Imaging the Patient with Epilepsy
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In patients with medication-refractory epilepsy, structural abnormalities can be seen in up to 85% of cases when employing a dedicated MR imaging protocol and when being read by trained Neuroradiologists. Most commonly encountered pathologies include mesial temporal lobe sclerosis (that can be uni- or bilateral and may occur as a “dual” pathology in conjunction with other epileptogenic lesions), malformations of cortical development (including disorders of neuronal proliferation, migration or organization) and epileptogenic tumors (such as gangliogliomas, dysembryoblastic neuroepithelial tumors). In addition other conditions such as vascular malformations, certain phakomatoses, encephaloceles, or infections can be present.
KeywordsEpilepsy Mesial temporal lobe sclerosis Disorders of development Epileptogenic tumors
To understand typical imaging criteria to identify and differentiate causes of medication refractory epilepsy
To understand the limitations of imaging for patients with medication refractory epilepsy if no dedicated Epilepsy MR protocol is used.
To appreciate the importance of additional clinical information when evaluating the patient with medication refractory epilepsy.
Approximately 4% of the general population will experience a seizure during their lifetime. Imaging findings of “first-ever” seizure patients are in most cases normal, and abnormalities are only present in approximately 15% of patients as seizures can be provoked by fever, sleep deprivation, stroboscopic lights, or drugs. However, an underlying lesion will lower the seizure threshold and thus make a patient more susceptible to experience a seizure. As “first-ever” seizures are a medical emergency the initial imaging modality of choice in these cases is an unenhanced CT head scan to exclude acute medical emergencies that may go along with seizures prior to a more extensive workup depending on clinical history and presentation. Imaging abnormalities encountered in patients experiencing their first-ever seizures include (but are not restricted to) virtually all diseases affecting the brain. As such you may find vascular abnormalities (such as microangiopathy, arteriovenous malformations (AVM), sinus thrombosis, hemorrhage, cavernomas, or stroke), tumors (metastases, primary tumors), infections (encephalitis, meningitis, abscess), sequelae of previous head injury, and toxic or metabolic conditions (e.g., PRES) in these patients.
In contrast to the “first-ever” seizure, patients diagnosed with “epilepsy” have recurrent and unprovoked seizures. Approximately 1% of the general population will be diagnosed with this condition and as seizures are recurrent and unprovoked, an underlying lesion is far more common as compared to patients with their first-ever seizure. Being “unprovoked,” lesions that can irritate the brain (i.e., are “epileptogenic”) may be present. On brain imaging, lesions will be seen in nearly 50% of patients; however, these are non-specific and can encompass a wide variety of underlying conditions that can provoke the recurrent seizure attacks. Imaging findings in patients with seizures include but are not restricted to: vascular conditions such as microangiopathy, previous ischemia, vascular malformations, previous hemorrhage or cavernomas, tumors (metastases, primary tumors), remote infections (encephalitis, abscess), previous head injury, congenital malformations, or toxic metabolic conditions. Imaging of choice in patients with epilepsy is MRI given the larger variety of potential underlying diseases.
The vast majority of patients with epilepsy can be treated satisfactorily with antiepileptic drugs. However, 0.4% of the general population will have recurrent and unprovoked seizures that do not respond to medication. These patients are potentially treatable with surgery, and surgical intervention is an appropriate consideration for 3% of people who develop epilepsy . The major focus of this chapter will be on the imaging findings in those patients who are diagnosed with “medication refractory” epilepsy, i.e., patients where the seizure focus is too strong to be controlled by medication which indicates that the underlying lesion has to have a strong epileptogenic potential. In these patients, structural imaging will find abnormalities in up to 85% of patients. Lesions with a strong epileptogenic potential are either close to epileptogenic structures or consist of abnormal neurons. Lesions that are often involved in medication refractory epilepsy are: mesial temporal lobe sclerosis (MTS) (primary or secondary to a long standing seizure disorder), malformations of cortical development, certain epileptogenic tumors (e.g., dysembryoplastic neuroepithelial tumors (DNET), temporal lobe gliomas gangliogliomas), vascular malformations, trauma, remote infection, and certain phakomatoses. Imaging findings in some of these conditions will be subtle which necessitates both a dedicated imaging protocol (as compared to a standard MR) and an “expert” experience in reading these types of scans. In a landmark study of von Oerzten et al. , the sensitivity of “non-expert” reports of standard MRI reports for focal lesions was 39%, while sensitivity of “expert” reports of standard MRI increased to 50%. “Expert” reports of epilepsy dedicated MRI protocols further increased the sensitivity in detecting subtle lesions to 91%. Dedicated MRI showed focal lesions in 85% of patients with “non-lesional” standard MRI. Neuropathological diagnoses were predicted correctly in 22% of “non-expert” standard MRI reports but by 89% of dedicated MRI reports. Thus, the combination of dedicated MRI protocols and dedicated radiologists trained in evaluating patients with medication refractory seizures increases significantly the sensitivity of MRI in this subgroup of patients. A multidisciplinary approach that involves close communication between epilepsy neurologists, neuroradiology, EEG, nuclear medicine, neuropsychology, and neurosurgery is an important feature of modern epilepsy management.
The necessity of expert MR reading with a dedicated imaging protocol is further highlighted by the fact that postsurgical seizure freedom is achieved significantly more often when a circumscribed, resectable epileptogenic lesion can be identified on MRI preoperatively compared to patients that are rated non-lesional . As pointed out by Wellmer et al. in 2013 [4, 5], the possible reasons for undetected epileptic lesions in standard outpatient MRI are insufficient clinical information from the referring clinician, routine MR protocols not optimized for the spectrum of epileptogenic lesions, and unfamiliarity with the spectrum of epileptogenic lesions. Wellmer pointed out that “because even the best focus hypothesis and most profound knowledge of epileptogenic lesions do not permit the detection of lesions when they are invisible on the MRI scan, the starting point for any improvement of outpatient MRI diagnostics should be defining an MRI protocol that is adjusted to common epileptogenic lesions.”
In a recent analysis performed by Wellmer et al. on the prevalence of epileptogenic lesions among 2740 patients the following pathologies were found: mesial temporal lobe sclerosis (32%), tumors (including low and high grade tumors as well as malformative tumors and benign epilepsy associated tumors) in approximately 17% of patients, cortical dysplasias in 11%, glial scars (including posttraumatic, post-ischemic, post-hemorrhagic, postinfectious/abscess, ulegyria, and postsurgical scars) in 11%, vascular diseases (cavernoma AVM, pial angiomatosis) in 5%, malformations of cortical development including nodular heterotopia, subcortical band heterotopia, polymicrogyria, lissencephaly, pachygyria, agenesis of corpus callosum, craniocephalic malformations, hemiatrophy, lobar dysgenesis, hemimegalencephaly, or hamartomas in 3%, and sequelae of encephalitis in 1% while in approximately 20% no lesion could be detected.
Lesion location—presumably related to the different epileptogenic potential in different brain regions—demonstrates preponderance for the temporal lobes (60%) followed by the frontal lobe (20%), the parietal lobe (10%), the periventricular white matter (5%), and the occipital lobe (5%). Lesions within the cerebellum or brainstem are not known to cause epilepsy.
Functional MRI (fMRI) can map eloquent cortex and provide information regarding language lateralization  (Fig. 10.3), and the use of diffusion tensor imaging (DTI) and tractography may help to avoid injury to the optic radiation during temporal lobe resection .
Radionuclide imaging can add useful information in selected cases . Subtraction of ictal and interictal SPECT co-registered to MRI (SISCOM) can show a seizure-induced hyperperfusion (Fig. 10.4), whereas 18FFDG-PET may show hypometabolism in the seizure onset zone. This is particularly useful in lateralization of temporal lobe epilepsy in the MR-negative patient.
Dipole source analysis using either EEG or MEG data can also be added for the localization of seizure activity.
In selected patients, i.e., those with medication refractory epilepsy, abnormalities can be found in a high percentage if images are performed with a dedicated imaging protocol, and expert read-out. A variety of non-radiological adjunct tests are available that may help in the localization of the seizure focus and preferably these challenging cases are therefore discussed in multidisciplinary conferences.
In the following we will discuss the imaging features of epileptogenic lesions highlighting imaging pearls and pitfalls.
10.1.1 Mesial Temporal Lobe/Hippocampal Sclerosis
Mesial temporal lobe sclerosis is the most commonly seen cause for medication refractory epilepsy and is characterized by an indistinct gray–white matter differentiation, abnormal high signal on T2/Flair sequences, and atrophy. In up to 20% of cases additional epileptogenic pathology is found in patients with mesial temporal lobe sclerosis.
10.1.2 Malformations of Cortical Development
In order to understand the different types of malformations of cortical development it is important to briefly review the embryology of normal brain development: During the seventh week of gestation, neuronal proliferation in the subependymal germinal matrix occurs. After the eighth week these cells migrate outward in multiple waves of radial outward migration aided by radial glial cell guidance in a process coined chemotaxis. The third and last part of the cortical development, the lamination, is the organization of the cells within different cortical layers, a process that is orchestrated by the subplate (the lowest layer of cortex). Chromosomal mutations, destructive events (ischemia/infections), or toxins may inhibit either of these three processes (proliferation, chemotaxis, or cortical organization) which will lead to abnormalities in stem cell development, migration, or lamination.
Malformations of cortical development are present in up to 25% of patients with intractable childhood epilepsy. They are associated with chromosomal alterations, congenital infections, or in utero ischemia. In addition to epilepsy these patients may have developmental delay and focal neurological deficits.
Malformations related to abnormal stem cell development include the focal or transmantle cortical dysplasias (balloon cell or type II FCDs) and the hemimegalencephalies.
Malformations related to abnormal migration are the lissencephalies, the agyria-pachygyrias, and the heterotopias.
Female carriers of the affected X-chromosome present with band heterotopias that is more present in the frontal lobes compared to the parietal lobes. Thus, if females present with band heterotopias, genetic counseling may be indicated as half of their male offspring may be affected by anterior agyria. The band may be thin or thick depending on the amount of arrested neurons during migration. Patients with a thick band have less normal cortex (that can be thinned) and thus present with a more severe developmental delay.
In addition to the “band heterotopia,” focal subcortical heterotopia can be present, on imaging, swirling, curvilinear bands of gray matter as well as thinned cortex, and paucity of the white matter are seen. The ipsilateral ventricle may be distorted and there can be an associated callosal hypogenesis.
In open-lip schizencephaly a cleft that is lined by gray matter reaches from the periphery to the ventricle, while in the closed-lip schizencephaly gray matter is reaching from the periphery to the ventricle and a dimple is seen in the ventricular wall. Schizencephaly can be multifocal and bilateral. The cortex lining the defect is polymicrogyric with ill-defined margins to the white matter. Finally, FCD type I (non-balloon cell) is a disorder of lamination. Imaging features are very subtle and only mild focal blurring of the gray–white matter junction may be present. This type of dysplasia is often undetectable on MRI.
Malformations of cortical development are commonly seen in pediatric patients with medication refractory epilepsy. Often these patients have some form of cognitive impairment or developmental delay.
10.1.3 Epileptogenic Tumors
While virtually all tumors may cause epilepsy, there are certain tumors that have a very high propensity of eliciting medication refractory seizures. As most of these are benign and just by means of location (i.e., within the cortical–white matter interface and with temporal lobe predilection) cause the seizures, these are often very good candidates for surgery. As a general discussion of all tumors is beyond the scope of this chapter, we will focus only on three tumors that are commonly associated with seizures: the gangliogliomas, the DNETs, and the tuber cinereum hamartomas.
10.1.4 Miscellaneous: Vascular Malformations/Trauma/Infection/Phakomatoses
Similar to the previous paragraph, it is beyond the scope to in detail describe imaging features of vascular malformations, infections or trauma that can go along with seizures and most of the entities are described in other chapters of this syllabus. We therefore only want to highlight few epilepsy-relevant facts and features of these miscellaneous conditions.
Brain AVMs can cause seizures due to previous hemorrhage and scarring, hemosiderin deposition (especially when close to the cortex), or gliosis. AVMs in the temporal lobe have a higher likelihood of producing seizure due to interference of the normal blood supply and drainage of potentially epileptogenic structures such as the hippocampus.
Patients with previous trauma can experience posttraumatic seizure disorder, especially after having sustained contusional hemorrhages of their temporal lobes as gliosis and hemosiderin staining can cause irritation of the surrounding cortex.
Neonatal anoxic ischemia or hypoxemia can cause ulegyria—i.e., a scar/defect of the cerebral cortex that mainly involves the cortex in the depth of the sulcus whereas the cortical crowns remain relatively unaffected. This peculiar pattern can be explained by the vascular supply of the gyri in the newborn that leads to a better perfusion of the apices of the gyri as compared to the depth of the sulci. There will be paucity of the white matter and, as the lesion occurred prior to complete myelination, a relatively mild gliosis. If the perinatal ischemia has only involved one hemisphere (perinatal stroke) a Dyke Davidoff Mason syndrome will ensue where stable hemiatrophy is present with hypertrophy of the skull and the sinuses, paucity of white matter, ventricular enlargement, and mild gliosis.
Rasmussen’s encephalitis is a presumably autoimmune mediated chronic inflammation of the brain that presents with progressive gliosis and volume loss. Patients experience seizures and a progressive hemiparesis.
Antero-basal temporal lobe encephaloceles are lesions that are either related to a congenital defect of the bone or to previous trauma. Brain tissue can extend into the pterygopalatine fossa through the bony defect at the base of the greater sphenoid wing in the region of the foramen rotundum and pterygoid process. The herniated brain demonstrates high T2/FLAIR signal and is believed to be the epileptogenic focus. Following resection of the abnormal brain tissue seizure freedom can be obtained in a very large proportion of cases.
Many other pathologies including tumors, vascular malformations, phakomatoses, or remote infections can cause medication refractory epilepsy especially if the structures involved are close to the mesial temporal lobe structures.
Neuroimaging in patients with refractory epilepsy will find abnormalities in as high as 85% of cases and therefore plays a crucial role in the identification of epileptogenic lesions and their possible surgical removal. A dedicated epilepsy protocol is necessary to identify these lesions and the MR should be interpreted in conjunction with EEG, MEG, neuropsychological testing, and clinical semiological data to increase the likelihood of identifying these often very subtle lesions.
Take Home Messages
When evaluating a dedicated seizure protocol MR, a structured approach is helpful that includes a detailed assessment of (a) the hippocampus and mesial temporal lobe structures, (b) the ventricular outline, and (c) the gyral and the sulcal anatomy.
Particular emphasis should be paid upon the T2/FLAIR signal within the cortex and hippocampus, its similarity to other regions of neo- and archicortex, the internal architecture of the hippocampus, the indentations of the pes hippocampi, the fornix and mammillary bodies, and the grey-white matter interface of the neocortex (blurring, gray matter thinning or thickening).
The malformations of cortical development can be differentiated into disorders of neuronal proliferation, migration and cortical organization.
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