Overview of presurgical assessment and surgical treatment of epilepsy from the Italian League Against Epilepsy



The Commission for Epilepsy Surgery of the Italian League Against Epilepsy (LICE) presents an overview of the techniques and methodologies of presurgical evaluation and of the surgical treatment of epilepsies. This overview is the result of the experience developed in the past years in the major Italian centers where programs of epilepsy surgery have been established, and it has the aim of offering a quick and easy reference tool for those involved in the treatment of patients with epilepsy. The sharing of different experiences has the additional aim of conforming and disseminating the employed techniques as well as the methods of selection and evaluation of patients. The synthetic coverage of the main issues concerning the presurgical workup and the available surgical options will hopefully provide a framework that may integrate and develop the contributions of every single center, in one of the more complex, challenging, and dynamic areas of neurological sciences.

Definition of Epilepsy Surgery

Surgical treatment of epilepsy can be defined as a kind of surgical approach, the primary objective of which is the treatment of focal epilepsy with seizures that resist antiepileptic medication. The aim of epilepsy surgery is to achieve the maximum relief from seizures, minimizing the side effects of drugs and the long-term combined effects of medication and repeated seizures. Presurgical evaluation of epilepsy has the main objective of defining the epileptogenic zone (the cortical region from which ictal discharges originate and spread) on which to operate. Clinical history, seizure semiology, electroclinical features, and imaging all contribute to formulate of a localization hypothesis. If a structural lesion is present in relation to seizures, surgical removal should be considered, even when the criteria for drug resistance are not met. When presurgical evaluation fails to indicate a role for “curative” surgery, various palliative options may still be considered, keeping in mind that the ultimate purpose of any surgical initiative is improving quality of life.

Definition of Pharmacoresistance

There are no universally accepted definitions for pharmacoresistance. According to the International League Against Epilepsy (ILAE) Commission on Therapeutic Strategies, epilepsy is pharmacoresistant after failure of achieving seizure freedom by two appropriate drugs, used at the most appropriate doses (Kwan et al., 2010). Three degrees of pharmacoresistance are recognized:

  • Grade 1, resistance to a primary drug; grade 2, resistance to two primary drugs used in sequence or in combination; grade 3, resistance to three primary drugs used in sequence or in combination (Perucca, 1998).

After a first antiepileptic drug (AED) is introduced, seizure control is achieved in 49.5% of patients (Brodie et al. 2012); add on treatment with a second drug provides seizure control in 13.3% more cases, and a third drug will be successful only in a further 3.7%. Therefore, after three drugs have been used at appropriate doses, more than 30% of patients will already be declared resistant to AEDs. Resistance to drugs can sometimes be established early on, whereas in other cases it may become obvious only after years of seizure control or exhibit a fluctuating course (Schmidt & Losher, 2005).

In children there is neither an established duration of epilepsy nor age-related criteria for defining pharmacoresistance (Cross et al., 2006; Gupta et al., 2006). In the first years of life it is often difficult to define syndrome subtypes. Seizure semiology is variable and often is not amenable to the terminology that is adopted for adult patients (Nordli et al., 1997). Focal or multilobar epilepsies are at times manifested as epileptic spasms, or hypomotor seizures, which are scarcely indicative of the area of seizure onset (Wyllie et al., 1996; Hamer et al., 1999). In addition, subjective symptoms cannot be assessed, interictal electroencephalography (EEG) abnormalities are often bilateral or multifocal (Jonas et al., 2005; Gupta et al., 2006) and etiologic factors are extremely variable.

In children, assessing the level of disability that is caused by seizure recurrence should always include the presumed effect of seizures on cognitive function and behavior, as well as the role of interictal EEG discharges originating from the epileptogenic network. Early intervention is crucial in epileptic encephalopathies in order to reduce the risk of cognitive stagnation or regression, which is higher in the first years of life. From this perspective, even severe cognitive impairment or behavioral disorders do not necessarily contraindicate epilepsy surgery. Early surgery carries a lower morbidity risk, even for large resections. The ideal candidate has recent-onset focal epilepsy in relation to a clearly identifiable epileptogenic zone, located outside eloquent cortical areas.

Etiologies Most Commonly Associated with Pharmacoresistant Epilepsies

There is a great variability of etiological factors that underlie epilepsies of potential surgical interest. Some etiologies are associated with characteristic syndromes and modalities of epileptogenesis (i.e., Rasmussen syndrome, low grade gliomas, focal cortical dysplasia, Sturge-Weber syndrome, tuberous sclerosis). The absence of a demonstrable structural brain abnormality, in a patient with severe drug-resistant epilepsy, does not contraindicate, per se, the interest of presurgical assessment for epilepsy.

Mesial temporal lobe epilepsy

Mesial temporal lobe epilepsy is by far the most studied condition in epilepsy surgery. About 50% of operated-on cases have this condition (Engel et al., 2012). Although emphasis was formerly given to a frequent history of early febrile seizures, more recent evidence indicates that type I focal cortical dysplasia (FCD) often co-occurs (Kuzniecky et al., 1999; Salanova et al., 2004; Blümcke et al., 2011).

Focal cortical dysplasia

There are different subtypes of FCD (Palmini et al., 2004; Blümcke et al., 2011): FCD types IIA and IIB (without or with balloon cells) have relatively homogeneous characteristics, including typical magnetic resonance imaging (MRI) appearance and EEG pattern (Tassi et al., 2002), most often extratemporal location and good outcome after surgery. Anatomic-electroclinical correlations are often made with sufficient precision to approach surgery, based on information obtained noninvasively. According to Gupta et al. (2006), FCD is the most frequent pathologic substrate of pediatric epilepsies of potential surgical interest. Because MRI does not necessarily reveal the entire extent of the dysplastic lesion, the best treatment results are obtained by resecting as much as possible of the dysplastic area. This approach is obviously hampered when eloquent cortex is involved.

Low-grade glioneuronal tumors

Dysembryoplastic neuroepithelial tumors and gangliogliomas are the subtypes of neoplasm that are most often associated with intractable focal epilepsy. These lesions exhibit only limited potential for growth or relapse after surgical removal. Their location is most often in the temporal lobe, and associated intralesional findings indicative of focal cortical dysplasia are possible (Prayson, 2008; Barba et al., 2011; Blümcke et al., 2011).

The decision of whether to extend the resection to extralesional areas depends on the anatomical-electroclinical findings in each patient. Nevertheless, it has been reported that lesionectomy alone provides the best seizure outcome in glioneuronal tumors located in the extratemporal and temporolateral sites (Giulioni et al., 2005, 2006), whereas lesionectomy associated with corticectomy offers the best outcome in temporomesial locations (Blümcke & Wiestler, 2002; Giulioni et al., 2006, 2009).


Polymicrogyria is often bilateral and involves the perirolandic and perisylvian regions (Guerrini et al., 2000; Guerrini, 2010). The polymicrogyric cortex may retain its functional properties, at least in part (Guerrini & Barba, 2010), and its removal carries a high risk of producing neurologic deficits. Polymicrogyria-associated epilepsy has variable expressions and is often accompanied by generalized seizures and EEG abnormalities. The boundaries of the polymicrogyric cortex are difficult to appreciate and the lesion may often be patchy or multifocal. Spontaneous seizure remission after school age is possible (Guerrini et al., 2008). Any surgical approach to epilepsy secondary to polymicrogyria should be undertaken with extreme caution.

Tuberous sclerosis

Tuberous sclerosis is characterized by multiple brain abnormalities (Cross et al., 2006). However, there may be a single epileptogenic zone that causes all or most seizures. In select cases, a single resection or a staged neurosurgical approach should be considered (Weiner et al., 2006; Teutonico et al., 2008; Moshel et al., 2010; Wu et al., 2010).

Multilobar or hemispheric dysplasia

Histologic abnormalities similar to those of FCD may be extensive and involve multiple lobes or one entire hemisphere (hemimegalencephaly). The resulting neurologic and cognitive impairment varies according to the severity of the structural abnormality. Hemispherectomy and hemispherotomy are surgical options for the management of these large hemispheric lesions (Villemure et al., 2000).

Sturge-Weber syndrome

In this syndrome early onset seizures, if frequent and prolonged, may be accompanied by progressive hemiparesis and cognitive impairment. In such circumstances early intervention in a specialized pediatric center is recommended (Cross et al., 2006). A limited resection, hemispherectomy, or hemispherotomy are all possible, according to the anatomic and clinical characteristics. Neurophysiological investigations are often of little help. Particular neurosurgical skills are necessary in order to approach the complex vascular abnormalities that are typical of the syndrome.

Hypothalamic hamartoma

Hypothalamic hamartoma may cause intractable epilepsy with gelastic, dacrystic, or drop attack seizures (Castro et al., 2007). Some patients exhibit precocious puberty, behavioral disorders, and cognitive impairment. The main surgical approaches include microsurgical ablation, endoscopic disconnection (Delalande & Fohlen, 2003), and stereotaxic radiosurgery (Regis et al., 2006). There is no consensus on the approach to be favored (Cross et al., 2006).

Rasmussen encephalitis

Onset of clinical manifestations is typically in school age, but adult-onset cases have also been described (Villani et al., 2006). Management and follow-up require particular experience (Bien et al., 2005; Cross et al., 2006; Gupta et al., 2006). In recent years, several immunomodulatory treatments have been employed in an attempt to slow down hemispheric tissue loss and the associated functional decline (Bien & Schramm, 2009). In most cases, however, hemispherectomy or hemispherotomy is the only potentially effective approach to the severe and progressive epilepsy syndrome and should be planned timely (Villemure et al., 2000).

Cavernous angioma

Cavernous angioma is often associated with focal drug-resistant epilepsy. Angiomas can be either isolated or multiple (Liguori et al., 2008). About 80% of patients experience an excellent outcome after surgery. Removal of perilesional hemosiderin is crucial for a good outcome (Baumann et al., 2007).

Presurgical Investigations



Video-EEG, by simultaneously recording video images and scalp/intracranial EEG activity, is the method of choice for evaluating electroclinical correlation (Cascino, 2002; Cross et al., 2006; Gupta et al., 2006; Nordli, 2006).

Use and indications

Patients whose seizures need to be recorded should be admitted to the ward if their attacks are not sufficiently frequent to allow recording as outpatients. Scalp recordings provide important information about electrical brain activity.

  • Interictal activity: the most relevant common interictal EEG features are asymmetries of background activity, reactivity to eyes opening, response to hyperventilation and intermittent photic stimulation, occurrence of epileptiform discharges or slow wave activity and their topography and activation during sleep.
  • Ictal activity: can be represented by a wide spectrum of EEG manifestations such as no visible changes, arrest reaction that can be diffuse or focal, localized “flattening,” low voltage fast activity that can be localized or diffuse, rhythmic spikes or spike-waves that can be diffuse or with variable localization, rhythmic slow waves, or transitory suppression of interictal activity. Assessment of ictal activity should always be performed taking into account the concomitant clinical manifestations.
  • Postictal activity: regional slowing of EEG activity after a seizure is sometimes useful to further characterize the area of seizure onset.

Monitoring is usually performed using the international 10–20 electrode placement system. Adaptations of this standard to the skulls of smaller children should be limited to the first 6 months of life. Zygomatic, supraorbital, or sphenoidal electrodes can be used in selected patients according to their specific characteristics. Reduction of antiepileptic medication is sometimes used to facilitate occurrence of seizures. Drug withdrawal should be partial and should be started by eliminating agents with shorter half-lives. If the recorded seizures have characteristics that permit interaction with the examiner and are of sufficient duration, the patient should be examined with various tests, according to clinical presentation. Clinical signs should always be described according to their temporal order of appearance; the patient should be continuously and interactively examined during the seizure and its clinical termination. In addition to the physical semiology of the attack, level of awareness, orientation in space and time, language, occurrence of vegetative manifestations, and memory should always be explored. Report of the video-EEG recording should always mention all the above aspects.

Magnetic resonance

MRI of the brain is mandatory and should be performed and assessed according to a specific hypothesis about what structures are involved in the epileptogenic zone (Gòmez-Ansòn et al., 2000; Barkovich et al., 2001; Colombo et al., 2003; Bernasconi et al., 2004). The following protocol is recommended for exploring focal epilepsy: (1) Axial SE, ≤3 mm; (2) fast spin echo (FSE) fluid attenuated inversion recovery (FLAIR) T2W, ≤3 mm, in at least two planes (preferentially coronal and sagittal); (3) coronal FSE T2W, ≤3 mm; (4) coronal FSE IR T1W, ≤3 mm; and (5) 3D volumetric gradient-echo T1W spoiled gradient echo (SPGR), fast field echo (FFE), turbo field echo (TFE), turbo fast low angle shot (TFLASH), magnetization prepared rapid gradient echo (MPRAGE) with reformatting in the three planes. In the first 2 years of life longer time to repetition (TR) and echo time (TE) are required than in the adult. Malformations of cortical development are better seen if an optimal contrast between white and gray matter is obtained. During myelination this contrast becomes less pronounced; if a first study is performed between 6 and 18 months, repeat MRI after myelination is complete (after 30 months) is advised. Contrast medium should be used when a tumoral lesion is suspected. Diffusion MRI, particularly diffusion tensor imaging, is being used increasingly for imaging white matter fiber tracts and their topography in relation to structural lesions. Image fusion of combined morphologic and functional techniques is particularly useful for surgical purposes.

Functional magnetic resonance imaging


MR methodology that highlights the functional activation of cortical areas. Functional MRI (fMRI) can explore specific physiologic tasks or abnormal activation profiles related to interictal or ictal epileptic activity.

Use and indications

It is possible to select tasks that are effective and reproducible in activating cortical areas of interest, in relation to motor, sensory, language, and memory functions. A specific protocol has been proposed for evaluating language and memory in epilepsy (Deblaere et al., 2002). Indexes of language lateralization by fMRI highly correlate with Wada indexes (Dym et al., 2011) and predict language deficits after anterior temporal lobectomy (Sabsevitz et al., 2003; Bonelli et al., 2012). A temporal fMRI index was more predictive than the Wada index (Sabsevitz et al., 2003), particularly in patients with Wada-fMRI discrepancies (Janecek et al., 2013). fMRI is also useful for localizing cortical representation of different language functions, and to obtain a lobar index of language lateralization, a kind of information that cannot be achieved using the Wada test (Abou-Khalil & Schlaggar, 2002).

Assessment of memory is particularly complex. The Wada test is not considered as a gold standard for this purpose. Although many of the tests that are used in healthy individuals cause bilateral activation of mesial temporal structures, planning a resection that implies amygdalo-hippocampectomy would require a more selective assessment (Golby et al., 2002; Rosazza et al., 2009). Prediction of verbal memory outcome after anterior temporal lobectomy using fMRI paradigms is weak. Binder et al. (2008) found a significant correlation between language lateralization and verbal memory outcome. This finding, if confirmed, would simplify presurgical fMRI evaluation in temporal lobe epilepsy.

During sensorimotor tasks, the characteristics of frequency and intensity of movement and stimuli can variably influence the extent and intensity of the response. An online monitoring of the performance should therefore be available to allow task repetition in poorly cooperative subjects.

A suggested three language task fMRI protocol for 1.5T scanner includes:

  • Localizer sequence (1′); gradient-echo echo planar imaging (EPI) sequence (TR 3000+1″ pause, TE 52, FA 90, 30 contiguous 4-mm slices CA-CP matrix 128*128, field of view (FOV) 256) (1′); instructions to the patient (1′); acquisition of the first fMRI task (100 EPI sequences, one every 4 s).

Every five scans two different conditions of activation are alternated, with one active and one of control, preferentially both in which instructions are given to the patient:

  • Second fMRI task (6′40″) (1′) (6′40″); gradient-echo T2* or T2 at high resolution (matrix 256*256, FOV 256) (3′); instructions to the patient; T1 volumetric (MPRAGE with isotropic 1 mm voxel) (5′). Total time 38 min.

Cognitive and neuropsychological evaluation in children

This is an essential step in presurgical evaluation and postoperative follow-up of children.


Children with epilepsy have a high prevalence of neuropsychological and behavioral disorders and should be assessed by highly specialized professionals. The team that is in charge of planning the surgical approach should always clarify to the patient and family that improved cognitive skills and behavior are not necessarily observed after operation, even when seizures are controlled (Wyllie et al., 1996; Cross et al., 2006; Gupta et al., 2006).

Appendix S1 includes a selection of protocols and assessment scales used in pediatric patients.

Cognitive and neuropsychological evaluation in adults

Neuropsychological evaluation is mandatory in adults when epilepsy surgery is to be considered and during postoperative follow-up. A battery of neuropsychological tests has the following purposes:

  1. Identifying the site of dysfunction, if any. This process may help to identify the epileptogenic zone. Concordance between area of epileptogenesis and area of dysfunction may influence the decision whether to perform invasive studies and the surgical strategy itself.
  2. Estimating the risk of memory deficit as a consequence of temporal lobectomy. Mesial temporal lobe structures (hippocampus, parahippocampal gyrus, entorhinal cortex) are of primary importance for memory functions. In most right-handed patients verbal memory and visuospatial memory are controlled by the left and right temporal lobes, respectively. The finding of a memory defect pointing to the side contralateral to the epileptogenic zone (i.e., verbal memory dysfunction in a patient with right temporal lobe epilepsy) suggests a high risk for postoperative amnesia. Such a circumstance might contraindicate surgery, or at the least represents an indication for additional investigations (Wada test) (Jones-Gotman et al., 1993; Loring, 1997)
  3. Assessing hemispheric dominance in dubious cases. The neuropsychologist tests the patient during the Wada test. By comparing the results obtained by sequentially inhibiting either hemisphere, information can usually be obtained about which side is dominant or if codominance occurs (Meador & Loring, 2005).
  4. Neuropsychological follow-up after surgery.

There is no consensus on a given battery of tests for this purpose. Appendix S2 indicates the main protocols and assessment scales used in Italian centers.

Assessment for psychopathology and quality of life


Epilepsy is often associated with psychiatric morbidity (Ottman et al., 2011). Psychiatric disorders could lead to severe consequences, such as suicide, and might represent a contraindication to epilepsy surgery (Derry et al., 2000; Boylan et al., 2004; Devinsky et al., 2005; Meldolesi et al., 2006).


Identifying presurgery and postsurgery psychiatric disorders and investigating risk factors for postsurgery psychiatric conditions.

Neuropsychiatric assessment before surgery and during follow-up is mandatory also in the pediatric population. However, there is no consensus on a given protocol for this purpose. Appendix S3 indicates the main protocols and assessment scales used in Italian centers.

Ancillary investigations


Some techniques for functional imaging are considered to be ancillary as their sensitivity and specificity are not universally recognized. Such techniques may, however, validate information collected with the above-reported methods.

Single photon emission computerized tomography

Single photon emission computerized tomography (SPECT) of the brain is a noninvasive method that may provide information on the location of the epileptogenic zone through regional variation of perfusion during seizures (ictal SPECT), immediately afterward (postictal SPECT), or interictally (interictal SPECT). Diagnostic accuracy of interictal SPECT is limited (20–70%). Ictal SPECT (injection at the initial ictal symptoms) may reveal an area of hyperperfusion that is congruent with the site of the ictal discharge in 70–97% of patients with temporal lobe epilepsy. The utility of ictal SPECT in extratemporal epilepsy is still unclear. Comparison of ictal versus interictal SPECT provides the most accurate information, as ictal hyperperfusion and interictal hypoperfusion are highly related to the epileptogenic zone (Lee et al., 2000).


The patient's EEG should be recorded during tracer injection. Injection should be performed as soon as the first symptoms or the initial ictal EEG changes appear (within 20–30 s). If a previous seizure has occurred, a delay of at least 2 h is advised. An attack may be precipitated pharmacologically in order to facilitate the procedure (Juni et al., 1998; Barba et al., 2007).

Interictal SPECT

Injection should be performed at least 3 h after the last seizure, which should have lasted no longer than 5 min, and after postictal manifestations have resolved. If status epilepticus or seizures in series have occurred, ensued by postictal motor or cognitive deficit, SPECT should be postponed for at least 24 h.

Positron emission tomography

Most interictal positron emission tomography (PET) studies demonstrate that approximately 70% of patients with partial seizures have reduced [18F]-fluorodeoxyglucose (18F-FDG) uptake in and around the focus in the interictal phase, reflecting the “functional deficit zone” (Sokoloff, 1991). The site of interictal hypometabolism corresponds to sites of ictal onset as shown by EEG, but ictal PET studies are difficult to perform.

The area of hypometabolism is consistently larger than the size of the MRI lesion, and this undoubtedly relates to the fact that 18F-FDG-PET overestimates the extent of epileptogenic tissue. In patients with hippocampal sclerosis, reduced metabolism is commonly seen in the mesial and anterolateral temporal cortex, possibly reflecting the route of functional inhibition.

Interictal hypometabolism is common in patients with mesial temporal lesions such as hippocampal sclerosis, small tumors, and hamartomas, with 85% to 100% sensitivity. Sensitivity in neocortical epilepsy is between 40% and 96%.

Patients with bilateral or distant homolateral hypometabolism have a worse surgical prognosis than those with unilateral focal hypometabolism.

Studies using PET and SPECT have been conducted with tracers for opioid receptors, benzodiazepine receptors, muscarinic cholinergic receptors, and histamine receptors. Increased levels of mu and delta opioid receptors and reduced benzodiazepine and muscarinic cholinergic receptors have been observed. In some cases, receptor imaging has provided additional localization information over flow/metabolism imaging alone. 11C-Flumazenil that depicts γ-aminobutyric acid (GABA)A receptor distribution may provide improved localization of seizure foci in comparison with 18F-FDG, although its availability is limited (Debets et al., 1997).

Invasive Presurgical Investigations



Stereo-EEG (SEEG) is an invasive technique that is based on the use of stereotactically implanted intracerebral electrodes (Cossu et al., 2005; Cardinale et al., 2013).

Use and indications

SEEG should be reserved for patients in whom noninvasive methods do not allow a definition of the epileptogenic zone. The strategy for electrode positioning is based on a localization hypothesis that is formulated according to the individual patient's characteristics. Structures to be explored include those from which the ictal discharge is supposed to originate, as well as areas where subsequent organization of the ictal event appears to take place, including areas of structural abnormality and eloquent areas. Reaching the intended target and avoiding bleeding are two main objectives that are better attained with the support of 3D MRI and/or cerebral angiography, if available. Electrical stimulation of brain structures is at times necessary to map the eloquent cortex or in an attempt to precipitate the patient's habitual seizures.

Complications and limitations

The rate of complications is around 5–6% and is mostly linked to hemorrhagic events. Infections are even less frequent (Cossu et al., 2005).


Stereo-EEG provides information that leads to an intervention in 95% of cases. However, patients who are explored with SEEG are those with the most difficult clinical presentations, such as, for example, those with normal brain MRI. This selection bias explains why the postoperative seizure outcome in patients undergoing SEEG is less satisfactory than in those undergoing in whom surgery is performed on the basis of noninvasive studies only.

Subdural electrodes


Subdural electrodes are applied directly on the surface of the cortex.

Scope and indications

As in SEEG, the objective of using subdural electrodes is the direct recording of electrical brain activity and mapping of cortical function through electrical stimulation. Subdural electrodes cannot reach deep structures, such as the depth of sulci, the hippocampus, and subcortical epileptogenic lesions (e.g., double cortex, nodular heterotopia); however, they may cover a large area of the brain. A formal craniotomy is required to implant electrodes, arranged as strips or large grids, in the subdural space. Needle electrodes are usually placed on the scalp for simultaneous surface and intracranial EEG recording. After study completion, the craniotomy is reopened; the electrodes and the epileptogenic area are removed in the same setting.

Complications and limits

Infection is the most frequent serious complication, with rates varying from 3% and 12% (Hamer et al., 2002; Burneo et al., 2006; Johnston et al., 2006; Musleh et al., 2006). Edema and bleeding are less often observed.


Subdural electrodes are highly contributory in localizing epileptogenic and eloquent cortical areas.

Other invasive techniques

Definition, purpose, and indications

A limited number of depth electrodes can be stereotactically implanted without a preceding stereoscopic angiography, provided that electrodes are implanted along a completely intraparenchymal trajectory, avoiding the depth of sulci. Neuronavigation is greatly helpful for supporting this approach. A combined subdural electrode-depth electrode approach is possible (Spencer et al., 1990).

Intraoperative electrocorticography has become an obsolete technique owing to the serious limitation it imposes.



Surgical approaches for the treatment of epilepsy can be subdivided into three main types: (1) resections, (2) disconnections, and (3) neuromodulation. These approaches have different objectives. The target of ablative surgery and disconnections is to cure epilepsy, with complete disappearance of seizures. The long-term effects of disconnections will need to be evaluated in the long term, as these procedures have been used for only a relatively short time. “Palliative” interventions aim at reducing the severity and frequency of seizures, without having the objective of abolishing them. Neuromodulation, callosotomy, and multiple subpial transections are examples of palliative surgery.

Curative surgery

Tailored resections


Tailored surgery is the counterpart of standardized surgery. Examples of standard resections are anteromesial temporal lobectomy and selective amygdalo-hippocampectomy (Schramm, 2008). Tailored resections are instead closely related to the characterization of the epileptogenic zone, based on the specific electroclinical findings obtained in a given patient (Lo Russo et al., 2003; Caicoya et al., 2007).

Scope and indications

The degree of individualization will depend on the accuracy with which the epileptogenic zone is characterized. This process will in turn depend on the level of evidence obtained with presurgical investigations, either invasive or not. Lesionectomy is the removal of a structurally abnormal area. The completeness of lesion resection is prompted by anatomic and functional factors, as well as by the nature of the lesion (neoplastic or nonneoplastic). Tailored resections can be sublobar, lobar, or multilobar, according to the combined anatomic-electroclinical evidence of the distribution of the epileptogenic zone (Lo Russo et al., 2006).

Complications and limits

Most series do not include postoperative mortality. In major series neurologic complications are at 5%, with 3% transient and 2% persistent morbidity (González-Martínez & Bingaman, 2008; Sasaki-Adams & Hadar, 2008). Neuropsychological (Alpherts et al., 2008) and psychiatric complications may appear de novo or be the expression of worsening of a preexisting condition.


Results of surgery and complications are reported in different series. Successful treatment (Engel class I) varies from about 33% in nonlesional cases, with multilobar resections, to 80% in temporal lobe resections (Lo Russo et al., 2006).

Standard resections

Anteromesial temporal lobectomy, amygdalo-hippocampectomy


Removal of the hippocampus and amygdala, associated (anteromesial temporal lobectomy) or not (selective amygdalo-hippocampectomy) with resection of the anterior portion of the temporal neocortex.

Scope and indications

To cure temporal lobe epilepsy associated with mesial temporal lobe sclerosis. The most used technique for selective amygdalo-hippocampectomy, described by Yasargil et al. (1985), implies removal of these structures through the microsurgical opening of the Sylvian fissure. This approach has been criticized (Kahane et al., 2002) and anteromesial temporal lobectomy is preferred in most centers.

Complications and limitations

Perioperative mortality is very low or not reported at all. Permanent morbidity is around 3% and includes hemiparesis, visual field defect, deficit of the third and fourth cranial nerves, and dysphasia (Engel et al., 2003).


Temporal lobe epilepsy is the type of epilepsy with the best surgical results, with an overall 70% of patients being rendered seizure free (Engel et al., 2003).



Ablation of one cerebral hemisphere.

Scope and indications

To eliminate epileptic seizures. This procedure is indicated when severe epilepsy is caused by large unilateral structural abnormalities that cause hemiparesis, such as hemimegalencephaly, large porencephalic cysts, Sturge-Weber syndrome, and Rasmussen syndrome. The contralateral hemisphere must be normal (Di Rocco & Tamburrini, 2006). This procedure carries a high risk of serious complications such as mortality due to hydrocephalus and hemorrhage in 6–7% of cases. Late complications are also serious and include hemosiderosis (now less frequent), hydrocephalus, and neurologic deterioration in up to 20% (Holthausen et al., 1997; Delalande et al., 2004; Di Rocco & Tamburrini, 2006).


Seizure control is reached in 80–90% of cases falling within Engel classes I and II (Holthausen et al., 1997; Di Rocco & Tamburrini, 2006).

Tailored disconnections


Anatomofunctional severing, rather than ablation, of the epileptogenic tissue, with preserved vascularization.

Scope and indications

Disconnection causes fewer complications than hemispherectomy. Cases of suspected neoplastic origin are excluded.

Results and complications

The number of published cases operated with this procedure is insufficient to draw firm conclusions.



Hemispherotomy is an alternative to hemispherectomy and implies the disconnection of the epileptogenic hemisphere from the subcortical structures and from the contralateral hemisphere.

Scope and indications

Three surgical techniques of hemispherotomy are described, all having the common goal of disconnecting the corpus callosum and the cortex through a surgical path passing through the ventricular system (Villemure & Mascott, 1995; Delalande et al., 2001; Cossu et al., 2012).

Functional hemispherectomy

This technique (Rasmussen, 1983) has introduced the concept of disconnecting fibers for the treatment of various hemispheric syndromes such as Rasmussen syndrome, hemimegalencephaly, and Sturge-Weber syndrome. The surgical procedure implies resection of the temporal lobe, of the posterior aspect of the frontal lobe, including the central gyrus, and of the anterior part of the parietal lobe (the so-called central lobe), accompanied by disconnection of the corpus callosum and subpial disconnection of the occipital lobe and of the residual frontal lobe.

Periinsular hemispherotomy

Represents an evolution of functional hemispherectomy, and differs from it owing to a reduced ablation but a more complete disconnection of interhemispheric structures (Schramm et al., 1995; Villemure & Mascott, 1995).

Vertical hemispherotomy

This technique (Delalande et al., 2007) implies a parasagittal parietal corticotomy, which allows sparing of the anterior cerebral artery and its branches. There is complete disconnection of the corpus callosum.

Complications and limits

The incidence of hydrocephalus is <3%; hemorrhagic events are observed in <2% of patients.


In adequately selected patient populations, complete seizure control is obtained in 90–100% of cases (Villemure & Daniel, 2006; Delalande et al., 2007; Marras et al., 2010).

Palliative surgery



This technique implies severing the interhemispheric commissures with the objective of limiting the interhemispheric spread of epileptic activity (Papo et al., 1990; Rossi et al., 1996; Cukiert et al., 2006).

Scope and indications

The procedure has been used to alleviate the consequences of epilepsies with tonic or atonic drop attacks, generalized tonic–clonic seizures, atypical absences with an atonic component, and complex partial seizures with bilateral frontal lobe manifestations.


Several techniques have been proposed: (1) cerebral commissurotomy (or “split brain”), including the corpus callosum and the underlying dorsal hippocampal commissure, the ventral hippocampal commissure between the fornices, the intermediate mass, and the anterior commissure (Bogen & Vogel, 1963); (2) frontal commissurotomy, including the section of the anterior two thirds of the corpus callosum as well as the anterior and ventral hippocampal commissures (Wilson et al., 1977); (3) anterior callosotomy, including the section of the anterior two thirds of the corpus callosum without the anterior and ventral hippocampal commissures (most used, at least as first step); (4) complete callosotomy, including all the corpus callosum with the splenium (in one or two stages).


Various series report a reduction in drop attack seizures of about 50–80% (Morrison & Duchowny, 2008). Microsurgical anterior callosotomy is preferred by most experts (Feichtinger et al., 2006).


Complete callosotomy is frequently complicated by the so-called disconnection syndrome, featuring unilateral tactile anomia, unilateral apraxia, and alexia. Postcallosotomy mutism is usually transient (1–10 days) if the splenium is spared.

Multiple subpial transections


This technique was originally introduced to treat focal epilepsies with primary involvement of the motor or language cortex (Morrell & Hanbery, 1969). The procedure suggests the selective severing of horizontally oriented intracortical fibers, with sparing of columnar cortical architecture and of its vascular supply (Morrell & Hanbery, 1969; Schramm et al., 2002).

Scope and indications

The proposed aim of this procedure is to prevent the ability of cortical areas to generate spike activity, while maintaining physiologic functions (Spencer et al., 2002). The usefulness of multiple subpial transections as a stand-alone procedure is debated.

Complications and limits

Residual neurologic deficits are expected in at least 25% of cases (Schramm et al., 2002).

Vagus nerve stimulation


Vagus nerve stimulation (VNS) is a therapeutic option for patients with drug-resistant seizures who are not eligible for curative surgical treatment or have declined it.

Scope and indications

The procedure aims at reducing seizure frequency and improving the patient's quality of life. The mechanism through which antiepileptic activity would arise is still unclear. It has been suggested that vagus nerve connections with the nucleus of the solitary tract activate ascending fiber tracts, in turn interacting with the mechanisms of cortical synchronization and desynchronization. There is no evidence to help selecting the most likely responders (Ben-Menachem et al., 1999).


The electrodes stimulating the vagus nerve are implanted (under general anesthesia) with an incision along the anterior edge of the left sternocleidomastoideus muscle (Biraben & Stefani, 2005). Stimulus intensity is adapted according to the patient's response.

Complications and limits

Hoarse voice, cough, dyspnea, and neck pain are commonly reported. Infections are the main complication (0.2–0.5%) and require removal of the device (Ben-Menachem et al., 1999; Biraben & Stefani, 2005; Rychlicki et al., 2006a).


It has been suggested that the positive effects of VNS appear within 1 year to subsequently reach a plateau. In controlled trials in patients with focal epilepsy, the rate of patients with seizure reduction >50% was 27%, whereas placebo responders were 15%. The rate of seizure-free patients is 2–5%. Many patients are reported to experience a reduction in severity and duration of seizure, even when their frequency is not affected (Ben-Menachem et al., 1999; Alexopoulos et al., 2006; Rychlicki et al., 2006b).

Deep brain stimulation


Deep brain stimulation (DBS) is a form of surgical treatment involving the implantation of a medical device, which sends electrical impulses to specific parts of the brain. DBS is still in a preliminary phase of application.

Scope and indications

Different deep brain structures have been identified as potential targets for the treatment of epilepsy. Stimulation of these anterior thalamic nuclei has been reported to result in a reduction of seizures in limbic epilepsy (Lee et al., 2006). The centromedian (CM) thalamic nucleus has been stimulated with contradictory results by different teams in small series (Velasco et al., 2000). Subthalamic nucleus (STN): a significant reduction in the number of seizures was reported by Chabardès et al. (2002) in four patients after bilateral stimulation of STN and substantia nigra, after 2–30 months follow-up. Posterior hypothalamus: Mirski and Fisher (1994) reported an increase of the epileptogenic threshold after high frequency chronic stimulation in an animal model. Caudate nucleus: there is experimental evidence that caudate stimulation reduces the spiking rate in the hippocampus, whereas clinical evidence has documented reduction of seizures and episodes of status epilepticus.

DBS is believed to act through antidromic cortical inhibition involving the epileptogenic area. The choice of the target is therefore crucial. Available literature indicates STN in focal motor epilepsy, CM in generalized forms, including Lennox-Gastaut syndrome, the hypothalamus or the anterior thalamic nuclei in limbic epilepsy (Loddenkemper et al., 2001).

The surgical technique is the same when adopted for movement disorders. Implantation is undertaken with a stereotactic approach. An impulse generator is implanted in the subclaviar region in the same surgical session.

Complications and limits

DBS is a palliative technique. The rate of complications is around 3% and is almost exclusively of the hemorrhagic type.


Available information derives from a limited number of observations. Velasco et al. (2006) reported >90% seizure improvement in Lennox-Gastaut syndrome after CM thalamic stimulation; Chabardès et al. (2002) reported 67–80% seizure reduction in motor cortex epilepsy with STN stimulation.


Minimum standard procedures are mandatory for the neuropathology laboratory dealing with brain tissue specimens removed from surgically treated patients with epilepsy. The two main areas of application discussed here are hippocampal sclerosis and malformations of cortical development. Tumors, including dysembryoplastic tumors, are dealt with in great detail in the World Health Organization (WHO) 2007 classification report (Louis et al., 2007).

The neuropathologist should be in the operating room during the operation and should precisely record the anatomic region from which the specimen is resected as well as its spatial orientation. Fixation: The anatomic specimen is fixed for a given time in relation to its size. Sampling: The neuropathologist measures and describes the specimen, sampling as orthogonally as possible to the cortical surface. Additional fragments should be frozen at −80°C for the purpose of subsequent molecular and genetic studies. Slices that are adjacent to the frozen tissue should also be stored to ensure that subsequent studies are not examining a tissue area that is remote from where histopathology was performed. Inclusion: in paraffin according to the laboratory protocol. Cutting: serial 3–10 μm sections. Staining: Hematoxylin and eosin staining is the minimum standard staining procedure. The use of additional staining procedures will be decided at the pathologist's discretion, based on the initial impressions. Immunohistochemistry: Some of the following antibodies are crucial and should be used systematically according to the diagnostic query: GFAP, MAP2, NeuN, anti-synaptophysin antibody, anti-tuberin antibody, anti-CD34 antibody.



As mentioned above, diagnosis should follow WHO criteria (Louis et al., 2007). A recent paper specifically addressed to epileptogenic tumors should also be considered (Thom et al., 2012).

Hippocampal sclerosis

This diagnosis should be made only upon finding reduction or disappearance of pyramidal neurons in different sectors of Ammon's horn; a grading score of hippocampal sclerosis has been recently proposed (Blümcke et al., 2013). The presence of gliosis is defined as hippocampal gliosis but not sclerosis. Diagnosing the histologic characteristics of amygdala is difficult. However, gliosis can usually be assessed.

Malformations of cortical development

This category includes a large number of structural abnormalities of the cerebral cortex, the characteristics of which are often anticipated with relatively high specificity by MRI. Focal cortical dysplasia offers some diagnostic challenges that are summarized in various classification systems (Tassi et al., 2002; Palmini et al., 2004; Blümcke et al., 2011).


Postsurgery outcome should be assessed at repeated follow-up evaluations, and a definite judgment should be formulated no earlier than 12 months after surgery. Engel's (1987) outcome classification system is universally adopted. There is no consensus on the time of follow-up evaluations, management of drug treatment, and investigations. If seizure control is achieved, treatment should be kept stable for at least 1 year, although exceedingly sedative drug regimens could be simplified even at 6 months, especially in children. It is also important to assess quality of life, behavior, and developmental skills (in children), and to avoid limiting the judgment on treatment success on only the number of seizures (Wyllie et al., 1996; Cross et al., 2006; Gupta et al., 2006; Lüders, 2008). Children should also undergo repeated neuropsychological assessment as part of follow-up.


Authors wish to thank Luisa Antinori, Carmen Barba, Cristina Bertin, Nadia Colombo, Daniela Di Giuda, Concezio Di Rocco, Giorgio Fagioli, Stefano Francione, Lorenzo Genitori, Liliana Grammaldo, Nicolò Meldolesi, Monica Morbi, and Lilia Volpi.


The authors have no conflicts of interest to disclose. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.