Myoinositol Abnormalities in Temporal Lobe Epilepsy
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Epilepsia, 44(6):815–821, 2003 Blackwell Publishing, Inc. C 2003 International League Against Epilepsy
Myoinositol Abnormalities in Temporal Lobe Epilepsy ∗ R. Mark Wellard, ∗ †Regula S. Briellmann, ∗ ‡James W. Prichard, ∗ Ari Syngeniotis, and ∗ †Graeme D. Jackson ∗ Brain Research Institute, †University of Melbourne, Austin and Repatriation Medical Center, Heidelberg West, Australia; and ‡Department of Neurology, Yale Medical School, New Haven, Connecticut, U.S.A.
Summary: Purpose: This study used magnetic resonance spectroscopy (MRS) to examine metabolite abnormalities in the temporal and frontal lobe of patients with temporal lobe epilepsy (TLE) of differing severity. Methods: We investigated myoinositol in TLE by using shortecho MRS in 34 TLE patients [26 late onset (LO-TLE), eight hippocampal sclerosis (HS-TLE)], and 16 controls. Single-voxel short-echo (35 ms) MR spectra of temporal and frontal lobes were acquired at 1.5 T and analyzed by using LCModel. Results: The temporal lobe ipsilateral to seizure origin in HSTLE, but not LO-TLE, had reduced N-acetylaspartate (NA) and
elevated myoinositol (MI; HS-TLE NA, 7.8 ± 1.9 mM, control NA, 9.2 ± 1.3 mM; p < 0.05; HS-TLE MI, 6.1 ± 1.6 mM, control mI 4.9 ± 0.8 mM, p< 0.05). Frontal lobe MI was low in both patient groups (LO-TLE, 4.3 ± 0.8 mM; p < 0.05; HS-TLE, 3.6 ±.05 mM; p < 0.001; controls, 4.8 ± 0.5 mM). Ipsilateral frontal lobes had lower MI (3.8 ± 0.7 mM; p < 0.01) than contralateral frontal lobes (4.3 ± 0.8 mM; p < 0.05). Conclusions: MI changes may distinguish between the seizure focus, where MI is increased, and areas of seizure spread where MI is decreased. Key Words: Myoinositol—MR-negative TLE—MR spectroscopy—Late-onset TLE.
The metabolites most easily detected by brain magnetic resonance spectroscopy (MRS) are N-acetylaspartate (NAA), choline-containing compounds (Cho), and creatine plus phosphocreatine (Cr). NAA is a robust metabolite, which coresonates with a related compound, N-acetyl aspartyl glutamate (NAAG). These two compounds are usually reported as a single resonance (NA). Low concentrations of NA are interpreted as a marker of neuronal loss or dysfunction (1). Variations in Cho are regarded as reflecting altered membrane turnover, and Cr is part of the brain’s energy-storage system. These metabolites are measured reliably by either long-echo MRS (TE >130 ms) or short-echo MRS acquisition (TE 0.7). Epilepsia, Vol. 44, No. 6, 2003
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Choline Creatine Myoinositol Glx NA
Temporal lobe metabolite concentrations in TLE patients and controls
Controls (32)
LO-TLE ipsi (26)
LO-TLE contra (26)
HS-TLE ipsi (8)
HS-TLE contra (8)
1.6 ± 0.4 5.5 ± 1.2 4.9 ± 0.8 13.1 ± 3.0 9.2 ± 1.3
1.6 ± 0.3 5.4 ± 0.8 4.8 ± 0.8 12.1 ± 2.9 8.6 ± 1.0
1.6 ± 0.3 5.5 ± 1.0 5.0 ± 0.9 11.8 ± 2.5 8.6 ± 1.0
1.9 ± 0.3 6.0 ± 0.8 6.1 ± 1.6a 13.0 ± 3.0 7.8 ± 1.9a
1.6 ± 0.5 5.5 ± 1.0 4.5 ± 1.0 13.7 ± 3.6 8.5 ± 2.1
Values expressed in mM. Results shown for ipsilateral temporal lobe (ipsi) and contralateral (contra) temporal lobe. TLE, temporal lobe epilepsy; Glx, glutamine + glutamate; NA, total N-acetylaspartyl content. a p < 0.05 compared with controls (analysis of variance, corrected for multiple comparisons). No significant difference was found between left and right temporal lobe metabolite concentrations (p > 0.1).
Technical aspects The effects of greater magnetic susceptibility in reducing spectral quality were apparent in spectra recorded from the TL, evident as greater baseline distortion and lower signal-to-noise ratio of NA (15.3 ± 4.6), relative to that recorded from the frontal lobe (38.1 ± 8.1; p < 0.0001, unpaired t test). Frontal lobe spectra also were of consistently narrower linewidth (3.5 ± 0.5 Hz) than were those from the TL (4.9 ± 0.77 and 7.0 ± 1.12 Hz, respectively; p < 0.0001, unpaired t test). In neither frontal nor TL spectra were there any differences in linewidth between groups, indicating that variability in spectral quality was unlikely to contribute to measured metabolite differences among groups. Figure 3 illustrates the higher quality of spectra recorded from right frontal lobe (left side) compared with the right TL (right side).
tients, suggesting that these changes are characteristic of the seizure focus. In both HS-TLE and LO-TLE, frontal lobe MI was reduced, a finding that appears to indicate secondary involvement of this brain region, to which TL
MRS and clinical findings No correlation was found between either the number of GTCSs or the duration of epilepsy and any metabolite in the temporal and frontal lobes (linear regression analysis, p > 0.2 for all comparisons). DISCUSSION This MRS study demonstrates metabolic changes in patients with two forms of TLE. Decreased NA and increased MI were present in the ipsilateral TL of the HS-TLE paTABLE 4. Frontal lobe metabolite concentrations in TLE patients and controls (n) Choline Creatine Myoinositol Glx NA
Controls (16)
LO-TLE (26)
HS-TLE (6)
1.8 ± 0.2 6.1 ± 0.7 4.8 ± 0.5 10.7 ± 1.5 10.4 ± 1.3
1.7 ± 0.3 5.9 ± 0.8 4.3 ± 0.8a 11.0 ± 2.1 9.8 ± 0.9
1.6 ± 0.2 6.0 ± 0.4 3.6 ± 0.5b 12.7 ± 2.7a 9.7 ± 1.3
Values expressed in mM. < 0.05; b p < 0.001, compared with controls (analysis of variance, corrected for multiple comparisons). See Table 3 for explanation of abbreviations. ap
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FIG. 2. Plots of frontal lobe myoinositol (MI) concentration, comparing control MI for (a) late-onset temporal lobe epilepsy (LOTLE) and hippocampal sclerosis (HS)-TLE groups, and (b) showing the distribution of MI concentrations for regions ipsilateral or contralateral to seizure focus for LO-TLE and HS-TLE combined. The mean and standard deviation are shown for each group by the open square and error bars (compared with controls: ∗p < 0.05; ∗∗p < 0.01, and ∗∗∗p < 0.001). a, b: Distribution of points composing the other component of the figure.
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FIG. 3. Spectra from right frontal lobe (left side; a–c) and right temporal lobe (right side; d–f) showing the spectral quality (higher from the frontal lobe). Spectra from controls (top row, a, d), late-onset (middle row, b, e) and hippocampal sclerosis (HS; bottom row, c, f) are shown. Metabolites chemical shifts are myoinositol (MI), 3.6 ppm; cholinecontaining compounds (Cho), 3.2 ppm; creatine + phosphocholine (Cr), 3.0 ppm; glutamine + glutamate (Glx), 2.3– 2.2 ppm; and total N-acetylaspartyl compounds (NA), 2.0 ppm. The MI component of the LCModel-fitted spectrum is inset. The dotted line marks the MI signal in each spectrum. Note the reduced NA in the HS temporal lobe (f) and reduced MI in HS frontal lobe (c).
seizure discharge commonly spreads. The degree of reduced frontal lobe MI was greater in patients with HS and on the side ipsilateral to the seizure focus in both patient groups (Fig. 1). This suggests to us that low frontal MI may reflect the degree of exposure of the frontal lobe to seizure discharge originating in the TL. The TL abnormalities in HS-TLE were expected and are consistent with other reports (5,7,16–19). Reduced NA is usually regarded as reflecting neuronal loss or dysfunction. Increased MI has been reported as a consequence of induction of Na+ /MI cotransporter (SMIT) after seizure activity (20) associated with glial proliferation in the seizure focus. This is consistent with the principal histopathologic features of TLE with HS, which are neuron loss and gliosis (21) and widespread molecular layer gliosis. The opposite MI change in the frontal lobes requires a different explanation, which we believe may lie in adaptation of normal brain tissue to constant invasion by seizure
discharge from an adjacent area. The role of MI as an organic osmolyte (3) supports this idea. Studies in animals have identified rapid reduction of MI as a mechanism of brain volume regulation after hyponatremia, with levels being slow to return to normal on normalization of the osmotic environment (22). Seizure discharge causes brain edema (23). TL seizures are known to spread to the frontal lobes, preferentially to the ipsilateral side, but both sides may be entrained by seizure discharge originating on either side (24). The finding that MI concentrations were reduced in both TLE groups distant to the seizure focus is not unprecedented. Others have reported observations of various brain abnormalities distant from the epileptic focus. Functional abnormalities in severe TLE, affecting regions more extensive than the seizure focus, have been documented by positron emission tomography (PET) (25), single-photon emission computed tomography (SPECT) (26,27), and also by MRS (8–10). A recent report also Epilepsia, Vol. 44, No. 6, 2003
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showed reduced frontal lobe NA in severe refractory TLE (28). The reduced frontal lobe MI may be due to either a short-term change after recent seizure activity or a cumulative effect of chronic seizures. Collection of accurate information on seizure history is difficult, because it must rely largely on reports of medically untrained people who vary in skill and motivation. Hence, comparison of MRS data with seizure-activity estimates may fail to identify important early signs of secondary brain damage caused by seizure discharge. The observation of reduced hemicranial volume in the hemisphere ipsilateral to the side of HS (29) and correlating with hippocampal T2 relaxation measurements indicates the presence of long-term changes as a consequence of secondary effects of seizures. This is consistent with MI being affected by overall exposure to seizure discharge. Observer bias cannot account for the MI findings, as the algorithm used by the LCModel software is rater independent. Data quality was not different across the groups. The LCModel software uses a set of reference spectra and external calibration to determine metabolite tissue concentrations. The concentrations reported in this study are consistent with those reported by others (7,30–32). Slightly higher concentrations were reported by one group (30) after correcting for tissue CSF content, but this is unlikely to affect our findings. Although changes in tissue composition associated with volume loss could alter the relative metabolite concentrations, the pattern of metabolite change observed in the patient groups, relative to controls, is unlikely to result from an alteration in grey/white matter content in the frontal lobe region examined, because the white matter concentration of MI is greater than that in grey matter (33). The change in MI concentration is unlikely to result from a reduction in frontal lobe volume, because other metabolite concentrations also would be expected to change in parallel. These factors suggest that the observed MI changes are metabolic. It is apparent from Fig. 1 that between the patient groups, a gradient in MI content of the frontal lobes is related to expected seizure load. This relation was observed when seizure load was estimated either with respect to the side most likely to experience seizure spread (the same hemisphere as the seizure focus) or in relation to the patient group with the greatest seizure frequency (HS-TLE). In the HS-TLE group, we also observed an increase of frontal lobe glutamine and Glx. We have no explanation for this observation, but elevated Glx may be due to the greater seizure load experienced by this group. Some AEDs have been associated with a reduction in the metabolite MI. Table 2 shows the range of drugs used by each patient group. The drugs [carbamazepine (CBZ), valproic acid (VPA)] associated with MI reduction (34) and hyponatremia (35) are not specific or ubiquitous in either group of patients. However, polytherapy was more Epilepsia, Vol. 44, No. 6, 2003
often used in the HS-TLE group. We therefore have no a priori reason to suspect a specific medication effect in either group. We doubt that unreported medication effects influenced our results, because eight patients in the LOTLE group were medication free at the time of measurement and were not different from medicated patients in the same group. In contrast to HS-TLE, LO-TLE patients showed no detectable TL abnormalities of MI. This could be a falsenegative result due to the effects of magnetic susceptibility variations that raise the threshold for MI detection in the TLs compared to the frontal lobes (Fig. 2). Alternatively, two pathophysiologic processes may occur simultaneously in the epileptic TL: the seizure-generation process due to primary pathology, and secondary effects of frequent local seizure discharge. How and in what volume of tissue this occurs is not known. Our voxels were large and included lateral temporal cortex as well as medial structures. Changes occurring in only a part of this region may not have been detected. Absence of abnormalities in NA, Cr, and Cho from the seizure-focus region in LO-TLE is consistent with the literature. No abnormalities of the NA/Cr ratio were reported in a small group of medicated TLE patients seizure free for ≥6 months (36). Only a few studies investigating newly diagnosed TLE (16,37,38) suggest that metabolite changes may be detected early in the course of the epilepsy process. Our study shows that after only 4 ± 0.9 GTCSs, metabolite changes occur in areas of seizure spread. This suggests that secondary seizure effects are present in patients with very mild seizure disorders and that MI may be a sensitive marker of these effects. Whether recency, frequency, or total number of seizures is the most important determinant of MI is not specifically addressed by the current study. Our interpretation of our results is that reduced frontal lobe MI is a consequence of either a short-term change after recent seizure activity or a cumulative effect from chronic seizures. The lack of any correlation of MI with seizure frequency may indicate a greater sensitivity of MI to recent seizure load or recent seizure discharge than to lifetime seizure load. However, chronic changes in organic osmolytes caused by frequent invasion of the frontal lobes by subclinical seizure discharge (spreading from the TLs) may be effective in initiating changes in MI. Such undetected chronic seizure activity may make frontal regions susceptible to cumulative effects of osmotic stress, which has been associated with chronic low MI concentrations (33), may eventually become permanent. MI could be a useful marker of the biologic effects of both overt and occult seizure activity, providing an important early sign of secondary brain damage. In summary, our finding of reduced temporal lobe NAA and increased MI in HS-TLE patients confirms previous reports. This increased MI in the focus most likely reflects
MYOINOSITOL IN TLE astrocytosis. Our new finding is reduced frontal lobe MI in all TLE patients, regardless of etiology. In this setting, reduced MI possibly reflects an osmolyte change due to the secondary effects of seizures. MI changes may distinguish between the seizure focus, where MI is increased, and areas of seizure spread where MI is decreased. Acknowledgment: This research was supported by the Sir Edward Dunlop Medical Research Foundation, the L.E.W. Carty Medical Research Foundation, the Brain Imaging Research Foundation, and the NHMRC. We acknowledge the support of the Comprehensive Epilepsy Program at the Austin and Repatriation Medical Center, Heidelberg, Prof. S. Berkovic and the First Seizure Clinic, Dr. M. Newton, and Dr. M.A. King.
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