Neuroimaging in epilepsy.

Epilepsy is the most common neurological disease worldwide and is second only to stroke in causing neurological morbidity. Neuroimaging plays a very important role in the diagnosis and treatment of patients with epilepsy. This review article highlights the specific role of various imaging modalities in patients with epilepsy, and their practical applications in the management of epileptic patients.

Introduction

A seizure is defined as a paroxysmal alteration in neurologic function due to excessive electrical discharge from the central nervous system. Epilepsy is defined as a condition of recurrent seizures, and medical intractability as recurrent seizures despite optimal treatment under the direction of an experienced neurologist over a 2-3-year period. Determining the underlying cause of a patient's seizure is the fundamental goal in the workup of epilepsy. Imaging of the brain provides valuable information in this regard. The main purposes of neuroimaging in epilepsy patients are to identify underlying structural or metabolic abnormalities that require specific treatment and to aid in formulating a syndromic or etiological diagnosis. Neuroimaging is even more important for those patients who have medically intractable seizures. Advances in technology to localize epileptogenic focus, especially with high resolution magnetic resonance imaging (MRI), have substantially improved the success of surgical treatment.

Structural disorders associated with seizure and detected on imaging can be categorized into the following groups [Figures 1–21]: hippocampal or mesial temporal sclerosis, cortical developmental malformations or neuronal migration disorders (cortical dysplasias, heterotopias, hemimegalencephaly, lissencephaly, schizencephaly, pachygyria, polymicrogyria, Rasmussen encephalitis), phakomatoses (Tuberous sclerosis, Sturge Weber syndrome, neurofibromatosis), vascular abnormalities (arteriovenous malformation, cavernous hemangiomas), infections (tuberculoma, neurocysticercosis), neoplasms (ganglioglioma, dysembryoplastic neuroepithelial tumor, low-grade gliomas, and cerebral metastasis in adults), stroke, post-traumatic epilepsy and miscellaneous conditions (gliosis, encephalocele).

Figure 1

T2-weighted oblique coronal images of brain of 17-year-old male with mesial temporal sclerosis showing marked atrophy, sclerosis and loss of normal morphology of right hippocampus with dilated ipsilateral temporal horn. Left hippocampus also shows mild atrophy and minimal sclerosis with prominent ipsilateral temporal horn

Figure 21

Plain (a) Axial T2W/T1W/coronal FLAIR and postcontrast (b) axial/sagittal/coronal images of brain of 15-year-old male who presented with epilepsy demonstrate a multiloculated cystic, cortex-based, right temporal lobe mass giving honeycomb appearance. The septae within the cystic mass show mild contrast enhancement. Diagnosis of DNET was confirmed on histopathology

T2-weighted axial image of brain of 20-year-old male with heterotopia shows mass of heterotopic gray matter in left fronto-temporo-parietal region indenting the body of lateral ventricle

T2-weighted axial image of brain of 9-month-old male child with non-lissencephalic cortical dysplasia shows shallow sylvian fissures giving figure eight appearance, polymicrogyria with shallow sulci and relative paucity of underlying white matter

T2-weighted FLAIR coronal image of brain of 7-month-old male child with focal lissencephalic cortical dysplasia shows agyric, severely disorganized thickened left temporal lobe cortex with poor corticomedullary differentiation and associated ipsilateral heterotopic grey matter

T2-weighted coronal image of brain of 6-year-old male child with Rasmussen's encephalitis, who had intractable seizures, shows unihemispheric focal cortical atrophy with grey and white matter hyperintensity

Axial noncontrast CT scan of brain of 6-month-old male child with tuberous sclerosis shows both subependymal and parenchymal calcifications

Axial noncontrast CT scan of brain of 3-month-old male child with Sturge Weber Syndrome shows hemispheric cerebral atrophy, ipsilateral parieto-occipital cortical calcification and enlarged bilateral choroid plexuses

Axial contrast enhanced T1W MRI of brain of 52-year-old male shows left frontal parenchymal arteriovenous malformation associated with large ipsilateral temporo-parietal bleed. The AVM nidus is seen as multiple intensely enhancing round and serpentine lesions with enlarged subependymal and superficial cortical draining veins. The arterial feeders were from left middle cerebral artery

T2-weighted coronal image of brain of 19-year-old male, who presented with seizure, shows small left posterior parietal lobe cavernoma

T1-weighted post contrast axial image of brain of 15-year-old female, who presented with seizure, shows left temporal lobe tuberculoma as two small conglomerate ring enhancing lesions

T1-weighted postcontrast sagittal image of brain of 17-year-old male, who presented with seizure, shows vesicular stage of neurocysticercosis as solitary high parietal ring enhancing lesion with eccentric nodule and minimal perifocal edema

T2-weighted and T1-weighted postgadolinium axial images of the brain of 15-year-old male, who presented with recurrent seizure, show left temporal lobe cystic lesion with eccentric enhancing mural nodule and mild perifocal edema. On histopathology the lesion proved to be ganglioglioma

T2-weighted and T1-weighted postgadolinium coronal images of brain of 13-year-old male, who presented with gradually increasing seizure, show right frontotemporal lobe mass with mass effect. The lesion show no enhancement on corresponding post-gad image. Stereotactic biopsy showed the lesion to be low-grade astrocytoma

T2-weighted FLAIR and T1-weighted postgadolinium coronal images of brain of 30-year-old male, who presented with increasing seizure, show relatively well-defined infiltrative predominantly right frontal lobe mass with contiguous extension into adjacent temporal lobe, genu of corpus callosum, and contralateral frontal lobe. The lesion show focal areas of hemorrhages but no enhancement in post-gad images. Stereotactic biopsy showed the lesion to be diffuse infiltrating astrocytoma

T2-weighted FLAIR coronal image of brain of 60-year-old male with renal cell carcinoma and recent onset seizure shows solitary right frontal lobe hemorrhagic metastasis with disproportional large perifocal edema and mass effect

T2-weighted FLAIR coronal image of brain of 45-year-old male who presented with sudden onset right-sided hemiplegia and seizure, shows left frontotemporal lobe acute infarct (DWI not shown)

T2-weighted axial GRE image of brain of 25-year-old male with post-traumatic seizure shows left frontal lobe hemorrhagic contusion

T2-weighted FLAIR coronal image of brain of 30-year-old male who presented with seizure shows bilateral old gliotic infarcts

T2-weighted axial image of brain of 13-year-old male with recurrent seizure shows basi-frontal meningo-encephalocele with schizencephaly

The role of imaging, in particular MRI, in dysembryoplastic neuroepithelial tumor (DNET) is important as this condition is encountered in significant number of patients undergoing surgery for intractable epilepsy. DNETs are benign tumors of young adults. Temporal lobe is the most common location, followed by frontal and parietooccipital lobes. Imaging [Figures 20 and 21] shows a predominantly cortical based gyral or nodular configuration mass, appearing hypodense on NCCT, hypointense on T1WI, hyperintense on T2WI and showing contrast enhancement in about 20-50% cases. They may resemble a simple or complex cyst showing peripheral ring enhancement or soap bubble appearance, respectively. These lesions lack edema and mass effect, and there is little or no white matter extension. Hemorrhage and calcification are uncommon. Diffusion-weighted imaging (DWI) and corresponding ADC mapping shows no diffusion restriction. MR spectroscopy (MRS) finding is non-specific although an elevated choline peak may be present. Important differential diagnosis include ganglioglioma and low-grade astrocytoma.[12]

Figure 20

Plain (a) Axial FLAIR/sagittal T1W/coronal T2W and postcontrast (b) axial/sagittal/coronal MRI of brain of 19-year-old male who presented with seizure demonstrate heterogeneous cortical/subcortical, T2W/FLAIR hyperintense and T1W hypointense, left parietal region mass showing no postcontrast enhancement. Diagnosis of dysembryoplastic neuroepithelial tumor (DNET) was confirmed on histopathological examination

Imaging Modalities

This article highlights the specific role of various imaging modalities in patients with epilepsy, and their practical applications in the management of epileptic patients.

The major utility of computed tomography (CT) scanning is in the initial evaluation of seizures, particularly in trauma, hemorrhage, infarction, tumors, calcified lesions and major structural changes. In perioperative patients, it is the imaging technique of choice as it can detect the bleed, hydrocephalus and assess electrode placement. However, the overall sensitivity of CT in patients with epilepsy is low (~ 30%), and because of poor resolution in the temporal fossa, CT is of no use in detecting mesial temporal sclerosis, the most common pathology in intractable temporal lobe epilepsy.[3]

MRI, with its excellent spatial resolution, soft tissue contrast, and multiplanar capabilities, is the imaging modality of choice in investigating patients with seizure disorder. The sensitivity of MRI in identifying epileptogenic foci in patients with medically refractory patients has been reported to be more than 80%. However, in patients with idiopathic generalized epilepsy, MRI has not been shown to be useful. The correlation of the MRI finding with clinical and electroencephalography (EEG) findings are essential to avoid false positive localization of epileptogenic focus.[4]

Routine scanning protocol for a patient with refractory epilepsy may include axial or coronal T1 and T2-weighted imaging, fluid-attenuated inversion recovery (FLAIR) imaging, and 3D volume acquisition sequences. Common 3D acquisition sequences include high-resolution T1-weighted magnetization prepared rapid acquisition gradient echo (MPRAGE) and fast spoiled GRASS (3D-FSPGR), where GRASS is gradient recalled echo acquisition in steady state. T1-weighted sequences are used to define the brain anatomy, and T2-weighted or FLAIR sequences are used to detect the brain pathologies. High-resolution 3D volume acquisition provides good T1-weighted contrast between gray and white matter and helps to detect subtle cortical dysplasias and internal structure of hippocampus in case of mesial temporal sclerosis.[5-7] For optimal assessment of hippocampus the imaging should be in hippocampal axis (oblique coronal plane) with thin slices and good signal-to-noise ratio. The application of contrast agent is indicated if there is suspicion of primary or metastatic tumor, infection or inflammatory lesion.

The specialized protocol includes quantitative volumetry and T2 relaxometry, MRS, functional MRI (fMRI), DWI and diffusion tensor imaging (DTI), and magnetic source imaging (MSI).

High resolution T1-weighted 3D volume gradient echo sequences are also used for quantitative measurement of volume of any particular region of interest. In the case of epilepsy this is usually the hippocampus. Volumetric analysis of the hippocampus can be performed both in adults and children with epilepsy, to detect more subtle volume deficits (atrophy) that may be missed by visual assessment alone. Volumetric measurements can be performed manually or with half or fully automated software, however, needs good knowledge of anatomical details. Longitudinal studies done to assess the progression of volumetric changes correlate with the seizure-associated damage.[8] T2 relaxometry is the quantitative determinant of the T2 relaxation time. To achieve this, several T2-weighted images are acquired at different echo times, and with these values an exponential decay curve is obtained to estimate the T2 decay rate of the imaged tissue. The tissues that have prolonged T2 are considered abnormal. In epileptic patients with hippocampal sclerosis, signal increase on T2-weighted images is typically observed in the hippocampus. The measured values of the hippocampal volume and the T2 times are correlated with each other, indicating that a marked volume loss is associated with a significant increase in T2 relaxation, reflecting the complex pathology of hippocampal sclerosis.[9]

Proton MR spectroscopy (MRS) has proven to be a sensitive measure to detect metabolic dysfunction in patients with temporal lobe epilepsy (TLE), particularly mesial temporal sclerosis (MTS) involving hippocampus. Twenty percent of patients with TLE have normal structural MRI scan and the findings in children generally tend to be more subtle than those in adults. MRS metabolite abnormalities may be found even in the absence of detectable structural abnormalities. NAA, NAA/Cho, NAA/Cr, and NAA/(Cho+Cr) all are decreased in atrophic hippocampi, as well as in nonatrophic hippocampi with abnormal EEG findings. Reduced N-acetylaspartate concentration suggests neuronal loss or dysfunction. TLE patients may also show increased choline and myoinositol signals, suggestive of gliosis. Studies of patients during or immediately after seizures (within 6 hours) may also show lactate increase in the epileptogenic focus. MRS also has promising role in the evaluation of patients with extratemporal epilepsy (frontal lobe epilepsy).[1011] In patients with structural MR evidence of malformations of cortical development (MCD) or neuronal migration disorders (NMD), MRS provides insight into both the pathology and true extent of the disease processes. Abnormally decreased NAA/Cr and Cho/Cr ratios have been noted in these lesions, as well as in the normal appearing brain contralateral to the lesion, when compared with gray and white matter of neurological controls.[1213] MRS is of particular importance in patients with brain tumors. The characteristic elevation of choline makes MRS a valuable tool for the diagnosis of tumors and their differentiation from other lesions. There is also evidence that MRS can differentiate between tumor types.[14] Neurotransmitter MRS studies have potential therapeutic impact in seizure patients. Glutamate and γ-amino-butyric-acid (GABA) can be measured using MRS editing techniques. Intracellular glutamate concentrations remain elevated in the epileptogenic hippocampus and neocortex, and contribute to the epileptic state by increasing cellular excitability.[15]

Surgical treatment of refractory focal seizure has been an important and effective means for seizure control. However, the surgical outcome is dependent on precise localization of epiletogenic focus and functional areas of the brain. The fMRI, plays a very important role in preoperative localization of epileptogenic focus and assessment of cognitive function in patients with refractory epilepsy. During focal seizure, cerebral blood flow and metabolism is considerably increased. fMRI using blood oxygen level dependent (BOLD) technique can detect these cerebral hemodynamic changes. The excellent spatial resolution of fMRI helps to study cortical activation during epileptic activity and define epileptogenic focus in originally activated area. The recent development of EEG-triggered fMRI which allows interpretable electroencephalographic data to be recorded during MRI scanning, has advantage of combining the spatial resolution of imaging with the temporal resolution of electrophysiology in precise localization of seizure foci, thus increasing the rate of successful resection of the epileptogenic focus. The EEG-triggered fMRI is highly reliable, repeatable and noninvasive tool in localization of the seizure foci of patients with intractable focal seizure. Combined video-EEG and fMRI in localization of seizure foci has also shown good results.[1617] Long-term epileptic activity in patients with epilepsy results in atypical distribution of cognitive function areas because of reorganization of cortical language and memory areas. Accurate localization of cognitive functional areas is necessary, to avoid their resection at the time of surgery, to modify surgical approaches for those patients at risk of language and memory deficit and to predict postoperative cognitive deficit after resection of seizure foci.[18]

The diffusion-weighted signal reflects the molecular motion of water in the intra and extracellular environments. In tissue components such as CSF, molecular motion is not restricted in any direction and is known as isotropic diffusion, detected by DWI. In tissues with linear arrangement of myelinated fibers such as white matter tracts, the molecular motion is restricted to the axis along the white tracts and is known as anisotropic diffusion, detected by DTI or tractography. In epilepsy, DWI is used to assess acute cerebral ischemia, tumors or infections, while DTI has been used to assess the degree of distortion of white matter tracts in case of developmental abnormalities and other lesions responsible for seizure. Anisotropy is reduced in areas of structural abnormalities suggesting structural disorganization of white matter.[1920]

Magnetoencephalography (MEG), also known as MSI when combined with structural imaging, has proved to be a new noninvasive tool for localization of epileptic focus. MSI is similar to EEG, but unlike EEG it detects magnetic rather than electric signal and is more accurate for localizing abnormal focus. It is increasingly useful for presurgical localization of epileptogenic lesions and stimulus-induced normal neuronal function to minimize postoperative neurological deficits.[21]

Besides purely structural imaging techniques like MRI, functional imaging studies like interictal positron emission tomography (PET), and ictal and interictal single photon emission computed tomography (SPECT) may provide additional information in some patients and thus aid in clinical decision making. PET and SPECT are usually not indicated for the majority of patients with epilepsy but has important role in the surgical candidates. The detection of cryptogenic lesions is the main goal of functional epilepsy imaging with PET or SPECT. PET utilizes an injection of tracer 18F-labeled deoxyglucose (18FDG) to measure brain metabolism. Interictal PET shows hypometabolism in the seizure focus, especially in TLE. Ictal PET is not practical due to extremely short half-life of the radiotracers used. PET remains a diagnostic modality for presurgical localization of the focus in temporal lobe and extratemporal epilepsy when MRI is normal.[22] SPECT utilizes injection of radio-labeled tracer Technetium99m hexamethyl-propyleneamineoxime (Tc-HMPAO) or ethyl cysteinate dimer (Tc ECD), which has very slow distribution once in the brain. The tracer is stable for several hours, allowing delayed imaging. The most useful study for presurgical evaluation is an ictal SPECT, which usually reveals increased blood flow at site of seizure onset. Interictal studies often show relative hypoperfusion at the site of seizure onset. The substraction of the interictal from the ictal SPECT, and then coregistration of the resulting images onto MRI (substraction ictal SPECT coregistration MRI - SISCOM) has shown to increase the accuracy of this method.[23]