With proper protocols, positron emission tomography/CT (PET/CT) scanners can provide excellent PET and CT brain scans. This article reviews the predominant applications of PET/CT neuroimaging in epilepsy and brain tumors. With advances in the treatment of brain tumor, it is important to have the accurate diagnoses, precise assessments of tumor grade, and better identification of recurrent viable tumors that PET/CT can offer.
is a Professor of Radiology, Director of NeuroNuclear Medicine,
and Chief of The Division of Nuclear Medicine, University of
Pittsburgh Medical Center Health System, Pittsburgh, PA.
Most combined positron emission tomography/computed tomography
(PET/CT) scanners are optimized for applications in body oncology
imaging and are more limited for use in neuroimaging examinations
than dedicated neuro-PET or neuro-CT equipment. With proper
protocols, however, most PET/CT scanners can provide excellent PET
and CT brain scans if the acquisition and reconstruction parameters
are appropriately selected. A previous article in a supplement to
addressed the type of radiopharmaceuticals used in central nervous
system (CNS) applications and the use of PET/CT for the evaluation
This article will highlight predominant applications of neuro
PET/CT in epilepsy and brain tumors.
Regional cerebral perfusion evaluation in patients with epilepsy
has proven to be of significant clinical value for epileptogenic
focus identification. The underlying pathophysiology for using
regional cerebral perfusion tracers in epilepsy is based on the
clinical observation that was first reported by Sir Victor Horsley
more than 100 years ago. He described (by direct observation of the
brain during surgery) an increase in cortical blood flow in the
area of seizure discharge. Therefore, the most valuable use of
single-photon-emission CT (SPECT) regional cerebral blood flow
(rCBF) tracers is to localize the epileptogenic focus during the
Epileptogenic focus localization using ictal rCBF
In order to perform these studies, the rCBF tracer must be
readily available at the patient's bedside, allowing for rapid
injection by a trained technologist or other personnel immediately
at the time of seizure onset. The ictal injection should be
performed in a rapid bolus fashion such that the entire tracer is
injected before the seizure abates. The patient is then stabilized
and transferred to the SPECT scanner to receive a brain SPECT scan,
which will indicate the regional cerebral perfusion at the time of
ictus. This method is feasible, since the tracer is irreversibly
trapped in the epileptogenic hyperemic region at the time of
seizure. During the period between injection and scan, there is
essentially no redistribution. The subsequent scan (albeit possibly
several hours after the injection) still shows hyperemia in the
region of the epileptogenic focus. Several articles characterize
the brain propagation patterns of the epileptogenic electrocortical
dis- charge and resultant rCBF hyperemia to allow for more accurate
localization of the epileptogenic focus in cases where ≥2 cortical
areas are seen to be hyperemic on the brain SPECT scan.
Figure 1 illustrates the value of ictal SPECT in a 9-year-old
right-handed boy who had a 7-year history of intractable seizures.
The patient averaged 20 to 30 seizures a day. The seizures were
characterized by an aura of tingling in the mouth, followed by
simultaneous extension of the legs and flexion of the right upper
extremities with nonpurposeful movements of both legs lasting 20
seconds. Multiple video electroencephalography (EEG) monitoring
studies showed stereotypical seizures with no ictal scalp
localization. Interictal activity revealed occasional sharp
discharges involving the right frontal central parietal regions.
Several CT and magnetic resonance imaging (MRI) studies were
normal. A technetium (Tc)-99m hexamethyl propyleneamine oxime
(HMPAO) brain SPECT scan was performed 2 hours after tracer
injection (Figure 1). The tracer was injected at the patient's
bedside 3 seconds after the seizure's onset (the seizure lasted
approximately 25 seconds). The ictal rCBF brain SPECT scan showed a
focal area of intense uptake in the right frontal lobe.
The result of the ictal brain SPECT scan was subsequently
coregistered with the MRI scan, and the placement of subdural grid
electrodes confirmed the epileptogenic focus location. Based on the
fusion image, the anatomic location was determined, the
epileptogenic focus was surgically excised, and the patient was
It has been shown that well-performed ictal SPECT in patients
with extratemporal lobe epilepsy has superior localization
capability as compared with interictal fluorine-18 (F-18)
2-fluoro-2-deoxy-D-glucose (FDG) PET. However, if ictal SPECT is
not available, identification of the epileptogenic focus during the
interictal state using F-18 FDG-PET can provide localization in
some cases. In cases of suspected temporal lobe epilepsy, the
preferred diagnostic imaging protocol is to perform interictal F-18
FDG-PET in addition to ictal and interictal SPECT.
F-18 FDG-PET brain assessment in the interictal state
Presurgical evaluation and the surgical treatment of nonlesional
neocortical epilepsy is one of the most challenging areas in
epilepsy surgery. FDG-PET shows hypometabolism in a majority of
patients with nonlesional temporal lobe epilepsy (TLE), even in the
absence of hippocampal atrophy. Interictal FDG-PET and ictal SPECT
were found to be useful as complementary and, sometimes,
One area in which F-18 FDG may play a role beyond localization is
to define the surgical margins since the extent of resection of the
region of hypometabolism on the preoperative FDG-PET is predictive
of outcome following surgery for non-lesional TLE.
Figure 2 illustrates concordance between abnormalities on MRI
and F-18 FDG-PET in a 16-year-old boy with temporal lobe epilepsy
and hippocampal sclerosis of the right mesial temporal lobe on MRI.
The MRI shows abnormal high signal intensity in the right
hippocampal region. The FDG-PET shows a corresponding area of focal
reduction of F-18 FDG uptake in the right hippocampal region. After
undergoing right temporal lobectomy, the patient was rendered
The localization of epileptic foci in patients who have
intractable extratemporal epilepsy remains a challenge in the
presurgical evaluation. The most common underlying pathology in
extratemporal neocortical epilepsy is microscopic cortical
dysplasia, which cannot be readily detected by current MRI
FDG-PET may not be as valuable in the evaluation of patients with
extra-temporal seizures, such as frontal lobe epilepsy, because of
Figure 3 illustrates the significant advantage of ictal SPECT as
compared with interictal F-18 FDG-PET. The patient is a 42-year-old
woman who experienced 1 to 2 brief seizures per day. Seizure
activity was thought to arise from the frontal lobe regions, but
video-EEG monitoring was nonlocalizing. The MRI scan was normal.
The F-18 FDG-PET brain scan was nonlocalizing. An ictal brain SPECT
scan showed significant hyperemia in the right frontal lobe. Figure
3 shows correlative images of the significant hyperemia on ictal
SPECT as compared with nonspecific reduction on FDG-PET. This
example illustrates the relative nonspecificity of mild areas of
reduction on an FDG-PET brain scan in cases of frontal lobe
epilepsy. In these cases, an ictal brain SPECT scan can provide
greater accuracy in diagnosis.
Figure 4 illustrates epileptogenic region localization in a
2-year-old girl with intractable partial epilepsy and developmental
delay. The EEG showed frequent and focal discharges from the right
frontoparietal region. In this case, the F-18 FDG-PET scan
localized the epileptogenic region suitable for grid placement and
invasive intracranial EEG monitoring.
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 presurgical evaluation. The goal of
functional imaging in these cases is to identify the epileptogenic
lesions and to differentiate them from the 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.
Figure 5 shows such a case in a 1-year-old boy with tuberous
sclerosis. Anatomically, there were several lesions that were
abnormal on the CT portion of the PET/ CT scan. These areas also
showed reduced FDG uptake on PET. Ictal SPECT (not shown) was able
to identify the dominant area of presumed epileptogenesis
associated with a large tuber in the right frontal lobe.
The role of PET neuroimaging in brain tumor
Since the introduction of CT in the mid-1970s and MRI in the
early 1980s, neuroimaging has become extremely important in the
diagnosis of primary and metastatic brain tumors. These various
neuroradiologic imaging techniques have also found new and
important applications in assisting with biopsy localization,
monitoring the effects of therapy, and differentiating recurrence
from radiation effect or necrosis.
The identification of viable tumor after therapy is a significant
clinical problem, since the distinction between necrosis and
residual or recurrent viable tumor cannot be accurately evaluated
by either CT or MRI.
Functional imaging can distinguish cerebral necrosis from viable
brain tumor and determine tumor grade.
More recently, FDG-PET imaging has been shown to be of value in the
prediction of tumor metabolic response to temozolomide versus
temozolomide plus radiotherapy in recurrent high-grade gliomas.
Therefore, the monitoring of therapeutic response by PET imaging is
now used to provide an early assessment of therapy efficacy and to
help the oncologist optimize the therapeutic management of brain
The use of F-18 FDG-PET has led to a more widespread capability in
allowing the evaluation of cerebral neoplasms as well as other
diseases of the brain that were previously imaged using SPECT
In addition, due to the relatively long half-life of F-18 (109
minutes), it can be transported regionally (within approximately 2
to 4 hours travel time from a cyclotron production facility),
enabling a centrally located production facility to supply several
camera sites. Figure 6 shows a PET scan with abnormal uptake of
F-18 FDG in a patient with a recurrent high-grade brain tumor
involving the anterior frontal lobe after 8 years of remission.
F-18-fluoro-3'-deoxy-3'-L-fluoro-thymidine PET for the
evaluation of viable brain tumor--
F-18-fluoro-3-deoxy-3-L-fluorothymidine (F-18 FLT) has recently
been developed as a proliferation tracer. Imaging and measurement
of proliferation with PET can provide a noninvasive staging tool
and a means to monitor the response to anticancer treatment.
In contrast to quiescent cells, proliferating cells synthesize
deoxyribonucleic acid (DNA) during the S phase of the cell cycle.
F-18-fluoro-3-deoxy-3-L-fluorothymidine is taken up by the cell via
both passive diffusion and facilitated transport by Na
-dependent carriers. Subsequently, F-18 FLT is phosphorylated by
thymidine kinase 1 (TK1) into F-18 FLT-monophosphate, after which
it is trapped in the cell (Figure 7). Thymidine kinase 1 is a
principal enzyme in the salvage pathway of DNA synthesis. The
enzymatic activity of TK1 is virtually absent in quiescent cells,
but in proliferating cells it reaches a maximum in the late G1 and
S phases of the cell cycle.
Therefore, the phosphorylation by TK1 forms the basis of F-18 FLT
as a proliferation tracer.
F-18-fluoro-3'-deoxy-3'-L-fluorothymidine has been used to
indicate tumor proliferation in both preclinical and clinical
The imaging of brain tumor proliferative activity has been
performed using semiquantitative measures of standard uptake
values. [F-18]-fluoro-3'-deoxy-3'-L-fluorothymidine imaging can be
correlated with stereotactic biopsies representing the Ki-67
proliferation index. Recurrent or residual viable tumor showed an
increased quantitative FLT utilization and can provide a useful
index to separate residual or recurrent viable tumor from radiation
or chemotherapy necrosis.
[F-18]-fluoro-3'-deoxy-3'-L-fluorothymidine is more specific for
detection of viable tumor proliferation, since the background
activity in normal brain is low (Figure 8), unlike F-18, which has
a high normal brain background. Figure 9 shows tissue histology and
staining with MIB-1 to allow correlation between F-18 FLT uptake
and the proliferation index Ki-67.
PET imaging of radiolabeled amino acids for brain tumor
Radiolabeled amino acids are becoming increasingly useful as
tracers for the delineation of tumors, particularly brain
neoplasms. Unlike FDG, the radiolabeled amino acids are not taken
up by normal cortical gray matter and provide a greater
target-to-background contrast, thus allowing better
characterization and differentiation of the tumor from the normal
cortical gray matter. The most commonly used PET amino acid
radiotracer to date has been l-[methyl-C-11] methionine (C-11 MET).
However, due to the 20-minute half-life of C-11-labeled tracers
that requires the need for in-house cy-clotron production, amino
acids labeled with F-18 are of particular interest because of their
advantageously longer half-life and possibility for commercial
availability. Recently, improved labeling procedures have overcome
some limitations of tracer synthesis for routine PET application.
The tracer 3,4-dihy-droxy-6-F-18-fluoro-L-phenylalanine (
F-FDOPA) is a new amino acid, which has been recently evaluated.
Both high-grade and low-grade tumors are well visualized with
F-FDOPA. The sensitivity for identifying tumors was substantially
F-FDOPA PET than with
F-FDG-PET at comparable specificities, especially for the
assessment of low-grade tumors. Therefore,
F-FDOPA PET may prove especially useful for imaging of recurrent
low-grade tumors and for distinguishing tumor recurrence from
By developing ictal and interictal SPECT capability in addition
to F-18 FDG-PET, the radiologist can better provide the
neurosurgeon with more definite presurgical location of
epileptogenic foci. With the advancement of new therapies for the
treatment of brain tumor, it is important to provide more accurate
assessment of tumor grade on initial diagnosis and better diagnosis
of recurrent viable tumor versus chemoradiation necrosis on early
follow-up PET scans after therapy for both low- and high-grade