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Quanti . tative Magnetic Resonance in Temporal Lobe Epilepsy: Relationshp to Neuropathology and Neuropsychological Function
Todd Lencz, BA,"? Gregory McCarthy, PhD,"t§ Richard A. Bronen, MD,$ Tammy M. Scott, MS,*$ Jaime A. Inserni, MD,? Kimberlee J. Sass, PhD,t Robert A. Novelly, PhD,#B Jung H. Kim, MD,** and Dennis D. Spencer, MD?
Magnetic resonance images (MRIs) were obtained from 25 patients with medically refractory epilepsy of temporal lobe origin (12 on the left, 13 on the right) and 14 right-handed control subjects. The hippocampi and temporal lobes were traced by computer on successive coronal images and the resulting measurements of area were summed for each region. The left and right hippocampi were symmetrical in the control subjects; however, for patients the hippocampus was smaller on the side of the seizure focus. Moreover, the left-right hippocampal ratio significantly differentiated the control subjects from each patient group. The left temporal lobe was significantly smaller than the right in control subjects. The epileptics' temporal lobes were smaller on the side of the seizure focus, compared to the temporal lobes in the control subjects. MRI hippocampal measurements were compared to hippocampal neuronal densities obtained postoperatively. Significant correlations were obtained between the ratio (side ipsilateral to f o c d s i d e contralateral to focus) of MRI hippocampal measurements and neuronal densities in all hippocampal subfields except CA2. Prior to surgery, patients were administered the Wechsler Memory Scale and the verbal Selective Reminding Test. Significant correlations existed between MRI measurements of the left hippocampus and the Wechsler logical memory percent retention scores and between the left temporal lobe measurements and the verbal Selective Reminding Test scores for patients with seizure foci in the left temporal lobe. Lencz
T, McCarthy G, Bronen R A , Scott TM, Inserni JA, Sass KJ, Novelly RA, Kim JH, Spencer DD. Quantitative magnetic resonance imaging in temporal lobe epilepsy: relationship to neuropathology and neuropsychological function. A n n N e u r o l 1992;31:629-637
Resective surgery has proved to be an effective treatment for the relief of medically intractable epilepsy, particularly complex partial seizure disorders of temporal lobe origin [11. Surgical efficacy, however, is dependent on precise localization of the seizure focus. The most accurate method presently used for the localization of seizure foci is chronic seizure monitoring from intracranially placed cortical and/or depth electrodes [2). However, the placement of intracranial electrodes is a major surgical procedure, with its attendant morbidity and expense. Noninvasive procedures that could provide significant localizing (or lateralizing) information might reduce the number of patients who require intracranial seizure monitoring and therefore reduce the morbidity associated with invasive seizure monitoring. The reduction of the time and expense associated with presurgical evaluation would have the added ben-
efit of allowing epilepsy surgery programs to offer resective surgery to more patients. Hippocampal sclerosis (HS), a pattern of neuronal loss and gliosis in the hippocampus, is the most frequent pathology associated with temporal lobe epilepsy C3, 41. Neuronal densities of granule cells and pyramidal cells are greatly reduced IS}, as are the levels of somatostatin and the number of somatostatincontaining neurons in the dentate hilus [6]. The presence of H S is predictive of a good outcome following temporal lobectomy with hippocampectomy 171. Presurgical imaging studies have demonstrated the efficacy of magnetic resonance imaging (MRI) in detecting abnormalities associated with epilepsy @- 161. However, a significant proportion, perhaps 50%, of epileptic patients have no visible structural lesions demonstrated by MRI or computed tomography (CT).
From the 'Neuropsychology Lab, Veterans Administration Medical Center, West Haven, and the Departments of ?Surgery (Neurosurgery), :Diagnostic Imaging, 4Psvchology, TNeurology, and '*Surgery (Neuropathoiogv). Yale University, New Haven, CT
Received Jul 23, 1990, and in revised form Aug 28 and Nov 6, 1991 Accepted for publication Nov 9, 1991 Address correspondence to Dr McCarthy, Neuropsychology Lab 116B1, VA Medical Center, West Haven, CT 06516
Copyright
0 1992 by the American Neurological Association 629
Recently, Jack and colleagues I17) demonstrated that quantitative measures of the hippocampus can be useful in detecting the side of seizure onset in patients with temporal lobe epilepsy. Jackson and coworkers { 18J demonstrated a unilaterally small hippocampus and increased T2 signal intensity associated with HS in a series of 81 patients with temporal lobe epilepsy. The purpose of this study was to investigate further the value of quantitative MRI measurements in identifying HS in patients with temporal lobe epilepsy and to compare these presurgical measures with neuronal densities obtained postoperatively from the hippocampus, and to neuropsychological test scores obtained preoperatively .
Materials and Methods Subjects Patients were drawn from the Yale-Veterans Administration (VA) Epilepsy Surgery Program and all were participants in a multiphase evaluation leading to resective surgery. Twenty-five patients with intractable complex partial seizures were studied. Twelve patients were determined to have onset in the left temporal lobe, while 1 3 had onset in the right temporal lobe. The side of seizure onset was determined by scalp electroencephalography (EEG) with simultaneous audio-video recording of at least three typical ictal events and, in 15 patients, with seizure monitoring from intracranial depth and subdural electrodes. The mean age of all patients was 20.8 years (range, 13-53 yr). Six of the 12 patients with left temporal lobe epilepsy (LTE) and 5 of the 13 with right temporal lobe epilepsy (RTE) were males. Nineteen of the patients were right-handed, and 20 were left hemisphere speech dominant as determined by the intracarotid amobarbital (Amytal) procedure. In addition to the 25 epilepsy patients, 14 neurologically normal volunteers, all of whom were exclusively righthanded as assessed by the Edinburgh handedness questionnaire 1191, were imaged on a 1.5-tesla GE Signa (Schenectady, N Y ) MRI system. A spin-echo, T1-weighted (repetition time [TR] (400mseclecho time [TE) 20 msec) and mulriecho T2-weighted sequences (TR 1700lTE 251501751100) were acquired in the coronal plane with a 16-cm field of view and a 5-mm contiguous slice thickness. The mean age of the volunteers was 28.6 years (range, 18-45 yr). All volunteers provided informed consent. The MRI obtained from both patients and control subjects were examined qualitatively by a neuroradiologist blinded to the quantitative measurements. Two patients had visible lesions that were later determined to be gliomas. A third patient was later found to have scarring on the parahippocampal gyrus, which was not evident on the MRIs on initial examination or review.
Measurement Differences in imaging protocol and analysis separated the 25 patients into two groups. The first group consisted of 19 patients [ 10 with LTE, 9 with RTE) and the second group consisted o f 6 patients (2 with LTE, 4 with RTE). The images obtained from the normal volunteers and the first patient
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group were transferred on magnetic tape to a VAXstation 3500 (Digital Equipment Corp, Maynard, M A ) for measurement. Images from the second patient group were not available on tape and so were digitized from films and measured using a Mac IIx system. O n both systems, operators circumscribed the regions of interest using a cursor-driven program, aided by contrast- and edge-enhancing filters. The pixel count within each region was then tabulated by computer. The operators knew whether an image was from the volunteer or patient group, but were blinded to the patient’s side of seizure onset, as additional patients with extratemporal lobe seizure onsets were also measured. The operators were also unaware of the patient’s diagnosis or the neuroradiologist’s report. The two patient groups did not differ in age at the time of study or age at the time of the first seizure. Each subject’s scans were checked for lateral rotation by comparing the left and right internal auditory canals (IACs). Patients whose IACs both appeared within the same image were labeled “unrotated,” while those whose IACs appeared in adjacent images were designated as “rotated.” Three of the control subjects had rotated images; none of the epileptic patients had rotated images. Measures of the hippocampus and temporal lobe were obtained for each hemisphere. The hippocampus was measured on the TI-weighted coronal images. As the basilar artery bifurcation is generally at the same level as the pes hippocampus, we measured the cross-sectional area of the hippocampus in the three successive images posterior to the pes. These three levels represent largely the midbody and posterior portion of the hippocampus, the same region from which neuronal cell densities have been measured 151. The hippocampus is well demarcated in these coronal images. We used the choroidal fissure as the superior boundary of the hippocmpus, thus including the white matter of the fimbria and alvtus into the measurement. Care was taken to exclude the cerebrospinal fluid (CSF) of the fissure and the temporal horn. The demarcation of the gray matter of the hippocampus and the white matter of the parahippocampal gyms was used as the inferior boundary. This boundary was traced from the bottom of the temporal horn back t u the circummesencephalic cistern (Fig lA, B). Two patients ( 1 with LTE, 1 with RTE) from the first group had no TI -weighted images available and so were not included in the analyses involving the hippocampus. The temporal lobe was measured on proton density images (TR 1700lTE 25), using the T2-weighted images at the same level to distinguish fat and CSF. The most posterior measurement was taken 15 mm posterior to the basilar artery. For control subjects and patients in the first group, measurements were taken in each successive anterior image until none of the temporal lobe could be discerned fa maximum of 13 levels). Only the three most posterior levels of temporal lobe were available for patients in the second group. For the three most posterior levels, tracing began at the most inferior point of the vertical sylvian fissure, proceeded to the horizontal sylvian fissure, and followed the temporal lobe around the circummesencephalic cistern and then lateral to the most superior point of the choroidal fissure. A line was drawn from this point to the starting point to close the region (Fig IC, D). At the next three anterior levels, the tracing proceeded similarly to the cistern and then continued to the superior
Fi g 1 . (A) T1-weighted (TR 400ITE 20) coronal image I cm posterior t o the basilar artery from a control subject. (B) The same image with the hippocampi traced. (C) Proton density ITR 17OOITE 25) coronal image 1 cm posterior to the basilar artery from a dzflerent control subject. ID) The same image with the temporal lobes traced. border of the pes or amygdala before connecting to the starting point. O n more anterior images, the temporal lobe was more easily measured, as it is surrounded almost entirely by CSF. Cross-sectional areas for both the hippocampus and the temporal lobe were summed across levels, yielding an approximation of “volume.” These measures were compared between hemisphere and subject group using analysis of variance (ANOVA).
Neuronal Densities Details on methods for calculating neuronal densities at this institution can be found in the article by Kim and colleagues [ S ] . Briefly, all patients underwent anteromedial temporal lobectomy and radical hippocampectomy. The hippocampus was cut at its posterior curve around the superior colliculus. A coronal section, 2 mm thick, was obtained from the midsection of the hippocampus, placed in 109 buffered formalin in the operating room, and then transferred to the laboratory for further fixation, dehydration, embedment in paraffin, and staining. The paraffin-embedded sections were 6 p m thick. Separate cell counts were obtained for C A I , CA2, CA3, the hilar area, and granular layer of the dentate gyrus. Neuronal nuclei were counted in areas measuring 200 x 400 IJ-m
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for the pyramidal cell fields and 50 x 100 bm for the granule cell layer. The neuronal counts were adjusted using Abercrombie’s formula (8 b m was used for the nuclear diameter of pyramidal neurons and 6 krn for granular neurons) [20). Five separate areas were counted for each subfield and the average for each subfield was computed. The counts of two blinded observers were averaged and reported as the mean cell count per cubic millimeter. In this study, the patients’ hippocampal neuronal densities were expressed as z scores from a normative mean for each subfield. Normative neuronal densities were established using tissue collected during autopsy of 14 adults (mean age, 38.0 yr) who died of nonneurological causes. An overall hippocampal measure, expressing the average of the S z scores for each patient, was also computed. Z score transformations of hippocampal neuronal densities were compared to MRI measures using the Pearson product-moment correlation and the Spearman rank-order correlation.
NeuvopJychologzcu/ iMeusure.r The relationship of neuropsychological test performance and quantitative MRI measures was assessed in the 19 patients comprising the first patient group. Prior to surgery, each patient was administered a battery of neuropsychological tests designed for clinical diagnostic purposes. The mean full-scale IQs (as measured by the Wechsler Adult Intelligence ScaleRevised {WAIS-R)) was 91, with a range of 68 to 117. Only those subjects with full-scale IQs above 70 were included in statistical analyses. Included in the battery was Russel’s adaptation of the Wcchsler Memory Scale (WMSj, which includes the logical memory (prose passage recall) and visual reproduction (abstract design) subtests. For both of the WMS subtests, immediate and delayed reproductions were tested and a percent retention score was computed (delayed recall/ immediate recall x 100). The verbal Selective Reminding Test (vSRT) was also administered to each patient. O n the first trial of the vSRT, the subject is read a list of 12 words and is immediately asked to recall them. O n subsequent trials (up to a limit of 121, the subject is reminded only of those words he or she failed to recall. Standard scoring of the vSRT yields five memory indices; however, these have been shown to be highly intercorrelated [2 11, so this study reports only the total recall score as a representative measure. Scores on these tests of clinical memory were compared with MRI measures of the hippocampus and temporal lobe using both Pearson product-moment correlations and Spearman rank-order correlations.
Results Hippocampal measures did not significantly differ berween left and right hemispheres in normal subjects (Fig 2). Temporal lobe measures, however, were significantly smaller for t h e left than the right hemispheres in normal subjects (F(1,13) = 11.4, p = O.005), a difference of 8c/( (Fig 3). T h e s e asymmetries were present in posterior, middle, and anterior sections of the temporal lobe, although they were somewhat larger anteriorly. T h e s e findings did not change when the analyses were repeated with the three rotated sub-
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Fig 2. Magnetic remnance imuging meu.iirvement.i of the lefi (Lj and right (R) hipporarripi in control .riibjects. patients u i t h left temporal lobe epilep.r.y (LTLE, N = 91, und patiev2t.i with right temporal lobe epilep.iy (RTLE, 71 = 8 ) . For both paiient grciupr. the hippocampus u)as smaller in the f o t d hemisphere than zn the norijicaf hemisphere. Nonforal hippoi-umpiin both patient groups uwe similar to hippocampi in control subjectf.
jects excluded. T h e subjects’ sex had n o effect o n hippocampal size or symmetry, but the females’ temporal lobes w e r e 12.4(7 smaller bilaterally than the males’ temporal lobes (F(l,b) = 5.35, p = 0.033). T h e symmetry of raw hippocampal and temporal measures was tested by ANOVA for t h e patients in t h e first group. Mean patient values, compared t o mean control values, are shown in Figures 2 and 3. Hippocampal measurements were significantly smaller o n the left side in t h e patients with LTE iF(1,8) = ’ . L , p = 0.028) and significantly smaller o n t h e right side in the patients with RTE (F(l,7) = 22.3, p = 0.002). Ebr most of t h e patients wirh LTE, temporal lobe measures were much smaller o n t h e left side, though the presence of a few outliers resulted in a smaller F value (F(1,9) = 4.7, p = 0.05‘);1. Temporal lobe measures did not differ between hemispheres for t h e patierits with RTE. To test t h e ability of hippocampal and temporal lobe measures t o discriminate normal subjects, patients with LTE, and patients with RTE, ratios were computed expressing left over right hemisphere measures. T h e computation of ratios permitted all patients, regardless of imaging protocol, to be considered together a5 scal-
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Fig 3. Magnetic rejonance imaging measurements of the left (L) and rikht (R) temporal lobes in control subjects, patients with It$ temporal lobe epilepsy (LTLE), and those w i t h right temporal lobe epilepsy (RTLE). The Left temporal lobe is smaller than the right in control subjects. This difference is exacerbated in the patients with lejit temporal lobe epilepsy, while the size of the left and right temporal lobes is similar for the patients with right temporal lobe epilepsji.
ing differences were eliminated. The distribution of hippocampal ratios for control subjects and patients is shown in Figure 4. Twenty-two of the 25 patients received a diagnosis of HS (ranging from borderline to severe) following pathological study of the excised hippocampus. These patients are represented in the second and third columns of Figure 4. The ratios for the group with left HS were less than 1.0, while the ratios for the right HS group were greater than 1.0, with most members of each group ( 7 5 p ) exceeding the normal mean by 1 or more standard deviations. The 3 patients with structural lesions did not receive a postoperative diagnosis of HS; these patients are represented in the fourth column of Figure 4. Both patients who had left temporal lobectomies were found to have temporal lobe gliomas, while the patient who had a right temporal lobectomy had scarring on the parahippocampal gyrus. For these 3 patients only, the hippocampus on the lesion side was larger than that on the unaffected side. Between group differences in the hippocampal ratio were tested by ANOVA, excluding the 3 patients without HS as well as 2 patients (1 with LTE, 1 with RTE) who had less than 80% reduction in seizure fre-
Fig 4 . Ratio (ldt hemispherelright hemisphere) of magnetic resonance imaging (MRI) measures of the hippocampus in control subjects (NML) andpatients w i t h l d t (LHS). right (RHS), or no hippocampal sclerosis ( N H S ) ,as diagnosed by postoperative study of excised tissue. Horizontal lines represent the mean ratio i1 standard deziation for control subjects. The circles represent control subjects, triangles represent patients w i t h left temporal lobe epilepsy, and squares represent patients with right temporal lobe epilepsy.
quency following surgery. Group differences were significant (F(2,29) = 34.8, p = 0.0001) and post hoc analyses (using Tukey's test) indicated that ratios in each group differed significantly from the others. Significant group differences were also found for the left/ right temporal lobe ratio (F(2,31) = 4.34, p = 0.02 19). Post-hoc analyses indicated that the ratios in the LTE and RTE groups differed significantly, but that neither differed significantly from the ratios of normals. There was no significant correlation between MRI measurements of the hippocampus and temporal lobe for either the left or right hemisphere.
Correlation with Neuronal Densities Correlations were performed to determine whether the degree of hippocampal asymmetry measured presurgically on MRIs was related to neuronal density in the hippocampal CA fields and dentate gyrus measured in the excised tissue. Neuronal densities for CA1, CA2, CA3, and the hilar area and granule cell layer of the dentate gyrus were obtained for 23 of our patients. The z score neuronal density measures (expressed against autopsy control values) from these five regions and an additional measure expressing the mean of the five z scores were correlated with the ratio of the hippocampal measures from the focal hemisphere divided
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Fig 3. Magnetic resonance image (MRI)-derived hippocampal rati0.r lfocallnonfocal)for patients with lefi temporal lobe epilepsy (triangles) and patients with right temporal lobe epilepsy (squares) plotted against hippocampal neuronal densities (expre.rsed as z .rc-ore dwiations from autopsli control JubjectJ,. Fearsun r = 0.56 (p = 0.01);Spearman p = 0.48 (p < 0.05).
by the measures of the nonfocal hemisphere. The Pearson correlations of all cell regions (except CA2) were positively correlated with this hippocampal ratio at p < 0.05, with correlations ranging from 0.41 to 0.53. The correlation between the mean of the neuronal density z scores and hippocampal ratio was 0.56 ( p = 0.01); a scatter plot of these two variables is presented in Figure 5. Significant correlations for these same regions were also obtained using the Spearman correlations, a measure more immune to the influence of outliers. Correlation with Neuropsychological Function The MRI measures of hippocampus and temporal lobe were expressed both as raw measurements, as well as ratios between hemispheres. Correlation analysis revealed a statistically significant relationship between vSRT recall scores and MRI measurements of the left temporal lobe. This relationship held true for both raw measurements of the left temporal lobe (n = 18, Y = 0.56, p < 0.05; Spearman p = 0.61, p < 0.01) and the ratio of left to right temporal lobe measurements for all patients (n = 18, r = 0.51, p = 0.50, p < 0.05). The left/right temporal lobe ratio for patients with LTE revealed the strongest correlation with vSRT 634 Annals of Neurology Vol 31 No 6 June 1992
scores, as shown in Figure 6 ( Y 0.84, p < 0.005; p = 0.93, p < 0.0005). The percent retention index of the WMS logical memory subtest was significantly correlated with MRI raw measurements of the left hippocampus for all patients (n = 16, r = 0.56, p = 0.52,p < 0.05). Further analysis, separating the LTE and RTE groups, revealed significant correlations between logical memory percent retention and left hippocampal measures for only the patients with LTE ( Y = 0.63, p < 0.08; p = 0.7 I , p < 0.05). Neither the right hippocampal nor the right temporal lobe measures were correlated with scores on any of :he memory testing procedures (verbal or nonverbal). I=
Discussion Previous studies have demonstrated that qualitative assessment of MRIs is a sensitive technique for detecting masses and other structural abnormalities associated with temporal lobe epilepsy [S-16, 181. For example, Jabbari and colleagues [lo] compared the yield of MRIs with the results of CT scans in patients with complex partial epilepsy and found that MRI disclosed a greater percentage of patients with focal cerebral abnormalities (as indicated by a change in signal intensity) than did CT (43 versus 26$%),and that MRI was better than CT in defining the extent of temporolimbic lesions. Similarly, Sperling and associates [ 161 found that T2-weighted MRIs were more valuable than CT or positron emission tomography (PET) for identifying
nonsclerotic epileptogenic lesions of the temporal lobes such as hamartomas, low-grade gliomas, and ectopias. Although Sperling and coauthors reported that no abnormalities were detected by MRI in patients with hippocampal sclerosis, Kuzniecky and coworkers Ell} reported abnormal signals on coronal T2weighted MRI in 11 of 14 patients with severe sclerosis and in 6 of 12 patients with mild to moderate sclerosis. They also reported that MRI was more useful than CT in identifying foreign tissue lesions and gliosis in patients with intractable temporal lobe seizures. Other groups confirmed the greater sensitivity of MRI over CT for identifying pathology [8, 3, 12, 13, 22}, including temporal lobe atrophy and asymmetries [14, 15) in patients with partial complex seizures, and reported that abnormalities identified by MRI corresponded to the epileptogenic focus as defined by EEG [13]. A recent study by Jackson and colleagues [lSl, using coronal images taken orthogonal to the long axis of the hippocampus, demonstrated that increased T2 signal and a unilaterally smaller hippocampus could be used to identify hippocampal sclerosis with a 91% sensitivity in 27 of their 81 patients who received this diagnosis. There remains, however, a sizable percentage of patients for whom qualitative analysis of MRI, as well as CT and PET, could be significantly aided by quantitative methods to help identify abnormalities. Quantitative MRI studies have the potential to reveal subtle disease-related changes in the size of brain structures that may not be apparent by routine clinical assessment and that may not be associated with a visible lesion. MRI can provide excellent detail in visualizing temporal lobe structures including the hippocampus E23). Control studies, using radiological contrast compounds as well as autopsy brain samples, have demonstrated the accuracy of quantitative analysis of MRI [24-26). Measurements of the temporal lobe and hippocampus volume have already proved useful in identifying structural correlates of developmental language disorders 1273 and schizophrenia [28]. In a study from this epilepsy center, Bronen and associates [29} compared hippocampal size (measured by hand by multiplying height by width) in coronal images to neuronal density in 11 patients (only 1 of whom was included in the present analysis). This study demonstrated that a measure made from films during a clinical reading could be useful for identifying HS. Studies by Jack and colleagues [17, 25, 30) extended this approach, using quantitative analysis of MRI to investigate differences in the temporal lobe and hippocampus in patients with temporal lobe epilepsy. Jack and colleagues {25, 30) obtained MRI volume measures in right-handed normal control subjects and reported asymmetries in both the temporal lobe and the hippocampus, with right hemisphere structures being significantly larger than the left ones. This same group
[l?}compared several MRI measures for their utility in identifying HS and localizing the side of seizure onset in a group of 41 patients with temporal lobe epilepsy and no visible structural lesion. They found that quantitative assessment of size differences between the left and right hippocampal formations on T1-weighted MRIs was 76% sensitive and 100% accurate in localizing the side of seizure onset, with the seizures considered localized if the difference in hippocampal sizes was more than 2 standard deviations removed from the normal difference. Similar measurements of the temporal lobes and qualitative analysis of T I - and T2weighted hippocampal images were less sensitive. Our results provided further evidence that quantitative analysis of hippocampal MRIs can accurately identify the laterality of the seizure focus in patients with intractable epilepsy associated with HS. We further demonstrated that the hippocampal MRI measures are significantly correlated with the neuronal densities measured postsurgically. In a recent study, Cascino and associates [ 3 11 also demonstrated that the severity of pathological alterations in the excised hippocampi of epileptic patients correlated with MRI volume measures. It should be noted that in the present study, the degree of correlation was strengthened by a group effect, namely the difference between those patients with HS and those who had another diagnosis. Nevertheless, as Figure 5 demonstrates, this trend was still evident for those patients with HS (i.e., those whose MRI hippocampal ratio was less than 1.0). Furthermore, the raw MRI measures demonstrated, as pathological studies performed after surgery cannot, that the hippocampus contralateral to the side of the seizure focus in both patient groups was similar to that in normal subjects (see Fig 2); in other words, only the focal hippocampus was abnormally small. MRI quantitative techniques were able to differentiate patients with HS as the etiology of their seizure disorder from other patients who did not have HS. The 3 patients in our sample who did not receive the pathological diagnosis of HS and who had relatively preserved neuronal densities also had hippocampal ratios (focal/nonfocal, as determined by EEG) that were greater than 1.0. Therefore, relative symmetry of the hippocampus, or divergence between MRI quantitative findings and EEG findings, may point to factors other than HS in apparently focal temporal lobe seizures. The ability of quantitative MRI analysis to distinguish patients with HS from those without could be useful for determining the nature and extent of surgical resection. We note anecdotally that for the 2 patients who had a less than 80% reduction in seizure frequency, the temporal lobe ratios were greatly discordant from the hippocampal ratios. For these patients, the hippocampus was smaller on the operared side while the tempoL e n a et al: Quantitative MRI in Epilepsy
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ral lobe was smaller on the unoperated side. While this may be a purely chance finding, it suggests that comparisons among multiple structural measures may prove useful in predicting surgical outcome. It should be noted that this discordance was also found in 3 (13%) of the 23 patients who had excellent surgical outcomes. In addition to demonstrating hippocampal atrophy in patients with HS, we found that the entire temporal lobe may be smaller on the side of the seizure focus (although these results were less robust statistically). Temporal lobe measures must be compared to the asymmetry (right side larger than the left) in temporal lobes found in normal subjects, which we found to be 8% and Jack and coworkers [30} found to be 496. This asymmetry appeared exacerbated in the patients with LTE, although this result was statistically marginal (see Fig 3). In the patients with RTE, the “normal” asymmetry of the temporal lobe was not found; rather the right temporal lobe was relatively smaller and therefore equal to the size of the left temporal lobe. Thus, symmetry of the temporal lobes may be indicative of right hemisphere pathology. Unlike Jack and coworkers C25, 301, we found no asymmetry in the size of the hippocampus in normal subjects. Another important finding was the correlation of quantitative MRI measures with measures of cognitive functioning. Many previous studies demonstrated that removal of the hippocampus results in memory impairments [32}, with the nature of the impairment being dependent on both the amount of tissue removed (reviewed by Jones-Gotman [3 31) and the lateralization of surgery [34-371. However, the contribution of the hippocampal resection to the performance deficits observed in these studies was potentially confounded by the fact that surgical manipulation was not limited to the hippocampus. The amygdala, uncus, and a portion of the temporal lobe neocortex and temporal stem were also excised. Studies of memory in patients with hippocampal pathology before they have undergone surgery may better demonstrate the memory impairment that can be attributed to hippocampal dysfunction. Such studies avoid the possible confounds of surgical manipulation. Sass and associates [40, 4 1} examined the relationship between presurgical memory performance and hippocampal neuronal densities obtained after surgical resection. Significant correlations were found between cell densities in one hippocampal subfield (specifically, CA3) and the presurgical performance on the memory component of the intracarotid amobarbital (Amytal) procedure C41, 421 as well as the percent retention index of the WMS logical memory subtest. Sass and associates [40) also found significant correlations between neuronal densities in CA3 and the hilus and scores on the vSRT in patients with left HS. 636 Annals of Neurology
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W e demonstrated significant correlations between left hippocampal MRI measures and the percent retention index of the WMS logical memory subtest. The present study also documented a significant correlation between vSRT performance and left temporal lobe measurements but not left hippocampal measure-. ments. Nevertheless, these findings do not conti-adicr those of Sass and associates [40], since current MRI technology does not allow for quantitative assessment of individual hippocampal subfields. Rather, this seeming discrepancy points to the relative strengths of each methodology. Postsurgical pathological studies allow for greater sensitivity and specificity within the hxppocampus, while the present study provided an opportunity to examine multiple areas of the brain in vivo. To date, only two other studies examined the correlation between MRI hippocampal measures and clinical memory test results. Barr and coworkers 1431 reported reduced hippocampal volumes on the side of the epileptic focus, and showed that these measures significantly correlated with performance on material-specific tasks of memory in a sample of 11 right-handeal patients with a history of febrile convulsions. Similarly, Press and colleagues [44} reported hippocampal abnormalities revealed by MRI in patients with amnesia. Our findings, in addition to those reported by Jack and colleagues [ 173, demonstrated that quantitative analysis of MRI of the hippocampi and temporal lobes provides a relatively inexpensive, noninvasive means of identifying the etiology and laterality of the seizure focus in patients with temporal lobe epilepsy. Our results showed that these measures are predictive of later pathological findings of the diseased hippocampus, and are useful in identifying the neural substrates of memory processes known to be impaired by temporal lobe epilepsy. While these results are promising, legitimate (.oncerns may be raised. For example, the specificity of a smaller hippocampus for seizures of hippocampal onset is as yet unknown. Whether extratemporal seizure onsets also show lateralized hippocampal atrophy is as yet undetermined. The use of difference or ratio measures helps compensate for scaling differences between images, but such measures also presume that one side is normal. While the group data presented here suggest that the hippocampus contralateral to the focus ‘was similar in size to the control hippocampi, individuals with bilateral atrophy might appear normal by ratio or difference measures. lmprovements in quantitative MRI techniques, so they can yield absolute measu.res of volume for each hemisphere, will certainly increase the sensitivity of this technique. This research was supported by the Veterans Adminiwarion, by National Institute of M e n d Health grant MH-05286, arid by National Institutes of Health grant NS-06208
References 1. Engel J Jr. Surgical treatment of the epilepsies. New York: Raven, 1987 2. Spencer SS. Surgical options for uncontrolled epilepsy. Neurol Clin 1986;4:669-695 3. Babb TL, Brown WJ. Pathological findings in epilepsy. In: Engel J Jr. ed. Surgical treatment of the epilepsies. New York: Raven, 1987:511-539 4. Babb TL, Brown WJ, Prerorius J, er al. Temporal lobe volumetric cell densities in temporal lobe epilepsy. Epilepsia 1984; 25:729-740 5. KimJH, Guimaraes PO, Shen MY, etal. Hippocampal neuronal density in temporal lobe epilepsy with and without gliomas. Acta Neuropathol (Berl) 1990;80:41-45 6. De Lanerolle NC, Kim JH, Robbins RJ, Spencer DD. Hippocampal interneuron loss and plasticity in human temporal lobe epilepsy. Brain Res 1989;495:387-395 7. Falconer MA. Genetic and related aetiological factors in temporal lobe epilepsy. Epilepsia 1971;12:13-31 8. Aaron J, New PFJ, Strand R, et al. NMR imaging in temporal lobe epilepsy due LO gliomas. J Comput Assist Tomogr 1984; 8:608-613 9. Bronen RA, Cheung G, Charles J, et al. Mesial temporal sclerosis: comparison of MR, CT, angiography, EEG, and pathology. AJNR 1989;10:897 10. Jabbari B, Gunderson CH, Wippold F, et al. Magnetic resonance imaging in partial complex epilepsy. Arch Neurol 1986; 43:869-872 11. Kuzniecky R, de la Sayette V, Ethier R, et al. Magnetic resonance imaging on temporal lobe epilepsy: pathological correlations. Ann Neurol 1987;22:341-347 12. Laster DW, Penry JK, Moody DM, et al. Chronic seizure disorders: contribution of MR imaging when CT is normal. AJNR 1985;6:177-180 13. Lesser RP, Modic MT, Weinstein MA, et al. Magnetic resonance imaging (1.5 resla) in patients with intractable focal seizures. Arch Neurol 1986;43:367-371 14. McLachlan RS, Nicholson RL, Black S, et al. Nuclear magnetic resonance imaging, a new approach to the investigation of refractory temporal lobe epilepsy. Epilepsia 1985;26:555-562 15. Schorner W, Meencke HJ, Felix R. Temporal lobe epilepsy: comparison of CT and MR imaging. AJR 1987;149:1231-1239 16. Sperling MR, Wilson G, Engel J Jr, et al. Magnetic resonance imaging in intractable partial epilepsy: correlative studies. Ann Neurol 1986;20:57-62 17. Jack CR Jr, Sharbrough FW, Twomey CK, et al. Temporal lobe seizures: lareralization with MR volume measurements of the hippocampal formation. Radiology 1990;175:423-429 18. Jackson G, Berkovic SF, Tress BM, er al. Hippocampal sclerosis can be reliably detected by magnetic resonance imaging. Neurology 1990;40:1869-1875 19. Oldfield RC. The assessment and analysis of handedness: the Edinburgh inventory. Neuropsychologia 1971;9:97-113 20. Abercrombie M. Estimation of nuclear population from microtome sections. Anat Rec 1946;94:239-247 2 1. Larrabee GJ, Curtiss G, Trahan DE. Age, education, and gender effects on the verbal Selective Reminding Test: level and pattern of performance. J Clin Exp Neuropsychol 1988;10:84 (Abstract) 22. Theodore WH, Dorwart R, Holmes M, et al. Neuroimaging in refractory partial seizures: comparison of PET, CT, and MRI. Neurology 1986;36:750-7 59 23. Naidich TP, Daniels DL, Haughton VM, et al. Hippocampal formation and related structures of the limbic lobe: anatomicMR correlation. Part I. Surface features and coronal structures. Radiology 1987;162:747-754
24. Filipek PA, Kennedy D N , Caviness VS, et al. Magnetic resonance imaging-based brain morphomerry: development and application to normal subjects. Ann Neurol I489;25:61-67 25. Jack CR Jr, Gehring DG, Sharbrough FW,et al. Temporal lobe measurements from MR images: accuracy and left-right asymmetry in normal persons. J Comput Assist Tomogr 1988; 12:21-29 26. Zhu XP, Checkley DR, Hickey DS, Isherwood I. Accuracy of area measurements made from MR images compared with computed tomography. J Comput Assist Tomogr 1986;10: 96-102 27. Filipek PA, Kennedy DN, Caviness VS, c r al. In vivo MRIbased volumetric bran analysis in subjects with verbal auditory agnosia. Ann Neurol 1987;22:410 28. Suddarh RL, Chrisriason GW, Torrey EF, et al. Anatomic abnormalities in the brains of monozygoric twins discordant for schizophrenia. N Engl J Med 1990;322:789-794 29. Bronen RA, Cheung G, Charles JT, et al. Imaging findings in hippocampal sclerosis: correlation with pathology. AJNR 1991; 1 2 93 3-940 30. Jack CR Jr, Twomey CK, Zinsmeister AR, er al. Anterior temporal lobes and hippocampal formations: normative volumetric measurements from MR images in young adults. Radiology 1989;172:549-554 31. Cascino GD, Jack CR Jr, Parisi JE, et al. Magnetic resonance imaging-based volume studies in temporal lobe epilepsy: pathological correlations. Ann Neurol 1991;30:3 1-36 32. Scoville W, Milner B. Loss of recent memory after bilateral hippocampal lesions. J Neurol Neurosurg Psychiatry 1957;20: 11-21 33. Jones-Gotman M. Commentary: psychological evaluationtesting hippocampal function. In: Engel J Jr, ed. Surgical rreatment of the epilepsies. New York: Raven, 1987:68-76 34. Jones-Gotman M. Right hippocampal excision impairs learning and recall of a list of abstract designs. Neuropsychologia 1986;24:193-203 35. Kimura D. h g h t temporal lobe damage. Arch Neurol 1963; 8:264-27 1 36. Milner B. Visually-guided maze-learning in man: effects of bilateral hippocampal, bilateral frontal, and unilateral cerebral lesions. Neuropsychologia 1965;3:317-338 37. Milner B. Brain mechanisms suggested by studies of the temporal lobes. In: Darley F, ed. Brain mechanisms underlying speech and language. New York: Grune & Stratton, 1967.122145 38. Milner B. Visual recognition and recall after right temporal-lobe excision in man. Neuropsychologia 1968;6:191-209 39. Warrington EK, James M. An experimental investigation of facial recognition in patients with unilateral cerebral iesions. Cortex 1967;3:317-326 40. Sass KJ, Spencer DD, Kim JH, er al. Verbal memory impairment correlates with hippocampal pyramidal cell density. Neurology 1990;40:1694- 1697 41. Sass KJ, Lencz T , Westerveld M, et al. The neural substrate of memory impairment demonsrrared by the inrracarorid Amytal procedure. Arch Neurol 1991;48:48-52 42. Rausch R, Babb TL, Engel J Jr. Crandall PH. Memory following intracarotid amobarbiral injection contralateral to hippocampal damage. Arch Neurol 1989;46:783-788 43. Barr WB, Ashtari M, Schaul N, Bogerts B. Relations between hippocampal volume and memory in patients with intractable seizures. J Clin Exp Neuropsychol 1990;12 :86 (Abstract) 44. Press GA, Amaral DG, Squire LR. Hippocampal abnormalities in amnesic patients revealed by high-resolution magnetic resonance imaging. Nature 1989;341:54-57
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Quanti . tative Magnetic Resonance in Temporal Lobe Epilepsy: Relationshp to Neuropathology and Neuropsychological Function
Todd Lencz, BA,"? Gregory McCarthy, PhD,"t§ Richard A. Bronen, MD,$ Tammy M. Scott, MS,*$ Jaime A. Inserni, MD,? Kimberlee J. Sass, PhD,t Robert A. Novelly, PhD,#B Jung H. Kim, MD,** and Dennis D. Spencer, MD?
Magnetic resonance images (MRIs) were obtained from 25 patients with medically refractory epilepsy of temporal lobe origin (12 on the left, 13 on the right) and 14 right-handed control subjects. The hippocampi and temporal lobes were traced by computer on successive coronal images and the resulting measurements of area were summed for each region. The left and right hippocampi were symmetrical in the control subjects; however, for patients the hippocampus was smaller on the side of the seizure focus. Moreover, the left-right hippocampal ratio significantly differentiated the control subjects from each patient group. The left temporal lobe was significantly smaller than the right in control subjects. The epileptics' temporal lobes were smaller on the side of the seizure focus, compared to the temporal lobes in the control subjects. MRI hippocampal measurements were compared to hippocampal neuronal densities obtained postoperatively. Significant correlations were obtained between the ratio (side ipsilateral to f o c d s i d e contralateral to focus) of MRI hippocampal measurements and neuronal densities in all hippocampal subfields except CA2. Prior to surgery, patients were administered the Wechsler Memory Scale and the verbal Selective Reminding Test. Significant correlations existed between MRI measurements of the left hippocampus and the Wechsler logical memory percent retention scores and between the left temporal lobe measurements and the verbal Selective Reminding Test scores for patients with seizure foci in the left temporal lobe. Lencz
T, McCarthy G, Bronen R A , Scott TM, Inserni JA, Sass KJ, Novelly RA, Kim JH, Spencer DD. Quantitative magnetic resonance imaging in temporal lobe epilepsy: relationship to neuropathology and neuropsychological function. A n n N e u r o l 1992;31:629-637
Resective surgery has proved to be an effective treatment for the relief of medically intractable epilepsy, particularly complex partial seizure disorders of temporal lobe origin [11. Surgical efficacy, however, is dependent on precise localization of the seizure focus. The most accurate method presently used for the localization of seizure foci is chronic seizure monitoring from intracranially placed cortical and/or depth electrodes [2). However, the placement of intracranial electrodes is a major surgical procedure, with its attendant morbidity and expense. Noninvasive procedures that could provide significant localizing (or lateralizing) information might reduce the number of patients who require intracranial seizure monitoring and therefore reduce the morbidity associated with invasive seizure monitoring. The reduction of the time and expense associated with presurgical evaluation would have the added ben-
efit of allowing epilepsy surgery programs to offer resective surgery to more patients. Hippocampal sclerosis (HS), a pattern of neuronal loss and gliosis in the hippocampus, is the most frequent pathology associated with temporal lobe epilepsy C3, 41. Neuronal densities of granule cells and pyramidal cells are greatly reduced IS}, as are the levels of somatostatin and the number of somatostatincontaining neurons in the dentate hilus [6]. The presence of H S is predictive of a good outcome following temporal lobectomy with hippocampectomy 171. Presurgical imaging studies have demonstrated the efficacy of magnetic resonance imaging (MRI) in detecting abnormalities associated with epilepsy @- 161. However, a significant proportion, perhaps 50%, of epileptic patients have no visible structural lesions demonstrated by MRI or computed tomography (CT).
From the 'Neuropsychology Lab, Veterans Administration Medical Center, West Haven, and the Departments of ?Surgery (Neurosurgery), :Diagnostic Imaging, 4Psvchology, TNeurology, and '*Surgery (Neuropathoiogv). Yale University, New Haven, CT
Received Jul 23, 1990, and in revised form Aug 28 and Nov 6, 1991 Accepted for publication Nov 9, 1991 Address correspondence to Dr McCarthy, Neuropsychology Lab 116B1, VA Medical Center, West Haven, CT 06516
Copyright
0 1992 by the American Neurological Association 629
Recently, Jack and colleagues I17) demonstrated that quantitative measures of the hippocampus can be useful in detecting the side of seizure onset in patients with temporal lobe epilepsy. Jackson and coworkers { 18J demonstrated a unilaterally small hippocampus and increased T2 signal intensity associated with HS in a series of 81 patients with temporal lobe epilepsy. The purpose of this study was to investigate further the value of quantitative MRI measurements in identifying HS in patients with temporal lobe epilepsy and to compare these presurgical measures with neuronal densities obtained postoperatively from the hippocampus, and to neuropsychological test scores obtained preoperatively .
Materials and Methods Subjects Patients were drawn from the Yale-Veterans Administration (VA) Epilepsy Surgery Program and all were participants in a multiphase evaluation leading to resective surgery. Twenty-five patients with intractable complex partial seizures were studied. Twelve patients were determined to have onset in the left temporal lobe, while 1 3 had onset in the right temporal lobe. The side of seizure onset was determined by scalp electroencephalography (EEG) with simultaneous audio-video recording of at least three typical ictal events and, in 15 patients, with seizure monitoring from intracranial depth and subdural electrodes. The mean age of all patients was 20.8 years (range, 13-53 yr). Six of the 12 patients with left temporal lobe epilepsy (LTE) and 5 of the 13 with right temporal lobe epilepsy (RTE) were males. Nineteen of the patients were right-handed, and 20 were left hemisphere speech dominant as determined by the intracarotid amobarbital (Amytal) procedure. In addition to the 25 epilepsy patients, 14 neurologically normal volunteers, all of whom were exclusively righthanded as assessed by the Edinburgh handedness questionnaire 1191, were imaged on a 1.5-tesla GE Signa (Schenectady, N Y ) MRI system. A spin-echo, T1-weighted (repetition time [TR] (400mseclecho time [TE) 20 msec) and mulriecho T2-weighted sequences (TR 1700lTE 251501751100) were acquired in the coronal plane with a 16-cm field of view and a 5-mm contiguous slice thickness. The mean age of the volunteers was 28.6 years (range, 18-45 yr). All volunteers provided informed consent. The MRI obtained from both patients and control subjects were examined qualitatively by a neuroradiologist blinded to the quantitative measurements. Two patients had visible lesions that were later determined to be gliomas. A third patient was later found to have scarring on the parahippocampal gyrus, which was not evident on the MRIs on initial examination or review.
Measurement Differences in imaging protocol and analysis separated the 25 patients into two groups. The first group consisted of 19 patients [ 10 with LTE, 9 with RTE) and the second group consisted o f 6 patients (2 with LTE, 4 with RTE). The images obtained from the normal volunteers and the first patient
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group were transferred on magnetic tape to a VAXstation 3500 (Digital Equipment Corp, Maynard, M A ) for measurement. Images from the second patient group were not available on tape and so were digitized from films and measured using a Mac IIx system. O n both systems, operators circumscribed the regions of interest using a cursor-driven program, aided by contrast- and edge-enhancing filters. The pixel count within each region was then tabulated by computer. The operators knew whether an image was from the volunteer or patient group, but were blinded to the patient’s side of seizure onset, as additional patients with extratemporal lobe seizure onsets were also measured. The operators were also unaware of the patient’s diagnosis or the neuroradiologist’s report. The two patient groups did not differ in age at the time of study or age at the time of the first seizure. Each subject’s scans were checked for lateral rotation by comparing the left and right internal auditory canals (IACs). Patients whose IACs both appeared within the same image were labeled “unrotated,” while those whose IACs appeared in adjacent images were designated as “rotated.” Three of the control subjects had rotated images; none of the epileptic patients had rotated images. Measures of the hippocampus and temporal lobe were obtained for each hemisphere. The hippocampus was measured on the TI-weighted coronal images. As the basilar artery bifurcation is generally at the same level as the pes hippocampus, we measured the cross-sectional area of the hippocampus in the three successive images posterior to the pes. These three levels represent largely the midbody and posterior portion of the hippocampus, the same region from which neuronal cell densities have been measured 151. The hippocampus is well demarcated in these coronal images. We used the choroidal fissure as the superior boundary of the hippocmpus, thus including the white matter of the fimbria and alvtus into the measurement. Care was taken to exclude the cerebrospinal fluid (CSF) of the fissure and the temporal horn. The demarcation of the gray matter of the hippocampus and the white matter of the parahippocampal gyms was used as the inferior boundary. This boundary was traced from the bottom of the temporal horn back t u the circummesencephalic cistern (Fig lA, B). Two patients ( 1 with LTE, 1 with RTE) from the first group had no TI -weighted images available and so were not included in the analyses involving the hippocampus. The temporal lobe was measured on proton density images (TR 1700lTE 25), using the T2-weighted images at the same level to distinguish fat and CSF. The most posterior measurement was taken 15 mm posterior to the basilar artery. For control subjects and patients in the first group, measurements were taken in each successive anterior image until none of the temporal lobe could be discerned fa maximum of 13 levels). Only the three most posterior levels of temporal lobe were available for patients in the second group. For the three most posterior levels, tracing began at the most inferior point of the vertical sylvian fissure, proceeded to the horizontal sylvian fissure, and followed the temporal lobe around the circummesencephalic cistern and then lateral to the most superior point of the choroidal fissure. A line was drawn from this point to the starting point to close the region (Fig IC, D). At the next three anterior levels, the tracing proceeded similarly to the cistern and then continued to the superior
Fi g 1 . (A) T1-weighted (TR 400ITE 20) coronal image I cm posterior t o the basilar artery from a control subject. (B) The same image with the hippocampi traced. (C) Proton density ITR 17OOITE 25) coronal image 1 cm posterior to the basilar artery from a dzflerent control subject. ID) The same image with the temporal lobes traced. border of the pes or amygdala before connecting to the starting point. O n more anterior images, the temporal lobe was more easily measured, as it is surrounded almost entirely by CSF. Cross-sectional areas for both the hippocampus and the temporal lobe were summed across levels, yielding an approximation of “volume.” These measures were compared between hemisphere and subject group using analysis of variance (ANOVA).
Neuronal Densities Details on methods for calculating neuronal densities at this institution can be found in the article by Kim and colleagues [ S ] . Briefly, all patients underwent anteromedial temporal lobectomy and radical hippocampectomy. The hippocampus was cut at its posterior curve around the superior colliculus. A coronal section, 2 mm thick, was obtained from the midsection of the hippocampus, placed in 109 buffered formalin in the operating room, and then transferred to the laboratory for further fixation, dehydration, embedment in paraffin, and staining. The paraffin-embedded sections were 6 p m thick. Separate cell counts were obtained for C A I , CA2, CA3, the hilar area, and granular layer of the dentate gyrus. Neuronal nuclei were counted in areas measuring 200 x 400 IJ-m
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for the pyramidal cell fields and 50 x 100 bm for the granule cell layer. The neuronal counts were adjusted using Abercrombie’s formula (8 b m was used for the nuclear diameter of pyramidal neurons and 6 krn for granular neurons) [20). Five separate areas were counted for each subfield and the average for each subfield was computed. The counts of two blinded observers were averaged and reported as the mean cell count per cubic millimeter. In this study, the patients’ hippocampal neuronal densities were expressed as z scores from a normative mean for each subfield. Normative neuronal densities were established using tissue collected during autopsy of 14 adults (mean age, 38.0 yr) who died of nonneurological causes. An overall hippocampal measure, expressing the average of the S z scores for each patient, was also computed. Z score transformations of hippocampal neuronal densities were compared to MRI measures using the Pearson product-moment correlation and the Spearman rank-order correlation.
NeuvopJychologzcu/ iMeusure.r The relationship of neuropsychological test performance and quantitative MRI measures was assessed in the 19 patients comprising the first patient group. Prior to surgery, each patient was administered a battery of neuropsychological tests designed for clinical diagnostic purposes. The mean full-scale IQs (as measured by the Wechsler Adult Intelligence ScaleRevised {WAIS-R)) was 91, with a range of 68 to 117. Only those subjects with full-scale IQs above 70 were included in statistical analyses. Included in the battery was Russel’s adaptation of the Wcchsler Memory Scale (WMSj, which includes the logical memory (prose passage recall) and visual reproduction (abstract design) subtests. For both of the WMS subtests, immediate and delayed reproductions were tested and a percent retention score was computed (delayed recall/ immediate recall x 100). The verbal Selective Reminding Test (vSRT) was also administered to each patient. O n the first trial of the vSRT, the subject is read a list of 12 words and is immediately asked to recall them. O n subsequent trials (up to a limit of 121, the subject is reminded only of those words he or she failed to recall. Standard scoring of the vSRT yields five memory indices; however, these have been shown to be highly intercorrelated [2 11, so this study reports only the total recall score as a representative measure. Scores on these tests of clinical memory were compared with MRI measures of the hippocampus and temporal lobe using both Pearson product-moment correlations and Spearman rank-order correlations.
Results Hippocampal measures did not significantly differ berween left and right hemispheres in normal subjects (Fig 2). Temporal lobe measures, however, were significantly smaller for t h e left than the right hemispheres in normal subjects (F(1,13) = 11.4, p = O.005), a difference of 8c/( (Fig 3). T h e s e asymmetries were present in posterior, middle, and anterior sections of the temporal lobe, although they were somewhat larger anteriorly. T h e s e findings did not change when the analyses were repeated with the three rotated sub-
632 Annals of Neurology
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Fig 2. Magnetic remnance imuging meu.iirvement.i of the lefi (Lj and right (R) hipporarripi in control .riibjects. patients u i t h left temporal lobe epilep.r.y (LTLE, N = 91, und patiev2t.i with right temporal lobe epilep.iy (RTLE, 71 = 8 ) . For both paiient grciupr. the hippocampus u)as smaller in the f o t d hemisphere than zn the norijicaf hemisphere. Nonforal hippoi-umpiin both patient groups uwe similar to hippocampi in control subjectf.
jects excluded. T h e subjects’ sex had n o effect o n hippocampal size or symmetry, but the females’ temporal lobes w e r e 12.4(7 smaller bilaterally than the males’ temporal lobes (F(l,b) = 5.35, p = 0.033). T h e symmetry of raw hippocampal and temporal measures was tested by ANOVA for t h e patients in t h e first group. Mean patient values, compared t o mean control values, are shown in Figures 2 and 3. Hippocampal measurements were significantly smaller o n the left side in t h e patients with LTE iF(1,8) = ’ . L , p = 0.028) and significantly smaller o n t h e right side in the patients with RTE (F(l,7) = 22.3, p = 0.002). Ebr most of t h e patients wirh LTE, temporal lobe measures were much smaller o n t h e left side, though the presence of a few outliers resulted in a smaller F value (F(1,9) = 4.7, p = 0.05‘);1. Temporal lobe measures did not differ between hemispheres for t h e patierits with RTE. To test t h e ability of hippocampal and temporal lobe measures t o discriminate normal subjects, patients with LTE, and patients with RTE, ratios were computed expressing left over right hemisphere measures. T h e computation of ratios permitted all patients, regardless of imaging protocol, to be considered together a5 scal-
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Fig 3. Magnetic rejonance imaging measurements of the left (L) and rikht (R) temporal lobes in control subjects, patients with It$ temporal lobe epilepsy (LTLE), and those w i t h right temporal lobe epilepsy (RTLE). The Left temporal lobe is smaller than the right in control subjects. This difference is exacerbated in the patients with lejit temporal lobe epilepsy, while the size of the left and right temporal lobes is similar for the patients with right temporal lobe epilepsji.
ing differences were eliminated. The distribution of hippocampal ratios for control subjects and patients is shown in Figure 4. Twenty-two of the 25 patients received a diagnosis of HS (ranging from borderline to severe) following pathological study of the excised hippocampus. These patients are represented in the second and third columns of Figure 4. The ratios for the group with left HS were less than 1.0, while the ratios for the right HS group were greater than 1.0, with most members of each group ( 7 5 p ) exceeding the normal mean by 1 or more standard deviations. The 3 patients with structural lesions did not receive a postoperative diagnosis of HS; these patients are represented in the fourth column of Figure 4. Both patients who had left temporal lobectomies were found to have temporal lobe gliomas, while the patient who had a right temporal lobectomy had scarring on the parahippocampal gyrus. For these 3 patients only, the hippocampus on the lesion side was larger than that on the unaffected side. Between group differences in the hippocampal ratio were tested by ANOVA, excluding the 3 patients without HS as well as 2 patients (1 with LTE, 1 with RTE) who had less than 80% reduction in seizure fre-
Fig 4 . Ratio (ldt hemispherelright hemisphere) of magnetic resonance imaging (MRI) measures of the hippocampus in control subjects (NML) andpatients w i t h l d t (LHS). right (RHS), or no hippocampal sclerosis ( N H S ) ,as diagnosed by postoperative study of excised tissue. Horizontal lines represent the mean ratio i1 standard deziation for control subjects. The circles represent control subjects, triangles represent patients w i t h left temporal lobe epilepsy, and squares represent patients with right temporal lobe epilepsy.
quency following surgery. Group differences were significant (F(2,29) = 34.8, p = 0.0001) and post hoc analyses (using Tukey's test) indicated that ratios in each group differed significantly from the others. Significant group differences were also found for the left/ right temporal lobe ratio (F(2,31) = 4.34, p = 0.02 19). Post-hoc analyses indicated that the ratios in the LTE and RTE groups differed significantly, but that neither differed significantly from the ratios of normals. There was no significant correlation between MRI measurements of the hippocampus and temporal lobe for either the left or right hemisphere.
Correlation with Neuronal Densities Correlations were performed to determine whether the degree of hippocampal asymmetry measured presurgically on MRIs was related to neuronal density in the hippocampal CA fields and dentate gyrus measured in the excised tissue. Neuronal densities for CA1, CA2, CA3, and the hilar area and granule cell layer of the dentate gyrus were obtained for 23 of our patients. The z score neuronal density measures (expressed against autopsy control values) from these five regions and an additional measure expressing the mean of the five z scores were correlated with the ratio of the hippocampal measures from the focal hemisphere divided
L e n a et al: Quantitative MRI in Epilepsy
633
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Fig 3. Magnetic resonance image (MRI)-derived hippocampal rati0.r lfocallnonfocal)for patients with lefi temporal lobe epilepsy (triangles) and patients with right temporal lobe epilepsy (squares) plotted against hippocampal neuronal densities (expre.rsed as z .rc-ore dwiations from autopsli control JubjectJ,. Fearsun r = 0.56 (p = 0.01);Spearman p = 0.48 (p < 0.05).
by the measures of the nonfocal hemisphere. The Pearson correlations of all cell regions (except CA2) were positively correlated with this hippocampal ratio at p < 0.05, with correlations ranging from 0.41 to 0.53. The correlation between the mean of the neuronal density z scores and hippocampal ratio was 0.56 ( p = 0.01); a scatter plot of these two variables is presented in Figure 5. Significant correlations for these same regions were also obtained using the Spearman correlations, a measure more immune to the influence of outliers. Correlation with Neuropsychological Function The MRI measures of hippocampus and temporal lobe were expressed both as raw measurements, as well as ratios between hemispheres. Correlation analysis revealed a statistically significant relationship between vSRT recall scores and MRI measurements of the left temporal lobe. This relationship held true for both raw measurements of the left temporal lobe (n = 18, Y = 0.56, p < 0.05; Spearman p = 0.61, p < 0.01) and the ratio of left to right temporal lobe measurements for all patients (n = 18, r = 0.51, p = 0.50, p < 0.05). The left/right temporal lobe ratio for patients with LTE revealed the strongest correlation with vSRT 634 Annals of Neurology Vol 31 No 6 June 1992
scores, as shown in Figure 6 ( Y 0.84, p < 0.005; p = 0.93, p < 0.0005). The percent retention index of the WMS logical memory subtest was significantly correlated with MRI raw measurements of the left hippocampus for all patients (n = 16, r = 0.56, p = 0.52,p < 0.05). Further analysis, separating the LTE and RTE groups, revealed significant correlations between logical memory percent retention and left hippocampal measures for only the patients with LTE ( Y = 0.63, p < 0.08; p = 0.7 I , p < 0.05). Neither the right hippocampal nor the right temporal lobe measures were correlated with scores on any of :he memory testing procedures (verbal or nonverbal). I=
Discussion Previous studies have demonstrated that qualitative assessment of MRIs is a sensitive technique for detecting masses and other structural abnormalities associated with temporal lobe epilepsy [S-16, 181. For example, Jabbari and colleagues [lo] compared the yield of MRIs with the results of CT scans in patients with complex partial epilepsy and found that MRI disclosed a greater percentage of patients with focal cerebral abnormalities (as indicated by a change in signal intensity) than did CT (43 versus 26$%),and that MRI was better than CT in defining the extent of temporolimbic lesions. Similarly, Sperling and associates [ 161 found that T2-weighted MRIs were more valuable than CT or positron emission tomography (PET) for identifying
nonsclerotic epileptogenic lesions of the temporal lobes such as hamartomas, low-grade gliomas, and ectopias. Although Sperling and coauthors reported that no abnormalities were detected by MRI in patients with hippocampal sclerosis, Kuzniecky and coworkers Ell} reported abnormal signals on coronal T2weighted MRI in 11 of 14 patients with severe sclerosis and in 6 of 12 patients with mild to moderate sclerosis. They also reported that MRI was more useful than CT in identifying foreign tissue lesions and gliosis in patients with intractable temporal lobe seizures. Other groups confirmed the greater sensitivity of MRI over CT for identifying pathology [8, 3, 12, 13, 22}, including temporal lobe atrophy and asymmetries [14, 15) in patients with partial complex seizures, and reported that abnormalities identified by MRI corresponded to the epileptogenic focus as defined by EEG [13]. A recent study by Jackson and colleagues [lSl, using coronal images taken orthogonal to the long axis of the hippocampus, demonstrated that increased T2 signal and a unilaterally smaller hippocampus could be used to identify hippocampal sclerosis with a 91% sensitivity in 27 of their 81 patients who received this diagnosis. There remains, however, a sizable percentage of patients for whom qualitative analysis of MRI, as well as CT and PET, could be significantly aided by quantitative methods to help identify abnormalities. Quantitative MRI studies have the potential to reveal subtle disease-related changes in the size of brain structures that may not be apparent by routine clinical assessment and that may not be associated with a visible lesion. MRI can provide excellent detail in visualizing temporal lobe structures including the hippocampus E23). Control studies, using radiological contrast compounds as well as autopsy brain samples, have demonstrated the accuracy of quantitative analysis of MRI [24-26). Measurements of the temporal lobe and hippocampus volume have already proved useful in identifying structural correlates of developmental language disorders 1273 and schizophrenia [28]. In a study from this epilepsy center, Bronen and associates [29} compared hippocampal size (measured by hand by multiplying height by width) in coronal images to neuronal density in 11 patients (only 1 of whom was included in the present analysis). This study demonstrated that a measure made from films during a clinical reading could be useful for identifying HS. Studies by Jack and colleagues [17, 25, 30) extended this approach, using quantitative analysis of MRI to investigate differences in the temporal lobe and hippocampus in patients with temporal lobe epilepsy. Jack and colleagues {25, 30) obtained MRI volume measures in right-handed normal control subjects and reported asymmetries in both the temporal lobe and the hippocampus, with right hemisphere structures being significantly larger than the left ones. This same group
[l?}compared several MRI measures for their utility in identifying HS and localizing the side of seizure onset in a group of 41 patients with temporal lobe epilepsy and no visible structural lesion. They found that quantitative assessment of size differences between the left and right hippocampal formations on T1-weighted MRIs was 76% sensitive and 100% accurate in localizing the side of seizure onset, with the seizures considered localized if the difference in hippocampal sizes was more than 2 standard deviations removed from the normal difference. Similar measurements of the temporal lobes and qualitative analysis of T I - and T2weighted hippocampal images were less sensitive. Our results provided further evidence that quantitative analysis of hippocampal MRIs can accurately identify the laterality of the seizure focus in patients with intractable epilepsy associated with HS. We further demonstrated that the hippocampal MRI measures are significantly correlated with the neuronal densities measured postsurgically. In a recent study, Cascino and associates [ 3 11 also demonstrated that the severity of pathological alterations in the excised hippocampi of epileptic patients correlated with MRI volume measures. It should be noted that in the present study, the degree of correlation was strengthened by a group effect, namely the difference between those patients with HS and those who had another diagnosis. Nevertheless, as Figure 5 demonstrates, this trend was still evident for those patients with HS (i.e., those whose MRI hippocampal ratio was less than 1.0). Furthermore, the raw MRI measures demonstrated, as pathological studies performed after surgery cannot, that the hippocampus contralateral to the side of the seizure focus in both patient groups was similar to that in normal subjects (see Fig 2); in other words, only the focal hippocampus was abnormally small. MRI quantitative techniques were able to differentiate patients with HS as the etiology of their seizure disorder from other patients who did not have HS. The 3 patients in our sample who did not receive the pathological diagnosis of HS and who had relatively preserved neuronal densities also had hippocampal ratios (focal/nonfocal, as determined by EEG) that were greater than 1.0. Therefore, relative symmetry of the hippocampus, or divergence between MRI quantitative findings and EEG findings, may point to factors other than HS in apparently focal temporal lobe seizures. The ability of quantitative MRI analysis to distinguish patients with HS from those without could be useful for determining the nature and extent of surgical resection. We note anecdotally that for the 2 patients who had a less than 80% reduction in seizure frequency, the temporal lobe ratios were greatly discordant from the hippocampal ratios. For these patients, the hippocampus was smaller on the operared side while the tempoL e n a et al: Quantitative MRI in Epilepsy
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ral lobe was smaller on the unoperated side. While this may be a purely chance finding, it suggests that comparisons among multiple structural measures may prove useful in predicting surgical outcome. It should be noted that this discordance was also found in 3 (13%) of the 23 patients who had excellent surgical outcomes. In addition to demonstrating hippocampal atrophy in patients with HS, we found that the entire temporal lobe may be smaller on the side of the seizure focus (although these results were less robust statistically). Temporal lobe measures must be compared to the asymmetry (right side larger than the left) in temporal lobes found in normal subjects, which we found to be 8% and Jack and coworkers [30} found to be 496. This asymmetry appeared exacerbated in the patients with LTE, although this result was statistically marginal (see Fig 3). In the patients with RTE, the “normal” asymmetry of the temporal lobe was not found; rather the right temporal lobe was relatively smaller and therefore equal to the size of the left temporal lobe. Thus, symmetry of the temporal lobes may be indicative of right hemisphere pathology. Unlike Jack and coworkers C25, 301, we found no asymmetry in the size of the hippocampus in normal subjects. Another important finding was the correlation of quantitative MRI measures with measures of cognitive functioning. Many previous studies demonstrated that removal of the hippocampus results in memory impairments [32}, with the nature of the impairment being dependent on both the amount of tissue removed (reviewed by Jones-Gotman [3 31) and the lateralization of surgery [34-371. However, the contribution of the hippocampal resection to the performance deficits observed in these studies was potentially confounded by the fact that surgical manipulation was not limited to the hippocampus. The amygdala, uncus, and a portion of the temporal lobe neocortex and temporal stem were also excised. Studies of memory in patients with hippocampal pathology before they have undergone surgery may better demonstrate the memory impairment that can be attributed to hippocampal dysfunction. Such studies avoid the possible confounds of surgical manipulation. Sass and associates [40, 4 1} examined the relationship between presurgical memory performance and hippocampal neuronal densities obtained after surgical resection. Significant correlations were found between cell densities in one hippocampal subfield (specifically, CA3) and the presurgical performance on the memory component of the intracarotid amobarbital (Amytal) procedure C41, 421 as well as the percent retention index of the WMS logical memory subtest. Sass and associates [40) also found significant correlations between neuronal densities in CA3 and the hilus and scores on the vSRT in patients with left HS. 636 Annals of Neurology
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W e demonstrated significant correlations between left hippocampal MRI measures and the percent retention index of the WMS logical memory subtest. The present study also documented a significant correlation between vSRT performance and left temporal lobe measurements but not left hippocampal measure-. ments. Nevertheless, these findings do not conti-adicr those of Sass and associates [40], since current MRI technology does not allow for quantitative assessment of individual hippocampal subfields. Rather, this seeming discrepancy points to the relative strengths of each methodology. Postsurgical pathological studies allow for greater sensitivity and specificity within the hxppocampus, while the present study provided an opportunity to examine multiple areas of the brain in vivo. To date, only two other studies examined the correlation between MRI hippocampal measures and clinical memory test results. Barr and coworkers 1431 reported reduced hippocampal volumes on the side of the epileptic focus, and showed that these measures significantly correlated with performance on material-specific tasks of memory in a sample of 11 right-handeal patients with a history of febrile convulsions. Similarly, Press and colleagues [44} reported hippocampal abnormalities revealed by MRI in patients with amnesia. Our findings, in addition to those reported by Jack and colleagues [ 173, demonstrated that quantitative analysis of MRI of the hippocampi and temporal lobes provides a relatively inexpensive, noninvasive means of identifying the etiology and laterality of the seizure focus in patients with temporal lobe epilepsy. Our results showed that these measures are predictive of later pathological findings of the diseased hippocampus, and are useful in identifying the neural substrates of memory processes known to be impaired by temporal lobe epilepsy. While these results are promising, legitimate (.oncerns may be raised. For example, the specificity of a smaller hippocampus for seizures of hippocampal onset is as yet unknown. Whether extratemporal seizure onsets also show lateralized hippocampal atrophy is as yet undetermined. The use of difference or ratio measures helps compensate for scaling differences between images, but such measures also presume that one side is normal. While the group data presented here suggest that the hippocampus contralateral to the focus ‘was similar in size to the control hippocampi, individuals with bilateral atrophy might appear normal by ratio or difference measures. lmprovements in quantitative MRI techniques, so they can yield absolute measu.res of volume for each hemisphere, will certainly increase the sensitivity of this technique. This research was supported by the Veterans Adminiwarion, by National Institute of M e n d Health grant MH-05286, arid by National Institutes of Health grant NS-06208
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