Advances in Neuroimaging: Surgical Localization

"If the patient's fits are local, frequently recur, and are always similarly localized, it is surely a necessary inference that there is some local disease in his nervous system … Local symptoms must of necessity depend on local lesions." John Hughlings Jackson, circa 1875 (1) In 1859, 24-year-old John Hughlings Jackson arrived in London on the completion of his medical training (2–4). Shortly thereafter, in 1862, he joined the staff at the National Hospital for the Paralyzed and Epileptic in Queen Square (2,3). The National Hospital was founded in 1857, and the reputations of the world-renowned institution and the brilliant Jackson would soon become inseparable (3). During his illustrious careers he introduced the basic concept of the partial or localization-related epilepsies (1–4). Previously, it had been assumed that epilepsy was only associated with generalized tonic-clonic seizure activity of lower brainstem origin (1,2,4). Jackson established the relationship between the localization of a structural intra-axial abnormality in the cerebral cortex and the epileptogenic zone, i.e., the site of ictal onset and initial seizure propagation (1–4). He also characterized the partial seizure types, documented the importance of the aura, introduced the concept of the "discharging lesion," and validated the effect of epileptic brain tissue localization on ictal behavior (1–4). Jackson emphasized the importance of identifying the "local lesion," which represented the functional or structural abnormality associated with the "partial external symptoms"(1,2). The neurological history and examination at that time were the only diagnostic tools available to search for the offending "local lesion"(1,2). Confirmation of the underlying pathology required a postmortem examination. Surgical treatment was introduced as a potential therapy for partial epilepsy in 1886 at Queen Square (5,6). Victor Horsley performed the first cortical resection on a patient of Jackson's who had a partial seizure disorder related to a remote head injury (5,6). A 22-year-old patient had been involved in a carriage accident that resulted in a skull fracture and frontal lobe encephalomalacia (5). The patient ultimately experienced a significant reduction in seizure tendency after surgical treatment. Horsley reported the favorable experience with surgery in three patients with partial seizures (5,6). The effectiveness of these initial operative procedures validated the basic hypotheses of Jackson concerning localization-related seizure disorders and demonstrated the importance of lesion-directed surgery in the treatment of partial epilepsy associated with a pathological substrate. The observations of Jackson provided the rationale for the innovations in the neuroimaging of epilepsy that would occur during the twentieth century. "In the study of any case of focal epilepsy the x-ray often provides the clinician with indispensable clues to localization." Wilder Penfield, 1954 (7) Wilder Penfield and his colleagues at the Montreal Neurological Institute popularized the use of surgical treatment for the management of intractable partial seizure disorders during the early and mid twentieth century (7–9). Penfield had realized the enormous potential of radiographic studies for surgical localization (7). The routine use of neuroimaging in patients with seizure disorders being considered for surgical treatment was introduced (8). Skull radiography, ventriculography, and pneumoencephalography were variably associated with imaging abnormalities in patients with partial epilepsy (7–9). Unfortunately, the limited diagnostic yield of these techniques was obvious (10). Only widely distributed, often multilobar, structural alterations or calcified lesions were associated with abnormal radiographic studies (7,10). Characteristically, radiography failed to image the brain or the pathology but may have demonstrated a secondary change such as ipsilateral ventricular enlargement or thickening of the calvarium (10). Radiographic studies were also associated with radiation exposure and may have involved an invasive procedure. Interictal EEG recordings, intraoperative electrical stimulation mapping, and electrocorticography were primarily used to delineate the localization of the epileptogenic zone and the extent of the operative resection necessary to significantly reduce seizure tendency (7–9). The introduction of x-ray computed tomography (CT) in the 1970s was an important development in the diagnostic evaluation of patients with epilepsy (11). CT proved useful in demonstrating selected intracranial "macroscopic lesions" associated with epilepsy (11). The introduction of CT made the routine use in chronic epilepsy of other radiographic studies obsolete. The potential limitations of CT in epilepsy included the low diagnostic yield for the common surgical pathologies, i.e., "microscopic lesions," inability to perform multiplanar imaging, radiation exposure, difficulty distinguishing gray and white matter structures, and bony artifact (12–15). "MRI has the same potential as had EEG over 50 years ago, to provide a new level of understanding of the basic mechanisms, the clinical features and the treatment of epilepsy." Simon Shorvon, 1994 (13) Investigators at Nottingham University first applied magnetic resonance imaging (MRI) to the study of the brain in 1980 (14). The introduction of MRI in epilepsy has been compared with the development of clinical EEG as a diagnostic tool in the 1930s (13). MRI has been shown to be superior in sensitivity and specificity to CT in identifying the intra-axial structural abnormalities associated with partial epilepsy (12–15). MRI has the potential to provide surgical localization in patients with the selected pathological findings underlying the epileptogenic zone (see later). This is a noninvasive technique that has no known biological toxicity and does not involve ionizing radiation (12–15). MRI is the structural neuroimaging procedure of choice in evaluating patients with partial epilepsy for surgical localization (15). Structural neuroimaging may be used preoperatively to identify patients with surgically remediable epileptic syndromes (15). MRI studies may also be performed to confirm the extent of corticoectomy and lesion resection postoperatively. The clinical application of MRI in patients with intractable partial epilepsy reintroduced the concept of lesion-directed surgery that had been used by Jackson and Horsley nearly one century earlier (15,16). MRI has allowed patients with intractable partial epilepsy being considered for surgical treatment to be separated into two groups: those with substrate-directed and those with non–substrate-directed disease (Table 1). Patients with substrate-directed partial epilepsy have one or more potentially epileptogenic structural abnormalities that may be coexistent with the epileptogenic zone (16). The MRI studies with varying degrees of sensitivity and specificity are abnormal and useful for surgical localization. The major pathological entities in this group include mesial temporal sclerosis (MTS), primary brain tumor, vascular anomaly, and malformations of cortical development (MCDs) (Table 1). The high diagnostic yield of MRI in patients with these disorders has been confirmed (Table 1)(12,15–27). A minority of patients with substrate-directed disease will be rendered seizure free on antiepileptic drug therapy. Patients with MTS and lesional pathology are considered to have a surgically remediable epileptic syndrome because the majority of patients experience a significant reduction in seizure tendency after epilepsy surgery (15,16,25,28–36). The prognostic importance of the extent of lesion excision has been confirmed (16,33–35,37,38). The preoperative evaluation in patients with substrate-directed partial epilepsy is designed to determine the epileptogenicity of the MRI-identified structural abnormalities. The pathological findings underlying the epileptogenic zone in patients with non–substrate-directed partial epilepsy include focal cell loss, gliosis, and an MCD (25). Commonly in this group, the surgical specimen reveals no specific histopathological alteration. By definition, MRI fails to reveal a potentially epileptogenic structural abnormality in these patients. MTS is the most common surgical pathology in patients with medial temporal lobe epilepsy (MTLE) (18–25,28,39). MRI findings in MTS include hippocampal formation atrophy and an increased mesial temporal signal intensity demonstrated on the T2-weighted image or with the fluid attenuated inversion recovery (FLAIR) sequence (Table 2 and Fig. 1) (18–20). Variably, there may be amygdalar and entorhinal cortex atrophy. MRI-based hippocampal formation volumetric studies (MRIVol) may provide objective and quantitative evidence for unilateral or bilateral hippocampal formation atrophy (18,27,28). MRIVol has important research applications and may be useful to identify subtle unilateral atrophy or bilateral symmetric atrophy. Visual inspection of MRI alone will allow detection of ∼90% of the cases of MTS (Table 2)(20,24). The hippocampal formation atrophy is most obvious using the T1-weighted image in the oblique-coronal plane. The high degree of specificity of unilateral MTS to indicate correctly the lateralization of seizure onset in patients with temporal lobe epilepsy has been confirmed (29,30,40). The identification of MTS in the surgically excised temporal lobe has been a favorable prognostic indicator of seizure control after epilepsy surgery (28–30). More than 90% of patients with unilateral MRI-identified MTS and concordant epileptiform discharges experience an excellent operative outcome, i.e., seizure free, auras only, or nondisabling seizures (29,30,35). The MRI findings in MTLE are predictive of neurocognitive outcome in patients undergoing an anterior temporal lobectomy (40). Patients with normal left hippocampal volumes are at greater risk for experiencing a significant decline in cognitive performance after a left medial temporal lobe resection than those with left hippocampal formation atrophy. A: MRI head (T1-weighted, oblique-coronal) indicates hippocampal formation atrophy in a patient with mesial temporal sclerosis. (Note: The right side of the brain is on the left side of the figure.) B: MRI head (FLAIR, oblique-coronal) shows an increased signal intensity alteration in the medial temporal lobe. (Note: The right side of the brain is on the left side of the figure.) Proton magnetic resonance spectroscopy (MRS) is another noninvasive imaging modality that may be used to demonstrate "focal neuronal damage or dysfunction" in patients with MTLE (41). MRS may be a reliable indicator of the epileptogenic zone in patients being considered for surgical treatment (41). The diagnostic yield of this technique was compared with that of MRIVol and EEG in 100 patients with temporal lobe epilepsy (Table 2)(41). The imaging modalities combined correctly lateralized the epileptic temporal lobe in 90% of patients. MRS was abnormal in 12 patients with normal MRIVol studies. Epilepsy is the most common presenting symptom in patients with low-grade and slow growing primary brain tumors (12,16,17,31,32–34). Almost invariably, MRI initially or on repeated examinations will reveal a structural intra-axial abnormality in these patients. The histopathology of these lesions includes the oligodendroglioma, fibrillary astrocytoma, pilocytic astrocytoma, mixed glioma, ganglioglioma, and a dysembroblastic neuroepithelial tumor (32). Imaging features common to all these tumors include the presence of a cortically based lesion, with sharply defined borders, little or no surrounding edema, and, with the exception of the pilocytic astrocytomas and gangliogliomas, little or no contrast enhancement (Table 2 and Fig. 2) (17). There are distinguishing imaging findings that may suggest the histopathology of the tumor; for example, gangliogliomas may be associated with a cystic lesion and a mural nodule. However, MRI typically is highly sensitive to identify neoplasms but histologically nonspecific. Complete resection of the primary brain tumor is usually associated with a seizure remission (16,31,32–34). Approximately 80–90% of patients undergoing complete resection of the low-grade neoplasm and the epileptogenic cortex are rendered seizure free (32–34). MRI head (T1-weighted, sagittal after gadolinium-DTPA injection) in this patient demonstrates a medial frontal lobe mass lesion with pathological enhancement. A grade III astrocytoma was excised. The common vascular anomalies associated with intractable partial epilepsy are the cavernous hemangiomas and arteriovenous malformations (AVMs) (17,33,34,36). Seizures may in fact be the only clinical manifestation associated with these lesions (16,36). Other vascular anomalies, such as venous angiomas and capillary telangectasias, are usually incidental findings and are rarely associated with a partial seizure disorder. MRI is essential for the recognition and diagnosis of cavernous hemangiomas and occult AVMs (angiographically negative vascular lesions) (17). Cavernous hemangiomas characteristically have a "target" appearance on T2-weighted images with a region of increased T2 signal intensity surrounded by an area of decreased signal produced by remote hemorrhage with hemosiderin-laden macrophages (Table 2 and Fig. 3) (17). The prior, often occult, hemorrhage associated with the cavernous hemangioma may be the reason for the proconvulsant effect of these lesions (36). The efficacy of surgical treatment in patients with vascular malformations has been demonstrated. Approximately 75% of individuals with cavernous hemangiomas and occult AVMs are rendered seizure free after complete extirpation of the lesion and excision of the epileptic brain tissue (36). MRI head (FLAIR, oblique-coronal) shows a right inferior temporal lobe cavernous hemangioma. (Note: The right side of the brain is on the left side of the figure.) MCD are an important etiology of symptomatic partial epilepsy (22,42–45). The use of MRI has allowed recognition of these lesions and demonstrated the frequency and importance of MCD in patients with intractable partial epilepsy being considered for surgical treatment (Table 2 and 4, 5) (42–45). A variety of developmental abnormalities have been recognized that are commonly associated with medically refractory seizures and neurocognitive decline (42–45). MCD could previously be diagnosed only by postmortem examination. Central nervous system insults can produce a MCD between the fifth and tenth weeks of gestation, when the telencephalon is developed, until the twenty-fifth week, when cell migration is completed (42–45). Patients with MCD usually experience seizure onset in the first three decades of life; however, these pathological lesions continue to be an important etiology for recurrent seizure activity in the older age groups. MRI head (T1-weighted, oblique-coronal) reveals a region of subcortical nodular heterotopia in the right temporal lobe. (Note: The right side of the brain is on the left side of the figure.) MRI head (T1-weighted, oblique-coronal) shows a large area of gray matter heterotopia in the right cerebral hemisphere. (Note: The right side of the brain is on the left side of the figure.) MRI is essential for the diagnosis and proper classification of these pathological lesions (22,42–45). The diagnostic yield of MRI in patients with MCD is variable and depends on the specific histopathological alteration and lesion location and extent of cortical involvement. The MCD have been classified by localization of the pathological lesions: generalized or diffuse disorders, unilateral disorders, focal disorders, and diffuse or focal disorders (43). The generalized disorders include lissencephaly, "double cortex" or band heterotopia, subependymal heterotopia, and megalencephaly. Hemimegalencephaly is a unilateral cortical developmental malformation. Focal disorders include the following: focal cortical dysplasia (FCD), polymicrogyria, schizencephaly, and focal subcortical heterotopia. Thin section three-dimensional volumetric MRI is extremely useful in evaluating these anomalies (Table 2)(43–45). It is difficult to resolve volume-averaged normal cortical infolding from true areas of abnormalities if the spatial resolution of the images is coarser than 1.5 mm. Reformatting of 1.5 mm three-dimensional SPGR MRI sequences is also helpful in this regard. FCD is the most common MCD considered for surgical resection (38). This MCD has been divided into types I and II based on the pathological classification (44–46). FCD type II is the more severe form of the disorder associated with cortical disorganization, white matter ectopias, and large abnormal balloon cells (46). FCD type I is characterized by an alteration of cortical lamination but does not contain evidence for balloon cells (46). Approximately 80–90% of patients with FCD will have an MRI-identified structural abnormality (Table 1)(45,46). The MRI findings may be very subtle and are most prominent in patients with FCD type II. The MRI changes include a blurring of the gray-white matter interface, focal cortical thickening, and an increased subcortical white matter signal intensity alteration (Table 1)(44–46). Fast multiplanar inversion-recovery images may be the most sensitive to demonstrate changes in FCD (46). The operative outcome in patients with FCD is less satisfactory than that in patients with other lesional epileptic syndromes (see earlier). Palmini et al. (38) reviewed the long-term surgical outcome of FCD in 26 patients at the Montreal Neurological Institute. The lesions were separated into two pathological domains: FCD and forme fruste tuberous sclerosis. The highly epileptogenic nature of these pathological substrates was confirmed. The epileptogenic zone often proved to be larger than the MCD. MRI was superior to CT in delineating these lesions. The extent of lesion resection was the most important determinant of operative outcome in the 26 patients. Seventy-seven percent of patients undergoing a complete or at least 50% resection of the region of MCD experienced an excellent operative outcome. Overall, 67% of the patients experienced a worthwhile improvement in seizure tendency. "SISCOM images have the potential to aid presurgical planning for intractable partial epilepsy by allowing a closer correlation between the site of ictal hyperperfusion and the brain anatomy, as well as any underlying structural abnormality." O'Brien et al., 1998 (47) The operative outcome in patients with non–substrate-directed partial epilepsy has been less favorable than that in individuals with an MRI-identified epileptogenic lesion (25,28,29). Patients with normal MRI studies and neocortical epilepsy of extratemporal origin in particular represent a diagnostic and therapeutic challenge for the surgical epileptologist. A prior Mayo Clinic study revealed that 25% of 37 patients undergoing an extratemporal cortical resection with a normal MRI study were rendered seizure free during short-term follow-up (25). Fifty-five percent of the patients experienced a worthwhile improvement in seizure frequency. Surgical treatment for extratemporal epilepsy may also be associated with a significant neurological deficit if the epileptogenic zone involves functional cortex (48). One study revealed acute postoperative complications in 13 of 29 of patients undergoing a large focal cortical resection for extratemporal epilepsy (48). Four of the 13 patients required a surgical procedure to treat the operative adverse effect. Ictal EEG monitoring and the electroclinical correlation have been used to determine the preoperative surgical localization. Extensive intracranial recordings are often necessary in these patients. Important issues that need to be considered include the location and technique for chronic intracranial EEG monitoring and potential morbidity associated with the operative resection (25). Despite the use of chronic intracranial EEG monitoring, these individuals may be surgical failures, i.e., no worthwhile improvement in seizure tendency or operative morbidity, or both. The reasons for the unfavorable operative outcome include difficulty localizing and lateralizing the epileptic brain tissue or inability to perform a total resection of the epileptogenic zone, or both. In selected patients, the ictal onset zone represents a continuum that is not anatomically circumscribed and may not be surgically remediable (25). Interictal functional imaging has proved to be disappointing in patients with non–substrate-directed partial epilepsy (47,49). Both interictal single-photon emission CT (SPECT) and positron emission tomography have a relatively low diagnostic yield in patients with a normal structural MRI undergoing surgical treatment for extratemporal epilepsy (47,49–51). Proton MRS may reveal abnormalities in these patients but largely remains an investigative diagnostic tool (52,53). Ictal SPECT has been shown to have important clinical applications in patients with partial seizure disorders (47,49,50,54–57). There is a consensus that ictal SPECT studies are more sensitive and specific than interictal examinations for lateralizing the site of seizure onset (49,50). The use of a radiotracer such as 99mTc-labeled ethyl cysteinate diethylester (Neurolite) provides a semiquantitative image of cerebral blood flow within 30–60 s after injection (47,56). The radiotracer is rapidly metabolized to hydrophilic compounds after crossing the blood-brain barrier and remains "trapped" for several hours. Potential limitations of ictal SPECT include poor spatial resolution and difficulty visually interpreting the side-by-side interictal and ictal images (50). Ictal SPECT injections should be performed by appropriately trained personnel in the epilepsy monitoring unit while the patient is undergoing long-term EEG recordings. Computer-aided subtraction peri-ictal, i.e., ictal and postictal imaging, SPECT coregistered to MRI (SISCOM) is a recently developed neuroimaging innovation that may demonstrate a localized cerebral blood abnormality that identifies the epileptogenic zone (see later) (50,54–57). The diagnostic yield of SISCOM has been evaluated in patients with non–substrate-directed partial epilepsy. O'Brien et al. (50) at the Mayo Clinic showed that visual side-by-side interpretation of the interictal and ictal SPECT scans proved less sensitive and specific than SISCOM in patients with intractable partial epilepsy interpretation of the SPECT scans were performed by two SISCOM images revealed a localized alteration in cerebral in of patients compared with of patients using visual side-by-side interpretation (50). The SISCOM studies were also shown to be more specific as by with the long-term EEG SISCOM reveals a localized alteration in of patients, and the functional change is concordant with the ictal onset zone in nearly of individuals Approximately 75% of individuals with partial epilepsy of extratemporal origin have a localized SISCOM alteration (Table Interictal and ictal SPECT scans hyperperfusion in the left anterior temporal lobe (Note: The left side of the brain is on the right side of the figure.) SISCOM studies in the patient from Fig. with partial epilepsy of left The MRI revealed atrophy of the that was not well SISCOM shows a region of focal hyperperfusion in the left cerebral anterior temporal lobe and sagittal of intracranial EEG recordings confirmed the diagnosis of left temporal lobe epilepsy. (Note: The left side of the brain is on the right side of the figure.) SISCOM reveals a focal region of hyperperfusion in the right frontal lobe in a patient with intractable partial epilepsy. Structural MRI was intracranial EEG monitoring using confirmed the epileptogenicity of the SISCOM The of the injection and the seizure may the diagnostic yield of SISCOM (50). The from seizure onset to the injection of the is of The injection should s after the seizure The seizure should be s in clinical may not be associated with an alteration in cerebral blood the effectiveness of SISCOM have been to and patients with partial or localization-related epilepsy being considered for surgical treatment who have experienced partial and generalized tonic-clonic the the localized SISCOM findings not the electroclinical correlation surgical treatment. The potential for SISCOM are in The detection of hyperperfusion or localized abnormalities may be a reliable indicator of the "local and be used to operative the presurgical and the focal cortical A localized SISCOM cerebral blood flow abnormality may provide a "target" to The relationship between the localized SISCOM alteration and the epileptogenic zone has been confirmed. SISCOM has also been shown to be of use in patients with potentially epileptogenic tuberous sclerosis or cavernous The prognostic importance of SISCOM studies in individuals undergoing surgical treatment for epilepsy has been established (50). Patients with SISCOM images that revealed a localized abnormality that is concordant with the ictal onset zone were more to experience an excellent outcome after epilepsy surgery than were individuals with or findings of the region of cerebral blood flow may be required for the patient to experience a reduction in seizure tendency More than 50% of patients with extratemporal epilepsy in one a focal MRI lesion and an cerebral blood flow abnormality experienced an excellent operative outcome only a minority of patients than with a or SISCOM study and a normal MRI experience an excellent operative outcome after an extratemporal neocortical excision (50). This to represent an unfavorable group for of epilepsy of antiepileptic or may be more in these patients. the clinical application of SISCOM in patients who were surgical and being considered for was evaluated Approximately of patients with an unfavorable operative outcome had a localized SISCOM abnormality during evaluation for surgery In nearly two of patients, the cerebral blood flow alteration was concordant with the site of that an resection of the epileptogenic zone may have been performed during the initial operative procedure. techniques have been introduced in the evaluation of patients with medically refractory partial seizure disorders being considered for surgical treatment to identify the "local of John Hughlings Structural MRI is the imaging procedure of choice in substrate-directed partial epilepsy. imaging procedures may be of limited ictal EEG recordings are performed in these patients to the relationship between the MRI alteration and the epileptogenic In selected pathological primary brain tumor or unilateral the studies are in EEG monitoring to the ictal onset zone is performed in these Patients with substrate-directed partial epilepsy may be highly favorable for surgical treatment. In individuals with non–substrate-directed partial the surgical pathology underlying the epileptogenic zone is not SISCOM is a functional imaging technique that may be useful to demonstrate a localized alteration in cerebral blood flow that is associated with the epileptic brain The diagnostic and prognostic importance of SISCOM has been shown in individuals with normal MRI studies who with epilepsy The for his in the of

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