Focal Cortical Dysplasia

Pediatric Neurology 49 (2013) 79e87

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Topical Review

Focal Cortical Dysplasia John N. Gaitanis MD a, *, John Donahue MD b a b

Department of Neurology and Pediatrics (Clinical), The Warren Alpert School of Medicine at Brown University, Providence, Rhode Island Department of Pathology and Laboratory, Medicine and Neurology, The Warren Alpert School of Medicine at Brown University, Providence, Rhode Island

article information

abstract

Article history: Received 15 July 2012 Accepted 31 December 2012

Focal cortical dysplasias are among the most common causes of intractable epilepsy in children. As the neuropathology of these conditions has been better clarified, the nomenclature has undergone numerous revisions. Their recognition has grown with the use of neuroimaging, and recent advances in imaging technology will further improve detection. Clinical, electroencephalographic, and imaging findings are often diagnostic, so it is imperative for the clinician to recognize the characteristic patterns. Treatment for developmental and behavioral disability remains largely symptomatic, and epilepsy medications are often ineffective. Epilepsy surgery, however, can be successful in selected patients. The basic science underlying the development of focal cortical dysplasias may lead to novel therapeutic approaches in the future. Ó 2013 Elsevier Inc. All rights reserved.

Introduction

Cortical formation spans weeks 8-24 of gestation [1] and can be divided into three stages: proliferation of undifferentiated cells, migration of neuroblasts (from the proliferative zone to their designated destinations), and cell differentiation (into mature neurons or glia). Disruption of any of these steps results in malformations of cortical development. Such malformations commonly result in epilepsy, cognitive impairment, and other neurological deficits. Malformations of cortical development are a heterogeneous group of disorders whose pathological features depend largely on the embryological timing of the defect [2]. Focal cortical dysplasia (FCD) represents a subset of malformations of cortical development in which there are abnormalities of cortical lamination, neuronal maturation, and neuronal differentiation. Neurons and glial cells in some types of focal cortical dysplasia exhibit immaturity. The large, dysplastic neurons of cortical dysplasia possess markers of neuronal immaturity, such as microtubuleassociated protein 2c, microtubule-associated protein 1b, and Nestin [3,4]. Balloon neurons contain abnormally large

* Communications should be addressed to: Dr. Gaitanis; Department of Neurology and Pediatrics (Clinical); The Warren Alpert School of Medicine at Brown University; 110 Lockwood St; Suite 342; Providence, RI 02903. E-mail address: [email protected] 0887-8994/$ - see front matter Ó 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.pediatrneurol.2012.12.024

amounts of cytoplasm and stain for both neuronal and glial markers [5], indicating a failure to commit to a specific cell lineage [6]. Balloon and dysplastic neurons are seen in cortical dysplasia and in the cortical hamartomas of tuberous sclerosis complex [7,8]. Evidence of disrupted neuronal migration, including disorganized or absent lamination, malpositioned neurons, and heterotopic neurons within the white matter [1] are also present. FCD must, therefore, involve abnormalities of both maturation and migration, indicating that dysplastic and balloon neurons lack the cellular machinery to migrate properly through the cortical plate [1]. History and classification

Focal cortical dysplasias were first described by Taylor et al. [9]. They presented the neuropathological findings of 10 patients in whom histology of resected epileptic foci revealed large, bizarre neurons littered throughout all but the first cortical layer. “Grotesque cells, probably of glial origin” with large, multiple nuclei surrounded by excessive cytoplasm, were observed along the depths of the affected cortex [9]. Since that initial report, the term FCD has been used to describe a wide array of derangements of cortical anatomy. Attempts have been made to better classify these disorders (Table 1). Mischel et al. [10] proposed a grading system correlating embryological timing with disease severity. They

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Table 1. Classification of FCD

Study and Year

Number of Patients/Methods

Findings/Classifications

Taylor et al. [9]

Grotesque cells with large multiple nuclei and excessive cytoplasm

Mischel et al. [10] Tassi et al. [11]

10 patients with epilepsy surgery resections 77 surgical specimens 52 cases

Palmini et al. [12]

Panel discussion

Blumcke et al. [13]

ILAE Task Force

Nine microscopic patterns correlating disease severity with embryological timing Three patterns described: (1) Architectural dysplasia (abnormal lamination with ectopic neurons) (2) Cytoarchitectural dysplasia (giant neurons throughout cortex) (3) Taylor-type dysplasia (balloon cells are present) Type I FCD (disturbance in cortical lamination without dysmorphic neurons) Type Ia (no cytoarchitectural abnormalities of pyramidal cells) Type Ib (cytological abnormalities of pyramidal neurons) Type II FCD (dyslamination with dysmorphic neurons) Type IIa (no balloon cells) Type IIb (balloon cells) Type I (dyslamination) Type Ia (abnormal radial lamination) Type Ib (abnormal tangential lamination) Type Ic (combined radial and tangential dyslamination) Type II (Dyslamination with dysmorphic neurons) Type IIa (no balloon cells) Type IIb (balloon cells) Type III (additional related pathology) Type IIIa (hippocampal sclerosis) Type IIIb (epilepsy-associated tumors) Type IIIc (adjacent vascular malformations) Type IIId (epileptic lesions acquired early in life)

Abbreviation: FCD ¼ focal cortical dysplasia

examined 77 surgical specimens of FCD and identified nine microscopic patterns of FCD. In 2002, Tassi et al. [11] proposed a classification system based on 52 cases. They organized FCD into three main types: (1) architectural dysplasia in which there was abnormal cortical lamination with ectopic neurons in the white matter, (2) cytoarchitectural dysplasia, in which giant neurons were seen throughout the cortex in addition to abnormal cortical lamination, and (3) Taylor-type dysplasia in which giant, dysmorphic neurons were observed. In Taylor-type dysplasia, cortical layering was barely discernible and balloon cells were present. Despite histological differences, clinical features were similar between groups. One key difference, however, was an electroencephalogram (EEG) pattern in Taylor-type dysplasia of repetitive, high-amplitude, fast spike, and slow waves interspersed between relatively flat periods. Patients with Taylor-type dysplasia also had a higher seizure frequency than in other groups. Though it has since been updated, the most common classification system used in the literature is that of Palmini et al. [12]. In it, FCD is divided into two categories: type I, in which there are disturbances of cortical lamination without dysmorphic neurons (Fig 1), and type II, in which dysmorphic neurons are observed (Fig 2). Each of those categories is further subdivided: type Ib specifies cytoarchitectural abnormalities of pyramidal neurons, and type IIb indicates the presence of balloon cells. In 2011, an International League Against Epilepsy task force revised the classification system of FCD based on neuropathological features with magnetic resonance imaging (MRI) correlation [13,14]. In it, a three-tired classification system was presented. FCD type I refers to isolated lesions presenting as either radial (type Ia) or tangential (type Ib) dyslamination. FCD type II involves dysmorphic

neurons in addition to dyslamination. If balloon cells are not present, it is termed type IIa, and if present, type IIb. FCD type III refers to situations in which related pathology is observed. Type IIIa is associated with hippocampal sclerosis, IIIb with epilepsy-associated tumors, IIIc with adjacent vascular malformations, and IIId with epileptic lesions acquired early in life (i.e., traumatic injury, hypoxicischemic injury, or encephalitis). In time, such classification systems will likely expand to include molecular markers and genetic findings. Differences in molecular expression support the current FCD subtypes. For example, type II lesions are more likely to express

Figure 1. Hematoxylin and eosin stain at 40 magnification. Note the absence of normal lamination in type 1 dysplasia. Dilated capillaries with amorphous content are present in this figure and are not to be confused with balloon cells, which were not seen in this sample.

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Figure 2. Hematoxylin and eosin stain at 100 magnification. Dysmorphic neurons in a patient with type IIb dysplasia. Also note the absence of lamination.

neuroglial progenitor proteins, such as Nestin, when compared with type I dysplasia. Type II FCD also has greater expression of progenitor cell proteins [15]. Expression of mammalian target of rapamycin complex I (mTORC1) is greater in type II FCD, resulting in aberrant phosphorylation of mTORC1 substrates [15]. Such findings may not only assist in establishing future classification systems, they may guide future treatment discoveries.

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80, in a majority of patients. They observed higher rates of cognitive impairment in FCD type II (67% and 68% for types IIa and IIb, respectively) versus FCD type I (38% and 57% for types Ia and Ib). In their study, children were more likely to exhibit cognitive delay than adults (67% of children versus 34% of adults with cognitive impairment). Cognitive impairment is also more common in patients with an early onset of epilepsy [17]. Other case series have not shown differences in neuropsychological profiles related to FCD subtypes [18]. Such inconsistencies in neuropsychological profiles may relate to other factors such as the age of epilepsy onset, frequency of seizures, and use of antiseizure medications. Psychiatric comorbidity can also be seen with FCD and is more common in patients with posterior lesions and early-onset epilepsy [17]. The most common manifestation of FCD is epilepsy. Epilepsy can occur at any age, but most commonly develops in childhood. Posterior lesions are associated with an earlier age of epilepsy onset (0.9 years) when compared with frontal (3.27 years), temporal (3.5 years), parietal (4 years), and central (7.5 years) foci [16]. The seizure frequency is generally high in FCD and seizures may occur daily [16]. Tassi et al. [11] reported an average seizure frequency of 39 per month. Status epilepticus occurs in just over one third of patients [17]. Seizures are partial (simple or complex) and can secondarily generalize. The semiology is dependent on the location of the lesion [19]. Epilepsy sometimes presents with an initial seizure in the setting of fever or as infantile spasms. Seizures from FCD are commonly refractory to medical treatment, and FCD accounts for up to 26% of pediatric epilepsy surgery cases [20].

Clinical features EEG Findings

The clinical consequences of FCD include neurological deficits, cognitive impairment, and epilepsy. WiddessWalsh et al. [16] reported neuropsychological dysfunction, as defined by a full-scale intelligence quotient of less than

Scalp EEG reveals rhythmic epileptiform discharges (REDs) that correlate spatially with the location of the lesion (Fig 3; Table 2) [21]. REDs are defined as a stereotyped

Figure 3. Rhythmic epileptiform discharges in a 5-year-old boy with type IIa dysplasia. The left posterior temporal onset of the discharges corresponded to the location of his epileptic focus on invasive electroencephalogram (EEG). The EEG is recorded in a bipolar anterior-posterior montage.

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Table 2. EEG findings in FCD

Scalp Recordings Intermittent sharp and spike waves Concordant with location of FCD in only 43% of patients [20] Rhythmic epileptiform discharges (REDs) Seen in half of FCD patients [16,20] Activated by NREM sleep Concordant with location of FCD in 80% of patients [20] Intracranial Recordings Interictal Spike wave discharges 50% concordance with FCD localization Continuous epileptiform discharges (CEDs) Overlie area of dysplasia in 82% of cases [20] When CEDs removed, good surgical outcome in 75% [21] Repetitive spike waves Paroxysmal fast activity Slow repetitive spike waves More common in type IIA FCD [22] Ictal Paroxysmal fast activity Most common ictal pattern in type IIA FCD [22] Repetitive spiking Most common ictal pattern in type I FCD [22] Paroxysmal fast with repetitive spiking Abbreviations: CED ¼ continuous epileptiform discharge EEG ¼ electroencephalogram FCD ¼ focal cortical dysplasia NREM ¼ non-rapid eye movement RED ¼ rhythmic epileptiform discharge

rhythmic sequence of repetitive sharp waves or spikes lasting for more than 1 second [21]. REDs are seen in approximately half of FCD patients [17,21], and are activated by non-rapid eye movement sleep. The spatial distribution of the lesion is concordant with REDs in 80% of patients [21]. Isolated, intermittent sharp and spike waves, however, poorly localize to the lesion and are concordant in only 43% [21]. Intermittent or continuous focal slowing is also observed [18]. Scalp EEG is nonlocalizing in less than one forth of patients [18]. Intracranial recordings reveal continuous epileptiform discharges (CEDs) (Fig 4; Table 2). CEDs can take one of three patterns: (1) recruiting/derecruiting pattern in which trains of rhythmic spikes progressively increased to a frequency of 12 to 16 Hz before slowing; (2) repetitive bursting pattern consisting of sudden bursts or trains of spikes at 10 to 20 Hz; or (3) continuous or rhythmic spiking consisting of rhythmic spikes or sharp waves at 1 to 8 Hz, for longer than 10 seconds [21]. CEDs always overlie the area of dysplasia and colocalize with the MRI defined lesion in 82% of surgical cases [21]. Moreover, when all cortical areas displaying CEDs on electrocorticography are removed, three fourths of patients have a favorable surgical outcome [22]. By contrast, interictal spikes on electrocorticography are concordant with the lesion in only about half of patients. A strong relationship is observed between REDs on scalp EEG and CEDs on intracranial recordings. Eighty percent of patients with REDs will have CEDs and their cortical location is always concordant [21]. Overall, 76% of patients with FCD will exhibit REDs or CEDs. In patients without FCD, however, both of these findings are extremely uncommon (only 1 of 40 in one series) [21].

Figure 4. Continuous epileptiform discharges (CEDs) on an interictal recording using subdural grid electrodes. The location of the CEDs corresponded with the location of the epileptic focus during ictal tracings.

Intracranial recordings differ depending on the grade of FCD (Table 2). For example, type IIa regions have more frequent interictal spikes than do type IIb areas [23]. Slow repetitive spikes are also more frequent in type IIa than in type I or type IIb FCD [23]. The ictal onset localizes to the area of FCD in the majority of type IIa patients. The most commonly seen pattern in type IIa is paroxysmal fast activity with or without repetitive spikes. Intracranial recordings show ictal onset over the region of FCD in only one third of type I FCD patients and the most common ictal pattern is repetitive spikes with no paroxysmal fast activity. In type IIb FCD, ictal changes are not seen over the area of FCD [23]. Rather, EEG changes occur in areas surrounding the lesion containing balloon cells. Balloon cells may therefore have decreased epileptogenicity. Areas containing balloon cells are also nonfunctional on direct electrical stimulation [24]. Magnetic Resonance Imaging

MRI remains the single most important way to identify FCD, but MRI has limitations in both detection of FCD and its ability to distinguish between histological grades. In a recent study, Kim et al. [25] found the overall sensitivity of MRI for detecting FCD to be 62%. A separate study found normal MRIs in approximately one fourth of patients [18]. The MRI findings that demonstrate FCD include increased cortical thickness, abnormal gyral/sulcal patterns, blurring of the gray/white junction, and T2 and fluid-attenuated inversion recovery (FLAIR) signal abnormalities within cortex or white matter (Table 3). Of these, blurring of the gray/white junction is the most frequently encountered abnormality (Fig 5), and the transmantle sign, which is seen exclusively in FCD type II, is the least common (Fig 6) [18]. Signal abnormalities are most commonly observed in white matter. Gray matter signal abnormalities, increased cortical thickness, and abnormal gyral/sulcal patterns are all specific for FCD type II. Areas of increased signal on FLAIR are more likely to contain balloon cells [24]. Mild malformations of cortical development (normal cortical architecture with abundant ectopically placed neurons) are less likely to show

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Table 3. MRI findings in FCD

Increased cortical thickness Associated with type II FCD Abnormal gyral, sulcal patterns Associated with type II FCD Blurring of the gray/white junction Most common finding in FCD [17] T2/FLAIR signal abnormalities within the cortex or white matter Transmantle sign is exclusive to type II FCD and is the least common pattern in FCD [17] Abbreviations: FCD ¼ focal cortical dysplasia FLAIR ¼ fluid-attenuated inversion recovery

abnormal features on MRI [18]. Patients with the same histological grade may have different imaging characteristics, indicating that MRI is limited in its ability to predict histology [18]. One example where common pathology results in different radiographic patterns is transmantle versus bottom of the sulcus dysplasia. In transmantle dysplasia, imaging reveals abnormal brain tissue extending through the entire mantle of the cerebrum, from the pia to the ventricular surface (Fig 6) [26]. Pathologically, the transmantle sign is associated with type IIb dysplasia. The other imaging finding associated with type IIb dysplasia is termed bottom of the sulcus dysplasia [27]. Bottom of the sulcus dysplasia is characterized by blurring of the gray/white matter junction and focal cortical thickening at the bottom of a sulcus [27]. On T2-weighted images, increased signal intensity involving the gray/white matter junction and subcortical white matter is observed as is a funnel-shaped tail that extends from the bottom of the sulcus to the ependymal surface (Fig 7). Given that both patterns share similar radiographic patterns and have the same underlying pathology, transmantle and bottom of the sulcus dysplasia likely represent different names for the same entity [28]. More advanced MRI techniques may improve sensitivity in diagnosing FCD. One such tool is 1H-magnetic resonance spectroscopy, which shows a decreased N-acetylaspartate

Figure 5. Loss of gray/white differentiation (arrow) in the left temporal lobe of an 8-year-old boy with intractable epilepsy. The patient was slightly rotated on this view, but hippocampal sclerosis was not observed and the hippocampi were symmetric in size. His seizures resolved after left temporal resection.

Figure 6. Transmantle sign (arrow) in a 3-year-old girl with type IIb dysplasia.

to total creatine ratio (Fig 8). Because N-acetylaspartate is a neuronal marker, impaired neuronal migration results in reduced levels. The choline to creatine ratio is also low, resulting from diffuse hypomyelination [29]. In the authors’ experience, magnetic resonance spectroscopy demonstrates these findings even in the absence of other signal abnormalities (unpublished data). Another useful MRI technology is diffusion tensor imaging, which provides an assessment of the amplitude (diffusivity) and the directionality of diffusion (anisotropy) [30]. It provides an assessment of white matter integrity and allows for the reconstruction of large white matter tracts. A study of three patients with FCD illustrated decreased subcortical connections of the dysplastic cortex [30]. The patients exhibited an ictal onset adjacent to (but not overlying) the

Figure 7. Bottom of the sulcus dysplasia in a 6-year-old girl with intractable epilepsy. Note the funnel-shaped tail that extends from the bottom of the sulcus to the ependymal surface (arrow). Pathology revealed focal cortical dysplasia IIb.

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Figure 8. Magnetic resonance (MR) spectroscopy in an 8-year-old boy with left temporal focal cortical dysplasia. Routine MR imaging sequences were normal, but on MR spectroscopy, a reduction in N-acetyl aspartate was observed over the left temporal lobe when compared to the right (arrows). A right temporal resection revealed type IIa dysplasia.

area of maximum FLAIR signal abnormality. Two of the patients had slow contiguous spread and their tractography revealed a reduced number and length of reconstructed fibers underlying the area of ictal onset. This pattern suggested limited connectivity to larger subcortical white matter tracts from the epileptogenic region. The slow propagation speeds of seizure spread in those patients were likely due to cortico-cortical propagation. Nuclear medicine

Positron emission tomography (PET) can assist in the identification of FCD, particularly in cases where the MRI is normal [31]. PET appears to be more sensitive for FCD than MRI, with an overall sensitivity of 83% [25]. The area of hypometabolism on PET is generally larger than the FCD, indicating that the functional deficit is larger than the epileptogenic zone [32]. Surgical outcomes appear improved with the use of MRI and F-18-fluorodeoxyglucosePET coregistration [31]. PET using [C11] PK11195 identifies areas of activated microglia and is a biomarker for inflammation. In one case report of a histologically proven FCD with activated microglia, PET using [C11] PK11195 revealed an area of focally increased radiotracer in the area of the dysplastic tissue [33]. Like PET, single photon emission computed tomography is also more sensitive than MRI. Its overall sensitivity for detecting FCD is 89% [24]. No statistical difference is seen when comparing the sensitivity of PET versus single photon emission computed tomography [25]. Treatment and outcome

The treatment of FCD remains largely symptomatic. Physical, occupational, and speech therapy may be needed for neurological or cognitive deficits. Epilepsy can be a major treatment challenge because it is often refractory to antiepileptic drugs. One possible explanation for drug resistance is the presence of drug efflux transporters. Such transporters, termed multidrug resistant proteins, prevent

antiepileptic drugs from achieving high concentrations in the brain, even when plasma concentrations are elevated. The best understood efflux proteins are the multidrug resistance gene-1 p-glycoprotein (MDR1) and multidrug resistance-associated protein-1 (MRP1). These transporters can efficiently remove antiepileptic drugs from the central nervous system and thereby limit their accumulation in the brain. In one study of 28 patients with FCD, MDR1, and MRP1 expression was intense in both neurons and reactive astrocytes of dysplastic tissue [34]. Multidrug transporters were overexpressed in the epileptogenic zone in patients with FCD [34]. This contrasts to 10 normal brain specimens in which no MDR1 expression was seen in neurons or astrocytes and MRP1 expression was very weak. Because the voltage-gated calcium channel blocker verapamil inhibits MDR1, it can theoretically improve seizure control by preventing efflux of antiepileptic drugs [35]. Clinical trials have not been performed to assess its role in FCD, but in the author’s experience, it has shown benefit in selected cases as an add-on to antiepileptic drugs. Because FCD is frequently medication resistant, epilepsy surgery is often required. Epilepsy surgery for FCD often has a favorable outcome. Overall, 40% to 75% of patients have an Engel class I outcome [11,16,36-39]. Success rates are better for children (70% class I) than for adults (56% class I) [16]. Seizure outcome following surgery is more favorable for FCD type II than for type I. Krsek et al. [18] reported seizure freedom in 75% of type IIb, 61% of type IIa, 49% of type 1a, and 45% of type Ib patients following surgery. Likewise, Tassi et al. reported Engel class I outcomes in 75% of patients with Taylor-type FCD (equivalent to IIb) and 62% in architectural dysplasia (equivalent to class I) [11]. This difference is most pronounced in children where as many as 75% of type II cases are seizure-free (compared with just 25% of type I patients) [18]. The poor outcome in type I may be due in part to the higher proportion of multilobar cases in type I. Type II patents also have better localizing MRI and EEG data. Complete resection of the lesion improves the likelihood of a favorable outcome [38]. Other factors important to epilepsy surgical outcome include the preoperative seizure frequency, presence of dual pathology (particularly mesial temporal sclerosis), and the ability to localize the focus preoperatively on MRI, PET, and EEG. In one series, poor surgical outcomes were predicted by incomplete resection of the epileptogenic area, mild pathologic features (because severe features are more likely to display MRI abnormalities), and the presence of secondarily generalized seizures [40]. Postoperative complications include nondisabling visual field defects, often transient sensorimotor deficits, and meningitis [37]. Another important consequence of epilepsy surgery is its effect on cognition. In 2011, Skirrow et al. [41] reported the long-term follow-up of 42 children who underwent temporal lobe surgery for intractable epilepsy caused by hippocampal sclerosis or dysembryoplastic neuroepithelial tumors. After 5 years of follow-up, 17 patients (41%) who underwent temporal resection for epilepsy demonstrated a statistically significant improvement in their full-scale intelligence quotients (as measured using a Wechsler intelligence scale). By comparison, only one control participant (9%) saw a similar improvement [41]. The authors concluded that temporal lobectomy in children with

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temporal lobe epilepsy was associated with improved longterm intellectual outcomes compared with those undergoing standard medical treatment. Studies exploring the cognitive effects of epilepsy surgery for FCD have been more limited. In 2010, RouleetPerez et al. [42] studied 11 children who underwent epilepsy surgery before age 6. Pre- and postoperative measurements of developmental quotients (using a Bayley Scale of Infant Development) were performed on all of the children. Four of the 11 children had FCD IIb and two had FCD type IIa. Two of the children with FCD IIb saw a rapid improvement in developmental quotient testing following surgery, two saw a loss, and the others were unchanged. Long-term, only one child with FCD type IIb showed continued developmental improvement; the remaining patients were stable in their testing and did not show significant catch-up long after surgery [42]. These findings suggest that surgery in FCD patients, most of whom have neocortical epilepsy, is less likely to yield improved developmental outcomes than is surgery for temporal lobe epilepsy. Relationship to tuberous sclerosis complex

In 1965, Perier described a patient with bizarre neurons and glia taken from epileptic tissue [43]. The patient was diagnosed with tuberous sclerosis complex (TSC) even though no other clinical features for the condition existed. The following year, Perot, Weir, and Rasmussen reported histological features of TSC in resected epileptic tissue of four patients in whom no other clinical features of the condition existed [44]. Taylor et al. saw a similarity between TSC and FCD, but remarked on five notable differences: (1) there were no cutaneous stigmata of TSC in patients with FCD (2) “candle-guttering” was not observed in FCD, (3) FCD patients had no family history of TSC, (4) the onset of epilepsy was later in individuals with FCD than those with TSC, and (5) intellectual disability is greater in TSC than in FCD [9]. Despite these differences, the histology of FCD resembled tuberous sclerosis to such an extent that Taylor et al. postulated that FCD represented a forme fruste of TSC. Because Taylor et al. described enlarged, bizarre appearing neurons in their FCD patients, their comparison between TSC and FCD is pertinent only for FCD type IIb. TSC is a multisystemic, dominantly inherited condition. It has a high rate of spontaneous mutations and more than half of all patients do not have an affected parent. Two genes cause TSC. Both result in similar clinical features. The TSC1 gene, located on chromosome 9q34, codes for a novel protein called hamartin, which indirectly links the cell membrane to the cytoskeleton [45]. TSC2, located on chromosome 16p13.3, encodes for the protein tuberin, which functions in cellular signaling pathways [45]. Hamartin and tuberin interact together as part of a larger protein complex [45], which functions to negatively regulate the mammalian target of rapamycin (mTOR) pathway [46,47]. Mammalian target of rapamycin and future treatment directions

mTOR regulates multiple cellular functions that may contribute to epileptogenesis. A variety of upstream

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signaling pathways regulate mTOR activity in response to nutrient and energy status, growth factors, and stress [48,49]. In turn, mTOR responds to these upstream signals by modulating downstream pathways, which mediate cellular growth, proliferation, metabolism, and survival. During anabolic states, upstream regulators activate mTOR, leading to increased protein synthesis, cellular growth, and proliferation [49]. In catabolic states, upstream pathways inhibit mTOR activity, decreasing protein translation and cellular growth [48]. Activation or inhibition of mTOR by upstream pathways is accomplished in part through the tuberous sclerosis gene products hamartin and tuberin. When hamartin and tuberin are nonfunctional, mTOR is active, resulting in increased cell growth and proliferation [50]. Although patients with type IIb FCD do not demonstrate the cutaneous or other systemic manifestations of TSC, they may have identical genetic alterations as TSC, including an increase in TSC1 polymorphisms and loss of heterozygosity at the TSC1 locus [51]. Hence, these disorders share common pathways. Alterations of the TSC1 gene are not the only impairment of the mTOR pathway in FCD. A separate gene regulating mTOR is adhesion molecule on glia (AMOG). Balloon cells and giant cells exhibit perisomatic staining for AMOG, and AMOG expression colocalizes with markers for mTOR activation [49]. The development of balloon and giant cells may therefore result from mTOR activation [52]. In early stages of epileptogenesis, mTOR is likely to affect astrocytic glutamate transporters and potassium channels [53]. Later stages of epileptogenesis are mediated via astrocyte proliferation and neuronal disorganization [53]. Because mTOR regulates protein synthesis and multiple other downstream cellular functions that influence neuronal excitability and epileptogenesis, it represents a possible target for future antiepileptogenic therapies. Rapamycin acts as an mTOR inhibitor and has shown efficacy in the treatment of subependymal giant cell astrocytomas in patients with TSC [54]. The role of abnormal mTOR signaling in the development of epilepsy itself has been delineated in most detail in knockout mice involving inactivation of the TSC1 gene, which typically develop seizures at around 4 weeks of age [53]. Early rapamycin treatment started before the onset of seizures prevents the subsequent development of epilepsy in these mice, whereas late treatment reduces seizure frequency in mice that already have epilepsy [55]. An important limitation, however, is that after rapamycin treatment is stopped, the neurological phenotype of these mice develops with a delay of several weeks, including the histopathologic abnormalities and epilepsy [55]. In addition to beneficial effects on epilepsy, rapamycin has also been shown to reverse learning deficits in a different TSC mouse model [56]. The reported effects of rapamycin in mouse models of TSC are of potentially high significance because they appear to be most consistent with antiepileptogenic, not simply seizure-suppressing, effects. In contrast to standard seizure medications that inhibit seizures by directly decreasing neuronal activity, there is no direct effect of rapamycin on neuronal excitability [57,58]. Furthermore, although available seizure medications dampen neuronal excitability primarily by binding immediately and directly to ion channels and neurotransmitter receptors, rapamycin

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interrupts the more gradual, progressive neuropathologic and cellular processes mediating epileptogenesis [55,59]. Although these findings are encouraging in supporting an antiepileptogenic action of rapamycin in TSC, continued, long-term treatment with rapamycin was necessary to maintain the beneficial effects. Once rapamycin is stopped, mTOR hyperactivation resulting from the underlying chronic genetic defect in the TSC1 gene is no longer suppressed and can proceed to trigger epileptogenesis. Human studies of mTOR inhibition are limited. Anecdotal reports suggest that mTOR inhibitors reduce seizures in patients with TSC [60]. In a study of 28 patients with TSC and subependymal giant-cell astrocytomas, an inhibitor of mTOR complex 1, Everolimus (RAD001, Novartis, Basel, Switzerland), demonstrated benefit for epilepsy [61]. Of 16 patients for whom video EEG data were available, nine had a decrease in seizure frequency, six had no change, and only one patient had increased seizures [61]. Epileptiform activity during “stage 2” sleep also improved. Further clinical trials are underway to establish the efficacy of mTOR inhibitors for epilepsy in TSC patients. If benefit is demonstrated in TSC, mTOR inhibition in type IIb FCD will still require further exploration. There is also a need for more information on the safety of mTOR inhibitors, especially for long-term use. Infections, likely related to immunosuppression, have been the main serious adverse effect [62]. Furthermore, as most of the beneficial effects of mTOR inhibition appear to cease on discontinuation of the drug in both animal models and clinical trials [55,62], mTOR inhibitors may represent a life-long treatment for TSC and FCD patients. Given the numerous physiologic functions of mTOR, the possible adverse effects of long-term use of mTOR inhibition on normal growth, development, and learning, especially in children, need to be studied in more detail.

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