11
Neuroimaging of Seizures
Byron Bernal and Nolan Altman
I. Is neuroimaging appropriate in patients with febrile seizures?
II. What neuroimaging examinations do patients with acute nonfebrile symptomatic seizures need?
III. What is the role of neuroimaging in patients with first unprovoked seizures?
IV. What is the most appropriate study in the workup of patients with temporal lobe epilepsy of remote origin?
V. When should functional imaging be performed in seizure patients and what is the study of choice?
194
Issues
䊏 The main goal of neuroimaging in seizures is to rule out focal lesions that could threaten the patient’s life (i.e., neoplasm or other intracra- nial space-occupying lesion).
䊏 The most important role of neuroimaging in epilepsy is to identify the structural substrate of the epileptogenic focus.
䊏 Neuroimaging is not recommended for a simple febrile seizure (limited evidence).
䊏 Computed tomography scan is the best imaging study in the evalua- tion of patients with acute nonfebrile symptomatic seizures because it detects important abnormalities, such as acute intracranial hemor- rhage, that may require immediate medical or surgical treatment (limited evidence).
䊏 Magnetic resonance imaging (MRI) is the neuroimaging study of choice in the workup of first unprovoked seizures (moderate evidence).
䊏 Focal neurologic deficit is an important predictor of an abnormality in the neuroimaging examination (moderate evidence).
䊏 Magnetic resonance (MR) evaluation should be performed in non- acute symptomatic seizure patients with confusion and postictal deficits (moderate evidence).
Key Points
Definitions
A seizure is a symptom; epilepsy is a disease. Seizures occur as the result of an electrical discharge in the brain. Epilepsy is a disease characterized by more than one seizure. The International League Against Epilepsy (1) has proposed a classification of the epileptic syndromes, epilepsies, and related seizure disorders. Five main parameters are considered: age, etiol- ogy (symptomatic, cryptogenic, or idiopathic), electroclinical features (gen- eralized vs. partial), prognosis (benign vs. malignant), and response to treatment (responsive vs. refractory epilepsy).
Numerous categories are produced from the combination of these factors, which creates confusion in the classification of seizures and epilep- sies not only for the general physician but also for specialists. Based on clinical findings, seizures are usually divided into symptomatic and non- symptomatic seizures. The term symptomatic indicates that the seizure is a symptom with an underlying cause. This may be systemic (e.g., hypona- tremia, hypocalcemia) or localized (e.g., tumor, cortical dysplasia, abscess).
Seizures are categorized as acute symptomatic or remote symptomatic, depending on how long the underlying cause predated the seizure. Acute symptomatic seizures occur as the result of a proximate precipitant, such as fever, electrolyte imbalance, drug intoxication, alcohol withdrawal, brain trauma, central nervous system (CNS) infection, or aggressive neoplasm.
In remote symptomatic seizures the lesion is preexistent and the seizure is the main or only symptom (e.g., cortical dysplasia, ganglioglioma, hippocam- pal sclerosis, scar, or gliosis). Nonsymptomatic seizures include crypto- genic and idiopathic seizures. In cryptogenic seizures (or epilepsy), no cause can be found, even though one is clinically suspected by focal electroen- cephalography (EEG) or lateralized neurologic examination. In idiopathic generalized epilepsy there are no focal clinical signs or clear macrostructural cause for the epilepsy. In these cases a genetic factor is presumed to be present. The term unprovoked seizures is used for seizures in patients without history or abnormal neurologic examination. They may turn out to be cryptogenic, idiopathic, or remote symptomatic after the appropriate workup. Partial seizures have a focal origin demonstrated by clinical semi- ology or EEG. Partial seizures are divided into simple and complex, the latter affecting the patient’s awareness.
䊏 Magnetic resonance should be performed in children with unexpected cognitive or motor delays or children under 1 year of age, with remote symptomatic seizures (moderate evidence).
䊏 Patients with focal seizures, abnormal EEG, or generalized epilepsy should be imaged (moderate evidence).
䊏 Magnetic resonance imaging is the imaging modality of choice in tem- poral lobe epilepsy (moderate evidence).
䊏 Ictal single photon emission computed tomography (SPECT) is the best neuroimaging examination to localize seizure activity (moderate evidence).
Epidemiology
The prevalence of epilepsy in industrialized countries is between 5 and 10 cases per 1000 persons (2); hence, epilepsy affects between 1.5 to 3.0 million in the United States. Higher prevalence of epilepsy has been reported in developing countries (3), with a few exceptions. The incidence of epilepsy is age dependent. It peaks at the extremes of life, ranging from 100 to 140 per 100,000 in neonates and infants, and about 140 cases per 100,000 persons in the elderly; 50% of cases occur under the age of 1 year or over 60 years of age (2). The incidence is lowest in early adulthood (25 per 100,000), followed by an increase during late adulthood (4). A different age- specific distribution is seen in developing countries, with a second peak in early adulthood (5,6).
Specific Epidemiologic Data
Febrile seizures affect children between 6 months and 6 years of age. The cumulative incidence of febrile seizures is 2% in children (7). The two most important predictors for first episode of febrile seizures are age less than 1 year and family history of febrile seizures (8). The overall incidence of febrile seizures recurrence is 35% (9). The recurrence of seizures after a focal febrile seizure lasting more than 15 minutes (complex febrile seizure) is two- to fourfold compared to an initial simple febrile seizure (10).
Acute afebrile symptomatic seizures affect 31 of 100,000 people per year and accounts for 40% of all new-onset afebrile seizures. The incidence is highest in the neonatal period (100 per 100,000 inhabitants), with a second peak in patients older than 75 years (123 per 100,000).
The probability of recurrent seizures after an initial unprovoked seizure is 36% by 1 year of age, and increases yearly up to 56% by 5 years (11). The presence of neurodevelopmental abnormalities increases the probability of future unprovoked seizures (12). The recurrence of all types of seizures ranges between 24% and 67% (13). Of all patients with recurrent seizures, up to 20%, may have a intractable epilepsy (14).
Overall Cost to Society
Murray et al. (15) analyzed the cost of neuroimaging in the U.S. health care system in 1994 for adult refractory epilepsy. Computed tomography (CT) was used in 60% of new and in 5% of existing cases of epilepsy, whereas magnetic resonance imaging (MRI) was requested in 90% of new and 12%
of existing cases (15). Cost was determined by multiplying the CT or MRI incidence rate of usage by the incidence of new-onset seizures and by the cost of the exam. The cost for an MRI of the brain in the U.S. is between
$1200 and $2000 (16). Therefore, the CT and MRI workup expenses of new-onset seizures in the U.S. is between $28,000 and $84,000 per 100,000 inhabitants per year.
A French cohort study on medical costs of epilepsy in 1942 patients (17) reported that neuroimaging studies accounted for 8% of the total health care costs for these patients.
Bronen et al. (18) have reported the economic impact of replacing CT with MRI for refractory epilepsy, based on the assumption that the higher
sensitivity of MRI in lesion detection would result in reducing the costs of interoperative electrocorticography otherwise needed to localize the site of the epileptogenic focus. They found that in 29 of 117 patients the replace- ment of CT by MRI eliminated the need for surgical placement of intracra- nial electrodes with potential savings of $1,450,000 in 29 patients.
Goals
The main goal of the neuroimaging in seizures and epilepsy is to rule out focal lesions that could threaten the patient’s life. Neuroimaging also allows the identification of the structural substrate of the epileptogenic focus. Neuroimaging may increase or decrease the pretest probability of having a particular etiology or confirm a clinical diagnosis.
Methodology
For each of the procedures MRI, CT, single photon emission computed tomography (SPECT), positron emission tomography (PET), magnetic resonance spectroscopy (MRS), and functional MRI (fMRI), a systematic review of the literature from January 1, 1982, to January 31, 2004, for abstracts in English and for human subjects only, was performed utilizing PubMed (National Library of Medicine, Bethesda, Maryland) with the fol- lowing terms: epilepsy, seizure, evidence-based review, and neuroimaging evi- dence. Titles and abstracts were reviewed to determine the appropriateness of content. Articles were excluded if they studied fewer than 30 patients, lacked pathologic verification, had no standard of reference, or had no sig- nificant influence on clinical decision making. Articles about MRI using less than 1.5 T were also excluded. The specificity, sensitivity, likelihood ratios, probability, predictors, and techniques were summarized for each procedure.
Seizures were divided into two main categories—new-onset seizures and established epilepsy—with particular emphasis on partial types. Adult and childhood epilepsy were addressed as well as febrile and temporal lobe epilepsy due to their clinical and radiologic importance.
Each of the selected articles was reviewed, abstracted and classified by two reviewers. Of a total of 606 abstracts, 131 articles met inclusion crite- ria and the full text was reviewed in detail.
I. Is Neuroimaging Appropriate in Patients with Febrile Seizures?
Summary of Evidence: Neuroimaging is not recommended for a simple febrile seizure (limited evidence).
Supporting Evidence: No level I or II (strong or moderate evidence) articles were found. In a level III article (limited evidence), Offringa et al. (19) reported an evidence-based medicine study for the management of febrile seizures and the role of neuroimaging in regard to detection of meningi- tis. The overall prevalence of meningitis detected by CT/MRI scans was
1.2% of 2100 cases of seizures associated with fever. This manuscript, as well as the study by the American Academy of Pediatricians (20) (limited evidence) suggests that CT and MRI are not recommended for a simple febrile seizure.
II. What Neuroimaging Examinations Do Patients with Acute Nonfebrile Symptomatic Seizures Need?
Acute nonfebrile symptomatic seizures occur in nonfebrile patients having neurologic findings pointing to an underlying abnormality. It excludes meningitis, encephalitis, abscess, and empyema.
Summary of Evidence: Computed tomography scan is the best imaging study in the evaluation of patients with acute symptomatology, as it is sensitive for finding abnormalities such as acute intracranial hemorrhage, which may require immediate medical or surgical treatment. It is also fast and readily available (limited evidence).
Supporting Evidence: No articles meeting the criteria for level I or II (strong or moderate evidence) were found. Several level III (limited evidence) studies were found as discussed. Eisner and colleagues (21) reported a study with 163 patients, who presented to the emergency room with first seizure (Table 11.1). All patients older than 6 years of age who had recent head trauma, focal neurologic deficit, or focal seizure activity underwent head CT. Of 19 patients, five (26%) had CT abnormalities, including one subdural hematoma, resulting in a change of medical care. Earnest and col- leagues (22) found CT abnormalities in 6.2% of 259 patients with alcohol withdrawal seizures. In 3.9% medical management was changed because of the CT result. Reinus and colleagues (23) retrospectively evaluated the medical records of 115 consecutive patients who had seizures after acute trauma and underwent a noncontrast cranial CT. An abnormal neurologic examination predicted 95% (19 of 20) of the positive CT scans p< .00004.
Henneman et al. (24) conducted a retrospective study on 333 patients with new-onset seizures, not associated with acute head trauma, hypo-
Table 11.1. Neuroimaging in acute symptomatic seizures (CT/MRI)
No. of % of
Author patients CT/MRI positive Comments
Eisner et al., 163 19 25 Positive results in 3% of the
1986 (21) total of patients
Earnest et al., 259 259 6.2 Only patients with seizures
1988 (22) after alcohol withdrawal were
included; 3.9% of patients resulted in significant treatment changes
Reinus et al., 115 ? 36 Post–acute head trauma (60
1993 (23) patients had previous seizure
disorder)
Henneman et al., 333 325 41 Seizures no associated with
1994 (24) head trauma
glycemia from diabetic therapy, or alcohol or recreational drug use. Of the 325 patients studied with CT scans, 134 (41%) had clinically significant results.
Bradford and Kyriakedes (25) reported an evidence-based review (limited evidence) of diagnostic tests in this population. The authors report a diagnostic yield of 87% for CT. Predictors of abnormal CT scans in patients with new onset of seizures had the following risk factors: head trauma, abnormal neurologic findings, focal or multiple seizures (within a 24-hour period), previous CNS disorders, and history of malignancy. The article concludes that there are supportive data to perform CT scanning in the evaluation of all first-time acute seizures of unknown etiology.
III. What Is the Role of Neuroimaging in Patients with First Unprovoked Seizures?
Summary of Evidence: Magnetic resonance imaging is the neuroimaging study of choice in the workup of first unprovoked seizures (moderate evi- dence). Neuroimaging is positive in 3% to 38% of cases. The probability is higher in patients with partial seizures and focal neurological deficit (Fig.
11.1). Neuroimaging is advised in children under 1 year of age and in those with significant unexplained cognitive or motor impairment, or prolonged postictal deficit. Significant neuroimaging findings impacting medical care are found in up to 50% of adults and in 12% of children.
Figure 11.1. Computed tomography (CT) vs. magnetic resonance imaging (MRI) sensitivity in nonacute symptomatic seizure. This figure illustrates the higher sensitivity of MRI in the detection of cortical dyspla- sia. The transverse CT (A) is compared to the MRI (B) in a child with intractable epilepsy and postural pla- giocephaly. The region of cortical dysplasia in the left parasagittal frontal lobe is clearly seen only on the MRI exam by the loss of gray–white matter interface and the increased T2-weighted signal intensity.
A B
Supporting Evidence: No level I (strong evidence) studies were available (Table 11.2). One level II study (moderate evidence) was found describing a cohort study in which neuroimaging studies were performed in 218 of 411 children (26); CT was performed in 159 and MRI in 59 cases. The cohort was followed for a mean of 10 years and none of the patients had evidence of neoplasm (accepted as the reference standard); 21% of the 218 exams were abnormal. The most frequent diagnoses were encephalomalacia (16 cases) and cerebral dysgenesis (11 cases). Six children had gray-matter migration disorders, which were seen only on MRI. In this study, a higher number of MRIs (34%) than CT studies (22%) were abnormal. In four cases (1.8%) the results altered both the diagnosis and the acute management of the patient. Children in this study who had a neurologic deficit (56% vs.
12%, p< .001), or abnormal EEG and partial seizures (p < .05) were more likely to have abnormal imaging.
A level III (limited evidence) case series study of 300 adults and children with an unexplained first seizure was reported by King et al. (27) in 1998;
92% of these patients had neuroimaging. A total of 263 patients had MRI and 14 had only CT. Epileptogenic lesions were found in 38 patients (13%).
Of these, 17 had neoplasms that changed the patient’s medical care. Mag- netic resonance imaging detected abnormalities in 17% of patients. Com- puted tomography was performed in 28 of the 38 cases, with lesions on MRI being concordant with MRI in only 12 cases. Computed tomography missed a cavernous angioma and eight tumors. Magnetic resonance imaging was done in 50 patients with generalized epilepsy and only one had a neoplasm causing partial epilepsy.
In pediatric studies, neuroimaging diagnostic performance was similar to that in the adult literature according to an evidence-based study by Hirtz et al. (28) (limited evidence). However, the overall effect of neuroimaging on medical management was less in children than in adults (28).
Table 11.2. Neuroimaging in first unprovoked seizure
% of
Author Patients CT/MRI positives Comments Shinnar et al., 218 186/59 34/22 1.8% significant
2001 (26) findings
King et al., 300 263/14 17/8
1998 (27)
Hirtz et al., (EBM 18–34 In children: significant
2000 (28) review) findings in less than 7%
Maytal et al., 66 66/20 21 None with significant
2000 (29) findings
Hopkins et al., 408 408/0 ? 3% tumors
1988 (30)
Schoenenberger 119 119/0 34 17% with significant
and Heim, 1994 findings
(31)
Garvey et al., 50 50/0 17 12% with significant
1998 (32) findings
The role of CT in evaluating children with new-onset unprovoked seizure was analyzed in a retrospective (limited evidence) study by Maytal et al. (29). Of 66 patients, 21.2% had abnormal CT results. The seizure eti- ology was clinically determined to be cryptogenic in 33 patients. Two of these children (6%) had abnormal nonspecific CT findings that did not require intervention. No abnormal CT results were seen in 13 cases with complex febrile seizures.
In a level III (limited evidence) study of 408 adults, CT scanning found tumors in 3% of patients. These patients were more likely to have recur- rent seizures (30). Other studies have shown a higher percentage of posi- tive imaging results in this population. A total of 119 adult patients with new-onset seizure underwent CT of the brain. Focal structural brain lesions were found in 40 patients (34%; 95% confidence interval, 25% to 42%). In 50% of the patients, the imaging findings prompt an important change in therapeutic management. The major predictor for finding a focal lesion on CT was the presence of a focal neurologic deficit (sensitivity of 50%, speci- ficity of 89%) (31). Another study evaluated 50 patients referred for CT from a group of 107 children with first unprovoked seizure. A total of 19 children had brain abnormalities on CT. Of these, six patients had signifi- cant changes in medical workup or treatment (32).
The Quality Standards Subcommittee of the America Academy of Neu- rology, the Child Neurology Society, and the American Epilepsy Society have published a special report on practice guidelines in the evaluation of first nonfebrile seizures in children (unprovoked seizure) based on evidence-based medicine (EBM) (28) (limited evidence). The selection cri- teria included some small sample studies that lack stringent EBM criteria.
This review article included studies in adults and in children. Analysis of the results found a range of 0% to 7% of children had lesions on CT that changed management of epilepsy (i.e., tumors, hydrocephalus, arachnoid or porencephalic cysts, and cysticercosis). Focal lesions on CT were more common in adults (18–34%).
Overall, MRI found more lesions than CT but did not always change medical management (i.e., atrophy, mesial temporal sclerosis, and brain dysgenesis). This report concluded that there is insufficient evidence to support the recommendation for routine neuroimaging after the first unprovoked seizure. Neuroimaging, however, may be indicated in cases of focal seizures associated with positive neurologic clinical findings. If a neu- roimaging study is required, MR is the preferred modality. Emergency imaging with CT or MR should be performed in cases of long-lasting pos- tictal focal deficit, or in those patients who remain confused several hours after the seizure. Nonurgent imaging studies with MRI should be consid- ered in children less than 1 year of age, significant and unexplained cogni- tive or motor impairment, a partial seizure, EEG findings not consistent with benign partial epilepsy of childhood, and primary generalized epilepsy.
IV. What Is the Most Appropriate Study in the Workup of Patients with Temporal Lobe Epilepsy of Remote Origin?
Summary of Evidence: Magnetic resonance imaging is the imaging modal- ity of choice in temporal lobe epilepsy (moderate evidence). The seizure focus may be lateralized by MR volumetric techniques. Magnetic reso-
nance sensitivity reaches 97% for hippocampal sclerosis using FLAIR (fluid-attenuated inversion recovery) imaging. Loss of digitations of the hippocampal head has a sensitivity of 92% for hippocampal sclerosis.
Quantitative measurement of hippocampal size has a higher sensitivity than qualitative inspection with 76% versus 71%, respectively.
Supporting Evidence: No level I (strong evidence) studies are available (Table 11.3). There is one prospective cohort level II study (moderate evidence) of neuroimaging in temporal lobe epilepsy of childhood (33).
Sixty-three children with new-onset temporal lobe epilepsy were included;
MRI was performed in 58 (92%) and CT in 48 (76%). The MRI was abnor- mal in 23 children (36.5%) and included unilateral hippocampal sclerosis (HS) in 12, bilateral HS in one, temporal lobe tumor in eight, arachnoid cyst in one, and cortical dysplasia in one. Computed tomography was Table 11.3. Neuroimaging in temporal lobe epilepsy (TLE) and other partial seizures
% of
Author Patients CT/MRI positives Comments
Harvey 63 48/58 23/36.5 Study done with two magnets:
et al., 1997 0.3 T and 1.5 T; etiologies: 13
(33) HS, 8 tumors, 1 cortical
dysplasia, 1 arachnoidal cyst, 1 hamartoma
Kramer et al., 143 117/42 (35) Study in children and
1998 (34) adolescents: 8 diffuse atrophy, 8
porencephalic cyst, 6 tumors, 6 neurocutaneous syndrome, 6 dysgenesis; neither an abnormality in the neurologic exam nor the type of seizure were predictors for finding a tumor
Lee et al., 274 0/186 97 Patients with intractable TLE;
1998 (36) 65% had HS, 32 had
abnormalities in the rest of the temporal lobe; 42 tumors in pediatric patients
Berg et al., 359 (312) (13.8) All pediatric patients; in 3
2000 (35) normal-CT cases the MRI was
abnormal; the strongest predictor of abnormal imaging was abnormal motor
examination
Sinclair et al., 42 39/42 31/64 Patients with intractable partial
2001 (37) epilepsy; postoperative
findings: 13 tumors, 8 HS, 5 dual pathology, 4 cortical dysplasia, 4 tuberous sclerosis, 1 porencephalic cyst
Spencer, 809 ? 43–55 370 patients with temporal lobe
1994 (38) abnormalities; the lowest % for
extratemporal lobe epilepsy Note: The reported data in parenthesis are not divided due to lack of further information.
positive in 23% of cases, which included all tumors, but failed to detect cases of HS. Computed tomography demonstrated calcifications in the posterior area of the hippocampus in one case that was not detected on MR. This lesion was shown to be a small hamartoma pathologically. The authors proposed three groups to classify partial seizures based on the relationship among neuroimaging findings, prior history, and age:
Group I: Developmental temporal lobe epilepsy (10 patients). Seizures begin in mid- to late childhood (mean age 8.2 years) and neurobehav- ioral problems are infrequent. This epilepsy is associated with tumors and malformations that are usually long-standing and nonprogressive cortical lesions such as gangliogliomas, dysembryoplastic neuroepithe- lial tumors, and pilocytic xanthochromic astrocytomas.
Group II: Temporal lobe epilepsy with hippocampal sclerosis (18 patients), included children with significant prior clinical history of neurologic insult, including complicated febrile seizures, hypoxic-ischemic encepha- lopathy, and meningitis.
Group III: Cryptogenic temporal lobe epilepsy (34 patients) in whom no etiology could be determined.
A level III study (limited evidence) by Kramer et al. (34) studied the pre- dictive value of abnormal neurologic findings on the neuroimaging of 143 children with partial seizures. Fifty patients had neuroimaging abnormal- ities and 36 had abnormal clinical findings. The neurologic exam findings of hemiparesis, mental retardation, and neurocutaneous stigmata were risk factors in predicting abnormal neuroimaging findings. However, the abnormality detected on neurologic examination or the type of seizure was not a predictive parameter in determining tumor resectability as shown by neuroimaging.
A level III study (limited evidence) by Berg and coworkers (35) reported the neuroimaging findings in a group of 613 children with newly diag- nosed temporal lobe epilepsy. A total of 359 patients had partial seizures.
Of this group, 312 (86.9%) underwent imaging; 283 had MRI alone or with CT. Relevant abnormalities were found in 43 (13.8% of those imaged). The strongest predictor of abnormal imaging was an abnormal motor exami- nation (odds ratio: 18.9; 95% confidence interval, 9.9% to 36.3%; p< .0001).
The MR findings in 186 of 274 consecutive patients who underwent temporal lobectomy for intractable epilepsy were retrospectively reviewed (moderate evidence) (Table 11.4) (36). This was a blinded study with
Table 11.4. MRI sensitivity and specificity in temporal lobe epilepsy
Item Sensitivity (%) Specificity (%) Reference
Hippocampal lesion 93 83 Lee et al.,
1998 (36)
Nonhippocampal temporal 97 97 Lee et al., 1998
lobe lesion
Global sensitivity for 83 97 Lee et al., 1998
tumor detection
High T2 signal for 93 74 Lee et al., 1998
hippocampal sclerosis
High FLAIR signal for 97 ? Jack et al.,
hippocampal sclerosis 1996 (43)
pathology as the reference standard. Magnetic resonance imaging detected 121 hippocampal/amygdala abnormalities (sensitivity and specificity of 93% and 83%, respectively) and 60 other abnormalities in the remainder of the temporal lobe (sensitivity and specificity of 97% and 97%, respectively).
Increased signal of the hippocampus on T2-weighted images had a sensi- tivity of 93% and specificity of 74% in predicting mesial temporal sclero- sis (Fig. 11.2). Forty-two temporal tumors were detected with a sensitivity and specificity of 83 and 97%, respectively.
The sensitivity of CT and MRI in temporal lobe pathology was recently reported by Sinclair et al. (37) (limited evidence). Forty-two pediatric patients were studied. All patients underwent temporal lobectomy for intractable epilepsy, hence providing histopathology as the reference stan- dard. Magnetic resonance imaging found abnormalities in 27 cases (64%) and CT scan in 12 of 39 cases (31%). Magnetic resonance imaging was clearly more sensitive than CT in the detection of pathology.
The MRI sensitivity in demonstrating the epileptogenic zone determined by EEG (a weak standard reference) was investigated in a level III study (limited evidence). The weakness of the reference standard is in part com- pensated by the number of cases. Pooled data of 809 patients, of whom 370 had temporal lobe abnormalities, were analyzed (38). The sensitivity of MR was 55% for temporal epileptogenic zones and 43% for extratemporal regions as determined by EEG.
Moore et al. (39) addressed the incidence of hippocampal sclerosis in normal subjects in a level III article (limited evidence). They studied 207 patients referred for hearing loss with high-resolution MR and found two cases of unsuspected HS. Retrospective chart review revealed that both
Figure 11.2. T2-inversion recovery MRI. The image corresponds to a patient with intractable epilepsy and EEG findings of left temporal origin. Coronal image at the level of the temporal lobes demonstrates left hip- pocampal sclerosis characterized by reduction in size, and increased signal intensity (arrows), compared to the normal right hippocampus.
patients had seizures. One of them had seizure onset 18 months prior to the MR study that was believed to be associated with hemorrhage from an arteriovenous malformation ipsilateral to the HS.
The most important neuroimaging findings in HS are small size (atrophy) and intense T2 signal of the hippocampus (Table 11.5). These signs have been quantified in a level III retrospective study (limited evi- dence) of 41 MRI of patients who underwent temporal lobectomy (40). The authors compared measurements of the left and right hippocampal for- mations and found them to have 76% sensitivity and 100% specificity for correct seizure lateralization.
Watson et al. (41) performed a comparison among different types of epilepsy with volumetric measuring of the hippocampus in 110 patients with chronic epilepsy of whom 81 had partial seizures (limited evidence) and 17 had pathologically proven HS. All 17 patients with HS had reduced absolute hippocampal volumes, greater than 2 standard deviations (SD) below the mean of the control group. The degree of reduced hippocampal size correlates well with the severity of the HS. Hippocampal volumes were within normal range in all patients with generalized epilepsy, and in extratemporal and extrahippocampal temporal lesions.
Oppenheim et al. (42) proposed that the loss of digitations of the hip- pocampal head on MRI be considered a major criterion of hippocampal sclerosis along with signal abnormality and reduced volume. In a level III case-series study (limited evidence) of 193 patients with intractable epilepsy evaluated retrospectively for atrophy, 63 patients were diagnosed as having mesial temporal sclerosis based on T2 signal changes and loss of digitations of the hippocampal head; 24 of these patients underwent surgery and HS was confirmed in all of them. A control group of 60 patients with frontal seizures and normal MRI was also studied. The digitations of the hippocampal head were evaluated in the two groups. Digitations were not visible in 51 and poorly visible in eight of the 63 patients with mesial temporal sclerosis. Of 24 hippocampi in which HS was confirmed histo- logically, 22 had no MRI-visible digitations. In the control group digitations were sharply visible in 55 and poorly visible in five. The sensitivity and Table 11.5. MRI sensitivity and specificity for hippocampal sclerosis Author Patients Sensitivity Specificity Comments
Spencer, 153 71 ? Review
1994 (38)
Moore et al., 207 100 100 Study conducted in
1999 (39) “normal volunteers”;
2 had HS and prior history of seizures in detail chart review
Jack et al., 41 76 100 Quantitative volumetric
1990 (40) measurement of the
hippocampus
Oppenheim, 63 92 100 Based on loss of
1998 (42) digitations in hippocampal
head
Jack et al., 36 97 ? FLAIR sequence was
1996 (43) compared to SE (91%
sensitivity)
specificity of complete loss of hippocampal head digitations in HS was 92 and 100%, respectively.
Jack et al. (43) in a level II study (moderate evidence) compared the accuracy of FLAIR sequence with that of conventional dual spin-echo (SE) sequence in the identification of increased signal of HS. The study was blinded and controlled with a reference standard criterion of the histopathologic examination. A total of 36 patients were included. The sensitivity was 97% for FLAIR versus 91% for SE in the diagnosis of HS.
The MRI findings as predictors of outcome of temporal lobectomy were assessed in a cohort (moderate evidence) study of 135 patients (44). Sixty months after surgery, 69% of patients with neuroimaging lesions, 50% with HS, and 21% with normal MRIs had no postoperative seizures. Outcome was worse in those with normal MRI examinations.
V. When Should Functional Imaging Be Performed in Seizure Patients and What Is the Study of Choice?
Summary of Evidence: Functional neuroimaging can provide additional data in seizure patients (Table 11.6). The sensitivity of SPECT for localiz- ing epileptogenic focus increases from interictal (44%) to ictal examinations (97%) (moderate evidence). The sensitivity is lower in cases of extratem- poral partial epilepsy in which only the ictal exam is reliable (sensitivity of 92%). Subtraction techniques of the interictal from the ictal study may be helpful; however, the ictal study remains the preferred examination.
Positron emission tomography (PET) is more sensitive than interictal SPECT in localizing temporal and extratemporal epilepsy but far less sen- sitive than ictal SPECT for the localization of epileptogenic foci. More research is needed on MR spectroscopy as a tool to lateralize the epilepsy
Table 11.6. Functional neuroimaging in epileptic focus detection No. of Ictal Postictal Interictal
Author Procedure patients Sen/Spec Sen/Spec Sen/Spec Comments
Spencer, PET 312 — — 84/86*
1994 (38) 33/95**
Spencer, SPECT 80 90/73* 90/73* 66/68* Compared
1994 (38) 81/93** 60/93** to EEG
False localization was found in 10–25%
Newton SPECT 177 97/* 71/* 48/*
et al., 92/* 46/** —
1995 (46)
Devous SPECT 624 97/* 75/* 44/* Compared
et al., 1998 to EEG and/
(45) or surgical
outcome Sen, sensitivity; Spec, specificity.
* In temporal lobe epilepsy.
** In extratemporal lobe epilepsy.
focus. Functional MRI can help to lateralize language in the workup of patients for epilepsy surgery (limited evidence). Functional MRI has a sen- sitivity greater than 91% for language lateralization, when the intracarotid Amytal test (Wada test) is used as the reference standard (Table 11.7). fMRI influences the seizure team’s diagnostic and therapeutic decision making (moderate evidence).
Supporting Evidence: No level I studies (strong evidence) were found. In the level II meta-analysis study (moderate evidence) reported by Spencer (38), ictal SPECT was performed in 108 patients. Eighty epileptogenic foci were localized by SPECT in the temporal lobe. In temporal lobe epilepsy the diagnostic sensitivity for ictal or postictal SPECT is 90% and the speci- ficity of 73%. In extratemporal lobe epilepsy ictal SPECT sensitivity decreases to 81% and specificity increases to 93% when using EEG criteria as the standard of reference. False localization was found in 5% of cases.
Interictal SPECT sensitivity and specificity were found to be significantly lower, at 66% and 68%, respectively, for temporal lobe, and at 60% and 93%, respectively, for extratemporal regions when compared to EEG. False local- ization was found in 10% to 25%. A later level II study (moderate evidence) by Devous et al. (45) presented a second meta-analysis of SPECT brain imaging in partial epilepsy (temporal and extratemporal). The pooled data were gathered from 624 interictal, 101 postictal, and 136 ictal cases. The vast majority of patients were adults. The reference standard was EEG or surgical outcome (162 cases). The results from this study showed that the sensitivity of technetium-99m labeled hexamethyl-propylene amine oxime (HMPAO) SPECT in localizing a temporal lobe epileptic focus increases from 44% in interictal studies to 75% in postictal studies and reaches 97%
in ictal studies. False positives, when compared to surgical outcome, were 4.4% for interictal and 0% for postictal and ictal studies.
Table 11.7. Functional MRI in language lateralization for epilepsy surgery
No. of Reference Sensitivity
Author Paradigm patients standard (%) Comments
Woermann Word 100 Bilateral 91 Cases with
et al., 2003 generation IAT localization-
(49) related epilepsy;
discordant categorization between fMR and IAT includes absence of IAT lateralization in 2 cases
Gaillard Reading 30 Bilateral 93 All cases
et al., 2002 and IAT temporal lobe
(50) naming epilepsy; no
disagreement with reference standard IAT, intracarotid amobarbital test.
A level III study (limited evidence) by Newton et al. (46) of 177 patients with partial epilepsy showed similar results. In 119 patients with known unilateral temporal lobe epilepsy, correct localization by ictal SPECT was demonstrated in 97% of cases. Postictal SPECT was correct in 71% of cases and interictal SPECT in 48% of cases. In extratemporal epilepsy, the yield of ictal SPECT studies was 92% and that of postictal SPECT studies was 46%. The interictal SPECT was of little value in extratemporal epilepsy.
Lewis et al. (47) reported a small level III case series (limited evidence) of 38 patients with seizures not associated with HS using subtraction tech- niques of interictal SPECT from ictal SPECT. In 58% of the studies the sub- traction images “contributed additional information” but were confusing in 9%.
In a level III study (limited evidence) of 312 patients pooled by Spencer (38), PET was compared to EEG for localization. A total of 205 patients had reduced temporal lobe metabolism of which 98% were concordant with EEG findings. Thirty-two patients had hypometabolism in an extratempo- ral location, which was concordant with EEG in 56% of cases. The abnor- malities in 75 patients were not localized by PET, 36 of whom had temporal lobe EEG abnormalities. The diagnostic sensitivity for fluorodeoxyglucose (FDG)-PET was 84% (specificity of 86%) for temporal, and 33% (specificity of 95%) for extratemporal epilepsy, respectively.
A level III study (limited evidence) of single-voxel proton MR spec- troscopy (MRS) was performed to lateralize seizures; MRS was compared with MRI and PET in a case series of 33 HS patients (48). Ratios <0.8 for N-acetylaspartate (NAA)/choline (Cho), and 1.0 for NAA/creatine (Cr) were regarded as abnormal. The sensitivity of MRS and PET in lesion lat- eralization was 85% for both, using MRI as the reference standard. False lateralization rates for MRS and PET were 3% and 6%, respectively. The concordance between MRS and PET was 73%. These results did not influ- ence medical decisions making.
Functional MRI is a new technique based on the ability to detect small amounts of paramagnetic susceptibility produced by blood-oxygen level changes linked to brain cortical activity. Although fMRI is still under inves- tigation and is without Food and Drug Administration (FDA) approval, it has shown promise as an examination that might replace the more inva- sive and expensive Wada intracarotid amobarbital exam in the lateraliza- tion and location of language in patients who are candidates for epilepsy surgery.
Most fMRI papers are based on small samples. One level III case-series paper (limited evidence) (49) describes procedures and results of language dominance lateralization in 100 patients with partial epilepsy performing a covert word generation task. The reference standard was a bilateral Wada intracarotid amobarbital test (IAT) performed in all cases. The results impacted clinical decision making. There was 91% concordance between both tests. Divergent results between the tasks included two cases in which the IAT showed absence of lateralization. Discordance was much higher in cases of left-sided extratemporal epilepsy (25%). In another level III case- series paper (limited evidence), Gaillard et al. (50) described the findings of language lateralization in a group of 30 patients with temporal lobe epilepsy. They used IAT in 21 cases as the reference standard. Eighteen cases had temporal resection and further follow-up. There were no diver- gent results (i.e., methods pointing to the opposite side). One case showed
bilateral fMRI activation and lateralized IAT. Two cases had bilateral IAT and left lateralized fMRI.
The Miami Children’s Hospital Group, in a prospective study (moder- ate evidence), enrolled prospectively 60 subjects to determine the role of fMRI in the diagnostic evaluation and surgical treatment of patients with seizure disorders. In 35 (58.3%) of the 60 patients, the seizure team thought that fMRI results altered patient and family counseling. In 38 (63.3%) of the 60 patients, fMRI avoided further studies including Wada test. In 31 (51.7%) and 25 (41.7%) of the 60 patients, fMRI altered intraoperative mapping plans and surgical approach plans, respectively. In five (8.3%) patients, a two-stage surgery with extraoperative direct electrical stimula- tion mapping was averted and resection could be accomplished in a one- stage surgery. In four (6.7%) patients, the extent of surgical resection was altered because eloquent areas were identified close to the seizure focus.
The authors concluded that fMRI influences the seizure team’s diagnostic and therapeutic decision making (51).
A recent study compared the costs of fMRI and IAT (Wada test) in the workup of language lateralization in patients who where candidates for epilepsy surgery (52). Two age-matched groups were studied prospec- tively. Twenty-one patients had fMRI and 18 IAT. Total direct costs of the Wada test ($1130.01 ± $138.40) and of fMRI ($301.82 ± $10.65) were signif- icantly different (p < .001). The cost of the Wada test was 3.7 times higher than that of fMRI.
Take Home Figure
Figure 11.3 provides a decision-making algorithon for children and adults with seizure disorders.
Figure 11.3. Algorithm for seizure disorders.
Future Research
• To define better the different seizure risk groups so neuroimaging can be tailored appropriately.
• To determine the advantages, limitations, indications, and pitfalls of new imaging studies such as functional MRI and MR spectroscopy.
• To determine the impact that imaging has in the outcome of patients with seizure disorders.
• To perform formal cost-effectiveness analysis of the role of imaging in patients with seizure disorders.
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