Monitoring Neuronal Damage in Temporal Lobe Epilepsy with Magnetic Resonance Imaging and Spectroscopy

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Monitoring Neuronal Damage in Temporal Lobe Epilepsy with Magnetic Resonance Imaging and Spectroscopy

Andrea Bernasconi, M.D.

Quantitative MRI techniques have the advantage of being reliable, reproducible and well tolerated by patients. These techniques could help in identifying patients that are at risk of secondary cerebral damage. Prospective longitudinal studies have the potential to adequately address the question whether epilepsy induces secondary brain damage. However, the appropriate time interval between MRI scans to quantify structural and functional brain changes remains to be determined. In this setting, MR-based methods to assess secondary neuronal damage could provide a surrogate marker for the acute evaluation of neuroprotective agents.

There is a controversy over whether seizures cause damage to the brain. Animal studies strongly suggest that even single seizures are harmful 1.

Hippocampal sclerosis is a common pathological finding associated with temporal lobe epilepsy (TLE) as demonstrated at autopsy 2,3 and in tissue resected during surgery 4-6. The etiology and pathogenesis of hippocampal sclerosis remain poorly understood. TLE appears to evolve from an initial precipitating injury, perhaps severe febrile seizures during childhood, which occurs many years before the onset of chronic epilepsy. It has been known for many years that convulsive status epilepticus may result in significant hippocampal and cerebral damage, likely to be due to excitotoxicity 7,8 . It is less clear whether repeated brief seizures such as individual tonic-clonic and complex partial seizures can cause secondary neuronal damage.

Non-invasive in vivo magnetic resonance imaging (MRI) studies have the potential to identify and quantify cerebral damage secondary to epilepsy. Volumetric MRI

Seizure-associated damage in TLE may be due to an early insult such as prolonged febrile convulsions in childhood 9 or be secondary to seizures themselves. Cerebral damage may be reflected in gray or white matter volume loss. The excellent anatomical resolution of T1-weighted MRI images allows a reliable manual segmentation of mesial temporal lobe structures such hippocampus, the amygdala and the entorhinal cortex. It has been shown that hippocampal atrophy on MRI correlates with hippocampal neuronal loss 10,11. These volumetric measurements are established methods to quantify damage in the mesial temporal lobe in patients with TLE and have demonstrated to be clinically useful in lateralizing the epileptic focus 12-15. Segmentation of the neocortical gray and white matter on MRI is also possible and can be done manually 16-18. However, such measurements are laborious. Automatic methods for segmenting the hippocampus and neocortex are available 19, but validation studies are needed in order to rely on their results.

Most cross-sectional studies have shown an association between hippocampal atrophy, seizure frequency and duration of epilepsy 20-24. In a study of 82 consecutive patients with refractory TLE, we found a negative correlation between the volume of the hippocampus ipsilateral to the seizure focus and duration of epilepsy, suggesting a progressive course in the disease. Also, the hippocampus was smaller in patients with frequent secondarily generalized seizures 25. Although cross-sectional studies provide a valuable information, they are limited mainly by the fact that small changes in structure over time may be masked by large biological variability across subjects. On the other hand, prospective longitudinal studies have the potential to adequately address the question whether seizures induce secondary brain damage. Prospective follow-up MRI studies, mainly limited to few single case reports, have documented the development of hippocampal sclerosis after severe initial injury, such as prolonged febrile seizures 7,26,27. A recent longitudinal quantitative MRI study of 24 patients with newly diagnosed and mild TLE showed ipsilateral hippocampal volume decrease of 9% over a period of 3.5 ± 0.7 years that was associated with the number of generalized seizures between the scans 28. Another longitudinal community-based study in 86 patients with newly diagnosed seizures who underwent serial MRI scans 3.5 year apart did not show an increased risk of seizure-induced structural cerebral damage 29. However, the power of the analysis in this study was limited by the heterogeneity of the epileptic syndromes and causes. On the other hand, structural changes may develop over a longer period that the design of the current longitudinal studies. This is supported by a recent observation in a patient in whom hippocampal atrophy became apparent 4.25 years after the beginning of habitual seizures 30.

Magnetic resonance spectroscopy

Magnetic resonance spectroscopy (MRS) shares the advantages of MRI in being non-invasive. Unlike conventional MRI, which provides structural information based on signals from water protons, proton magnetic resonance spectroscopic imaging (1H-MRSI) provides information about the chemical composition of the brain. 1H-MRSI spectra as acquired from studying TLE are characterized by three major peaks: N-acetylaspartate (NAA), creatine (Cr) and choline. Using specific antibodies, it has been demonstrated that NAA is localized exclusively in neurons and their projections throughout the central nervous system 31-33. Therefore, NAA is used as a putative neuronal marker, and a reduction in NAA levels as assessed by 1H-MRSI has been a useful tool for quantifying neuronal and axonal integrity in vivo.

The most common application of MR spectroscopy in epilepsy has been the non-invasive lateralization of the epileptic focus. 1H-MRSI reveals abnormally low resonance intensities of NAA/Cr within the temporal lobes of TLE patients 34-38. The abnormally low NAA/Cr is not restricted to the hippocampus, but is found diffusely within the ipsilateral and, in about half the patients, within the contralateral temporal lobe as well 39.

The ability of MRS to detect abnormalities (about 80%) is similar to the ability of structural MRI to detect hippocampal volume loss 40. When the two methods are combined, the ability to detect abnormalities increases to 93% 40. Abnormalities of metabolite profiles may be found in temporal lobes of patients with normal hippocampal volume 41,42 indicating that MRS may be more sensitive for detecting pathology.

Because NAA is measured in a voxel, e.g. a unit of volume, reduction in NAA is probably due to a decreased density of neurons related either to neuronal loss, neuronal shrinkage or increase in water or other cells. Although one might assume that reduction in NAA/Cr density observed in TLE results from Wallerian degeneration of the neurons lost within the hippocampus, the extent of the abnormality, which involves also the temporal lobe white matter, is too great to be explained by this phenomenon alone. There is increasing evidence from experimental 43,44 and clinical data 45-48 indicating that NAA reduction is not only due to a decrease in neuronal density, but also to neuronal metabolic dysfunction. Examining 14 patients with intractable TLE before and after surgery, Cendes 38 observed that postoperatively NAA/Cr increased to the normal range ipsilateral to the seizure focus in patients who became seizure free. In contrast, NAA did not change in those who continued having seizures after surgery. The same pattern was observed on the contralateral side. These results imply that NAA in TLE is, at least in part, a dynamic marker of neuronal dysfunction associated with ongoing seizures.

Previous MRS studies have shown contradictory evidence concerning the effect of repeated seizures on neuronal function in TLE. Using 1H-MRS, Vermathen et al. 46 studied a group of patients with extra-temporal neocortical epilepsy and showed that hippocampal NAA/Cr was not reduced, in contrast to patients with TLE. These authors argued that seizures did not cause secondary hippocampal damage. Garcia 49 found a negative correlation between NAA and seizure frequency in patients with both frontal and temporal lobe foci, but no correlation with duration of epilepsy. On the other hand, Duc 50 found a negative correlation between NAA and duration of TLE.

We conducted a cross-sectional study of 82 consecutive patients with medically refractory TLE who had no lesion on high quality conventional MRI other than hippocampal sclerosis. Two-dimensional 1H-MRSI scans, were acquired by using a standardized protocol described in detail in previous publications 25,38,51 in a region of interest including both temporal lobes. Linear regression analysis (Figure 1) showed a significant negative correlation between duration of epilepsy and both NAA/Cr ipsilateral to the seizure focus (r = -0.30, p = 0.006) and NAA/Cr contralateral to the focus (r = -0.32, p = 0.004). The negative correlation between NAA and the duration of epilepsy we found suggests that progressive neuronal dysfunction may occur in both temporal lobes in patients with TLE, even when seizures originate in only one temporal lobe.

NAA/Cr ipsilateral to the seizure focus was more reduced than NAA/Cr contralateral, an observation that confirms previous work from our group and others 36,38,52-54. However, the rate of change of NAA/Cr (e.g., the slope of the regression lines on Figure 2) was the same for both temporal lobes, implying that whatever the cause of this decline, it affects both sides is similar fashion. This relationship is maintained even when the two regression lines are extrapolated back to time zero, suggesting that ipsilateral NAA/Cr is lower than contralateral NAA/Cr even at a very early stage of the epileptic disorder. These findings are consistent with the notion that neuronal damage in the temporal lobes of patients with mesial TLE is acquired at an early stage of the disease and is in agreement with data in children with TLE 55,56.

There was no significant correlation between NAA/Cr on either side and frequency of complex partial seizures. However, patients with generalized tonic-clonic seizures (n = 27) had lower NAA/Cr ipsilateral to the focus (t = 2.505, p = 0.015) and lower NAA/Cr contralateral (t = 2.498, p = 0.014) than patients who had no or only rare generalized tonic-clonic seizures (n = 54). There was no significant difference in NAA/Cr of either side between patients with and patients without a history of prolonged febrile convulsions.

Complex-partial seizures did not appear to cause progressive dysfunction given the lack of correlation between seizures and NAA/Cr in either temporal lobe. However, generalized tonic-clonic seizures were associated with lower NAA/Cr bilaterally, suggesting that this type of seizure is more importantly related the to the metabolic dysfunction we are detecting. Whether they are the cause or effect of this metabolic dysfunction remains unknown. This association of generalized tonic-clonic seizures with temporal lobe neuronal dysfunction echoes the autopsy results of Mouritzen-Dam 57, which showed increased hippocampal cell loss in patients with frequent generalized tonic-clonic seizures. The correlation with generalized tonic-clonic seizures may not be surprising given the considerably easier task of accurately estimating numbers of generalized tonic-clonic seizures. Difficulties in estimating the frequency of partial complex seizures may provide an insurmountable obstacle for addressing the role of brief isolated seizures in TLE even when results of longitudinal studies will be available 58.

Our results also showed that unilateral NAA abnormality does not progress over time to become bilateral. Compared to the normal controls, 33 (40%) patients had bilaterally reduced NAA/Cr. They had significantly lower NAA/Cr ipsilateral to the focus than patients with unilaterally reduced NAA/Cr. Student’s t-test revealed that these patients did not significantly differ in their age, age of onset, duration, or frequency of complex partial or generalized tonic-clonic seizures.

In summary, the results of our cross-sectional study suggest that NAA reduction in TLE is present at the time of the onset of clinical seizures, is bilateral but predominates on the side of the EEG focus, progresses over several years and is worsened by frequent generalized tonic-clonic seizures. Whether these findings represent irreversible neuronal loss or neuronal dysfunction is unclear, partly because of the cross-sectional and retrospective nature of the data.

Other MRI techniques

New acquisition techniques such as diffusion tensor imaging (DTI) and perfusion MRI has been recently added to the armamentarium of methods for investigating the cause and consequences of epilepsy 59-62. DTI is a method for identifying the motion of water molecules in the brain. The two main parameters determined by DTI are diffusivity and fractional anisotropy. Increased diffusivity is likely to correlate to neuronal loss and gliosis 63. DTI has been shown to identify abnormalities that can not be detected on conventional MRI 62,64. Serial DTI scans could have the potential to detect subtle changes secondary to seizures. However, the degree of reliability and the reproducibility of DTI data remain to be determined. The role of perfusion MRI in quantifying neuronal dysfunction in vivo has not been explored.

Extra-hippocampal neuronal damage and dysfunction

In early studies of surgically resected specimens of patients with TLE, the term mesial temporal sclerosis was introduced to describe widespread pathological changes of the hippocampus, the amygdala and the surrounding cortical areas 65. An increasing number of MRI studies have demonstrated that in TLE volumetric abnormalities are indeed not limited to the hippocampus, but involve the parahippocampal gyrus, particularly the entorhinal cortex 13,66-68. Furthermore, atrophy and neuronal dysfunction may involve the temporal extra-mesial and extra-temporal neocortical areas {Lee, Andermann, et al. 1998 3071 /id}{Marsh, Morrel, et al. 1997 1663 /id}{Mueller, Suhy, et al. 2002 3792 /id}69. Extra-hippocampal neuronal damage or dysfunction is usually diffuse and bilateral. The assessment of extra-hippocampal structures, in addition to mesial structures, could provide information possible differences in the distribution of secondary cerebral damage.


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