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18F-Labeled 2-Deoxy-2-fluoro-D-glucose Positron-Emission Tomography Scans for the Localization of the Epileptogenic Foci: Health Technology Assessment: Number 12

U.S. Department of Health and Human Services, Public Health Service Agency for Health Care Policy and Research
A40370

Prepared by: S. Steven Hotta, M.D., Ph.D.

July 1998

AHCPR Pub. No. 98-0044

View the Medline Citation and Related Citations using PubMed

Prepared by: S. Steven Hotta, M.D., Ph.D.

July 1998

AHCPR Pub. No. 98-0044

View the Medline Citation and Related Citations using PubMed

Abstract

The localization of epileptogenic foci that are amenable to curative epilepsy surgery may be accomplished by noninvasive surface electroencephalogram (EEG) recordings, clinical observations, computed tomography (CT), magnetic resonance imaging (MRI), and neuropsychologic tests. Other tests, such as invasive EEG, 18F-fluoro-deoxyglucose-positron-emission tomography (FDG-PET or PET) scans, and single-photon-emission computed tomography (SPECT) scans, have also been used at various epilepsy centers to help identify candidates who might benefit from such surgery.

Interictal PET scans have demonstrated hypometabolism in areas concordant with the epileptogenic foci indicated by other diagnostic tests such as EEG and MRI. However, PET scans have also shown no abnormality in many patients with EEG-indicated epileptogenic foci; in others, the scans have shown abnormal metabolism in areas that were discordant with the epileptogenic foci. Although substitution of the noninvasive PET scan for the invasive EEG recordings would be desirable, the available data were insufficient to determine whether PET scans might serve as a reliable substitute for EEG. A positive PET scan might contribute independent information for identifying the epileptogenic site but could be noncontributory or confusing when hypometabolism is not seen or is seen in presumably normal brain areas. It is not evident from the data in the literature to what extent confirmatory PET scan findings might contribute to the management of patients with complex partial seizures.

Foreword

The Center for Practice and Technology Assessment (CPTA) evaluates the risks, benefits, and clinical effectiveness of new or established medical technologies. In most instances, assessments address technologies that are being reviewed for purposes of coverage by federally funded health programs.

The CPTA assessment process includes a comprehensive review of the medical literature and emphasizes broad and open participation from within and outside the Federal Government. A range of expert advice is obtained by widely publicizing the plans for conducting the assessment through publication of an announcement in the Federal Register and solicitation of input from Federal agencies, medical specialty societies, insurers, and manufacturers. The involvement of these experts helps ensure inclusion of the experienced and varying viewpoints needed to round out the data derived from individual scientific studies in the medical literature.

The CPTA analyzed and synthesized data and information received from experts and the scientific literature. The results are reported in this assessment. Each assessment represents a detailed analysis of the risks, clinical effectiveness, and uses of new or unestablished medical technologies. If an assessment has been prepared to form the basis for a coverage decision by a federally financed health care program, it serves as the Public Health Service's recommendation to that program and is disseminated widely.

The CPTA is one component of the Agency for Health Care Policy and Research (AHCPR), Public Health Service, Department of Health and Human Services.

Douglas B. Kamerow, M.D., M.P.H., Director, Center for Practice and Technology Assessment
John M. Eisenberg, M.D., Administrator, Agency for Health Care Policy and Research

Abbreviations

Acc:: Accuracy

ART:: Arrhythmia research technology

BBB:: Bundle branch block

CAD:: Coronary artery disease

CAST:: Cardiac arrhythmia suppression trials

CFR:: Case fatality rate

CHF:: Congestive heart failure

CI:: Confidence interval

CT:: Computed tomography

dQRS:: Duration of the filtered QRS complex > 106 ms

ECG:: Electrocardiogram

EEG:: Electroencephalogram/electroencephalography

FD:: Frequency domain

FDA:: Food and Drug Administration

FDG-PET:: Fluorodeoxyglucose-positron-emission tomography

FU:: Followup

HCFA:: Health Care Financing Administration

IDC:: Idiopathic dilated cardiomyopathy

i-EEG:: Invasive electroencephalography

LAS:: Low amplitude signal

LVEF:: Left ventricular ejection fraction

LVH:: Left ventricular hypertrophy

MeSH:: Medical subject heading

MI:: Myocardial infarction

MRI:: Magnetic resonance imaging

MUGA:: Multigated acquisition

NPV:: Negative predictive value

NS:: Not stated

NSR:: Normal sinus rhythm

NYHA:: New York Heart Association

PES:: Programmed electrical stimulation

PET:: Positron-emission tomography

PPV:: Positive predictive value

RMS:: Root mean square voltage during the last 40 ms of the QRS complex <25 µV

RNV:: Radionuclide ventriculography

SAEGG:: Signal-averaged electrocardiography

SD:: Sudden death

1SD:: One standard deviation

Se:: Sensitivity

s-EEG:: Surface/sphenoidal electroencephalography

Sp:: Specificity

SPECT:: Single-photon-emission computed tomography

STA:: Spectral turbulence analysis

TD:: Time domain

VAT:: Ventricular activation time

VF:: Ventricular fibrillation

VLP:: Ventricular late potentials

VT:: Ventricular tachyarrhythmia

Introduction

Resective temporal lobe surgery, the removal of the epileptogenic zone or an amount of cerebral tissue necessary and sufficient for seizure control, has been shown to be an effective treatment for appropriately selected patients with drug resistant, complex partial seizures.(1-5) The success of such surgery depends, in part, on the accurate localization of the epileptogenic foci and whether these foci can be safely resected. In recent years, noninvasive technologies that can augment the electrophysiologic and neuropsychologic information needed for the localization of the epileptogenic foci have included computed tomography (CT), magnetic resonance imaging (MRI), positron emission tomography (PET), and single-photon-emission computed tomography (SPECT). Epileptogenic foci are most often identified by electroencephalograms (EEG). Some patients with foci that are poorly localized by noninvasive EEGs require intracranial electrode recordings for the localization of their foci. The surgical implantation of intracranial electrodes exposes patients to risks for serious complications; therefore, the use of PET or SPECT scans as an alternate noninvasive means to localize the foci has been under investigation.

PET and SPECT scans are technologies that record functional changes in brain areas that appear to be associated with the epileptogenic zone. Images from PET scans show the hypometabolism of glucose, while images from SPECT scans show blood hypoperfusion in the epileptogenic areas during the interictal period. Both metabolism of glucose and perfusion increase at the same sites when seizures commence. Interictal PET and SPECT scans and ictal SPECT scans appear to be clinically useful in the presurgical evaluation of patients with intractable, complex partial seizures.

This report summarizes our evaluation of the published information on the correlations of abnormalities seen on PET and SPECT scan images with the EEG-identified epileptogenic foci in patients who experience complex partial seizures. In addition, we reviewed the correlation of the sites indicated by PET and SPECT scans with the sites removed by surgery in patients having good outcomes. This assessment was undertaken at the request of the Health Care Financing Administration for an evaluation of the safety, effectiveness, and clinical utility of PET, using 18F-labeled 2-deoxy-2-fluoro-D-glucose (FDG) in the diagnosis and management of patients with focal or partial epilepsy.

Methods

A computer literature search of the MEDLINE and Healthline databases from 1977 through 1996 was used to obtain references for review. Key words were "epileptic surgery" and "localization of epileptogenic foci." Additional references were obtained from citations in the retrieved articles. From the approximately 400 articles retrieved, data were extracted and analyzed from articles that reported on patients who received two or more diagnostic tests. All reports were on series of patients. Selection criteria for inclusion in the reports (e.g., exclusion of subjects with structural lesions) often were not clear and were not consistent between centers.

Background

The estimated incidence rate for epilepsy is 30/100,000.(6) Of the estimated 1 million Americans who have epilepsy, the majority have partial epilepsy that appears to respond to medical therapy. An estimated 100,000 patients with partial epilepsy who fail medical management are thought to be potential candidates for epilepsy surgery. Currently, about 1,500 epilepsy surgeries are performed per year in the United States at an estimated cost per case of $25,000-$100,000.(7-9)

The goals of presurgical evaluation of potential candidates for epilepsy surgery are (1) identifying and delineating the epileptogenic foci and (2) determining whether the foci overlap brain areas that also serve essential functions.(10-12) The decision to proceed with epilepsy surgery can be made in many cases without the use of invasive EEG, PET, or SPECT and can result in good postsurgical outcomes. However, when a detailed history, careful observation of the seizures, and review of electrophysiologic, neuropsychologic, and structural imaging tests do not provide converging evidence, other diagnostic tests may be needed to localize the epileptogenic site. For such patients, along with others whose CT and MRI scans show a lesion at the suspected epileptogenic foci, good surgical outcomes can be expected.(6, 13, 14) Because of the successful results of epilepsy surgery, efforts have been made to identify more candidates for surgery by incorporating other tests in the presurgical evaluation and localization of the epileptogenic foci. These tests, such as intracranial EEG, PET, and SPECT, may help to localize the epileptogenic foci in patients who do not have demonstrable structural lesions and are without localized EEG recordings.

Review of Published Data

Table 1. Use of invasive electroencephalography to localize epileptogenic foci
Localization by
s-EEG
Localization by
i-EEGb
ReferenceNo. of PatientsPatient SelectionaNo.PercentageNo.Percentage
Gaillard(15) 16Selected1275425
Gaillard(16) 18Consecutive1478422
Jack(17) 53Consecutive499348
Markand(18) 99Consecutive86871313
Leiderman(19) 45Selected32711329
Theodore(20) 32Referred17531547
Valk(21) 11Selected982218
Chee(22) 40Retrospective29731128
Theodore(23) 53Referred31592242
Swartz(24) 37Selected21571643
SadZot(25) 57Selected20353765
Leiderman(26) 28Referred18641036
Rowe(27) 51Selected18353365
Grunwald(28) 40Consecutive25631538
Engel(29) 264Unspecified913517366
Rowe(30) 32Consecutive7222578
Ryding(31) 14Unspecified1072429
Engel(32) 25Consecutive1768832
Engel(33) 50Consecutive23462754
Summary96552955 (22-93)43645 (8-78)

Note: Data describe localization of epileptogenic foci in patients with intractable complex partial seizures by surface/ sphenoidal electroencephalography (s-EEG) or by invasive electroencephalography (i-EEG).

a

Selected=selected from an unspecified number of patients; consecutive=patients seen as enrolled in study; referred=patients referred to study clinic.

b

Patients whose epileptic foci were presumably not satisfactorily localized by s-EEG. Some were confirmed as having seizures originating bilaterally, whereas others were not localized by i-EEG or s-EEG.

Table 1 shows the percentage of patients whose epileptogenic foci were localized by invasive means compared with those whose foci were identified by surface EEG. Thadani et al(6) estimated that about 20 percent of his surgically treated epileptic patients could be selected on the basis of convergent findings obtained by MRI scanning, interictal and ictal EEG recordings, clinical seizure characteristics, and neuropsychologic testing. These individuals could be expected to do well postoperatively. A large majority of epileptic patients, therefore, may need multiple tests to localize the potentially resectable foci.

The data in Table 1 suggest, however, that less than half of the epileptic patients required intracranial EEG recordings for possible localization of the foci. The proportion of patients requiring invasive EEG varied from a low of 8 percent to a high of 78 percent in the various reports. The actual proportion at any given epilepsy center is not clear.(16-18, 28, 30, 32, 33)

Table 2. Correlation of interictal positron-emission tomography with electroencephalography in epileptic patients
Patients With Foci Lateralized by EEGIpsilateral Foci With PETbContralateral Foci With PETb
ReferenceNo. of PatientsaNo.PercentageNo.PercentageNo.Percentage
Ho(34) 35351002983411
Gaillard(16) 1818100168900
Gaillard(15) 16138196900
Radke(35) 3030100258300
Sadzot(25) 573765297813
Ryvlin(36) 2020100178515
Debets(37) 22221001777418
Engel(29) 15311676786787
Stefan(38) 10880810000
Franck(39) 2118861362211
Theodore(40) 36174713 c9300
Engel(33) 503672287838
Summary4683707928276196

Note: The correlation of hypometabolic areas with unilateral epileptogenic foci were identified by either s-EEG or I-EEG.

a

Patients selected from among an unspecified number of patients.

b

Positron-emission tomography image shows hypometabolism ipsilateral to or contralateral to the epileptogenic foci lateralized by electroencephalography.

c

Positron-emission tomography data available in only 14 of 17 EEG-foci-identified patients.

Table 2 shows the reliability of PET images using FDG to demonstrate hypometabolism in brain areas that correlate with the epileptogenic foci identified by EEG. Although hypometabolism usually correlated with the EEG-indicated foci, some of the images appeared to show hypometabolic areas that were contralateral to the EEG-identified foci. Of the 370 patients with EEG-identified foci, FDG-PET images showed an ipsilateral hypometabolic area in 282 (76 percent) of the patients. The percentage of foci identified by FDG-PET varied from 62-100 percent in the reports. Seven of the 12 studies reported that in one or more patients, the PET image showed a hypometabolic area that was contralateral to the EEG-identified foci.

In a relatively large series of patients, Engel et al(29) reported that of the 116 patients, FDG-PET scans showed hypometabolism ipsilateral to the EEG-identified foci in 78 (67 percent) of the patients and hypometabolism contralateral to the foci in 8 (7 percent) of the patients. Leiderman et al(19) suggested that interictal, regional hypometabolism seen in FDG-PET scans correlated with the EEG-defined epileptogenic site in 70-80 percent of the patients with partial epilepsy and that the occasional noncorrelation of the PET scans may be caused by the dynamics of the metabolic changes over time.

Table 3. Correlation of interictal single-photon-emission computed tomography with electroencephalography in epileptic patients
Patients With Foci Lateralized by EEGIpsilateral Foci With ii-SPECTbContralateral Foci With ii-SPECTb
ReferenceNo. of PatientsaNo.PercentageNo.PercentageNo.Percentage
Newton(41) 73731003650912
Carrilho(42) 2626100155828
Franceschi(43) 2828100621210
Spina(44) 402870124300
Harvey(45) 1515100149317
Launes(46) 47471003166613
Yaxin(47) 402358939313
Duncan(48) 6327431141933
Verhoeff(49) 282589936312
Ryvlin(36) 2020100115500
Jabbari(50) 584374204700
Rowe(27) 514690183937
Duncan(51) 309305600
Cordes(52) 5237713081924
Duncan(53) 301757105900
Kawamura(54) 443068930413
LaManna(55) 191895179416
Rowe(30) 3230941757310
Mitsuyoshi(56) 2417711165318
Ryding(31) 14139396918
Lee(57) 16148896417
Stefan(38) 10880675113
Stefan(58) 16138196900
Summary77660778322536110

Note: The correlation of hypoperfusion sites was demonstrated by interictal single-photon-emission computed tomography (ii-SPECT) with the unilateral epileptogenic foci identified by either s-EEG or i-EEG.

a

Patient selection criteria were not explicit. Some patients may have been included in more than one of the cited reports.

b

Hypoperfusion site by SPECT found ipsilateral to or contralateral to the epileptogenic foci lateralized by EEG.

Abbreviations: s-EEG=surface/sphenoidal electroencephalography; i-EEG=invasive electroencephalography.

Interictal SPECT scans of the distribution of 99mTc-D, L-hexamethylene-propyleneamine oxime (HMPAO) have demonstrated hypoperfusion at the epileptogenic foci. Table 3 shows the correlation of these SPECT abnormalities with foci localized by surface EEG and/or intracranial electrode recordings. The reported results were highly variable, with SPECT images showing areas of hypoperfusion ipsilateral to the EEG-identified foci in only 322 (53 percent) of the 607 patients with EEG-lateralized epileptogenic foci; the percentage varied from 6-94 percent in the various reports. Interictal SPECT images showed hypoperfusion in an area contralateral to the EEG-identified foci in about 10 percent of the scans, ranging from 0-33 percent, as seen in the individual reports.

Table 4. Correlation of ictal and postictal single-photon-emission tomography with electroencephalography in epileptic patients
Patients With Foci Lateralized by EEGIpsilateral Foci With I-/p-SPECTbContralateral Foci With I-/p-SPECTb
ReferenceNo. of PatientsaNo.PercentageNo.cPercentageNo.Percentage
Ho(34) 353510033/35 i9426
Newton(41) 7373100 49/50 i 22/31 p 97 72 0 2 0 5
Harvey(45) 151510014/15 i9300
Marks(59) 118735/7 i7100
Newton(60) 121210012/12 i10000
Rowe(61) 51458831/45 p6900
Rowe(30) 32329423/30 p7700
Lee(57) 16148813/14 i9300
Ryding(31) 14141002/2 i10000
Ictal SPECT128/135 i95
Postictal SPECT76/106 p72

Note: The correlation of hypoperfusion sites was shown by ictal or postictal single-photon-emission computed tomography (I-SPECT or p-SPECT) with unilateral epileptogenic foci identified by either s-EEG or i-EEG.

a

Patients selected from among unspecified number of patients.

b

SPECT scans showed hypoperfusion sites that were either ipsilateral or contralateral to the epileptogenic foci lateralized by EEG.

c

numbers represent those showing hypoperfusion over the number of patients that were successfully injected with the tracer compound during the periictal period.

Abbreviations: s-EEG=surface/sphenoidal electroencephalography; i-EEG =invasive electroencephalography;

i=ictal SPECT results;

p=postictal SPECT results.

Ictal and postictal SPECT images have been obtained with HMPAO or 123I-N, N, N'-trimethyl-N'-(2-hydroxy-3-methyl-5-iodobenzyl)-1, 3-propanediamine (HIPDM). These studies showed areas of hyperperfusion that were better correlated with the EEG-localized epileptogenic foci than the hypoperfusion seen on interictal SPECT images. As seen in Table 4, ictal SPECT scans showed hyperperfusion at the EEG-identified foci in 128 (95 percent) of the 135 patients; postictal scans obtained in 106 patients showed hyperperfusion ipsilateral to the EEG-lateralized foci in 76 (72 percent) of patients. Ictal scans did not show any discordant hyperperfusion in any of the images, but two of the postictal scans did show hyperperfusion discordant or contralateral to the EEG-identified foci.

Good outcomes, defined as becoming seizure free or having a reduction in seizure frequency of more than 75 percent, have been reported for a majority of patients who have had epilepsy surgery. These outcomes may reflect, in part, the careful evaluation and selection of patients before brain surgery. The number of patients identified who benefited from the use of invasive EEG and noninvasive PET and SPECT scans is not clear. Tables 5 and 6 summarize studies on the correlations of presurgical FDG-PET and SPECT scans to patients who had good surgical outcomes.

Table 5. Correlation of fluorodeoxyglucose-positron-emission tomography scans with surgical outcomes
ReferenceNo. of Patients Who Received Operationsa

No. With Good Outcomeb
No.Percentage

PET Scan Concordant With Good Outcome
No.Percentage
Comments
Gaillard(16) 9 adults 8 FU=11-38 897/888Pathologic lesions were found in 6/9 patients.
Gaillard(15) 10 children 9 FU=3-82 909/9100Ten of 13 patients with unilateral EEG focus underwent operations. Nine of 13 patients showed hypometabolism psilateral to EEG focus. Selection criteria for surgery were not stated.
Theodore(20) 32 26 FU=32 S.D.=18 8115/2658Surgical decision was based only on EEG data. Fifteen of 16 (93%) patients with positive PET had good outcome, and 10/16 (63%) with negative PET had good outcome. MRI abnormality was evident in 18 of 26 patients with good outcome.
Heinz(62) 27 24 FU=>12 mean=21 8917/2471MRI identified 20/24 (83%) of improved patients. MRI identified 17/19 (89.5%) of histologic abnormalities. PET identified 15/19 (79%) of histologic abnormalities.
Valk(21) 11 11 FU=24-48 10010/1191All patients were selected on basis of probable mesial temporal gliosis and had no structural lesions by MRI. Epileptogenic focus localized by ictal and interictal EEGs. Two patients required subdural electrode EEG. One of 2 patients requiring subdural EEG had normal PET scan.
Chee(22) 38 32 FU=12 8425/3278Retrospective study. PET was concordant with 29/31 (93.5%) EEG foci. Excluded patients with extratemporal foci.
Radke(35) 30 26 FU=24-40 8724/2692Retrospective study. Selection criteria for surgery were not stated. One of 25 positive PET was not significantly improved.
Theodore(23) 53 39 FU=14-29 7435/3990Surgical decision was based only on EEG data. Twenty-two of 53 (42%) patients had subdural EEG. PET may have obviated subdural EEG in 8/22 (38%) patients. Seven of 46 positive PET were not significantly improved.
Swartz(24) 34 340 FU=20-71 1028/3482PET showed false lateralization in one patient. Sixteen of 37 (45%) patients required intracranial EEG.
Olson(63) 8 children 7 FU=4-27 887/7100Two seizure-free patients had focal hypometabolism congruent with removed site and also showed additional EEG sites. Hypermetabolism was seen at epileptic focus in patient with electrical discharges.
Summary252216/25286 (74-100) 178/21682 (58-100)

Note: Data are from studies of patients with intractable complex partial seizures who had FDG-PET scans in addition to the usual presurgical evaluations. Surgical decisions apparently were made without consideration of the PET scans in most studies.

a

Patients selected for these studies were not specified, nor were the criteria used to proceed with the surgery.

b

Good outcomes included seizure-free patients and, in most cases, those who had seizure frequency reductions greater than 75 percent.

Abbreviation: FU=followup, given in months.

Table 5 shows that, of the 216 patients who had good surgical outcomes, 178 (82 percent) showed FDG-PET abnormalities that were congruent with the sites removed by surgery; the decision to proceed with the epilepsy surgery was made without consideration of the PET image in most of the studies. The percentage of patients with good outcomes that were identified by FDG-PET scans varied from a low of 58 percent by Theodore et al(20) to a high of 100 percent by Gaillard et al(15) and Olson et al.(63) The latter two reports were results obtained in epileptic children. Among the 38 patients with good outcomes, FDG-PET scans were normal in 10.(20) The scans showed hypometabolism contralateral to the ictal site in one patient(24) and hypermetabolism at the epileptic foci in one patient.(63) Of the 36 patients who had no improvement, 8 showed FDG-PET abnormalities at the resected sites.(23, 35)

Table 6. Correlation of single-photo-emission computed tomography with surgical outcomes

Reference
No. of Patients Who Received Operationsa
No. With Good Outcomeb
No.Percentage
SPECT Scan
Concordant With
Good Outcome
No.Percentage
Comments
Jack(17) 53 43 FU=12-40 81 19/43 Interictal (HMPAO) 45Surgery based on ictal and interictal electroclinical criteria. Four of 53 had depth electrode EEG. Patients with structural lesions excluded.
Markand(64) 90 68 FU=6-97 76 46/56 Ictal (HIPDM) 12/22 Postictal (HMPAO) 82 55 Eighty-six of 99 (87%) foci localized by interictal and ictal EEG (noninvasive). Thirteen localized by intracranial EEG. Facile ictal injection of HIPDM, but not HMPAO (require reconstitution time).
Adams(65) 15 15 FU=2-27 100 4/4 Postictal (HMPAO) 100Five of 20 had less than 1-month FU and were not included in analysis. Nineteen of 20 correctly localized by EEG without invasive subdural EEG. Eight of 20 (40%) pathologic foci identified by interictal SPECT. No intracranial electrode studies.
Markand(18) 38 33 FU=5-42 87 31/33 Ictal (HIPDM) 23/33 Interictal (HIPDM) 94 70 Surgery decision based on ictal and interictal EEG; confirmatory localization by SPECT helpful in 16/38 (42%) of patients; no intracranial EEG. Ictal SPECT may have identified 31/33 or 94% of patients with good outcome. Thirty-one of 34 (91%) of ictal SPECT scans show temporal localization.
Rowe(61) 413790 26/37 Postictal (HMPAO) 70Seizure foci were determined to be clearly unilateral in 45/51 by ictal EEG with intracerebral or sphenoidal electrodes.
Grunwald(28) 40 28 FU=>12 70 19/28 Interictal (HMPAO) (seizure-free patients) 68Surgery was directed by surface EEG, video-EEG monitoring, and electrocorticogram in 15 patients. Nine of 28 (32%) seizure-free patients showed contralateral interictal hypoperfusion. Ten of 40 (25%) were reported to have improved seizure frequency with 2/40 showing no improvement.
Summary: ictal and postictal SPECT 119/15278 (55-100)
Summary: interictal SPECT236187/23679 (70-100)61/10459 (45-70)

Note: Patients with intractable complex partial seizures who had SPECT scans in addition to the usual presurgical evaluations. The scans were obtained in the interictal, postictal, and/or ictal period. The basis for the selection of patients for surgery was not stated in some of the studies.

a

Patient selection for these studies was not specified.

b

Good outcome included seizure-free patients and, in most cases, those who had seizure frequency reductions greater than 75 percent.

99m

Abbreviations: FU=followup, given in months; HIPPDM=I-N, N, N'-trimethyl-N'-(2 hydroxy-3-methyl-5-1231-iodobenzyl)-1, 3-propanediamine; HMPAO=Tc-D, L-hexamethylene-propyleneamine oxime.

Table 6 shows the varying correlations of the presurgical SPECT images with the EEG-localized epileptogenic foci in patients with good surgical outcomes. Surgical decisions were based on electrophysiologic, neuropsychologic, and other information without consideration of the SPECT images. Good outcomes were observed in 187 (79 percent) of the 236 patients. Of those patients with good outcomes, 152 had either an ictal or postictal SPECT scan with 119 (78 percent), showing hyperperfusion at the site removed by surgery. The better correlation of ictal SPECT scans in these patients was reported by Markand et al,(64) where 46 (82 percent) of 56 ictal SPECT images showed hyperperfusion at the site corresponding to the epileptogenic foci; only 12 (55 percent) of 22 postictal images showed hypermetabolism corresponding to the foci. In comparison, interictal SPECT scans done in 104 patients with good outcomes showed hypoperfusion at the site removed by surgery in 61 (59 percent) of the patients. Grunwald et al(28) reported that interictal hypoperfusion contralateral to the resected epileptogenic site was seen in only 9 (32 percent) of the 28 seizure-free patients.

Discussion

Patients with intractable complex partial seizures often have surface EEG findings that indicate a focus that does not agree with the clinical symptoms or a focus that is bilateral, contralateral, or diffuse and nonlocalizing. In attempts to localize the epileptogenic foci in these patients, intracranial electrode recordings, FDG-PET scans, SPECT scans, and magnetoencephalography(66) have been used in some epilepsy centers.

In the management of epilepsy patients, the possible role of FDG-PET scans depends on the reliability with which PET images can show hypometabolic areas that correspond to the EEG-identified foci. Ultimately, in patients with good outcomes, the area with the localized PET abnormality should correspond to the resected area. From the reports in Table 2, PET images have shown hypometabolic areas that were concordant with the EEG-identified foci in about 76 percent of the cases. This suggests that if PET were to be used as a confirmatory test, about a quarter of the "epileptogenic foci" might not be seen. Of greater concern, some of the PET scans showed hypometabolic areas that were discordant with the EEG-identified foci. Without knowing which of the two "foci" is actually epileptogenic when the EEG recording and the FDG-PET scan are not in agreement, the resection of foci localized by EEG may have resulted in good outcomes in 80-90 percent of the patients with agreement of FDG-PET scans in 82 percent of these cases (Tables 5 and 6). Some of the patients who showed no improvement may have had a seizure focus localized by PET scans in the contralateral, unresected area. However, Theodore et al(20) reported that positive PET scans have an excellent positive predictive value of 93 percent (15/16 positive scans), while 10 of the 16 remaining patients with negative PET scans also had good outcomes (Table 5). In sum, PET scans did not detect the epileptogenic sites or indicate discordant foci in 63 percent of their patients.

Although invasive EEG may be helpful in localizing the epileptogenic site, patients are exposed to the risks associated with the intracranial implantation of the electrodes. Whether PET scans might serve as an alternative to invasive EEG and, therefore, avoid these risks would depend on the correlation of the FDG-PET scans with the invasive EEG recordings. According to a retrospective review of 147 patients by Engel et al,(29) FDG-PET scans might have substituted for depth electrode recordings in about 90 percent of the patients. Mazziotta(67) estimated that PET scans might obviate the need for invasive EEGs in about 33-50 percent of patients, and Theodore et al(23) reported that PET scans may have substituted for 8 (38 percent) of the 22 subdural electrode recordings. Thus, the extent to which and under what circumstances noninvasive PET scans might effectively substitute for invasive EEGs remains uncertain.

The false localization of the epileptogenic foci by FDG-PET scans in some patients is of great concern if FDG-PET scans are substituted for invasive EEG. Except for Engel et al,(29) who implied that the seizure origin site may have been indicated by the PET scan and not by the invasive EEG in two patients, others have found that the invasive EEG foci correlated with the seizure origin site. For example, Sperling et al(68) found that the removal of the EEG-identified area resulted in good outcomes in two patients who had FDG-PET abnormalities in the contralateral areas. Sadzot et al(25) noted that one patient, whose PET scan showed a focus in the contralateral temporal lobe, became seizure-free after temporal lobectomy on the side of the focus defined by intracranial EEG. Levesque et al(69) reported that FDG-PET may falsely lateralize 2 percent and falsely localize 6 percent of the patients. Similar false localization of the foci with FDG-PET scans in children who had good surgical outcomes with the resection of the EEG-identified foci have been reported.(70)

In comparison to PET scans, interictal SPECT scans do not appear to be particularly reliable; only about half of the patients with EEG-localized foci showed interictal SPECT abnormalities that were concordant with the EEG-identified foci (Table 3). In addition to the relative inability to identify the foci, interictal SPECT scans tended to show hypoperfusion in areas contralateral to the EEG-identified foci in a substantial number of patients. Although some reports, such as those by LaManna et al,(55) Harvey et al,(45) and Cross et al,(71) appear to contradict this by finding that almost all of the foci were identified by interictal SPECT, most epilepsy centers suggest that interictal SPECT is not a very reliable method for the demonstration of the foci.

Ictal and postictal SPECT scans, on the other hand, have shown a greater reliability for demonstrating hyperperfusion at the EEG-identified foci. Ictal SPECT scans appear to be more reliable for identifying almost all (95 percent) of the foci, whereas the postictal SPECT scans are less reliable (Table 4). Ictal SPECT scans seem to be the preferred method for demonstrating the epileptogenic foci. However, the timing of injection of the radiolabeled compound for ictal or postictal scans seems to be very critical, because the hyperperfusion spreads away from the foci very rapidly after the onset of the seizure and subsides quickly afterwards.(59, 60, 71) Although postictal scans have shown hyperperfusion at the foci in a significant number of patients, the reliability of detecting hyperperfusion postictally depends heavily on the timing of the injection of the tracer and on the rate of change in the perfusion at the foci and in other areas of the brain. Rowe et al(60) noted that a delay in injecting the tracer after cessation of the seizure markedly changed the hyperperfusion as seen on the postictal scans. If the tracer was injected within a minute of seizure cessation, scans of the area showed hyperperfusion in most patients similar to ictal scans. This rapid change in perfusion was illustrated in a child with temporal lobe epilepsy, as reported by Cross et al.(71) The ictal scan obtained by injecting the tracer 55 seconds after onset of the seizure showed focal hyperperfusion of the left temporal lobe. The postictal scan obtained by injecting the tracer 43 seconds after seizure cessation showed medial hyperperfusion of the left temporal lobe with lateral hypoperfusion. Thirty minutes after seizure cessation, the interictal scan, obtained by the injection of the tracer, showed hypoperfusion of the whole left temporal lobe. This rapid spread of hyperperfusion to other parts of the brain and the hypometabolism in areas surrounding the epileptogenic foci have led to difficulties in interpretation of the images and accurate identification of the foci.

Whether PET or SPECT scans might be useful in predicting surgical outcome has yet to be determined. Tables 5 and 6 showed that FDG-PET scans identified about 82 percent and SPECT scans a variable percentage of patients who had good surgical outcomes. Normal PET scans in some of the patients who had good outcomes, and positive scans for the resected tissue in some who showed no change in seizure status, are of significance and require further study with regard to FDG-PET scans. SPECT scans, on the other hand, showed abnormal perfusion in varying numbers of patients, depending on whether the scan was done during the interictal, ictal, or postictal state. Interictal SPECT scans identified only 45-70 percent of patients, and postictal and ictal SPECT scans identified 55-100 percent of patients with good surgical outcomes. In comparison to PET scans and other modes of SPECT scans, ictal SPECT scans appear to be the most reliable for identifying seizure foci. Ho et al(34) retrospectively reviewed selected patients with well-lateralized temporal lobe epilepsy and showed that ictal SPECT scans correctly identified more of the foci (94 percent) than FDG-PET (83 percent) with no disagreement between the two independent interpreters of the images. However, the procedures for obtaining a reliable ictal SPECT image, especially the timing of the injection of the tracer compound, need further investigation.

Outside Comments

The following comments were among those received in response to our Federal Register request for information. The National Association of Epilepsy Centers stated that noninvasive EEG recordings provide the most important information for localizing an epileptogenic region in patients with medically refractory epilepsy. The noninvasive recordings may falsely localize or falsely lateralize the foci in 10-20 percent of the patients and necessitate the use of other tests to determine the location of the foci and the suitability of these patients for surgery. Although these statements are in agreement with our findings, we do not agree with the recommendation that FDG-PET scans be performed as a confirmatory test in all patients, because the majority of patients may be found suitable for surgery based on noninvasive EEG recordings and other information such as clinical symptoms and neurologic/neuropsychologic test results. Consequently, although a confirmatory PET scan may be useful, these expensive scans may be needed in only a minority of the patients.

Comments received from the Institute for Clinical PET do not clarify when PET scans might be appropriate except that the scans may help increase the certainty of the localization of the ictal onset zone and optimize the selection of the intracranial electrode placement sites. In agreement with our findings, the Institute acknowledges that FDG-PET scans detect temporal lobe hypometabolism in only 70-90 percent of the patients with temporal lobe epilepsy and that the hypometabolism is falsely lateralized in some cases.

U.S. Public Health Service Comments

The National Institutes of Health stated that the sensitivity of FDG-PET scans is approximately equal to that of properly performed MRI and ictal SPECT for identifying an area that corresponds to the epileptogenic foci. A relatively limited use for PET scans in patients who have normal MRI scans and in children with secondary generalized epilepsies such as Lennox-Gastaut syndrome or infantile spasms is suggested.

Summary

Currently available methods for the localization of epileptogenic foci in patients with intractable complex partial seizures have led to the identification and selection of patients who have subsequently undergone curative epilepsy surgery. A majority of these patients (about 75 percent) have become seizure-free or have had their seizure frequency reduced by greater than 75 percent. Noninvasive surface EEG recordings and information obtained from clinical observations, CT and/or MRI, and neuropsychologic tests have enabled the identification of most of these patients. Other tests, such as invasive EEG, PET scans, and SPECT scans, have been used at various epilepsy centers to identify additional candidates who might benefit from surgery and to improve the probability of obtaining good surgical outcomes.

In many epileptic patients, PET and SPECT scans may be useful for the presurgical identification of epileptogenic foci or confirmation of the foci indicated by EEG. FDG-PET scans have shown hypometabolic areas that correspond to the foci localized by EEG in about 70-80 percent of the patients. Interictal SPECT scans have shown hypoperfusion at the EEG-identified foci in about 50 percent of the patients. However, both methods appear to miss a substantial number of EEG-identified foci and both appear to indicate abnormalities that are discordant with the EEG localization. This discordance seems to be more prevalent with interictal SPECT. Ictal SPECT scans seem to avoid this problem and demonstrate abnormal hyperperfusion in areas that coincide with the EEG-identified foci. Postictal SPECT scans are less reliable, especially if tracer is not injected within a very short time after cessation of the seizure.

It is not clear whether PET or SPECT scans can independently localize epileptogenic foci and identify additional patients as candidates for epilepsy surgery, or whether they simply serve as supplemental means of localizing the foci. Although PET or SPECT may show functional abnormalities that correspond to the EEG-foci, the definitive proof that PET or SPECT scans can identify the epileptogenic foci and predict the eventual surgical outcome is lacking.

Interictal SPECT scans are not particularly useful in identifying either EEG-identified foci or the patients with good surgical outcomes. Postictal SPECT scans may more reliably identify the foci, but ictal SPECT scans would be the most reliable means of identifying the epileptogenic foci and the patients likely to benefit from epilepsy surgery. Although the sparseness of the data for ictal SPECT scans prevents any conclusions about its reliability and utility in diagnosis and management of epileptic patients, the results to date indicate that there are possibilities that ictal SPECT might serve as an alternative method to invasive EEG in patients who have epileptogenic foci that are difficult to localize.

Intracranial electrode recordings have been used to clarify the ambiguous findings of surface EEGs. They may identify some patients as candidates for epilepsy surgery among those who would not have been considered for surgery. The presently available information does not show that PET or SPECT scans have led to the similar identification of additional patients. More data are necessary to determine when and under what conditions the FDG-PET scans can be relied upon as a substitute for the management of epileptic patients. In view of the difficulties of interpreting some of the PET images, a concordant finding with PET may confirm the epileptic foci, but if the scan is discordant, the true foci may be in question. Further studies are needed to address (1) the presurgical identification of the epileptogenic foci in the 82 percent of the patients who had good surgical outcomes, (2) the finding of hypometabolic foci in the resected tissue in patients who had no postsurgical improvement in their epileptic status, and (3) the apparent false localization of the foci in some patients (especially those who had good surgical outcomes). The results of such studies are needed before a role for FDG-PET scans in complex partial seizure can be defined.

Glossary

Computed tomography (CT):: Photographic outline of structures resulting from computer analysis of data.

Contralateral:: Opposite side.

Electroencephalogram (EEG):: Graphic recording of electrical brain activity.

Epileptogenic foci:: Brain site of origin of seizure.

Fluorodeoxyglucose-positron-emission tomography (FDG-PET):: Computed tomographic image of internal distribution of derivative of glucose labeled with radioactive fluoride.

Hypometabolism:: Decreased utilization of nutrient in tissue.

Hypoperfusion:: Decreased circulation of blood to tissue.

Ictal:: Active seizure phase.

Ictal SPECT (I-SPECT):: Computed tomographic image of internal distribution of radiolabeled chemical during a seizure.

Interictal:: Interphase between seizures.

Invasive or intracranial electroencephalography (I-EEG):: Electroencephalogram recorded with electrodes in the cranium.

Ipsilateral:: Same side.

Magnetic resonance imaging (MRI):: Computed tomographic image of varying magnetic resonances in cells of the body.

Noninvasive EEG:: Electroencephalogram recorded with electrodes on surface of the head.

Positron emission tomography (PET):: Computed tomographic image of internal distribution of radiolabeled chemical.

Postictal SPECT (p-SPECT):: Computed tomographic image of internal distribution of radiolabeled chemical immediately after seizure stops.

Reliability:: Dependability.

Resective temporal lobe surgery:: Removal of temporal lobe by surgery.

Single-photon-emission computed tomography (SPECT):: Computed tomographic image of internal distribution of radiolabeled chemical.

Surface/sphenoidal:: Outside of the cranium.

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