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. The hippocampus is a main constituent of the allocortex ( 39 ). It is situated in the mesia l temporal lobe and occupies the \202 oor of the inferior horn of the lateral ventricle f rom the level of the corpus amygdaloideum up to the splenium of the corpus callosum. Three major parts can be distinguished: the dentate gyrus (or fascia den- tata), the cornu ammoni s, and the subiculum. The dentate gyrus consists of three laminae: the molecular layer, the granular layer, and an ill-de \201 ned plexiform layer. Small nerve cells usually referre d to as \200\230granule cells \200\231 dominate in the dentate gyrus. The perikarya of gra nule cells assemble tightly together and form a clear-cut band. The basal tip of the soma s hows a distinct axon hillock from which a relatively thick axon is generated which enters t he cornu ammo- nis and forms synaptic contacts with the pyramids of the 3rd and the 4th sec tor (mossy \201 bre system). The apical dendrites ramify within the molecular layer and r eceived topographically restricted efferents from the collateral hippocampus and ipsilatera l tractus perforans. The granule cell layer is functionally regarded as \200\230gate keepe r \200\231 of the hippocampus, as it receives the majority of axonal input. A helpful and i nteractive overview of the parahippocampal \200\223 hippocampal network is presented in van Strien et al. ( 40 ). Focal cortical dysplasia type III This entity is newly introduced into the ILAE FCD classi \201 cation system and refers to a compilation of cortical abnormalities associ- ated with and adjacent to another principal lesion (Fig. 4. 3 ). A most prominent example refers to FCD Type IIIa encountered in mesial temporal lobe epilepsy (MTLE) patients with hippocampal sclerosis (formerly classi \201 ed mostly as FCD Type Ia in Palmini \200\231s system ( 5 )). This diagnosis was probably very much fostered by abnormal anterior temporal lobe white matter signal changes detectable by MRI as well as from ictogenic EEG patterns evolving in dependent from hippocampal location. Yet, not all patients showed histomorphologically con \201 rmed and approved FCDs. Thom et al. suggested, that one easy to recognize FCD Type II Ia variant should be termed \200\230temporal lobe sclerosis \200\231 (TLS), as its pathoge nesis is reactive rather than malformative ( 34 ). This hypothesis is supported by recent \201 ndings from Garbelli et al. using high-resolution 7T MRI in the temporal lobe in HS p atients ( 35 ). They suggest the origin of abnormal white matter intensities (accompanied b y anterior temporal lobe atrophy) in MTLE-HS patterns to derive from punctate myelin loss b eing of reactive/ degenerative nature rather than malformative. The very similar postoperat ive seizure control in patients with a principal lesion, compared to those without any asso ciated FCD, further argue against an independent origin and pathogenesis ( 14 ). However, a total of four subtypes have been proposed by the new ILAE classi \201 - cation system (Ta ble 4. 2 ): FCD Type IIIa, when associated with hippocampal sclerosis; FCD Type IIIb, when associated with tumors; FCD Type IIIc, when associated with vascular malforma- tions; and F CD Type IIId when associated with any other principal lesion acquired during early life. Ea rly head injury, bleeding, or in \202 ammation are amongst the most frequent causes for FC D Type IIId. The new FCD category has not yet been clinically well described, although many patients were included in cohorts of previously published Palmini FCD Type I series ( 6 ). Hippocampal neuropathology in MTLE The human hippocampus is particularly prone to generate seizures and to perpetuate chronic focal temporal lobe epilepsies (TLEs). The end stage of the disease often results in a pathomorphological pattern recognized as hippocampal scleros is (HS; synonym Ammon \200\231s horn sclerosis, Table 4. 1 ). In HS patients, diagnostic MR I protocols (T2, FLAIR) prove severe atrophy of the affected hippocampus and histopathologi cal examination of surgical resec- tions identi \201 es segmental neuronal cell loss in th e pyramidal cell layer of the cornu ammonis, most dramatically affecting CA1 and CA4 ( 41 , 42 ). In a large series of 3311 patients suffering from TLE, HS can be identi \201 ed in 48 % . Within our entire cohort of 4512 epi- lepsy patients undergoing surgical resection f or various aetiologies, HS was recognized in 35.2 % , with 5 % presenting as dual pathology , 44 Fig. 4.2 (See also Color plate 2.) Clinicopathological \201 ndings in FCD Type II. A) FCD Type IIa in an 18-year-old female patient with refractory seizures from age 5 years, that would start with sensory disturbance in the left foot. Coronal T2 FLAIR did not reveal de \201 nitely abnormal signal intensities, which is often reported for FCD Type IIa. Indeed, histopathological inspection showed characteristic hallmarks of FCD Type IIa (see (E) and ( F)) in surgical specimen obtained from the indicated brain region (arrowhead). MRI \201 g ure kindly provided by Dr Duncan (London, UK). B) Proton density imaging reveals a hyperint ense signal change in the left frontal lobe of the patient with drug-resistant seizures, ta pering from the depth of the gyrus towards the ventricle ( \200\230transmantle sign \200 \231, arrowhead). C) Interictal EEG recording from the scalp surface of the patient shown i n (B). Arrows point to characteristic \200\230brushes \200\231, which can be often recogni zed in patients with FCD Type IIB. D) The peculiar electrographic pattern ( \200\230brushes \200\231) becomes more evident when recording is obtained from depth electrodes implanted into the lesion (patient with histopathologically con \201 rmed FCD Type IIB). (C) and (D) were kindly provided by Dr Sprea \201 co (Milan, Italy). E \200\223F) Dysmorphic neurons revealed by HE (E), or neuro \201 lament immunostaining (SMI311 (F)) are typical \201 nd ings in FCD Type IIa and IIb. G \200\223H) Balloon cells revealed by HE (H), or vimentin im munostaining (H) can be seen only in FCD Type IIb. Scale bars in (E) \200\223(H) = 20 m. CHAPTER 4 developmental neurobiology, neuroanatomy, and neuropathology 45 Fig. 4.3 (See also Color plate 3.) Associated FCDs Type III. A1) This abnormal pattern of s uper \201 cial cortical lamination (arrows) was associated with hippocampal sclerosis in a n MTLE patient and should be diagnosed as FCD Type IIIa. It is similar to that described by Thom et al. as temporal lobe sclerosis ( 34 ). Scale bar = 200 m (applies also to (A2) and (B2)). Another characteristic FCD Type IIIa pattern is that of heterotopic \200\230len tiform \200\231 neuronal islets in the white matter of the temporal lobe in MTLE-HS patient s (A2). B1) Dysembryoplastic neuroepithelial tumor of the right mesial temporal lobe. Court esy of Dr Macaulay (Halifax, Canada). B2) Persisting vertical microcolumns can be observed in the vicinity of long-term epilepsy associated tumors and should be diagnosed as FCD Type IIIb. C) Leptomeningeal vascular malformations (asterisk) usually associate with abnormal lamination in adjacent neocortex (FCD Type IIIc) marked by an arrow. D) These massive corti cal lamination abnormalities were registered adjacent to a glial scar (acquired by perinata l head trauma) and classify as FCD Type IIId. Such lesions can be progressive in nature and were \201 rst described by Marin-Padilla et al. in 2002 ( 93 ). i.e. in combination with tumors or scars. Although the pathogen- esis of HS remains to be i denti \201 ed, clinical histories follow a char- acteristic schedule in most patients. App roximately 50 % of patients suffered from an \200\230initial precipitating injury \200\231 before the age of 4 years ( 41 ). In this cohort, complex febrile seizures are the most fr e- quently noted events. Birth trauma, head injury, or meningitis were other early childhoo d lesions observed in TLE patients. The mean age at onset of spontaneous complex partial se izures is 11.5 years ( 43 ). As a matter of fact, structural, molecular, or functional anal ysis can usually not be obtained at this early and clinically silent period and the diagnos is of HS is veri \201 ed after a long period of unsuccessful antiepileptic medication. The mean age at the time of surgery is 34.6 years wi th a history of epileptic seizures for 23.3 years. As in most other series reported so far, both genders were equally affected and a family history of TLE was very rare indicat- ing that hereditary factors do not play a major role in HS associated TLE. HS is characterized at the histopathological level by segmental pyramidal cell loss in CA1 (Sommer \200\231s sector), CA3, and CA4, whereas CA2 pyramidal and dentate gyrus granule ce lls are more seizure resist- ant ( 44 ). Notwithstanding, several interneuronal cell popula tions are also affected, i.e. neuropeptide Y- and somatostatin-immunoreactive oxford textbook of epilepsy and epileptic seizures 46 interneurons and/or mossy cells in the CA4 sector ( 45 , 46 ). Neuronal cell loss is invari ably associated with reactive astrogliosis, which results in stiffening of the tissue and e stablished the tradi- tional term of \200\230Ammon \200\231s horn sclerosis \200\231 ( 44 ). An intriguing ques- tion relates to the mechanisms of selective neuronal vulnerability b etween these morphologically similar neuronal cell populations. This topic is a matter of o ngoing studies and will not be further discussed. Major pathomechanisms include, besides ma ny others, abnormal neuronal circuitries (aberrant mossy \201 bre sprouting) ( 47 ), and molecular rearrangement/plasticity of ion channel and neurotransmitter receptor expression ( 29 , 48 ). 6 years), whereas in HS Type 3 and normal appearing hippocam- pus (no HS) the \201 rst ev ent appeared beyond the age of 13 and 16 years, respectively. The proposed HS classi \201 cation system allows some prediction of postsurgical outcome ( 54 , 55 ). The most favorable outcome was achieved in patients presenting with HS Type 1a and HS Type 1b ( > 83 % seizure freedom), whereas only half of patients with atypi- cal HS patterns (Type 2 and Type 3) became seizure free. However, this classi \201 cation system will need further con \201 rmation in inde- pendent patient cohorts to assess its interobs erver reliability. Meanwhile, Thom and colleagues published another HS classi \201 ca- tio n system describing similar cell loss patterns ( 56 ). Differences with respect to postsurg ical outcome need, however, clari \201 cation. Despite electrophysiological evidence for m esial temporal lobe generation of seizures, a cohort of approximately 20 % of MTLE cases do not show microscopical features of neuronal cell loss ( 54 ) and cell density measurements were not signi \201 cantly different from age-matched autopsy controls (10 % difference i n neuronal cell densities, either up or down, are obtained already by standard deviation fr om human control values!). We designated this group as \200\230no hippocampal sclerosis (n o HS) \200\231. This observation has been frequently reported in neuropathological surveys of similar HS series ( 41 , 42 ). The epileptogenic pathomechanisms of hippocam- pal seizur e generation remains to be further determined, but is suggested to be similar to kindling i n animal TLE models. Clinical studies assume MTLE as a heterogenic entity with differ- ent aetiologies and clini cal histories ( 49 \200\22351 ). Hence, neuropatho- logical investigations describe differe nt patterns of neuronal cell loss within hippocampal sub \201 elds and adjacent temporal l obe structures ( 46 , 52 , 53 ). An intriguing issue is, therefore, to identify determining factors on hippocampal pathology patterns. A reliable neuropathological classi \201 catio n system will be helpful to separate distinct pathological subgroups and to better predict postsurgical seizure control. We have recently proposed a clinicopathological classi \201 cation system for hippocampal cell loss in MTLE patients ( 54 ). Five distinct patterns wer e recognized (Table 4. 3 ), which associated with speci \201 c clinical histories or a pro bability for post- surgical seizure control ( 54 , 55 ). The largest group of HS cases presents with a classical or severe pattern of segmental neur onal cell loss affecting CA1, CA3, and CA4 (Table 4. 3 ; Fig. 4. 4 ). There are, however, c onsiderable simi- larities between HS Type 1a (classical pattern) and 1b (severe pat- tern) . It is the degree of CA3 and CA2 pyramidal cell loss which makes the difference. This dist inction is reasonably similar to Wyler scores W3 and W4 ( 52 ). Correlation with clinical d ata pointed to an early age of preceding events (<3 years) as important predictor of classi cal and severe hippocampal pathology pattern. Dentate gyrus pathology in TLE patients It remains an intriguing observation, that dentate granule cell loss signi \201 cantly associates with de \201 cient memory acquisition and recall in TLE patients ( 57 \200\22359 ). Indeed, the population of dentate granule cells i s pathologically affected in the majority of HS patients. Lesional patterns in this anatomi cal distinct compartment range from granule cell dispersion (GCD), which occurs in almost 5 0 % of patients ( 59 ) to severe cell loss in HS Type 1a and 1b (Fig. 4. 4 ). Neuropatholog ical criteria for granule cell alterations include increased granule cell lamination above 10 layers with smaller perikarya and larger intercellular gaps, as well as ectopic cluster and bilamination into the molecular layer. Since grading scales for granule cell pathology are not yet internationally stand- ardized, clinicopathological studies yielded complementa ry but also controversial results ( 59 \200\22363 ). Two atypical variants are characterized either by severe neuronal loss restricted to sector CA1 (HS Type 2) or to CA4 (HS Type 3). In HS Type 2, preceding events were documented at a later age (mean Table 4.3 Neuropathological grading scale of hippocampal sclerosis Pattern of neuronal loss a and gliosis (complete samples) Our current understanding of these intriguing pathology pat- terns were much in \202 uence d from developmental neurobiology studies of the dentate gyrus and its propensity to genera te neurons throughout life. Assembly of the granule cell layer follows different migration streams building \201 rst its internal limb (Fig. 4.4 A), from which newly generated gran ule cells progressively expand into lat- eral direction, thus forming the external limb ( 6 4 ). Most intrigu- ingly, the neurogenic capacity of the dentate gyrus maintains throughout life, also in human brain ( 65 ). Within the adult mam- malian hippocampus, multipotent pr ecursor cells have been char- acterized in the dentate gyrus, residing directly below the g ranule cell layer ( 66 ). These cells proliferate upon diverse functional and molecular sti muli, generate migratory neuroblasts, and further dif- ferentiate into granule cells upon m igration into the dentate gyrus ( 67 , 68 ). Migratory guidance is provided by a scaffold o f radial glial cells within the dentate gyrus as well as from Reelin molecules secreted by Cajal \200\223Retzius cells ( 69 \200\22371 ). Newborn granule cells DG b 0 \200\2232 1 \200\2232 0 \200\2232 0 \200\2232 0 \200\2231 CA4 1 \200\2232 2 0 1 \200\2232 0 CA3 0 \200\2231 2 0 0 \200\2231 0 CA2 0 \200\2231 1 \200\2232 0 0 0 CA1 2 2 1 \200\2232 0 0 Type 1a c Type 1b c Type 2 c Type 3 c No HS c Class Semiquantitative microscopic examination based on formalin- \201 xed, paraf \201 n-embedd ed surgical specimen (4 \200\2237 m section thickness), H&E, CV/LFB, NeuN (recommended), and GFAP stainings. Grading scale is de \201 ned as following: 0 = no obvious neuronal lo ss or glio- sis only; 1 = neuronal loss or gliosis (GFAP) but moderate or patchy; 2 = sever e neuronal loss (majority of neurons) and \201 brillary gliosis. a Please note limitation s of visual inspection as \201 rst visible sign of cell loss is usually 30 \200\22340 % cell loss (H&E stains, shown by quanti \201 ed neuronal density measuremen ts). Quantitative methods will be more reliable for scoring. b Granule cell layer is normal (score = 0), dispersed (score 1; can be focal), or shows sev ere granule cell loss (score 2; can be focal). c If surgical specimen is anatomically well-preserved (en bloc resection recommended). CHAPTER 4 developmental neurobiology, neuroanatomy, and neuropathology 47 Fig. 4.4 (See also Color plate 4.) Microscopic anatomy of the developing human hippocampus and in MTLE patients with hippocampal sclerosis. A) Human hippocampal development at 17th W oG. Scale bar = 500 m. The \201 gure should also illustrate the particular development of the dentate gyrus, which retains its neurogenic propensity throughout life. The dentate gyrus matrix is bending through the dentate notch and form the internal limb (DGi). From h ere, newly generated granule cells were continuously integrated and form the external limb (DGe) ( 64 ). B) Human hippocampus at birth (42nd WoG). Scale bar = 1 mm (applies also to ( C) and (D)). All hippocampal sectors were clearly visible (CA1 \200\2234). The term \200 \230hilus \200\231 should be restricted to the rodent hippocampus, and is not de \201 ned by Lorente de No ( 38 ). The same applies for the term \200\230endfolium \200\231, which i s not a proper anatomical terminology for this region. The dashed line should indicate that the DGi is likely the portion of the DG maintaining its neurogenic capacity throughout lif e. C) Severe hippocampal sclerosis (HS Type 1b, Table 4. 3 ) in an adult patient with febri le seizures at age 3 years and onset of spontaneous recurrent and drug-resistant seizures s ince his 14th year of life. NeuN immunohistochemistry with haematoxylin counterstaining (4 m thin paraf \201 n embedded section; applies to all images shown here). Note that rest ricted cell loss in DGi, compared to the mid portion or DG3 area. Experimental data has sho wn that this patterns correlates with the patient \200\231s ability to store and recall mem ory with this isolated hippocampus/hemisphere (Wada-testing; ( 58 )). D) A patient with lim bic encephalitis and late onset of her MTLE. The surgical specimen showed restricted cell l oss within the CA4 region. This rare pattern is classi \201 ed as atypical HS (Type 3, Tab le 4. 3 ). E) Normal appearance of the human dentate gyrus with densely packed granule cell s and sharp borders to subgranular and molecular layers (10 \227 magni \201 cation, bar = 100 m, refers also to (F) \200\223(K)). F) Granule cell pathology with signi \201 cant granule cell loss indicated by thinning of dentate gyrus and cell free gaps (asterisk). G) Granule cell dispersion with spreading of granule cells into the molecular layer (arrow): H) Bilaminar architecture of the granule cell layer (arrows). K) granule cell dispersion wi th spreading of granule cell clusters into the molecular layer (arrow), as described by ( 6 2 ). GC, granule cell layer; ML, molecular layer. functionally integrate into the trisynaptic hippocampal pathway ( 72 \200\22374 ), expand d endrites into the molecular layer and axonal col- laterals into the CA3 region (mossy \201 bres), where they form synap- tic connections on large excrescences of pyramidal neuro ns within stratum lucidum ( 75 ). The time period from proliferation to func- tional integr ation has been estimated in the range of 4 weeks in adult rodents, although maturation of n ewborn neurons extends over several months ( 74 ). In the mouse, axons reach the CA3 region about 2 weeks after neurogenesis ( 76 ). In adult rats, the number of newborn hippocampal neurons per day has been estimated to approximate 9000 or 250,000 per month, respectively ( 77 ), while cell prolife ration in humans is likely to be much lower ( 78 ). The number of new and functionally inte grated neurons is, however, challenged by apoptosis and most newborn cells die within 1 \200\2232 weeks after their birth ( 79 ). The obvious association between HS and GCD leads to the hypothesis, that newly built granul e cells aberrantly integrate into the dentate gyrus and disturb the trisynaptic hippocampal pathway, thereby increasing seizure susceptibility ( 80 ). Recurrent mossy \201 bre spro uting (mossy \201 bres are axonal projections of oxford textbook of epilepsy and epileptic seizures 48 granule cells) has long been recognized in animal models of TLE ( 81 ) as well as in surgic al human hippocampal specimens ( 82 ). Indeed, seizure-induced granule cell neurogenesis an d/or disper- sion may then represent a major pathomechanism underlying hip- pocampal seizur e activity ( 80 ). Further studies on this intriguing topic challenged this assumption. Irr adiation of hippocampal pre- cursor cells did not abolish mossy \201 bre sprouting after experimen- tal induction of status epilepticus ( 83 ), and fostered the discussion on the r elevance of neurogenesis to architectural abnormalities within the epileptogenic hippocampu s and to the etiology of TLEs ( 84 ). However, newborn granule cells not only anatomically and functionally integrate into the granule cell layer (as destined) or ectopically into th e molecular layer (GCD) but also ectopically into CA4 ( 85 ). Ectopic granule cells at the CA4/CA3 boundary have been first identified and functionally characterized in animal models for TLE ( 86 ). Using immunohistochemical preparations for Prox-1 , a homeobox gene speci \201 cally expressed in postmitotic dentate granule cells ( 68 ), a signi \201 cant numbe r of ectopic granule cells can now be reliably recognized in rat models as well as human su rgical specimens ( 85 ). These \201 ndings are compatible with the notion that aberrant a natomical organization of the epileptic hip- pocampus contribute to increased seizure susce ptibility and that neurogenesis is critically involved in this process. The majority of \201 ndings points to a predominately young age of seizure-induced neurogenesis, which cont ributes to aberrant network integration and seizure progression. The decreased propensity o f neurogenesis in chronic TLE stages, whether re \202 ecting a depletion or exhaustion of the precursor cell pool ( 87 ), would rather result in the well-rec- ognized cell loss patt erns and severe cognitive deterioration ( 57 ). This hypothesis is in good agreement with a recently proposed pathogenic model on the \200\230two faces \200\231 of seizure-related n eurogene- sis in human TLE ( 84 ). differentiation capacity of adult stem cells with the same patient \200\231s memory perform ance, when each hemisphere was tested separately using the Wada test. Our results suggest t hat encoding new memo- ries is also related to the regenerative capacity of the hippocampus in the human brain. Acknowledgements The author is grateful to Drs Angelika M hlebner (Wien/Erlangen) and Rola nd Coras (Milan/Erlangen) for their critical comments. The work is supported by the Europea n Community (LSH-CT- 2006-037315 EPICURE). References 1 . Meencke HJ . Pathology of childhood epilepsies . Cleve Clin J Med 1989 ; 56(Suppl Pt 1) : S111 \200\223 20 ; discussion S121 \200\2233 . 2 . Barkovich AJ , Kuzniecky RI , Jackson GD , Guerrini R , Dobyns WB . A developmental and genetic classi \201 cation for malformations of cortical development . Neurology 2005 ; 6 5 : 1873 \200\223 87 . 3 . Guerrini R , Dobyns WB , Barkovich AJ . Abnormal development of the human cerebral cortex: genetics, functional consequences and treatment options . Trends Neu rosci 2008 ; 31 : 154 \200\223 62 . 4 . Taylor DC , Falconer MA , Bruton CJ , Corsellis JA . Focal dysplasia of the cerebral co rtex in epilepsy . J Neurol Neurosurg Psychiatry 1971 ; 34 : 369 \200\223 87 . 5 . Palmini A , Najm I , Avanzini G , Babb T , Guerrini R , Foldvary-Schaefer N , et al. Terminology and classi \201 cation of the cortical dysplasias . Neurology 2004 ; 62 : S2 \200\223 8 . 6 . Blumcke I , Vinters HV , Armstrong D , Aronica E , Thom M , Sprea \201 co R . Malforma tions of cortical development and epilepsies . Epileptic Disord 2009 ; 11 : 181 \200\223 9 3 . 7 . Chamberlain WA , Cohen ML , KA Gyure , Kleinschmidt-DeMasters BK , Perry A , Powell SZ , et al. Interobserver and intraobserver reproducibility in focal cortical dysplasia (malformations of cortical development) . Epilepsia 2009 ; 50 : 2593 \200\223 8 . The hippocampus serves a major role in all aspects of conscious, declarative memory, i.e. s emantic memory for facts and concepts, episodic memory, and spatial memory ( 88 ). Notwiths tanding, bilateral damage of both hippocampi induces profound antero- grade amnesia in huma ns. ( 89 ). Neuropsychological lesion studies, functional imaging in humans, as well as exp erimental animal models linked memory function particularly with the dentate gyrus ( 90 ). Thus, standardized cognitive evaluation programs in epi- lepsy patients submitted to surgic al treatment offer the unique opportunity to study such higher brain function in humans. Ev idence has already been achieved pointing to the impact of den- tate granule cell neurogene sis on learning and behavior in rodents ( 91 , 92 ). We have studied this issue in human hi ppocampus obtained from epilepsy surgery. Comparing memory performance (tested by amobarbit al anesthesia (Wada test) in patients subse- quently submitted to surgical resection of eit her the left or right hippocampus) with the extent of hippocampal cell loss within the inte rnal limb identi \201 ed granule cell density as most signi \201 cant predictor accountin g for 78 % of the total memory capacity in an individual patient ( 57 ). It \200\230sugges tively \200\231 points to neurogenesis as neurobiological substrate of memory acquisition ( rather than sei- zure etiology) and that a run-down of the neurogenic propensity in chronic seizure disorders compromises higher cognitive brain function. Indeed, we experimentally c on \201 rmed this hypothesis when isolating, proliferating, and differentiating adult huma n stem cells from the dentate gyrus of TLE patients with HS ( 58 ). There was a highly sign i \201 cant correlation between the proliferation and 8 . Blumcke I , Sprea \201 co R. An international consensus classi \201 cation for focal cortical dysplasias . Lancet Neurol 2011 ; 10 : 26 \200\223 7 . 9 . Bl mcke I , Thom M , Aronica E , Armstrong DD , Vinters HV , Palmini A , et al. The cl inico-pathological spectrum of Focal Cortical Dysplasias: a consensus classi \201 cation p roposed by an ad hoc Task Force of the ILAE Diagnostic Methods Commission . Epilepsia 2011 ; 52 : 158 \200\223 74 . 10 . Cepeda C , Andre VM , Levine MS , Salanion N , Miyata H , Vinters HV , et al. Epilepto genesis in pediatric cortical dysplasia: The dysmature cerebral developmental hypothesis . Epileps y Behav 2006 ; 9 : 219 \200\223 35 . 11 . Hildebrandt M , Pieper T , Winkler P , K olodziejczyk D , Holthausen H , Blumcke I. Neuropathological spectrum of cortical dysplasia in children with severe focal epilepsies . Acta Neuropathol 2005 ; 110 : 1 \200\223 11 . 12 . Blumcke I , Pieper T , Pauli E , Hildebrandt M , Kudernatsch M , Winkler P , et al. A distinct variant of focal cortical dysplasia type I characterized by magnetic resonance ima ging and neuropathological examination in children with severe epilepsies . Epileptic Disor d 2010 ; 12 : 172 \200\223 80 . 13 . Krsek P , Pieper T , Karlmeier A , Hildebrandt M , Ko lodziejczyk D , Winkler P , et al. Different presurgical characteristics and seizure outcom es in children with focal cortical dysplasia type I or II . Epilepsia 2009 ; 50 : 125 \200 \223 37 . 14 . Tassi L , Garbelli R , Colombo N , Bramerio M , Lo Russo G , Deleo F , et al. Type I f ocal cortical dysplasia: surgical outcome is related to histopathology . Epileptic Disord 2 010 ; 12 : 181 \200\223 91 . 15 . Rakic P , Ayoub AE , Breunig JJ , Dominguez MH . Decision by division: making cortical maps . Trends Neurosci 2009 ; 32 : 291 \200\223 301 . 16 . Sprea \201 co R . Are some focal cortical dysplasias post-migratory cortical malformaitons? Epileptic Disord 2010 ; 12 : 169 \200\223 71 . 17 . Hadjivassiliou G , Martinian L , Squier W , Blumcke I , Aronica E , Sisodiya SM , et al. The application of cortical layer markers in the CHAPTER 4 developmental neurobiology, neuroanatomy, and neuropathology 49 39 . Braak H . Architectonics of the human telencephalic cortex . In: Barlow HB , Bizzi E , Florey E , Gr sser OJ , van der Loos H (eds) Studies of Brain Function , Vol. 4 , pp. 1 \200\223147. Berlin : Springer . 1980 . evaluation of cortical dysplasias in epilepsy . Acta Neuropathol 2010 ; 120 : 517 \200\223 28 . 18 . Mountcastle VB . The columnar organization of the neocortex . Brain 40 . van Strien NM , Cappaert NL , Witter MP . The anatomy of memory: an interactive overvi ew of the parahippocampal-hippocampal network . Nat Rev Neurosci 2009 ; 10 : 272 \200\223 82 . 1997 ; 120(Pt 4) : 701 \200\223 22 . 19 . Angevine JB , Jr , Sidman RL . Autoradiographic study of cell migration during histoge nesis of cerebral cortex in the mouse . Nature 1961 ; 192 : 766 \200\223 8 . 41 . Blumcke I , Thom M , Wiestler OD . Ammon \200\231s horn sclerosis: a maldevelopmental disorder associated with temporal lobe epilepsy . Brain Pathol 2002 ; 12 : 199 \200\223 211 . 20 . Rakic P . Speci \201 cation of cerebral cortical areas . Science 1988 ; 241 : 170 \200\223 6 . 42 . Thom M , Zhou J , Martinian L , Sisodiya S . Quantitative post-mortem 21 . Hansen DV , Lui JH , Parker PR , Kriegstein AR . Neurogenic radial glia in the outer s ubventricular zone of human neocortex . Nature 2010 ; 464 : 554 \200\223 61 . study of the hippocampus in chronic epilepsy: seizures do not inevitably cause neuronal los s . Brain 2005 ; 128 : 1344 \200\223 57 . 43 . Blumcke I . Neuropathology of focal epileps ies: a critical review . 22 . Rakic P . Evolution of the neocortex: a perspective from developmental Epilepsy Behav 2009 ; 15 : 34 \200\223 9 . biology . Nat Rev Neurosci 2009 ; 10 : 724 \200\223 35 . 44 . Sommer W . Die Erkrankung des Ammonshorns als aetiologisches Moment der Epilepsie . Ar ch Psychiat Nervenkr 1880 ; 308 : 631 \200\223 75 . 45 . Blumcke I , Suter B , Behle K , K uhn R , Schramm J , Elger CE , et al. Loss 23 . Hubel DH , Wiesel TN , Stryker MP. Orientation columns in macaque monkey visual cortex demonstrated by the 2-deoxyglucose autoradiographic technique . Nature 1977 ; 269 : 328 \200\223 30 . of hilar mossy cells in Ammon \200\231s horn sclerosis . Epilepsia 2000 ; 41 : S174 \200 \223 80 . 24 . Nadarajah B, Parnavelas JG. Modes of neuronal migration in the developing cerebral cor tex . Nat Rev Neurosci 2002 ; 3 : 423 \200\223 32 . 25 . Crome L . Infantile cerebral glio sis with giant nerve cells . J Neurol 46 . de Lanerolle NC , Kim JH , Williamson A , Spencer SS , Zaveri HP , Eid T , et al. A re trospective analysis of hippocampal pathology in human temporal lobe epilepsy: evidence for distinctive patient subcategories . Epilepsia 2003 ; 44 : 677 \200\223 87 . Neurosurg Psychiatry 1957 ; 20 : 117 \200\223 24 . 26 . Fauser S , Sisodiya SM , Martinian L , Thom M , Gumbinger C , Huppertz HJ , et al. Multi-focal occurrence of cortical dysplasia in epilepsy patients . Br ain 2009 ; 132 : 2079 \200\223 90 . 47 . Sutula TP , Cascino G , Cavazos J , Parada I , Ramirez L . Mossy \201 ber synaptic r eorganization in the epileptic human temporal lobe . Ann Neurol 1989 ; 26 : 321 \200\223 3 0 .