Dr. Gupta is currently Chief Resident at University of Texas (UT) at Houston. She graduated with honors and received her MD in 1993 from All India Institute of Medical Sciences. She later completed her internship at UT Houston. Dr. Gupta will remain at UT Houston to begin a fellowship in MR Imaging in 2003.

Magnetic resonance (MR) imaging plays a pivotal role in every aspect of the diagnosis and management of temporal lobe epilepsy. Mesial temporal sclerosis (MTS) is the most common epileptogenic lesion in human epilepsy. This review focuses on the 1) normal anatomy of the hippocampus; 2) MR features of MTS and its mimics; 3) functional MR imaging as well as newer modalities such as MR spectroscopy and diffusion tensor imaging; 4) the role of MR in surgery of temporal lobe epilepsy; and 5) other lesions that may cause temporal lobe epilepsy, such as tumors, vascular malformations, and dysplasias. MR techniques are crucial for a complete workup of a patient with seizures because the ultimate goals of treatment are relief from intractable symptoms and prevention of disastrous postresection complications, such as speech and memory loss.

The International Classification of Epilepsies and Epileptic Syndromes classifies clinical epilepsy into two broad categories: idiopathic (primary) and symptomatic (secondary) disorders. ¹ Primary epilepsies are genetically transmitted seizures that are not associated with other neurological disturbances or structural pathology and are usually benign. Secondary epilepsies, in contrast, are seizures resulting from a specific pathologic substrate that can be genetic or acquired.

Both primary and secondary epilepsies are further divided into generalized disorders (where the brain is diffusely and bilaterally involved) and localization-related or focal disorders (seizures originate from a localized cortical region). Temporal lobe epilepsy constitutes nearly two-thirds of focal epilepsies ² and is responsible for most cases of complex partial seizures. Temporal lobe epilepsy can be further divided into the following three categories.

Mesial temporal lobe epilepsy (MTLE) : The "pathological substrate" of MTLE is mesial temporal sclerosis (MTS). In addition to being the lesion most commonly associated with complex partial seizures (60% to 85% of cases), ^3,4 it is also the most common structural abnormality in human epilepsy. ⁵

Lesional temporal lobe epilepsy : This category is associated with specific structural abnormalities, including developmental disorders, neoplasms, infections, trauma, and immune-mediated disorders, such as Rasmussen's syndrome. ³ These lesions account for a minority of cases of temporal lobe epilepsy. They could be located either in the mesial temporal lobe or more distant neocortical areas with projections on the temporal lobe structures.

Cryptogenic temporal lobe epilepsy : This category has no associated identifiable structural abnormalities and is a diagnosis of exclusion.

Mesial temporal lobe epilepsy is not only the most common form of human epilepsy but is also often medically intractable. However, it is frequently amenable to surgical treatment with excellent seizure control. High-resolution magnetic resonance (MR) imaging and other MR techniques play a pivotal role in patient workup, case prognostication, treatment planning (including surgery), and subsequent follow-up. MR technique is also critical in helping to elucidate the pathophysiology of MTLE.

What is MTS?

Mesial temporal sclerosis is the most common lesion seen in patients with complex partial seizures. It is characterized by pyramidal cell loss and astrogliosis in the mesial temporal lobe, hippocampal formation, amygdala, parahippocampal gyrus, and the entorhinal cortex. Radiologists must be very familiar with the detailed anatomy of the mesial temporal lobe in order to guide patient management accurately, especially surgical resection. The MR features of MTS are subsequently described.

Anatomy of the mesial temporal lobe

The hippocampus forms an arc running rostrocaudally in the mesial temporal lobe. The hippocampus has a head (pes hippocampus), body, and tail. The head has prominent digitations (Figure 1), whereas the body does not. The superficial portion of the body lies adjacent to the fimbriae that extend superomedially to form the thin crura of the fornices, and the tail lies in the floor of the atrium. The hippocampal sulcus separates the subiculum, which occupies the medial/superior curvature of the parahippocampal gyrus (Figure 2). The hippocampus, fornix, and mamillary body are components of a single limbic circuit (circuit of Papez). The hippocampal fibers project to the mamillary body via the fornix. The majority of the fibers come from the subiculum. This circuitry explains how hippocampal neuronal damage leads to atrophy of the fornix and mamillary body by wallerian and transneuronal degeneration.

The hippocampus has two major parts: the cornu ammonis (hippocampus proper) and the dentate gyrus (which is separated by the hippocampal sulcus). ^6,7 The cornu ammonis ⁸ (Figure 3) has four sectors: CA1, which is adjacent to the subiculum; CA2, which is at the superior aspect of the cornu ammonis; CA3, which is at the curve; and CA4, which is enveloped by the dentate gyrus. This lamellar pattern of the hippocampus can be readily identified by MR imaging ^9-11 (Figure 4). Two different types of MTS can be identified pathologically ⁸ : Classic Amnion horn's sclerosis, or classic hippocampal sclerosis , which has pyramidal cell loss in CA1, CA3, and in the dentate hilum, with sparing of CA2; and end folium sclerosis, in which only the end folium cells are involved.

Although MTS is a bilateral process, one side is affected more than the other in 80% of patients. Usually, the more severely affected side is the origin of the patient's seizures. Cases in which both sides are equally affected generally respond less favorably to temporal lobectomy.

MR features of MTS

Primary sign-- A small atrophic unilateral hippocampus (Figure 5) with loss of both the normal architecture and that of normal digitations of the head. The atrophic hippocampus is bright on both T2-weighted (T2W) and fluid-attenuated inversion recovery (FLAIR) images (Figure 6). Visual assessment of size, architecture, and signal intensity changes is quite sensitive, with the eye being able to detect asymmetry of 14% or more. ¹²

Secondary signs-- Unilateral atro-phy of the mamillary body , ¹³ fornix columns (circuit of Papez) ¹⁴ (Figure 5), and the amygdala . In patients who have undergone temporal lobectomy, the frequency of detection of these signs increases and may represent wallerian degeneration and deafferentation of the circuit. ¹⁵

Unilateral dilatation of the temporal horn (a less reliable secondary sign) (Figure 5).

Unilateral atrophy of the collateral white matter bundle and loss of gray-white demarcation in the ipsilateral anterior temporal lobe . The anterior temporal lobe signal change has been associated with earlier onset of seizures, ¹⁶ earlier age at antecedent event, and greater seizure load. This change may be related to the postulated causative initial cerebral insult rather than the effect of cumulative damage from seizures. Because the appearance is similar to the immature development of a temporal lobe, it may represent abnormal myelin or arrested development ¹⁷ and suggest maldevelopment as a possible cause of temporal lobe epilepsy.

Anatomic variants that may mimic pathology

A right-handed individual has been shown to have a larger right hippocampus and amygdala. Left-handed individuals show no difference in size between the sides. ¹⁸ Similar size variations showing the right hippocampus larger than the left were found in healthy volunteers by Jack et al. ¹⁹ A mean difference of 0.3 cm ³ ( P <0.001) was noted.

In the immediate postictal phase, the resulting edema that involves the hippocampus may hide the underlying atrophy ²⁰ or mimic disease (encephalitis, neoplasm, etc.).

Technical overview

Standard imaging planes and sequences

A set of sagittal and axial T1-weighted (T1W) spin-echo (SE) images are obtained initially (repetition time [TR] 500, echo time [TE] min full). These are useful to define normal anatomy. This is followed by an axial conventional SE T2W sequence (TR 2500, TE min full/90), which is sensitive for most pathology. Compared with conventional SE, foci of hemorrhage are less evident on fast SE and, in such cases, a gradient-echo sequence may be used. Since the majority of the lesions are in the temporal lobe, a modified coronal plane perpendicular to the long axis of the hippocampus (Figure 7) is the optimal plane for imaging the hippocampi. A set of such oblique coronal images is obtained through the entire hippocampus using both FLAIR (TR 10,000, TE 156, T1 2200) and fast SE T2W (TR 5000, TE 102, echo train length [ETL] 8) techniques. Fluid attenuated inversion recovery (Figure 6) increases the conspicuity of parenchymal lesions in the subcortical/periventricular white matter and hippocampal formations. On this sequence, signal intensity changes are most striking; this is related to the increase in tissue-free water that reflects the underlying astroglial proliferation. However, it has limited use in children with immature white matter containing normal areas of hyperintensity. ²¹ Finally, an axial three-dimensional (3D) fast spoiled gradient-recalled acquisition steady-state high-resolution thin-slice acquisition is obtained using a very short TR and TE. This provides a strong T1W contrast between the gray and white matter. ²² The thin (1.5- to 2.0-mm) contiguous slices help detect subtle cortical mantle and hippocampal migrational anomalies. A 3D T2W acquisition may be useful in preoperative planning, stereotactic surgery, or even as a neuronavigational tool. Furthermore, in cases of focal abnormalities associated with mass effect that are suspicious for tumors etc., gadolinium-based contrast may be administered. Both axial and coronal T1W images are then obtained.

Other useful and emerging MR techniques

Magnetic resonance spectroscopy (MRS). This technique is a means for noninvasive chemical analysis of the brain. Proton spectroscopy is widely used with both single or multivoxel techniques. It primarily analyzes choline (Cho), creatine (Cr), and N-acetylaspartate (NAA) levels. In temporal lobe epilepsy due to MTS, ipsilateral reduction of NAA, increases in Cho and Cr, and significant reductions in NAA/Cho and NAA/Cr ratios have been observed. ²³ Lateralization by MRS compares well with hippocampal atrophy seen on MR imaging and MR volumetry in temporal lobe epilepsy (Figure 8). Decreased NAA activity has been found in cases without hippocampal atrophy as well. Also, in cases with bilateral changes on MRS, maximal loss of NAA corresponds to the more severely affected side on MR imaging. A decline in NAA peak may represent both neuronal loss and/or neuronal/ glial dysfunction, ²⁴ whereas the increase in Cho and total Cr concentrations has been related to gliosis. When discordant results are present (eg, maximal NAA activity decrease contralateral to MR hippocampal changes), a dual pathology and a lower probability of successful surgical outcome may be expected. ²⁵ Postictal studies may reveal an additional lactate peak reflecting a phase of anaerobic metabolism (seen within minutes of seizure onset and persisting for several hours. ²⁶ Other changes that can be identified are an increased myoinositol peak in the ipsilateral temporal lobe ²⁷ correlating with the extent of hippocampal sclerosis. In addition, patients with MRI-negative temporal lobe epilepsy show an increase in glutamate-glutamine signal and a less marked decrease in NAA, when compared with cases of MRI-positive temporal lobe epilepsy.

Volumetric MR imaging. This is a means of objectively quantifying size. Measuring size can be accomplished by manually tracing the hippocampus or by using the grid method. It is particularly useful for patients with anatomical variants, bilateral hippocampal atrophy, or for those with unsuspected disease. However, it is not useful in cases with segmental hippocampal involvement. ²⁰ The normal, ipsilateral hippocampal volume is approximately 2.8 mL.

T2 relaxometry. This is used to quantify the T2 signal in the hippocampus. It measures the decay in signal intensity at different TEs in a series of T2W images acquired in the same slice. In MTS, the relaxation time has proven to be lengthened by 10 milliseconds. The definition of a normal hippocampus by this method is very precise, and the diagnosis of MTS does not depend on a side-to-side comparison. Thus, both cases of mild and bilateral hippocampal sclerosis can be diagnosed. ^28,29

Diffusion tensor imaging (DTI). This technique is a noninvasive imaging means to study the intrinsic diffusion properties of the white matter.
A recent study on white matter
changes in patients with temporal lobe epilepsy ³⁰ showed lower diffusion anisotropy in ipsilateral white matter structures like the corpus callosum, external capsule, and internal capsule. This may relate to a less tightly packed neuronal network or deficient myelin. Similar changes have been identified by others in white matter regions beyond the temporal lobe and may represent global changes of epilepsy. Whether this is the cause or effect of epilepsy is yet to be determined.

Functional MR imaging (fMRI). This method uses the blood-oxygen-level dependent contrast technique. Deoxyhemoglobin is paramagnetic and can be detected on T2W images as low or decreased signal intensity. In contrast, oxyhemoglobin is diamagnetic and exerts little effect. Thus, when with contiguous nonstimulated areas, an activated cortex has increased metabolism and blood flow and corresponding higher signal intensity. The principal application of fMRI lies in the preoperative localization of the motor strip, memory, and language cortex. In this aspect, it produces information complementary to the intracarotid amobarbital Wada's test. ³¹ Before temporal lobectomy, fMRI can be used to locate regions responsible for memory and speech (Broca's and Wernicke's areas), ie, the eloquent cortex. It can also identify the seizure focus (since declarative memory depends on the integrity of the mesial temporal lobe region, and the seizure focus is usually deficient in this function). ³² Its potential clinical value in studying the effects of long-term drug treatments, such as carbamazepine, in patients with epilepsy is being evaluated. ³³

Newer techniques. The future holds great promise with newer methods on the horizon. The sensitivity of the magnets has improved and MR microscopy has been experimented with to trace the circuit of Papez using manganese (Mn2+) injected subcutaneously (a potential MR contrast agent). Watanabe and colleagues ³⁴ were able to delineate the principal cell layers of the hippocampal formation (CA2 and CA3) and dentate gyrus in living mice. At present, these techniques are not applicable to human imaging.

Other pathologic substrates seen in temporal lobe epilepsy

Pathologic substrates account for a minority of cases of temporal lobe epilepsy. However, high-resolution MR imaging is vital to their diagnosis and surgical treatment.

Developmental disorders

Focal cortical dysplasias are the most common disorders causing developmental epilepsy (Figure 9). The MR hallmark is a macroscopically thickened cortex (normal thickness is 4 mm). Neuronal heterotopia is another common cause that may be nodular or laminar in appearance (Figure 10). Other associated lesions are hemimegalencephaly, schizencephaly, lissencephaly (agyria), and pachygyria (broad flat gyri).

Neurocutaneous syndromes (phacomatosis)

In patients with tuberous sclerosis, cortical tubers cause seizures, and those with Sturge-Weber syndrome (encephalotrigeminal angiomatosis) have a pial angioma that represents a developmentally impaired venous outflow abnormality.

Vascular malformations

Most venous angiomas and capillary telangiectases are clinically silent. However, approximately 50% of patients with arteriovenous malformations (Figure 11) and cavernous hemangiomas may experience seizures. Epileptogenesis in cavernous angiomas is attributed to irritation and compression from mass effect and exposure of brain tissue to blood breakdown products and associated gliosis.

Neoplasms

Seizures associated with neoplasms are usually of recent onset. Gliomas, most commonly astrocytomas (Figure 12), account for nearly 80% of the primary neoplasms presenting with seizures. Pleomorphic xantho-astrocytomas are rare tumors typically seen in the temporal lobes of children with a history of seizures. Both gangliogliomas (Figure 13) and dysembryoplastic neuroepithelial tumors are also associated with pediatric seizures and have a predilection for the temporal lobe. ³⁵ Other tumors, such as meningiomas and cerebral metastases, are related to late-onset or elderly seizure/epilepsy cases.

Infections

Seizures are common in patients with acute cerebral infections (viral encephalitis and bacterial and aseptic meningitis) as well as those with brain abscesses, aspergillosis, and other fungal infections. Patients developing acute central nervous system infections before 4 years of age have a higher propensity to develop hippocampal sclerosis. In certain parts of the world, cysticercosis and tuberculosis are leading infectious causes of seizures in general. ³⁶

MR imaging in surgery of epilepsy

The goal of resective epilepsy surgery is the complete resection (disconnection) of the epileptogenic zone with preservation of the eloquent cortex. The operative strategy is influenced by the presumed pathology (provided by MR imaging) and by the extent and location of the lesion. Historically, invasive recordings were required before most epilepsy surgeries, but indications have dramatically changed since the introduction of high-resolution MR imaging, since it uncovers structural lesions in a high percentage of cases. No invasive recordings are required before performing a temporal lobectomy in patients who are MRI-positive for MTS and have concordant interictal and ictal surface electroencephalogram (EEG) recordings, functional imaging, and clinical findings. Invasive testing is needed if there is evidence of bilateral MTS, if there are discordant results, and/or if EEG and additional neuroimaging techniques have been unable to lateralize the culprit epileptogenic zone. Once depth (Figure 14) or subdural (Figure 15) electrodes are used to lateralize the lesion, they can be seen clearly on MR imaging. Both their placement (occipital temporal or orthogonal temporal) and associated complications (hemorrhage, infection, infarction, gliosis, etc.) can then be accurately evaluated.

Currently, at least three surgical techniques are in common use ³⁷ : Selective microsurgical resection (as in MTS, subpial resections, etc.); functional hemispherectomy (frontal/ temporal lobectomy); and corpus callosotomy (Figure 16).

Conclusion

MR techniques play a pivotal role in the complete workup of patients with temporal lobe epilepsy. While MR imaging provides morphologic details, newer techniques like MRS, volumetric MR, T2 relaxometry, and even fMRI can help assist and confirm the epileptogenic focus. Accurate localization of the focus helps accomplish the ultimate goal of treatment, ie, surgical resection with the preservation of the eloquent cortex and preventing or predicting devastating memory and speech complications. To achieve this, a solid foundation in anatomic knowledge of the mesial temporal lobe and the most common lesion, mesial temporal sclerosis, is key. The future is even more exciting as the anticipated growth of MR techniques, especially MR microscopy, may help unravel the molecular and histopathologic substrates of epilepsy.

Acknowledgment

The author is grateful to Larry A. Kramer, MD, for reviewing the manuscript and providing both the images and guidance. Special thanks to Sandra A.A. Oldham, MD, for her encouragement and support. The author is also grateful to Daniel A. Klepac for technical assistance with the images.