in epilepsy is 2-deoxy-2[¹⁸F]fluoro-D-glucose (FDG; half-life: 110 minutes), which measures glucose metabolism. FDG is transported in tissue and phosphorylated to FDG-6-phosphate in the same manner as glucose. However, FDG-6-phosphate is not a substrate for the next step of glycolysis. Because it cannot immediately leave the cell, phosphorylated FDG gets trapped within the cell, and its location and quantity can be measured by PET. Under steady-state conditions, FDG uptake reflects the glucose metabolic rate. In the brain, this rate is highly related to the synaptic density and functional activity of the brain tissue.

Because brain glucose metabolism undergoes age-related changes, particularly in the early childhood, practitioners should be aware of this pattern while interpreting pediatric FDG PET scans. Metabolic rates of glucose in cerebral cortex at the time of birth are usually approximately 30% less than those of adult values. They reach adult values by the second year of life, exceeding them by the third year, and reach the peak values (almost double the adult values) by 3 to 4 years of age, when a plateau is reached. This plateau persists until approximately 10 years of age, then gradually the glucose metabolic rates decline to reach adult values by the age of approximately 16 to 18 years. The glucose metabolism pattern and visual appearance on PET scans also changes with age. In the newborn, glucose metabolic activity is most prominent in primary sensory and motor cortex, thalamus, brain stem and cerebellar vermis, cingulate cortex, amygdala, and hippocampus. Between ages 2 and 4 months, glucose use increases in parietal, temporal, and primary visual cortex (medial occipital or calcarine cortex), as well as in the basal ganglia and cerebellar hemispheres. Between 6 and 8 months of age, glucose use increases in the lateral and inferior prefrontal regions, with medial and dorsal frontal cortex becoming active between 8 and 12 months of age. The adult pattern is seen by 1 year of age.2,3

Interictal FDG PET typically shows reduced radiotracer uptake (hypometabolism) in the epileptogenic region ( Fig. 10.1 ). The hypometabolism can result from a variety of mechanisms, including neuronal loss, diaschisis, or reduction in synaptic density. It appears that cortical hypometabolism may be associated with duration, frequency, and severity of the seizures, hypometabolism is usually found in only one fourth of children with new onset epilepsy compared with 80 to 85% of adults with intractable seizures.4 Persistent or increased seizure frequency may lead to enlargement of the hypometabolic area, whereas seizure control may be associated with decrease in the size of hypometabolic cortex or even its resolution.5 The time interval between PET acquisition and the most recent seizure also may affect the extent and severity of the cortical abnormality, with shorter duration having a positive effect on the extent and severity of the hypometabolism.6

During the ictal phase, metabolism increases many fold in the epileptic region; however, because FDG PET shows cumulative FDG uptake over a period of 30 to 45 minutes, the final images can be variable and complex, depending on the exact nature of the underlying pathology, seizure duration, seizure evolution, and net summation effects of ictal, postictal, and interictal metabolism. Therefore, ictal FDG PET is not very reliable and is often difficult to interpret, and EEG monitoring should be performed during the FDG uptake period to rule out any clinical or subclinical seizure. Because ictal FDG PET is virtually not done, in all the subsequent discussion, we use the term FDG PET in place of interictal FDG PET.

Because FDG PET usually shows a larger area of hypometabolism extending beyond the epileptogenic region, it cannot be reliably used to precisely determine the surgical margin. However, it can be used for lateralization and general localization of the seizure focus. Further, this information can help in making an a priori hypothesis about subsequent subdural electrode placement, which may be very useful, particularly in cases of normal MRI ( Fig. 10.2A ). However, use of more specific tracers, as discussed here, can help in providing a more precise delineation of the epileptogenic tissue; this becomes particularly important in a developing pediatric brain and when the epileptic focus potentially involves eloquent brain regions (primary motor, speech, or visual areas).

Other PET tracers with the potential for detecting epileptic brain regions include ¹¹C-flumazenil (FMZ), which binds to α subunits of the GABA_A-benzodiazepine receptor and ¹¹C-alphamethyl-L-tryptophan (AMT), which measures tryptophan metabolism. FMZ binding or FMZ VD (volume of distribution) is high at 2 years of age and then decreases exponentially with age until adult values are reached at approximately age 20 years. The order of brain region (from highest to lowest FMZ binding) at 2 years of age is as follows: primary visual cortex, superior frontal cortex, medial temporal cortex, temporal lobe, prefrontal cortex, cerebellum, basal ganglia, and thalamus. FMZ binding in medial temporal lobe is robust enough for its good visualization (compared with FDG PET, in which the medial temporal region, particularly hippocampus, is often not well visualized). This is one of the main reasons for an important role of FMZ PET in epileptic patients in whom medial temporal lobe abnormalities are suspected. AMT is an analog of tryptophan, the precursor for serotonin synthesis, but, unlike tryptophan, AMT is not incorporated into protein in significant amounts. AMT is converted to α-methyl-serotonin (AM-5HT) by tryptophan hydroxylase, and it accumulates in neurons and nerve terminals along with the releasable pool of serotonin. After intravenous injection, AMT accumulates in the brain for the first 20 minutes (less than 2% of the injected dose is present in the brain at peak values), after which a plateau is reached and maintained for up to 60 minutes, with no right–left asymmetry in normal subjects.

SPECT

In SPECT, rotating γ cameras (detectors) are used to image the distribution of the injected radiotracer in the organ of interest. For this purpose, 1 to 3 detectors and only γ ray emitting radioisotopes are used. For the purpose of brain and particularly for epilepsy, SPECT is mostly used to study brain perfusion, with hexamethyl propylene amine oxime (HMPAO) and ethylene cysteine dimer (ECD) labeled with 99mTc being the most common radiotracers used for this purpose. HMPAO readily crosses the blood–brain barrier and approximately 80% is extracted by brain during the first pass. Once inside the neurons and glial cells, HMPAO gets trapped because it is oxidized by glutathione into a nondiffusible compound. A total of 4 to 7% of the injected activity is trapped within the brain, reaching its peak in 1 to 2 minutes. ECD is another lipophilic compound that, like HMPAO, gets trapped inside neurons because of its transformation into a hydrophilic compound that cannot diffuse back. Its first pass extraction is 60 to 70%, with a maximum of 6 to 7% injected activity accumulating in the brain 1 to 2 minutes after the injection. The brain can be imaged subsequently, and the resulting image provides a snapshot of perfusion immediately after the injection. This is the basis for applying brain SPECT in epilepsy, because the ictal and interictal phases are usually associated with increased or decreased blood flow, respectively, in the epileptic foci. However, during seizure, the cerebral blood flow changes rapidly with time, depending on the seizure type and its mode of propagation. Therefore, early radiotracer injection is imperative to catch the blood flow changes in the epileptic zone, during seizure. Similarly, knowledge of the exact time of injection (because it takes approximately 20 to 30 seconds for the radiotracer to reach the brain from an arm vein) and seizure duration is very important for the correct interpretation of the SPECT images. Delayed injection of radiotracer may show a variable pattern of blood flow changes associated with seizure evolution in the epileptic zone and mode and pattern of seizure propagation, depending on the time of injection. Also, because seizure propagation is usually from the temporal to the frontal lobe or from posterior (parietooccipital lobes) to anterior cortical regions (temporal and frontal lobe),7–10 interpretation of ictal SPECT can be very challenging if the exact timing of radiotracer injection and seizure onset is not known, unless injection is synchronized with video-EEG monitoring.

During the ictal phase, blood flow in the epileptic region can increase up to 300%, which can be seen as an area of hyperperfusion in ictal SPECT.11 A true ictal SPECT (tracer injected immediately after the onset of the seizure and SPECT images showing perfusion at that point of time) shows an area of hyperperfusion in the epileptogenic region, surrounded by an area of hypoperfusion, which becomes more prominent at the end of the ictal phase. This surrounding area of hypoperfusion may be caused by steal syndrome (shift of blood flow to the seizure focus) or this area may function as an inhibitory zone trying to limit the seizure spread.12 Interictal SPECT (tracer is injected when patient is not having any clinical or subclinical seizure and SPECT images show the baseline perfusion pattern) shows hypoperfusion or normal perfusion in the epileptogenic region. Even when present, hypoperfusion may be very mild and sometimes difficult to distinguish from the surrounding normal brain on visual examination. The main role of interictal SPECT currently is to assist in the evaluation of ictal SPECT, visually or quantitatively, using statistical parametric mapping (SPM) or SISCOM (subtractionictal SPECT coregistered to MRI, i.e., the interictal SPECT images are subtracted from the ictal images and the results are displayed on coregistered MR images), by providing a baseline blood flow. Use of these registration techniques can increase the sensitivity and specificity of ictal SPECT. Studies have shown that SPM can increase the sensitivity of SPECT scan over visual analysis.13–15 However, lack of age-matched control subjects can make its use difficult, particularly in children younger than 6 years of age.16 SISCOM, conversely, appears to be very useful in children. The probability of localizing an ictal onset zone has been reported higher with SISCOM, compared with ictal EEG and MRI.17,18 Use of SISCOM can help in revisiting and detecting subtle changes in MRI, which were initially reported normal.19 Studies have shown that the area of the resected SISCOM abnormality is associated with the surgical outcome; the larger the area of resected SISCOM abnormality is, better the outcome will be.17,20

The major limitation of SPECT in the pediatric population is that it is difficult to acquire good interictal or ictal brain SPECT because children may have very frequent and short-lasting seizures (such as infantile spasms or myoclonic epilepsy). Another limitation is the poor spatial resolution (10–15 mm) of SPECT, compared with FDG PET (~5–6mm), which becomes even more crucial in small pediatric brains.

Epileptogenic Region

Related posts:

5 Invasive Electrophysiological Monitoring 4 EEG and Noninvasive Electrophysiological Monitoring 7 Magnetoencephalography 6 Extra-operative and Intra-operative Electrical Stimulation 11 Coregistration and Newer Imaging Techniques 13 Preoperative Neuropsychological and Cognitive Assessment

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