MR imaging throws light on causes of epilepsy

An epileptic seizure is the external manifestation of a functional cerebral disorder that can affect 10% of the world's population. Virtually any brain abnormality can irritate vulnerable neurons and produce epileptic seizures. The nature and characteristics of the seizure depend on the part of the brain involved in the disturbance.

Most epileptic patients achieve good seizure control through treatment with antiepileptic drugs. Around 20% to 30% of sufferers will continue to have epileptic manifestations despite drug treatment. The majority of these patients will have symptomatic or cryptogenic location-related epilepsy, which may be treated successfully with surgery.

The prime aim of epilepsy surgery is to address specific disorders responsible for triggering seizures in order to bring symptomatic relief without causing another disability.¹ This means that out of the large and heterogeneous group of disorders linked to epilepsy, those syndromes in which seizures start at a single point (focus) in the brain are of most interest for surgery. These syndromes are subclassified according to the site of the focus (frontal, temporal, parietal, and occipital lobe epilepsies) and are further divided according to etiology.

A clear distinction is made between epileptic seizures and epilepsies. Seizures are classified according to clinical seizure type and EEG expression (ictal and interictal) and are defined as electroclinical seizure types. Syndromes are defined as an epileptic disorder characterized by a cluster of signs and symptoms customarily occurring together.²

The International League Against Epilepsy (ILAE) and the International Bureau for Epilepsy (IBE) have proposed new definitions for epileptic seizures and epilepsies. They define an epileptic seizure as "a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain," and epilepsy as "a disorder of the brain characterized by an enduring predisposition to generate epileptic seizures, and by the neurobiologic, cognitive, psychological, and social consequences of the condition." Their definition of epilepsy requires patients to have undergone at least one epileptic seizure.³ Epilepsies are classified into syndromes by the ILAE and the IBE according to seizure types, etiology, patient's age at onset, EEG changes, and MRI/CT findings.

A ROLE FOR MRI

Advances in MRI have changed the workup of epilepsy dramatically. The role of radiologists was previously limited to ruling out gross pathology, such as occupying lesions, as the cause of seizures. Structural epileptogenic abnormalities can now be detected, localized, and differentiated on MRI, and a proper preoperative evaluation performed.

The limbic system is anatomically complex, and its small, deep structures are difficult to image. Improvements to the spatial and temporal resolution of MRI have made it easier to identify and delineate the cause of epilepsy in most patients. This is especially relevant for patients with drug-resistant focal epilepsy. Good agreement between MRI and EEG data can improve the likelihood of surgical success. The probability of a seizure-free outcome for patients with temporal lobe epilepsy is 82% if the lesion is concordant with EEG results. This drops to 56% for patients with an unremarkable MRI. In frontal lobe epilepsy, the probability of an excellent outcome is 72% with a concordant lesion and 41% when no abnormality is detected.^4,5

MRI is well established as the imaging technique of choice for patients with epilepsy. CT may be used if MRI is not available in cases in which an acute neurological insult has led to seizures. Tumors, infarcts, and major malformations are usually detectable on CT. More subtle abnormalities, such as hippocampal sclerosis, sub-ependymal nodular and band heterotopias, focal cortical dysplasia, and small tumors, can be detected on MRI if appropriate sequences are chosen.^6,7 Newer MR-based techniques, such as MR spectroscopy, functional MRI, and fMRI/electroencephalography, are increasingly being used to detect metabolic changes, abnormalities of cerebral flow, and cortical activation associated with epilepsy.⁸

An MRI examination should be performed in all epilepsy patients, with the exception of those with a definitive diagnosis of idiopathic generalized epilepsy or childhood benign rolandic epilepsy with centrotemporal spikes. MRI is particularly indicated in patients fitting one or more of the following criteria:⁶

• onset of partial seizures is recent;
• onset of generalized or unclassified seizures occurred in the first year of life or adulthood;
• evidence of deficit shows on neurological examination;
• seizure control does not occur with first-line anti-epileptic drugs; and
• seizure control is lost or a change occurs in the pattern of seizures.

Good-quality images are important for accurate lesion detection. MRI should be performed at a field strength of 1.5T or higher using a standardized protocol and a quadrature head coil. The combination of images acquired in this manner can, with appropriate clinical information, improve localization of the suspected epileptogenic zone in 85% of cases.⁹

The development of phased-array surface coils and 3T imaging has significantly increased our ability to detect lesions and to define their extent and character (Figure 1). Imaging at 3T benefits from a higher signal-to-noise ratio and higher T2 contrast than that achieved with 1.5T. Experienced review of 3T phased-array MRI yields additional diagnostic information in 48% of patients compared with routine clinical reads at 1.5T. In 37.5% of cases, this additional information will lead to a change in clinical management.¹⁰

A protocol for epilepsy imaging should include:

• T1- and T2-weighted sequences to cover the whole brain in at least two orthogonal planes with the smallest slice thickness possible;
• axial FLAIR (fluid-attenuated inversion recovery) to help in the differential diagnosis of areas of high signal on T2-weighted MRI and to increase the conspicuity of periventricular lesions (due to its ability to null increased signal intensity of the cerebro-spinal fluid) (Figure 2);^11,12
• oblique coronal T2-weighted turbo spin-echo sequence, at a 2-mm slice thickness, oriented perpendicular to the long axis of the hippocampus to demonstrate any increase in T2 signal intensity;
• axial T2* sequence covering the whole brain, showing the paramagnetic properties of chronic blood degradation products and calcium as "blooming" artifacts (ideal for characterizing some vascular lesions, such as cavernomas); and
• T1-weighted sagittal 3D fast field-echo with an inversion recovery pulse, to obtain multiplanar reconstructions with almost isometric spatial resolution.

Multiplanar reformatting is useful for simulating the surface of the brain and gaining an indication of gyral morphology. The inversion recovery pulse enhances gray-white matter differentiation, which is crucial for analyzing the cortical structure.Although the routine use of gadolinium contrast is not indicated, it can be helpful to clarify some findings.

¹³

Coronal and axial sequences should be oriented perpendicular and parallel to the temporal lobe main axis, especially when studying temporal epilepsy.Diagnostic assessments based on these MRI data will be entirely visual and subjective. It is consequently mandatory that readers be able to demonstrate expertise in this area.

^14,15

KEY CEREBRAL ABNORMALITIES

Hippocampal sclerosis is the single most common pathology underlying partial seizure disorders that do not respond to drug therapy but are amenable to surgical treatment.^16,17 Two-thirds of patients with hippocampal sclerosis become seizure-free after anterior and medial temporal lobe resection. Optimization of surgical treatment requires that the location and size of the focus, and the extent to which other brain regions are affected, be determined.¹⁸

Identification of hippocampal sclerosis relies on a proper appreciation of the hippocampal anatomy and the use of optimally oriented scanning planes. The hippocampus is a curved structure with a concave surface facing the brain stem. To minimize partial volume effects, the hippocampus is best evaluated orthogonal to and along its long axis.^7,19

Coronal T1-weighted MRI will demonstrate cell loss and astrogliosis indicative of hippocampal atrophy. T2-weighted MRI will demonstrate increased signal intensity, though because this is a nonspecific finding it should be correlated with high-resolution, good-quality T1-weighted anatomical images. Other features of hippocampal sclerosis include disruption of the internal structure of the hippocampus,²⁰ atrophy of the ipsilateral fornix and adjacent temporal structures, and dilatation of the ipsilateral temporal horn.

Several techniques have been used to estimate the volume of brain structures, most commonly the hippocampus, amygdala, and temporal lobe. Differences in volume (usually a reduction) when compared with normative data can suggest that focal pathology is the cause of seizure onset. It should be remembered that patients may have normal volumes, a unilateral abnormality, or bilateral abnormalities.

Volumetric information is generally interpreted in conjunction with quantitative T2-weighted data. A hippocampal asymmetry of 20% or greater will usually be apparent to skilled neuroimaging specialists. Smaller degrees of asymmetry require quantification.²¹ We use a manually driven cursor to outline the hippocampus on contiguous 2-mm-thick coronal T2-weighted slices, generating cross-sectional contour maps. Improvements to technology and software have helped to automate assessments of hippocampal volume. The methodology of volumetry is still demanding and time-consuming, though, requiring a postprocessing computer and a skilled operator.

Malformations of cortical development have been identified as causes of epilepsy and neurodevelopmental deficits. These abnormalities are increasingly being recognized in patients with seizure disorders that were previously regarded as being cryptogenic.⁸ Malformations of cortical development can be subdivided into four basic categories depending on the phase in which arrest of neuronal development took place. Each category is subdivided into generalized and focal.

Neuronal migration anomalies were first described in the mid-19th century. They were previously observed as postmortem findings in patients with drug-resistant epilepsy. Advanced neuroimaging techniques have made it possible to diagnose these anomalies accurately and noninvasively (Figure 3). Sixty percent of patients with refractory epilepsy have been found to have a neuronal migration anomaly. The postsurgical outcome is excellent for the 42% of patients with a focal disorder.²²

Cavernomas are the most common type of vascular lesion to cause epilepsy. Surgery will stop seizures in around 70% of patients. MRI typically demonstrates a well-circumscribed range of blood products, which presumably trigger the seizures by irritating nearby paren-chyma. Blooming artifacts on T2*-weighted imaging can be used to clarify the blood components.

Developmental neoplasms caused by abnormal glial proliferation can often cause refractory epilepsy. This group of neoplasms includes ganglioglioma, a benign neuronal tumor that is generally rare but is most commonly seen in young patients. Ganglioglioma and low-grade brain neoplasms together make up 10% to 30% of the underlying pathology in patients with chronic intractable epilepsy.^23,24 Accurate identification and localization of these lesions is important for the planning of surgical resection, which carries a good chance of seizure control.

Ganglioglioma shows low signal intensity on T1-weighted MRI, high signal intensity on T2-weighted MRI, and may enhance after injection of gadolinium contrast. Imaging findings are not specific, however (Figure 1).⁸ Differenting these tumors from other entities with similar origin and imaging characteristics, such as cortical dysplasia, can be difficult.

NEUROIMAGING DEVELOPMENTS

The development of neuroimaging techniques has revolutionized the investigation and treatment of epilepsy. MRS, SPECT, PET, diffusion-weighted imaging, perfusion-weighted imaging, and fMRI can all obtain data on cerebral metabolism and blood flow noninvasively. This may have significant consequences for the medical and surgical treatment of patients with epilepsy. Invasive seizure monitoring could be avoided altogether in certain patients. Results from these modalities may also influence which patients are referred for surgery and the nature of the procedure undertaken.

MRS can provide information on the molecular composition and concentration of a chosen volume of cerebral tissue. Variations in the main mo-lecular compounds, such as N-acetyl-aspartate, creatine, choline, lactate, and lipids, are measured interictally to find focal abnormalities consistent with the seizure focus (Figure 4). MRS is a sensitive tool for epilepsy lateralization and may indicate bilateral disease when conventional MRI is normal or shows unilateral pathology. It is used mainly as a research tool at present.^25-27

Cortical activation MRI, or fMRI, is based on the measurement of blood oxygen level-dependent signal changes, that is, localized reductions in the blood oxygenation level secondary to neuro-nal activation in a delimited area of cortex. This tool, which is still limited to research, can locate the areas of cortex responsible for language, motor activity, sensory perception, and memory.²⁸

SPECT provides information on the uptake of radiopharmaceuticals (tracers) in certain areas of the brain. The technetium-99m-labeled compounds hexamethylpropyleneamine oxime and ethyl cysteinate dimer are commonly used before epilepsy surgery to obtain information about cerebral blood flow. Interictal scans often show an area of reduced uptake at the site of seizure onset (Figure 5). More reliable information is provided by injecting the tracer at the start of a seizure (ictal scan) or just afterwards (postictal). This shows an area of increased uptake at the site of seizure activity.

Subtraction of ictal SPECT coregistered with MRI is a novel computer-aided technique. Interictal SPECT images are first subtracted from ictal SPECT images. The resulting image is then superimposed on the patient's MRI to combine functional and structural data.²⁹PET uses oxygen-15-labeled water and fluorine-18 FDG to obtain information on blood flow and glucose metabolism respectively. It provides better spatial resolution than SPECT.

REVOLUTIONIZED EVALUATION

MR imaging has revolutionized the evaluation of epilepsy, particularly in patients with medically uncontrollable seizures who might respond to surgery. MRI is able to identify and localize anatomic abnormalities, select surgical candidates, and guide surgical resection.

Given the improvements in MRI hardware and postprocessing methodologies, the proportion of cryptogenic cases has decreased. Today the principal causes of refractory epilepsy are considered to be hippocampal sclerosis, developmental anomalies, and intracranial mass lesions.

The development of new neuro-imaging techniques has revolutionized the investigation and treatment of epilepsy. Noninvasive methods for obtaining data on cerebral function and metabolism promise to have significant impact on the medical and surgical management of epileptic patients. These results, however, must always be put in context using structural MRI.

DR. OLEA-COMAS, DR. GUTIÉRREZ-JARRÍN, DR. GARCÍA-CAMACHO, and DR. PIÑERO-GONZÁLEZ are radiologists in the neuroradiology department at the University Hospital Virgen del Rocío in Seville, Spain.

References

1. Bronen RA. Epilepsy: the role of MR imaging. AJR 1992;159(6):1165-1174.
2. Proposal for revised classification of epilepsies and epileptic syndromes. Commission on Classification and Terminology of the International League Against Epilepsy. Epilepsia 1989;30(4):389-399.
3. Fisher RS, van Emde Boas W, Blume W, et al. Epileptic seizures and epilepsy: definitions proposed by the International League Against Epilepsy (ILAE) and the International Bureau for Epilepsy (IBE). Epilepsia 2005;46(4):470-472.
4. Kuzniecky R, Burgard S, Faught E, et al. Predictive value of magnetic resonance imaging in temporal lobe epilepsy surgery. Arch Neurol 1993;50(1):65-69.
5. Mosewich RK, So EL, O'Brien TJ, et al. Factors predictive of the outcome of frontal lobe epilepsy surgery. Epilepsia 2000;41(7):843-849.6. Kuzniecky RI. Neuroimaging of epilepsy: advances and practical applications. Rev Neurol Dis 2004;1(4):179-189.
7. Wieshmann UC. Clinical application of neuroimaging in epilepsy. J Neurol Neurosurg Psychiatry 2003;74(4):466-470.
8. Duncan JS. Imaging and epilepsy. Brain 1997;120(Pt 2):339-377.
9. Grant PE. Structural MR Imaging. Epilepsia 2004;45(Suppl 4):4-16.
10. Knake S, Triantafyllou C, Wald LL, et al. 3T-phased array MRI improves the presurgical evaluation in focal epilepsies: a prospective study. Neurology 2005;65(7):1026-1031.
11. Von Oertzen J, Urbach H, Jungbluth S, et al. Standard magnetic resonance imaging is inadequate for patients with refractory focal epilepsy, J Neurol Neurosurg Psychiatry 2002;73(6):643-647.
12. Wieshmann UC, Free S, Everit A, et al. Magnetic resonance imaging in epilepsy with a fast FLAIR sequence. J Neurol Neurosurg Psychiatry 1996;61(4):357-361.
13. Rydberg JN, Hammond CA, Grimm RC, et al. Initial clinical experience in MR imaging of the brain with a fast fluid-attenuated inversion-recovery pulse sequence. Radiology 1994;193(1):173-180.
14. Mc Bride MC, Bronstein KS, Bennett B, et al. Failure of standard magnetic resonance imaging in patients with refractory temporal lobe epilepsy. Arch Neurol 1998;55(3):346-348.
15. Von Oertzen J, Urbach H, Jungbluth S, et al. Standard magnetic resonance is inadequate for patients with refractory focal epilepsy. J Neurol Neurosurg Psychiatry 2002;73(6):643-647.
16. Cascino GD, Hirschorn KA, Jack CR, Sharbrough FW. Gadolinium-DTPA-enhanced magnetic resonance imaging in intractable partial epilepsy. Neurology 1989;39(8):1115-1118.
17. Bruton CJ. The neuropathology of temporal lobe epilepsy. Oxford, U.K.: Oxford University Press, 1988:1-158.
18. Babb TL, Brown WJ. Pathological findings in epilepsy. In: Engel J Jr, ed. Surgical treatment of the epilepsies. New York: Raven Press, 1987:511-540.
19. Vermathen P, Laxer KD, Schuff N, et al. Evidence of neuronal injury outside the medial temporal lobe epilepsy: N-acetylaspartate concentration reductions detected with multisection proton MR spectroscopic imaging-initial experience. Radiology 2003;226(1):195-202.
20. Berkovic SF, Andermann F, Olivier A, et al. Hippocampal sclerosis in temporal lobe epilepsy demonstrated by magnetic resonance imaging. Ann Neurol 1991;29(2):175-182.
21. Van Paesschen W, Sisodiya S, Connelly A, et al. Quantitative hippocampal MRI and intractable temporal lobe epilepsy. Neurology 1995;45(12):2233-2240.
22. Campos-Castelló J, López-Lafuente A, Ramírez-Segura R, et al. [Epileptic signs in alterations of neuronal migration]. Rev Neurol 1999;28(Suppl 1):S14-19. Spanish.
23. Thadeu P, Mertens A, Rocha H. Ganglioglioma. Comparison with other low-grade brain tumours. Arch Neuropsychiatr 2006;64(3-A):613-618.
24. Rousseau A, Kujas M, Bergemer-Fouquet AM, et al. Surviving expression in ganglioglioma. J Neurooncol 2006;77(2):153-159.
25. Willmann O, Wennberg R, May T, et al. The role of 1H magnetic resonance spectroscopy in pre-operative evaluation for epilepsy surgery. A meta-analysis. Epilepsy Res 2006;71(2-3):149-158.
26. Kuzniecky R, Palmer C, Hugg J, et al. Magnetic resonance spectroscopic imaging in temporal lobe epilepsy. Arch Neurol 2001;58(12):2048-2053.
27. Park SW, Chong KH, Kim HD, et al. Lateralizing ability of single-voxel proton MR spectroscopy in hippocampal sclerosis: comparison with MR imaging and positron emission tomography. AJNR 2001;22(4):625-631.
28. Detre JA. fMRI: applications in epilepsy. Epilepsia 2004;45(Suppl 4):26-31.
29. Van Paesschen W. Ictal SPECT. Epilepsia 2004;45(Suppl 4):35-40.