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Fink-Jensen A , Suzdak PD , Swedberg MD , Judge ME , Hansen L , Nielsen PG . The gamma-aminobutyric acid (GABA) uptake inhibitor, tiagabine, increases extr acellular brain levels of GABA in awake rats . Eur J Pharmacol 1992 ; 220 ( 2 \200\2233 ): 197 \200\223 201 . Mechanisms of action of carbamazepine and its derivatives, oxcarbazepine, BIA 2-093, and BI A 2-024 . Neurochem Res 2002 ; 27 ( 1 \200\2232 ): 121 \200\223 30 . 117 . Lynch BA , Lambeng N , Nocka K , Kensel-Hammes P , Bajjalieh SM , Matagne A , et al . The synaptic vesicle protein SV2A is the binding site This page intentionally left blank CHAPTER 4 Developmental Neurobiology, Neuroanatomy, and Neuropathology of Epilepsy Ingmar Bl mcke small proportion (7 % ), thorough and systematic histomorpholog- ical analysis cannot ident ify a speci \201 c anatomical alteration. Introduction Histopathological brain abnormalities can be recognized in 93 % of patients su ffering from intractable focal seizures and submitted to epilepsy surgery treatment (Table 4. 1 ). These numbers are similar to those obtained from earlier postmortem studies in prim ary and secondary generalized seizure disorders ( 1 ). In our hands, hippoc- ampal sclerosi s (synonyms: Ammon \200\231s horn sclerosis, mesial tempo- ral sclerosis), long-term epilep sy associated glio-neuronal tumors (gangliogliomas, dysembryoplastic neuroepithelial tumors ), and malformations of cortical development (e.g. focal cortical dyspla- sia, polymicrogyr ia) were most frequently encountered. Other lesions comprise vascular malformations (cavern omas, arteriov- enous malformations), glial scars (ischaemic or traumatic brain injuries) o r brain in \202 ammation (Rasmussen encephalitis). In a The history of neuropathological studies in brains of patients with intractable epilepsy is , however, often characterized by a con- troversial debate concerning the primacy of struct ural abnormali- ties in seizure genesis. In this regard, only an interdisciplinary approach will be successful in identifying the \200\230epileptogenic poten- tial \200\231 of disti nct morphological alterations and should include clini- cal faculty as well as basic scienc es. In this chapter, I will focus on our recent advance in classifying the morphological sp ectrum of focal cortical dysplasias (FCDs) and hippocampal sclerosis (HS). As both lesions are likely to result from insults compromising brain development and/or early postnatal mat uration, anatomical data of neocortical and hippocampal development will also be included t o comprehensively review and better understand the complex and Table 4.1 Surgical specimens collected by the European Epilepsy Brain Bank Entity Var. Number Age OP Hemisphere Gender Onset Duration HS 1591 34.6 659 L/611 R 786 M/805 F 11.5 23.3 DUAL 218 24.8 78 L/112 R 127 M/91 F 9.7 14.6 LEAT 1236 28.5 407 L/397 R 638 M/565 F 16.5 12.8 GG 570 25.4 184 L/158 R 285 M/263 F 12.7 13.5 DNT 189 26.3 59 L/68 R 105 M/84 F 15.2 12.3 Dysplasia 577 18.5 228 L/242 R 299 M/276 F 5.6 12.4 FCD I 66 11.5 35 L/26 R 16 M/33 F 3.5 7.2 FCD II 216 18.4 76 L/96 R 112 M/104 F 4.1 14.1 Vascular 271 36.4 91 L/108 R 157 M/114 F 23.5 13.4 Scars 239 25.2 92 L/91 R 147 M/90 F 10.3 14.8 Encephalitis 73 22.0 26 L/29 R 43 M/29 F 13.9 9.4 No lesion 307 29.2 117 L/58 R 161 M/146 F 12.7 16.1 All data were obtained from the European Epilepsy Brain Bank. Histopathological evaluation and clinical histories are as following: Var.: frequent variants of speci \201 c entities are highlighted; HS: hippocampal sclerosis; DUAL: dual pathologies; LEAT: long-term epileps y associated tumors; GG: ganglioglioma; DNT: dysembryoplastic neuroepithelial tumor; FCD: f ocal corti- cal dysplasia; Age OP = age of patients at surgery (in years); Hemisphere: L (l eft), R (right); Gender: F = female, M = male; Onset = age at onset of spontaneous seizure activity (in years); Duration = duration of seizure disorder before surgical treatment (in years). oxford textbook of epilepsy and epileptic seizures 40 distinctive histopathology of FCD and that local interactions of dys- mature cells with nor mal postnatal neurons promote seizures ( 10 ). often diverse lesion patterns to be recognized. It will be a future task to deduce speci \201 c prognostic or predictive values from these pathol- ogy patterns and whether they wil l be helpful for diagnostic and treatment purposes in these dif \201 cult-to-treat epilept ic disorders. Focal cortical dysplasia Type Ia The ILAE classi \201 cation system introduced this new FC D subtype, because it is likely representing a speci \201 c clinicopathological entity ( 1 1 , 12 ). Patients are young and have early seizure onset, severe psycho-motor retardation, and mild hemispheric hypoplasia with- out magnetic resonance visibility of any other lesio n ( 12 , 13 ). Drug resistance is frequent and surgical resection procedures achieve seizur e control in only 50 % of affected children ( 14 ). However, brain surgery can be helpful a s palliative strategy to reduce seizure burden, thereby accelerating developmental delay. N europatho- logical hallmarks include abnormal cortical layering affecting both radial migra tion and maturation of neurons (Fig. 4. 1 G, H). This aberrant pattern resembles those neur odevelopmental minicol- umns described by the \200\230radial unit lineage model \200\231 ( 15 ). Furthermore, cortical thickness is often decreased and recent MRI data con- \201 r med a signi \201 cantly smaller hemisphere ipsilateral to the ictal onset ( 12 ). In addit ion, neuronal cell density tended to be increased and neuronal body area decreased, which m ight point towards immaturity of the neuronal cells of these lesions. These \201 ndings a re consistent with the recently introduced concept of postmigrational FCD ( 16 ). However, to date, there are no molecular-biological or genetic data available to clarify or even sug gest the underlying pathomechanism in this difficult-to-treat-epileptic disorder. Recent st udies addressed aberrant expression of layer-speci \201 c markers in FCD variants ( 17 ). Indeed, cortical tissue obtained from patients that would be classi \201 ed to the new FCD Type Ia was char- acterized by abnormal expression of transcription factors Tbr1 and Otx1 in layer 2 and Map1B was abnormally expressed in vertical microcolumns. In addition, immatu re cell types (expressing Otx1 , Pax6 , and Tbr2 ) were also noted, suggesting activation o f progeni- tor cell populations or a persisting immature phenotype. These data suggest that abundant vertical microcolumnar arrangements may result from severely compromised cortical maturation, in which neuroblasts that migrated along the radial glial scaffold into the co rtex cannot equally distribute within their appropriate cortical layers. Neocortical pathology in focal epilepsies Malformations of cortical development (MCDs) are increasingly recognized in patients suffering from intractable focal epilepsies ( 2 ). The histopathological spectrum of MCDs is large, ranging from prominent to only minute changes. Whereas schizencephalic brain lesions, hemimegalencephaly, polymicrogyria, nodular or band heterotopia can be reliably diagnosed in vivo , FCDs often escape imaging techniques (magn etic resonance imaging (MRI)) and may vary considerably in their size and localization ( 3 ). Hence, I will particularly focus on the peculiar histopathological aspects of FCD, eithe r appearing as an isolated lesion within the cerebral hemi- sphere, or in conjunction with another principal lesion, i.e. HS, glio-neuronal tumor, or glial scarring. The term \200\230focal cortical dysplasia (FCD) \200\231 was coined in 1971 by David Taylo r and colleagues to describe localized malformative brain lesions in a series of 10 patient s with drug-resistant epilepsy ( 4 ). Meanwhile, the term has also been applied to refer to a wide range of derangements of cortical anatomy and numerous classi \201 cations of thes e structural abnormalities have been proposed. Hence, the histopathological, clinical, and neuroradiological classi \201 cation of these lesions remains dif \201 cult or even contr oversial. The most widely recognized classi \201 cation system was published by Palmini et al. in 2004 ( 5 ). It was the report of an international working group, hence only a small contribution and recognition of neu- ropathology data was included. Unfortunately, this cl assi \201 cation has not yielded a reliable prediction of proposed FCD variants and postsu rgical seizure control ( 6 ). This applies in particular to so- called Type I FCDs. A recen tly published neuropathological study showed that inter- and intraobserver reproducibility of FCD Type I cases were in the range of only 50 % when using the Palmini system ( 7 ). A T ask Force of the International League Against Epilepsy (ILAE) was addressing this clinicall y important issue and rede \201 ned clinicopathological FCD subtypes ( 8 , 9 ). The new \200\230ILAE FCD clas- si \201 cation system 2011 \200\231 (Table 4. 2 ) also takes into a ccount insights from experimental neurodevelopmental studies, i.e. sustained plas- ticity a nd neurogenesis in the postnatal brain, which is compro- mised by various pathogenic condit ions. Similarly, the \200\230dysmature cerebral developmental hypothesis \200\231 suggeste d that there is partial failure in later phases of cortical development that might explain the To better understand this intriguing histomorphological pheno- type, I will brie \202 y re view moving aspects of human cortical devel- opmental referring mainly to the seminal work of Pasko Rakic and Vernon Mountcastle on the columnar organization of the human brain. Table 4.2 ILAE consensus classi \201 cation system for FCD Isolated FCD Type I (Fig. 4. 1 ) FCD Ia: abnormal radial (vertical) cortical lamination FCD Ib: abnormal tangential (horizontal) cortical lamination FCD Ic: abnormal radial and tangential cortical lamination Isolated FCD Type II (Fig. 4. 2 ) FCD IIa: with dysmorphic neurons FCD IIb: with dysmorphic neurons and balloon cells Associated FCD Type III (Fig. 4. 3 ) FCD IIIa: cortical lamination abnormalities in the temporal lobe associated with HS FCD IIIb: cortical lamination abnormalities adjacent to a glial or glio-neuronal tumor FCD IIIc: cortical lamination abnormalities adjacent to vascular malformation FCD IIId: cortical lamination abnormalities adjacent to any other lesion acquired during ea rly life The three-tiered ILAE classi \201 cation system of FCD distinguishes isolated forms (FCD T ype I and II) from those associated with another principal lesion, i.e. hippocampal scleros is (FCD Type IIIa), tumors (FCD Type IIIb), vascular malformations (FCD Type IIIc), or lesi ons acquired during early life (i.e. traumatic injury, ischemic injury or encephalitis, FCD Type IIId). CHAPTER 4 developmental neurobiology, neuroanatomy, and neuropathology 41 Fig. 4.1 (See also Color plate 1.) FCD Type Ia compared to normal development and anatomy o f the human neocortex. A) The developing human neocortex reviewed at 17th week of gestation (WoG). Cortical neurons (stained purple by thionine) arise from radial glial cells, the ep ithelial stem cells that line the ventricle. Radial glial cells in the ventricular zone (VZ ) generate intermediate progenitor cells that migrate into the subventricular zone (SVZ). T he outer subventricular zone (OSVZ) is massively expanding at this time period and most lik ely contribute to the evolutionary advance underlying cortical size and complexity in human brain ( 21 ). CP, cortical plate; IZ, intermediate zone; MZ, marginal zone; SP, subcortica l plate (also see (D)). B) Expansion of the cortical plate at 19th WoG. Migrating neurons f ollow an inside-out pattern forming different pyramidal cell layers. C) The hexalaminar cor tical architecture is fully developed in the premature brain (35th WoG), with prominent rad ial (vertical) columnar arrangements still being visible (4 m thin paraf \201 n section s were used for all preparations shown here). Note the similarity with a surgical specimens obtained from a 15-year-old child with epilepsy and FCD Type Ia (G \200\223H). D) This wel l-recognized model of radial neuronal migration that underlies cortical organization is bas ed on ( 20 ). The cohorts of neurons generated in the VZ traverse IZ and SP, containing \200\230waiting \200\231 afferents from several sources (cortico-cortical connections (CC), thalamic radiation (TR), nucleus basalis (NB), monoamine subcortical centers (MA)), and \201 nally pass through the earlier generated deep layers before setting in at the interfac e between the cortical plate (CP) and marginal zone (MZ). MN, migrating neurons; RG, radial glial cell. E \200\223F) Adult human temporal neocortex (NeuN immunohistochemistry). Scale bar in E = 200 m (applies also to G); in F = 50 m (applies also to (H)). G \200\223H ) Fifteen-year-old child with drug-resistant epilepsy and severe psycho-motor retardation. Seizure onset was recorded from only one hemisphere and histopathological analysis revealed persistent vertical microcolumns in the temporal and occipital lobe specimen. Note that ne urons are also signi \201 cantly smaller (arrow in (H)), compared to controls shown in (F) . NeuN immunohistochemistry. oxford textbook of epilepsy and epileptic seizures 42 Columnar organization of the neocortex The six-layered human neocortex is a convoluted ribb on with a surface area of approximately 2600 mm 2 , and 3 \200\2234 mm thickness. It contai ns up to 28 \227 10 9 neurons and a similar amount of glial cells ( 18 ). The earliest eve nt in the formation of the neocortex is the generation of a horizontal layer called the pre plate, composed of a super \201 cial sublayer of the earliest corticopetal nerve \201 br es, and the earliest generated neurons. These are the Cajal \200\223Retzius cells and a low er layer of cells that will become the subplate. Subsequent waves of migrating neurons form the cortical plate in an inside to outside temporal sequence creating future layers VI \200\223II of the mature neo- cortex ( 19 ). This general pattern of migration and cortical plate formation has been observed in a number of mammalian species, and is particularly pr onounced in primates. The cortical plate is inserted into the preplate, splitting it into a n outermost marginal zone, the future layer I, and a lower, thick, and partially transient band called the subplate (Fig. 4.1 A). Neurons migrating to the neo- cortex move along radi al glial \201 bres that form palisades linking the neural epithelium and the developing c ortical plate ( 20 ). The time of generation of a neuron determines its \201 nal laminar (vertical) position in the mature cortex. It is probable that humans acquire their full com plement of neocortical neurons during the 2nd trimester. at the end of corticogenesis, and a growing body of evidence suggests that most essential f eatures of cortical neurons, and differ- ences between them, are programmed genetically dur ing development. The gene expression pro \201 les that de \201 ne neuronal properties are broadly controlled by transcription factors, which activate or repress the transcription o f a multitude of downstream genes. Focal cortical dysplasia Type Ib and Ic The 2011 ILAE classi \201 cation of FCD further sp eci \201 es cortical lami- nation abnormalities that affect horizontal layering (FCD Ib) o r both vertical and horizontal layering (FCD Ic). As for all new FCD Type I variants, they should occur as an isolated feature and not be associated with any other structural brain l esion (described later in the chapter). To the best of my knowledge, FCD Type Ib or Ic are very rare and there is still no systematic analysis available charac- terizing clinically p henotypes, etiology, or pathogenesis. Focal cortical dysplasia Type II It becomes evident from the aforementioned anatomical and developmental data that any (genetic or environmental) insult during early time windows and involving one or more of the lead- ing neurodevelopmental processes of corticogenesis, wil l deter- mine cortical malformation and thus predispose the affected brain to enhanced seiz ure susceptibility. The most prominent and better studied example is that of FCD Type II (F ig. 4. 2 ), which is charac- terized as cortical malformation with an almost complete disru p- tion of lamination (with the exception of layer 1). In addition, distinct cytological ab normalities are present, which differentiate nowadays FCD Type IIa (dysmorphic neurons with out balloon cells) from FCD Type IIb (dysmorphic neurons and balloon cells). Dysmorphic neu rons were likely to be \201 rst described by Crome ( 25 ). They are morphologically the s ame in both Type II variants and microscopically characterized by severe abnormalities. Neu ronal cell diameters and cell nucleus diameter are signi \201 cantly enlarged, Nissl subst ance is aggregated and displaced towards the cell membrane, and phosphorylated and non-phos phorylated neu- ro \201 lament isoforms accumulate in their cytoplasm (Fig. 4. 2 ). In the center of the lesion, dysmorphic neurons cluster in large aggre- gates. They are distribut ed throughout the cortical thickness and dislocate also into the white matter. However, dis tant from the core of the main lesion, isolated dysmorphic neurons can also be observed. In addition, multiple FCD Type II lesions have been recognized and individually contribute to seizure generation ( 26 ). Balloon cells are the distinguishing hallmark of FCD Type IIb. They present with a large cell body and opalescent glassy eosi- nophilic cytoplasm (using h aematoxylin and eosin (H&E) stain), which lacks Nissl substance. Multiple nuclei are often present. Balloon cells can occur at any cortical location (including layer 1) and are often found in the underlying white matter. Balloon cells commonly accumulate intermediate \201 laments vimentin and nestin, which can be used as histopathological markers ( 27 , 28 ). Balloon cells have gross histomorphological similarities with giant cells, and can be ob served in cortical tubers from patients with tuberous sclerosis complex (TSC). The TSC1/TSC 2 signaling pathway (including insulin growth factor receptor and mTOR) is, therefore, a pr omising candidate pathomechanism for FCD Type II ( 29 , 30 ). The basic unit of the mature neocortex is the \200\230minicolumn \200\231, a narrow chain of neurons extending vertically across the cellular layers II \200\223VI, perpendicular to the pial surface ( 18 ). Each minicol- umn in primates contains 80 \200\223100 neurons, exc ept for the striate cortex where the number is 2.5 times larger. Minicolumns contain all th e major cortical neural cell phenotypes, interconnected in the vertical dimension. The mini column is produced by the iterative division of a small cluster of progenitor cells in the neuroepithe- lium or is derived from neurogenic radial glia in the intermediate zone ( 21 , 22 ). A cortical column is a complex processing and dis- tributing unit that links a numbe r of inputs to a number of outputs via overlapping internal processing chains. Cortical eff erent neu- rons with different extrinsic targets are partially segregated; those of layers II/III project to other cortical areas, those of layers V/VI to subcortical structures. The most widely studied columnar organi- zation is that of the visual cortex ( 23 ), con \201 rming preferential input to neighboring \200\230ocular dominance columns \200\231 by stim uli delivered to one or the other eye. There are two broad classes of cortical neurons that differ in their mode of migration, mor phology, and functional characteris- tics. They also originate from different embryonic are as. Projection neurons (glutamatergic excitatory) extend axons to distant targets and are g enerated from progenitors of the neocortical germinal zone (located in the dorsolateral wal l of the telencephalon). Inhibitory interneurons (gamma-aminobutyric acid (GABA)ergic) are those that make local connections and are primarily generated from progenitors in the gangl ionic eminence, the primordium of the future basal ganglia, located in the ventral forebrai n. The cells generated in the ganglionic eminence follow a long tangential migratory route to reach the cortical plate and form the majority of non-pyramidal neurons (i.e. cortical i nterneurons). While neocor- tical cells born in the ventricular zone utilize radial glia as scaffold to migrate to the developing cortical plate, tangentially migrating neurons move in close association with axons of the corticofugal \201 bre system ( 24 ). All these neu rons will be located in distinct layers CHAPTER 4 developmental neurobiology, neuroanatomy, and neuropathology 43 The hippocampal formation The anatomy of the human hippocampus has a long and contro- versi al history since its \201 rst description by Julius Caesar Arantius in 1587, who was a pu pil of the famous Italian anatomist Andreas Vesalius ( 36 ). Arantius compared the anatomic al elevations within the inferior horn of the lateral ventricles with that of a seahorse (g enus Hippocampus ), with the animal \200\231s head pointing either to the third ventricle o r the anterior part of the temporal lobe. This controversy was further promoted by another term introduced by de Garengoet in 1742. He compared the mesial view of the hippoc- ampus w ith the Ammon \200\231s horn adopted from the Egyptian god Ammun Kneph ( 36 , 37 ). It is t he pyramidal cell layer of the various hippocampal subregions that is microscopically recog nized as cornu ammonis (CA areas) these days and, indeed, also resembles a ram \200\231s ho rn (Fig. 4. 4 ). The anatomical classi \201 cation of hippocam- pal sub \201 elds is no l ess contradictory with many classi \201 cation systems available. This may also result fro m differences between rodent and human hippocampus. The classi \201 cation introduced by L orente de No in 1934 is mostly used, designating four hippocam- pal sectors, namely CA1 to CA4 ( 38 ). The transition areas between CA1 and subiculum or between the CA3 \200\223CA4 r egions remain, however, dif \201 cult to clarify using routine staining techniques. Determination of characteristic molecular genetic alterations for speci \201 c FCD variant s will further advance our clinicopathological classi \201 cation system and help to ident ify molecular pathways with potential therapeutic relevance. As a matter of fact, the mTOR inhibitor rapamycin, and its derivative everolimus, have recently been shown bene \201 cia l for tumor reduction in TSC patients and likely translate also into drug treatment of epil epsies ( 31 ). As children and adolescents frequently develop drug resistance and surgical resection offer s complete seizure control in up to 80 % of all patients ( 6 ), high-resolution imaging is an important tool for clinical management of patients with FCD Type II. Indeed, most FCD Ty pe IIb lesions can be detected by presurgical MRI. They usually present with a \200\230tra nsmantle sign \200\231 in FLAIR ( \202 uid attenuated inversion recovery) sequences ( 28 , 32 ). In contrast, FCD Type IIa lesions are less clearly visible by structural MRI but may be detect- able using specialized post-processing protocols ( 9 ). In addition, a distinct ive pattern of repetitive, high amplitude, fast spikes, fol- lowed by high amplitude slow w aves, interspersed with relatively \202 at periods can be detected in FCD Type IIb. Durin g drowsiness and slow sleep, fast spikes become more prominent, increase in frequency and t end to spread into contiguous non-lesional areas ( 33 ). During REM sleep, there is a marke d decrease in these electri- cal abnormalities.