Natural History

The natural history of medically intractable epilepsy has demonstrated the prognosis to be poor,² especially as children with temporal lobe epilepsy of early onset can be affected in all areas of cognitive functions and intelligence as well as behavior and psychosocial skills. The cognitive impairment of pharmacoresistant epilepsy of early onset is postulated to be related not only to the continuous seizures and their electrophysiological abnormalities on a developing brain but also to different overlapping factors. These factors include the constant need for anticonvulsant drugs, the presence of multiple medication regimens, and the use of near-toxic doses in case of status epilepticus, as demonstrated in animals models.^3,4 An onset of uncontrolled seizures under the age of 3 carries the worst prognosis, with a low IQ and motor delays with tonic and myoclonic features and spasms.⁵ Other adverse prognostic factors are the presence of daily complex partial seizures, at least five episodes of grand mal, at least one episode of status epilepticus, and a long duration of seizures prior to control.⁶

Classification of Temporal Lobe Epilepsy

The most recent classification of the International League Against Epilepsy reports mesial temporal lobe epilepsy (MTLE) with hippocampal sclerosis as a specific electrophysiological syndrome.⁷ MTLE represents a large percentage of all localization-related epilepsy and has a strong association with an early injury before the age of 4 years, particularly febrile seizure, which may be present in 40% of cases. The seizures arise in the hippocampal and parahippocampal areas and in the amygdala. MTLE also presents common diagnostic features including unilateral interictal and ictal electroencephalography (EEG) and magnetic resonance imaging (MRI) features showing sclerosis of the mesial structures, resistance to medical therapy, and responsiveness to selective resection.

The pathogenesis of this syndrome represents a special substrate: the so-called mesial temporal sclerosis (MTS). The cause of MTS is unclear. An association with a history of febrile seizures has been proposed⁸ and it is suggested to be associated with complex features of febrile seizures.⁹ However, this connection has been questioned.¹⁰ Instead of being the consequence of recurrent temporal lobe seizures the MTS is frequently associated with a history of unusual febrile seizures in childhood with a later development of complex partial seizures. From a histopathological point of view the mesial structures show a loss of neurons with gliosis in the hippocampus associated with a modification of the normal gray matter architecture. Especially there is an involvement of the Sommer’s sector, the end folium, and the CA3 regions.¹¹ MTS tends to be more common in adults than children but occurs frequently in association with cortical dysplasia in these patients, accounting for the early onset of epilepsy in this group.^12,13 Despite the multitude of clinical and basic science studies on MTS the cause and maintenance mechanisms of epileptogenicity are not fully understood.

Lesional temporal lobe epilepsy may be seen in the presence of many different histopathological entities such as tumors (astrocytoma, dysembryoplastic neuroepithelial tumor, ganglioglioma) (Fig. 51.1), vascular malformations, and developmental lesions (cortical dysplasia, neuronal heterotopias and others). Even in patients with long-lasting histories of seizures when the hippocampus has been resected, the neuronal loss is small (up to 25%) and there is no architectural reorganization (see Fig. 51.1).^14,15

FIGURE 51.1 Magnetic resonance imaging (MRI) of lesional temporal lobe epilepsy cases. A, MRI of a 24-year-old woman who had seizures since the age of 14 years. Seizures were characterized by bilateral auditory illusions, loss of consciousness, oral automatisms, skin pallor, left mydriasis, and tonic posture of the right upper limb. Duration was typically about 2 minutes, followed by postictal anomia. Frequency was one seizure a week. MRI showed an anterior left temporal lesion (top left: axial T1-weighted with gadolinium image; below left: coronal T1-weighted with gadolinium image; top right: axial T2-weighted image; below right: coronal fluid-attenuated inversion recovery [FLAIR] image) extended to the insula and mesencephalon. Interictal and ictal activity was left temporal. The patient underwent anterior temporal lobectomy including the lesion and the mesial structures (uncus, amygdala, and hippocampus). She is seizure-free 30 months after surgery. Pathological examination revealed a dysembryoplastic neuroepithelial tumor (DNET). B, A 41-year-old man with seizures since the age of 36 developed drug-resistant epilepsy symptomatic of left temporal cavernoma (left: coronal FLAIR image; right: coronal inversion recovery [IR] image). Seizures were always the same and consisted of epigastric aura, loss of contact, oral automatisms, and dystonic postures of the right hand. Patient underwent lesionectomy, and 4 years afterward continues to have seizures (Engel IIc). C, MRI of 39-year-old man who developed seizures at the age of 19 years after head injury. Seizure semiology never changed; the patient had left blinking and motionless staring, appearing as if petrified. After seizure onset he was never seizure-free. Video-electroencephalography (EEG) and stereo EEG showed interictal and ictal acitvity involving the anterior temporal lobe. MRI showed an anterior and mesial lesion of the left temporal lobe (left: axial T2-weighted image; right: axial T1-weighted image with gadolinium). The patient submitted to an anterior temporal lobectomy including the lesion, the uncus, and the amygdala. Three years after surgery the patient is seizure-free. The pathological examination showed a fibrillary astrocytoma (WHO [World Health Organization] grade II). D, A 26-year-old woman developed nocturnal generalized tonic-clonic seizures at the age of 14 years with monthly frequency. The MRI scan showed an anterior left temporal lobe lesion (left: axial T2-weighted image; right: axial T1-weighted image with gadolinium). The video-EEG during sleep showed two seizures characterized left version, dystonic posture of the right hand, and delayed automatisms. The ictal EEG showed a fast activity of low amplitude on the left anterior temporal lobe, spreading to the posterior temporal lobe and then to the ipsilateral suprasylvian region. The patient underwent a left anterior temporal lobectomy including the lesion, the uncus, and the amygdala. Pathological examination revealed an oligodendroglioma (grade II WHO). Forty months after surgery the patient is seizure-free. E, MRI of a 19-year-old woman with seizure characterized by epigastric aura, behavioral arrest, right version of the head and eyes, pallor, and oral automatisms. Sometimes the patient had secondary generalized tonic-clonic seizure. Seizures began at age 9. Duration of attack was about 30 seconds with a daily frequency (3-4 episodes). MRI scans (left: coronal T2-weighted image; right: axial T2-weighted image) showed a left mesial temporal lesion, with calcification, involving the parahippocampus, gyrus, and uncus. The patient underwent a left anterior temporal lobectomy including the lesion, the uncus, the amygdala, the head, and the anterior third of the hippocampus body. For 2 years the patient has been seizure-free.

(Courtesy of Dr. Roberto Spreafico and Dr. Flavio Villani, Division of Epilettologia Clinica e Neurofisiologia sperimentale, Fondazione Istituto Neurologico Carlo Besta, Milan, Italy.)

Seizure Semiology

Temporal lobe seizures may originate in hippocampal and immediately adjacent structures or arise from extrahippocampal neocortical regions. The clinical differentiation of hippocampal and extrahippocampal temporal lobe epilepsy may help guide the extent of resection.¹⁶ The presence of an aura with experiential phenomena, such as a feeling of depersonalization or familiarity, or visual or auditory illusions is associated with a neocortical temporal ictal origin. In 70% of cases the epigastric aura occurs in the setting of mesial temporal lobe epilepsy; however, this rate significantly increases (98% of cases) if the abdominal aura evolves into an automotor seizure.¹⁷ Fearful and olfactory auras are commonly associated with involvement of the amygdala, whereas gustatory auras may occur in the hippocampal region or arise from extrahippocampal neocortical regions.¹⁸ The “déjà vu” onset needs a concomitant activation of hippocampus and temporal neocortex and it is not specific for the activation of hippocampus or neocortex.

Usually the ictal behavior shows different patterns including behavioral arrest and motionless staring that are described as typical symptoms of mesial temporal origin. Oral automatisms (chewing, lip smacking, tongue protruding, and lip pursing) and manual automatisms (manual exploratory behavior, grabbing, and rubbing) are both associated with temporal lobe epilepsy (TLE).¹⁹ The early onset of automatisms is frequently associated with a primary involvement of the mesial temporal lobe; moreover, the association of ipsilateral hand automatism with simultaneous contralateral dystonic posturing allows a correct lateralization. Contralateral head rotation just before seizures and secondarily generalized and unilateral tonic and dystonic posturing can be of value in localization, but they are not always accurate.²⁰ A variety of autonomic symptoms, including elevated blood pressure, tachycardia, skin pallor, pilomotor erection, and mydriasis, have been reported in the course of MTLE seizures.²¹ Ictal speech and postictal dysphasia has been demonstrated to be consistent with seizure onset in the dominant hemisphere; in addition, active testing of postictal reading ability indicated a seizure focus in the language-dominant hemisphere. It has been reported that early postictal nose wiping is a reliable lateralizing sign pointing to the ipsilateral hemisphere.²²

Temporal lobe seizures are more likely to occur during wakefulness, whereas frontal lobe seizures have a greater chance of occurring during sleep, implying that sleep has distinct effects on seizure threshold in different brain regions.²³ Furthermore, sleep can influence the extent of seizure spread, such that seizures in temporal lobe epilepsy are more likely to secondarily generalize during sleep than during wakefulness.^24,25

Noninvasive Evaluation

The semiology, interictal and ictal scalp video-EEG, and imaging (anatomical, metabolic, and functional) as well as neurocognitive evaluation, represent the armamentarium of evaluation for surgical candidacy in the patient with pharmacoresistant epilepsy. Most evaluations would include interictal scalp recordings and inpatient video-EEG to capture typical seizures. However, the best outcomes are found in patients with concordant MRI and interictal scalp EEG concordant for unilateral MTLE.³⁵ In fact, lack of concordance with interictal EEG and other studies is a worse predictor of surgical outcome than ictal disconcordance. However, in all but the most straightforward of cases, several typical clinical spells are usually of value to be recorded by inpatient EEG.

Imaging of MTLE by MRI has made the diagnosis of hippocampal sclerosis much more straightforward, in addition to a variety of evolving imaging tools.³⁶ Fine-cut coronal sequences perpendicular to the axis of the hippocampus are particularly useful. Coronal fluid-attenuated inversion recovery (FLAIR) sequences suppress the cerebrospinal fluid signal and enhance the increased tissue free-water signal characteristic of mesial temporal sclerosis. Volumetric hippocampal MRI studies through serial thin-cut coronal images permit a comparison of the volumes of both hippocampi, unmasking eventual differences in volume between the normal and the affected mesial structure (Fig. 51.2A and B).³⁷ Recent advances in high-field MRI have been particularly helpful in identifying subtle abnormalities in hippocampal or neighboring mesial temporal structures.^38,39

FIGURE 51.2 Right hippocampus sclerosis. Magnetic resonance imaging (MRI) coronal fluid-attenuated inversion recovery (FLAIR) image (A) showed a hyperintensity of the right hippocampus that also appeared smaller than on the contralateral side. Intraoperative picture (B) showing the head and the anterior third of the right hippocampus. At the MRI coronal inverson recovery (IR) image (C) the right hippocampus appeared small with an enlargement of the temporal horn. Sections of the hippocampus, shown in D, stained, respectively, with thionin (E) for cytoarchitectonic control, and with anti-NeuN (F and G) to detect neuronal nuclei (NeuN). Note the evident neuronal cell loss in the pyramidal cell layer of CA1 (indicated by asterisks in E and F) visible both in thionin- and NeuN-stained sections. The granule cell layer (GC) appears bilaminated, and dispersed (arrow in F), and significant loss of granule cells can be observed in the higher magnification (G).

(Courtesy of Dr. Roberto Spreafico and Dr. Flavio Villani, Division of Epilettologia Clinica e Neurofisiologia sperimentale, Fondazione Istituto Neurologico Carlo Besta, Milan, Italy.)

Magnetic resonance spectroscopy (MRS) can also detect abnormalities in various metabolites using the proton signal.^40,41 Nuclear medicine studies are also employed, primarily interictal positron emission tomography (PET) and ictal/interictal single-photon emission computed tomography (SPECT). Fluorodeoxyglucose (FDG) PET looks for interical hypometabolism. It can be helpful in identifying surgical candidates in the setting of normal MRI scans, and also may detect those with bilateral disease with poorer outlook for seizure freedom.⁴² However, the area of hypometabolism demonstrated by FDG PET often shows greater extent than foci demonstrated by EEG or MRI. Although PET is a sensitive diagnostic method, it provides only approximate localization of the epileptic zone and may not be adequate for precise localization, though it may be useful for differentiating between TLE of mesial or lateral origin.⁴³

SPECT studies require injection very soon after seizure onset for maximal accuracy. The use of SPECT image registration to subtract an ictal from interictal injection, when coregistered with the anatomical MRI, can result in useful ictal localization information, even with a normal MRI scan.⁴⁴

Invasive Evaluation

When noninvasive methods do not indicate the seizure focus, invasive diagnostic recordings can be used. When bilateral MTLE is of concern, bitemporal electrodes can be used. The two strategies most often employed are depth electrodes that penetrate the brain structures, or subdural electrodes that are passed subtemporally and medially toward mesial structures. Though these methods are typically used on a less favorable group of patients, good outcomes can be achieved in this subset and are generally well tolerated.⁴⁵ Invasive monitoring indications and interpretation can be more challenging in the pediatric population because of the frequent temporal and extratemporal neocortex involvement.⁴⁶

Neuropsychology

A thorough neuropsychological evaluation is part of the presurgical assessment for medically intractable seizures.⁴⁷ Neuropsychological testing can help lateralize the seizure focus^48,49 because dominant temporal lobe epilepsy is typically associated with verbal memory deficits as a predominant factor. Excessive speech difficulties, global memory problems, or extensive difficulties in other domains should raise concerns as to the localization of medial temporal lobe epilepsy.

Neuropsychological testing is also critical to assess for the emotional, behavioral, and psychiatric disorders that are very common in this population.⁵⁰ Depression in particular can be quite significant, and many preoperative factors and expectations can impact surgical decision making, perceived benefit from surgery, and quality of life outcomes.⁵¹

Testing is also important to establish language dominance and define memory risks preoperatively. The cerebral amytal test has long been used to determine dominance and assess the effect on memory of anesthetizing one hemisphere through intracarotid injection.⁵² The test is invasive and there is variability in its use. Because right-handed patients with right-sided lesions have a very small chance of being dominant,⁵³ some of these patients, for example, may not require extensive study of dominance through intracarotid amytal testing. Functional MRI can make assessment of dominance and memory, but the exact tests and their reliability are still a subject of debate.⁵⁴ The precise language test to be used in functional MRI is unknown, but some batteries have been quite successful in establishing dominance.^55,56 Memory in particular is difficult to assess by either method.⁵⁷