Hippocampal and parahippocampal seizures


Historical note and nomenclature

In 1880, John Hughlings Jackson described the symptomatology of “dreamy states,” and in 1889, he described other variants of “uncinate fits” as “a particular variety of epilepsy,” which subsequently were called “psychomotor seizures” by Gibbs and colleagues and “temporal lobe seizures” by Jasper and Kershman (Gibbs et al 1938; Jasper and Kershman 1941). Although Anderson and then Jackson and Beevor had noted the association of temporal lobe tumors with olfactory hallucinations and dreamy states (Anderson 1886;Jackson and Beevor 1890), it was the postmortem finding of a small cystic lesion restricted to the uncinate gyrus in a patient who had suffered from seizures with dreamy states, elaborated automatisms, and amnesia (Jackson and Colman 1898) that led Jackson and Stewart to the concept of “uncinate fits” with “origin of the discharge… in a region of which this gyrus [ie, the gyrus uncinatus] is part…” (Jackson and Stewart 1899).
Jackson and Stewart described masterly the most characteristic symptomatology of the mesial temporal lobe seizures (Jackson and Stewart 1899). Insights into temporal lobe function with description of the nowadays classical aura-types, automatisms (mainly of the oroalimentary type and including deambulation), and amnesia were fostered by results of stimulation and ablation in monkey experiments reported by Ferrier (Ferrier 1876). However, the verification of the tight relation in humans of certain temporal lobe structures, specifically the anterior mesial ones, with the observed and described variety of symptoms and signs did not happen until the era of epilepsy surgery, with reproduction of these symptoms by electrical brain stimulation as well as electroencephalographic, pathological, anatomical, and physiological studies (Penfield and Erickson 1941; Paillas and Subirana 1950; Penfield and Kristiansen 1951; Feindel et al 1952; MacLean 1952;Penfield 1952; 1954; 1959; Bickford et al 1953; Feindel and Penfield 1954; Penfield and Jasper 1954; Penfield and Rasmussen 1957; Baldwin and Bailey 1958; Daly 1958; Talairach et al 1958; Adey 1959; Gloor 1960;Jasper 1960; Lennox 1960; Feindel 1961; Crandall et al 1963; Gloor and Feindel 1963; Green 1964; Bancaud et al 1965; Robb 1965; Margerison and Corsellis 1966; Ounsted et al 1966; Schneider et al 1969; Williams 1969; Mark and Irvine 1970; Wieser 1983).
Based on a stereoelectroencephalographic study on the electroclinical features of psychomotor seizures, Wieser proposed 5 localization-related subtypes: the temporobasal limbic type, the temporal pole type, the frontobasal-cingulate type, the opercular (insular) type, and the posterior neocortical temporal type (Wieser 1983).
With regard to the pathology of mesial temporal lobe epilepsy, Bouchet and Cazauvieilh presented as early as 1825 very important autoptic data with pathologies in the Ammon’s horn in 7 out of 18 patients who suffered from epilepsy and psychiatric symptoms (“mental alienation seizures“) (Bouchet and Cazauvieilh 1825; 1826). At that time, these lesions were believed to be an effect, rather than a cause, of epilepsy. Jackson recognized limbic-type seizures and associated them with lesions in mesial temporal structures but not with Ammon’s horn sclerosis (Jackson 1931-1932). Sommer and Bratz both suggested that Ammon’s horn sclerosis might be an epileptogenic lesion (Sommer 1880; Bratz 1899), and subsequent evidence has accumulated suggesting that distinctive structural damage, ie, hippocampal sclerosis, is typical for temporal lobe epilepsy. This pathology was accurately described and illustrated by Bratz, with destruction of the pyramidal cells in Sommer’s sector (or what we would call today, sector CA1), preservation of the cells in the neighboring subiculum, and cell loss in the hilus of the dentate gyrus and adjacent sector CA3 but preservation of neurons in sector CA2 and of the dentate granule cells (Bratz 1899). Granule cell dispersion is a common finding in hippocampal sclerosis in patients with intractable focal epilepsy. It is considered to be an acquired, post-developmental rather than a pre-existing abnormality, involving dispersion of either mature or newborn neurons, but the precise factors regulating it and its relationship to seizures are unknown. Thom and colleagues recently presented 2 cases of granule cell dispersion with associated CD34-immunopositive balloon cells, a cell phenotype associated with focal cortical dysplasia type IIB, considered to be a developmental cortical lesion promoting epilepsy (Thom et al 2008).
The ILAE Task Force on Classification and Terminology proposed a diagnostic scheme for describing individual patients (Engel 2006); their scheme includes lists of generally agreed-upon epileptic seizure types and epilepsy syndromes. The ILAE also published a glossary of terms to be used when describing ictal phenomena (Blume et al 2001). This work represents a major progress as acknowledged by the ILAE General Assembly, which approved the new diagnostic scheme of the Task Force in Buenos Aires in 2001. However, none of the work so far has negated the current 1981 classification of epileptic seizures and the 1989 classification of epilepsies, epilepsy syndromes, and related disorders. The Cleveland group participated in the ILAE Task Force on Classification and Terminology, but Lüders and colleagues proposed a somewhat different seizure classification based exclusively on ictal semiology and conceptually concentrating on the so-called symptomatogenic zone (Luders et al 2000). The symptomatogenic zone is 1 of 5 zones that must be determined to define the “epileptic focus.” The epileptogenic zone, on the other hand, is more closely related to the epileptic syndrome.
The ILAE Task Force on Classification and Terminology used the following criteria in identifying specific seizure types as possibly unique diagnostic entities: pathophysiologic mechanisms (including electrophysiological features, neural networks, and neurotransmitter evidence if known), neuronal substrates, response to AEDs, ictal EEG patterns, patterns of propagation and postictal features (or lack of them), and epilepsy syndromes that are associated with a seizure type.
Although the dichotomy of focal (partial) versus generalized seizures has been criticized, the ILAE Core Group retained the terms “focal” and “generalized” with the understanding that the former does not necessarily imply that the epileptogenic region is limited to a small circumscribed area, nor does the latter imply that the entire brain is involved in initiation of the epileptogenic process. Therefore, in the category “focal onset (partial) seizures,” 2 subclasses appear:

Focal onset (partial) seizures

(1) Neocortical (without and with local spread)
(2) Hippocampal and parahippocampal, with a further specification according to spread patterns:
(2.1.) With ipsilateral propagation to:
(a) neocortical areas (includes hemiclonic seizures)
(b) limbic areas (which includes gelastic seizures)
(2.2.) With contralateral spread to:
(a) neocortical areas (hyperkinetic seizures)
(b) limbic areas (dyscognitive seizures with or without automatisms [psychomotor]).
Besides the anatomical substrates of focal seizure manifestations, including their dynamic aspects that usually involve propagation (spatio-temporal seizure organization), and clinical manifestations, which can reflect discharges at the site of ictal onset or sites of propagation (anatomo-electro-clinical seizure analysis), the ILAE Core Group suggested investigation of a number of other factors, including factors that might distinguish between focal seizures due to discretely localized lesions (as occur with focal symptomatic epilepsy) and focal seizures due to more distributed network disturbances, maturational factors, modes of precipitation, pathology, and pathophysiologic mechanisms of seizure initiation (eg, hypersynchronous ictal onsets, which most commonly occur in the hippocampus, versus low voltage fast ictal onsets, which most commonly occur in the neocortex).
Dyscognitive seizures with or without automatisms are not exactly synonymous with the current term “complex partial seizures,” which were defined on the basis of impaired consciousness only and do not necessarily involve limbic areas. Dyscognitive seizures with or without automatisms, as well as the term “psychomotor,” conforms more to the original intent of the term “complex partial seizures” in the 1970 ILAE Classification of Epileptic Seizures. It is implied that mesial temporal limbic areas and their immediate connections are involved in the clinical manifestations, although seizures may have been initiated elsewhere.
Hippocampal and parahippocampal seizures are closely linked with mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS). MTLE-HS has been summarized based on the Istanbul Expert Meeting of the ILAE Commission on Neurosurgery of Epilepsy (Wieser 2004). However, MTLE-HS probably consists of more than one syndrome, and it is not certain whether features of patients with hippocampal sclerosis clearly differentiate them from those with other mesial temporal lesions. In the current classification, this syndrome is listed under the category “epilepsy syndromes by age of onset and related conditions, with less specific age relationship” (Engel 2006).
As may be expected, the literature on this topic is extensive; a PubMed search for the topic “hippocampal epilepsy” revealed 5300 hits, whereas a search for “hippocampal seizures” revealed 3393 hits, “parahippocampal epilepsy” 206 hits, and “parahippocampal seizures” 98 hits

Clinical manifestations

Hippocampal and parahippocampal seizures show unique characteristics. In comparison with some frontal lobe seizures that cause brief and clustered seizures with little or no postictal disturbances and nocturnal predilection, hippocampal and parahippocampal seizures are less-frequent events with profound postictal disturbances and have slower propagation. Hippocampal and parahippocampal seizures almost always require local spread for clinical manifestation, which may involve the insula, amygdala, hypothalamus, and other limbic structures. Contralateral propagation is slow for hippocampal seizures versus fast for neocortical seizures (Wieser 1986).
Hippocampal and parahippocampal seizures as seen in association with mesial temporal lobe epilepsy complex partial seizures” with initial arrest (motionless stare), followed by oroalimentary and other automatisms. Vegetative-autonomic signs and symptoms are prominent and may involve cardiovascular, pupillary, gastrointestinal, sudomotor, vasomotor, and thermo-regulatory functions. Auras occur frequently in isolation and typically consist of autonomic features. Epigastric auras are common and include abdominal discomfort, nausea, emptiness, tightness, churning, butterflies, malaise, pain, and hunger. Such sensations may rise to the chest or throat.

typically are characterized by auras evolving into “

Experiential phenomena include affective, mnemonic, or composite perceptual phenomena and illusory or composite hallucinatory events. They may appear alone or in combination. Included are feelings of depersonalization. These phenomena have subjective qualities similar to those experienced in life but are recognized by the subject as occurring outside of actual context.
Affective components include fear, depression, joy, and (rarely) anger.
Mnemonic components reflect ictal dysmnesia such as feelings of familiarity (déjà-vu) and unfamiliarity (jamais-vu).
Hallucinatory perceptions have no corresponding external stimuli, whereas illusions are alterations of actual percepts and involve visual, auditory, somatosensory, olfactory, or gustatory phenomena.
The term dyscognitive describes events in which disturbance of cognition is the predominant or most apparent feature. Components of cognition are perception (symbolic conception of sensory information), attention (appropriate selection of a principal perception or task), emotion (appropriate affective significance of a perception), memory (ability to store and retrieve percepts or concepts), and executive function (anticipation, selection, monitoring of consequences, and initiation of motor activity including praxis, speech).
Emotional experiences such as fear, dysmnesias (dreamy states, déjà-vu, déjà-vecu, déjà entendu, and other kinds of recollections), alterations of self-perception (in time and space), focal sensory phenomena with olfactory or gustatory symptoms, and vague bilateral sensory phenomena such as tingling are relatively common in hippocampal and parahippocampal seizures with ipsilateral spread to the amygdala and anterior neocortical temporal regions. Vignal and colleagues recently restudied dreamy states (Vignal et al 2007). They had observed a total of 15 sensations of déjà vecu, 35 visual hallucinations consisting of the image of a scene and 5 “feelings of strangeness.” These were recorded during 40 stimulations in 16 subjects and 15 spontaneous seizures in 5 subjects; 45% of dreamy states were evoked by stimulation of the amygdala, 37.5% by the hippocampus, and 17.5% by the parahippocampal gyrus. During both spontaneous and provoked dreamy states, the electrical discharge was localized within mesial temporal lobe structures, without involvement of the temporal neocortex.
Automatisms consist of more or less coordinated, repetitive, motor activity usually occurring when cognition is impaired and for which the subject is usually amnesic afterward. They often resemble a voluntary movement and may consist of an inappropriate continuation of ongoing preictal motor activity. Automatisms may be ictal or postictal, de-novo or reactive. Ictal automatisms associated with temporal lobe seizures frequently consist of oroalimentary symptoms, such as lip-smacking, lip-pursing, chewing, licking, tooth-grinding, or swallowing. Gestural automatisms are also frequently observed and are often unilateral, ie, fumbling, picking, or exploratory movements with the hand, directed toward self or the environment. They may resemble movements intended to lend further emotional tone to speech. Mimetic automatisms are facial expressions suggesting an emotional state, often fear. Hyperkinetic automatisms are a hallmark for frontal lobe seizures. They involve predominantly proximal limb or axial muscles and produce irregular sequential ballistic movements, such as pedaling, pelvic thrusting, thrashing, or rocking movements. The emergence of an intense affective and behavioral state during a temporal lobe seizure could be related to the involvement of a network of structures including the anterior temporal lobe, orbitofrontal cortex (Bartolomei et al 2002), and thalamus. In a (1)H magnetic resonance spectroscopy study of temporal lobe epilepsy patients, Hetherington and colleagues found that the ratio of N-acetyl aspartate to creatine (NAA/Cr), a measure of neuronal injury and loss, was significantly reduced in both the ipsilateral and contralateral hippocampi and thalami (Hetherington et al 2007). NAA/Cr in the ipsilateral hippocampus was significantly correlated with the ipsilateral and contralateral anterior and posterior thalami, putamen, and contralateral hippocampus. Müller and colleagues found clear differences in T2 relaxation patterns and rate in temporal lobe epilepsy with versus without mesial temporal sclerosis (Mueller et al 2007).
Clonic or tonic clonic motor phenomena indicate supra-Sylvian seizure spread. An exception is dystonic posturing, which might indicate ictal involvement of the striopallidar system. Kotagal and colleagues have pointed out that posturing of one extremity is a valid lateralizing sign pointing to contralateral ictal onset (Kotagal et al 1989). Secondary generalization can occur, particularly in children, but is relatively infrequent in adults receiving standard AEDs.
Consciousness typically is gradually lost or at least clouded in hippocampal and parahippocampal seizures with spread to the opposite hemisphere.
Typical for the semiology of seizures in mesial temporal lobe epilepsy are varying degrees of postictal confusion with amnesia for the ictal event as well as persisting postictal memory deficit. Postictal aphasia with left temporal lobe seizures also is typical.
The ictal semiology of seizures involving the limbic system is particularly rich, a finding that is well expressed by the French term “elaboré.” Unfortunately, the English term “elaborate“ has not exactly the same meaning; therefore, the Commission on Classification and Terminology of the International League against Epilepsy in 1964 decided to speak of partial seizures with complex symptomatology. In the 1969 paper, a footnote is included explaining that the term “complex“ implies an “organized, high-level cerebral activity“ (Commission on Classification and Terminology of the International League Against Epilepsy 1969; 1981; 1989). If the impairment of consciousness is used as a major criterion for classification, operationally it refers to the degree of awareness or responsiveness of the patient to externally applied stimuli.
The clinical overall gestalt of mesiobasal limbic seizures can be best described within the following groups. First there are those seizures that from the viewpoint of an observer appear absence-like (“fausses absences“) (Paillas et al 1949); a second group is characterized by “psychomotor symptoms” and automatisms. Third is a group of seizures with predominant psychosensory or pure psychic intellectual, cognitive, and emotional symptoms. It is tempting to correlate these seizure types with the localization-related subtypes classification (Wieser 1983). However, at present only some relatively vague correlations have been obtained. Many symptoms seem to depend on a characteristic seizure discharge constellation; that is, they depend on the type of propagation along preferential pathways and appear within a characteristic “march of symptoms.”
Absence-like seizures express themselves with an initial motionless stare, the “arrest reaction” (Wieser 1983), and are more or less identical with Delgado-Escueta’s “type I complex partial seizures” (Delgado-Escueta and Walsh 1985). Clinically, one observes clouded consciousness associated with a stare of 10 to 20 seconds, often with the expression of fearful astonishment followed by abrupt and restless looking around and discrete tongue movements. Without the EEG, the differentiation from true 3-per-second spike-wave absences may sometimes be difficult. However, complex partial seizures with the arrest reaction usually lack the palpebral cloni and the sursum-vergens of the bulbi, seen in 3-per-second spike-wave absences. Moreover, during a true 3-per-second spike-wave (petit mal) absence, the patient usually has a vacant and dull but not a fearful and tensed look.
The predominance of automatisms characterizes the second seizure type, which usually starts with a short arrest reaction but then evolves rapidly into the “automatic” phase. The clouding of consciousness is usually more pronounced, and recovery is slower. Automatisms have been classified into eupraxic (well-adapted) and dyspraxic (mal-adapted), but practically this is not very helpful. Gastaut and Gastaut differentiated them into (1) automatisms that represent a continuation of the previous activity and (2) de-novo automatisms (Gastaut and Gastaut 1951). Within the de-novo automatism, one can distinguish (a) reactions of the already confused patient to environmental stimuli; these stimuli are inadequately interpreted, and, therefore, the reactions are usually mal-adapted. Another type of de-novo automatisms might be (b) reactions of the patients to ictal experiences (“reactive automatisms“). Finally (c) archaic motor patterns can be released. Although extremely rare, antisocial and aggressive behavior might be witnessed (Wieser 1983), and eupraxic urination or defecation and spitting automatisms are described (Hecker et al 1972). Along with the psychopathological classification, a symptomatic one can be employed and is preferred by clinicians differentiating between oroalimentary, mimic, gestural, verbal, and ambulatory automatisms. In mesial temporal lobe epilepsy, the oroalimentary automatisms are most frequent and consist of degustation and deglutination, lip-smacking, pursing lips, chewing, and swallowing. As a rule, marked autonomic symptoms are associated with oroalimentary automatisms, and both correlate fairly well with epileptic discharges of the amygdala and periamygdalar region. It is important to note that automatisms are not bound to temporal lobe seizures. They can also be observed with frontal and parietal onset seizures, although with different characteristics (Geier et al 1976; 1977; Walsh and Delgado-Escueta 1984).
Phenomenologically, a third seizure type might be differentiated with marked psychosensorial symptoms. Psychosensorial symptoms are illusions and hallucinations that affect one sense only (unimodal) or more than one (polymodal), and this in simultaneous or successive fashion. As psychosensorial and pure psychic symptoms require identification and memorization, in a global sense the consciousness must be intact; therefore, these symptoms usually are reported very early in the course of a seizure as an “aura“ or a “primictal [signal]“ symptom.
Psychosensorial symptoms are classified according to their nature into (1) elementary (simple), and (2) structured (ie, complex, elaborate, or formed), and according to their sensorial quality (visual, auditory, somesthetic, vertiginous, olfactory, or gustatory). Moreover, “positive” and “negative” symptoms can be differentiated. As a rule, in mesial temporal lobe epilepsy, elementary hallucinations do not occur, and well-structured hallucinations occur only rarely. Occurring more often, however, are delusions.
Visual illusions may express themselves as distorted perceptions of an object’s size (macropsia-micropsia) and distance (teleopsia). An object may appear with an inclination (plagiopsia), or flattened and elongated (dysplatopsia). The object’s contour may be perceived as undulated or indistinct, eventually fragmented, or as being replaced by a halo. The objects may be perceived as without color (achromatopsia) or with an unnatural color, most often red (erythropsia) or yellow (xanthopsia). The 3-dimensional apperception of an object might be absent (astereognosia) or enhanced. An object may be perceived as doubled or even multiplied (monocular diplopia, polyopia) and can perseverate (palinopsia). Finally the movement of an object can be judged as being accelerated (quick-motion) or slowed down (slow-motion).
Auditory illusions can be described in a similar way. Sounds can be apperceived more intensively or less intensively. They can be apperceived as coming closer whilst becoming louder or, on the contrary, to move away whilst decreasing in intensity. Sounds’ rhythm, tonality, and timber can be experienced as altered, and they can be experienced as perseverating. Rarely, the illusion of an echoing of the patient’s proper phrases may be reported.
Somesthetic illusions may refer to some parts of the body or to its entirety. The apperception of size, form, and weight may be altered (statesthetic illusions), or the patient may have the feeling of a displacement of a body part, which is in reality immobile (kinesthetic illusion), or, on the contrary, the patient may have no experience at all of a real movement.
Vertiginous illusions are often described as a sensation of instability of the body, and true vertigo is relatively rare, but ictal vertigo has been documented in neocortical temporal posterior seizure onset (Penfield and Jasper 1954; Wieser 1987a).
Olfactory illusions are typically confined to hyperosmias and parosmias. Ictal olfactory hallucinations in patients with temporal lobe epilepsy are often combined with gustatory hallucinations. They are usually unpleasant and often reported as of a “metallic“ character. Gustatory sensations can be classified as hypergeusia or parageusia. Olfactory auras are more often associated with tumoral than with nontumoral temporal lobe epilepsies.
As a general rule, elementary illusions and hallucinations point to an ictal onset in or near the primary sensory areas, whereas complex ictal hallucinations are typical for ictal onset in or ictal propagation to associated areas. As Penfield as well as Gloor and colleagues have pointed out, most complex ictal hallucinations, produced either by electrical stimulation or occurring spontaneously with epileptic discharges, are experiential phenomena in the sense of being recollections of past experiences (Penfield 1952; Gloor et al 1982).
Seizures characterized by the predominance of psychic symptoms constitute the third category of psychomotor seizures. Following Jackson’s classical description, one can differentiate between intellectual and affective-emotional phenomena. Jackson’s description of the “dreamy state” (état de rêve) includes (1) recollections in the sense of déjà vu, déjà-entendu, déjà-vécu; (2) unfamiliarity or unreality (jamais vu, jamais entendu, or jamais vécu); (3) forced thinking, including what the French called “pensée parasite”; and (4) the rapid recollection of the past, the so-called “panoramic vision.” Emotional auras are relatively rarely reported; Gowers stated that he found them in 15 out of 25 patients with auras (Gowers 1885). The most common is fear, often associated with a restlessness and irritability. Sadness (“aura de tristesse”) (Offen et al 1976), pleasure, elation, exhilaration, satisfaction, and the “eureka-feeling“ are well documented. According to Lennox, about 0.9% of auras have a pleasurable quality (Lennox 1960).
Some aura symptoms may not have counterparts in human experience and cannot be described; this “strange feeling“ is, in fact, very often reported. Moreover, some patients experienced auras in the past but no longer have them. For example, during monitoring, a patient will consistently press the alarm button at the beginning of a seizure yet deny any warning afterwards. This could be due to seizure-related retrograde amnesia (Engel 1989; Engel et al 1998) and may indicate the development of a contralateral (“mirror focus“) seizure.
Ictal autonomic phenomena can be divided into “visceromotor” symptoms and “viscerosensitive“ sensations. Measurable autonomic visceromotor changes occur during the course of most temporal lobe seizures. When they characterize the clinical picture, the terms “visceral“ or “autonomic seizures“ may be used (Penfield and Jasper 1954; Gastaut 1973). According to the effector systems, one can distinguish between (1) cardiovascular, (2) respiratory, (3) pupillary, (4) sudo-and pilomotor, (5) salivation, (6) gastrointestinal, and (7) genitourinary.
Cardiovascular symptoms are very frequent and include tachy- and bradycardia, as well as arrhythmias, hypertension, flush, or pallor. A vast amount of experimental work has shown the importance of the amygdala, in particular its central nuclear group, and the functionally connected perifornical so-called HACEAR (hypothalamic area controlling emotional responses) (Ben-Ari 1981; Smith and DeVito 1984). Although the direction and type of heart rate and blood pressure changes during seizures, electrostimulation and induced afterdischarges vary considerably; in our experience a slowing of the heart rate predominates in association with amygdalar discharges (Stodieck and Wieser 1986). Britton and colleagues found that ictal bradycardia most often occurs in association with bilateral hemispheric seizure activity and is not a consistent lateralizing sign in localizing seizure onset (Britton et al 2006).
A short respiratory arrest or a deep inspiration is common in the initial seizure phase and can be reproduced by mesiobasal limbic electrical stimulation (Nelson and Ray 1968; Wieser 1983). In the later course of complex focal seizures, hyperpnea as well as hypopnea may occur.
Pupillary dilatation (ie, mydriasis) is a very common symptom associated with the arrest reaction. Mydriasis is sometimes asymmetrical (Wieser 1987a). Miosis and hippus pupillae have been observed. A feeling of “shivering cold“ is sometimes associated with piloerection (Wieser et al 2005). Salivation is a common sympton, but lacrimation or nasal secretion is more rarely encountered. According to the study of Shah and colleagues, hypersalivation as a prominent ictal finding in complex partial seizures of temporal lobe origin is more likely to be of nondominant temporal lobe origin (Shah et al 2006).
Gastrointestinal symptoms, such as vomiting, borborygmus, and eructation represent often major seizure symptoms (Jacome and Fitzgerald 1982). Ictal vomiting has been related to right temporal lobe seizure onset.
There are occasional reports of penile erection or even ejaculation during partial seizures (Stoffels et al 1981).


The oldest phylogenetic parts of the cortex are different from the 6-layered iso- or neocortex and are subsummarized under the term allocortex (Vogt and Vogt 1919).
The allocortex consists of the archicortex (hippocampus and subiculum), the paleocortex (in essence, olfactory cortex), and the peri-archicortex (in essence, area entorhinalis, regio retrosplenialis, and cingularis). At the base of the temporal lobe, the fissura rhinalis represents the border between allo- and isocortex.
Functionally, the most important difference between allo- and neocortex is that the allocortex does not receive direct thalamic afferences, whereas the neocortex does (Creutzfeldt 1983). The efferent pyramidal cells of the allocortex receive their inputs directly from the afferent fibers; that is, the output neurons are at the same time the input neurons.
Phylogenetically, in parallel with the increasing neocorticalization, the percentage of allocortex in relation to the total cortex steadily decreases. In humans, the allocortex comprises only 4% of the total cortex. Broca coined for that region the term “grand lobe limbique” but without giving cytoarchitectonic references (Broca 1878).
A part of the allocortex and its pathways has close anatomical and functional relations to the bulbus olfactorius and is, therefore, named rhinencephalon. In the older literature, the term rhinencephalon has been used in a broader connotation, including the totality of the allocortex and its subcortical connections. The rhinencephalon in the narrow sense, however, comprises only the bulbus olfactorius to the regio prepiriforms, the amygdala, and regio septalis, and periseptalis.
The term limbic system is more comprehensive and embraces, according to the original definition of Papez, the allocortex and the connections of the hippocampus, ie, the fornix, the corpus mamillare, and further on from here, over the Vicq d’Azyr bundle (tractus mamillothalamicus), the anterior thalamic nucleus (Papez 1937). From the thalamus there are projections to the anterior cingulate cortex, and from the cingulum back to the hippocampus. Thus, this limbic circuit, proposed as a kind of reverberating circuit, includes the cingulate gyrus, which receives thalamic inputs and, thus, represents neo- or “transitional” cortex. Within the concept of the limbic system, the hippocampal-cingulate connections are considered to be of less importance, and several authors emphasize the connections of the limbic core structures to the hypothalamic regions, as well as (via nucleus accumbens) to the striopallidar system that controls motor functions.
Initially Papez proposed the limbic circuit as a kind of “mediator of emotions” (Papez 1937); later he coined the term “visceral brain” (Papez 1958). Nauta enriched the limbic system concept with the limbic midbrain area (Nauta 1958).

Hippocampal formation

In 1587, Arantius described the hippocampus, comparing the protrusion on the floor of the temporal horn to a sea-horse, a “hippocampus” (Arantius 1587). Winslow in 1732 suggested “ram’s horn” (Winslow 1732). In 1742, Garengeot probably introduced the term “Cornu Ammonis” by analogy with the Egyptian god Ammon (Ammun Knegh) (Duvernoy 1988).

In current, most frequent terminology, the terms Cornu Ammonis and pes hippocampus are used synonymously. The name hippocampus applies to the entire ventricular protrusion and consists of 2 cortical laminae, rolled up one inside to other: the Cornu Ammonis and gyrus dentatus. The subiculum and entorhinal area represent a transitional cortex between the Cornu Ammonis and the rest of the temporal lobe and are sometimes joined to the hippocampus, constituting a functional unit–the hippocampal formation (Chronister and With 1975).
From its deepest level to the surface, ie, from the ventricle towards the hippocampal sulcus, the Cornu Ammonis is divided into 6 layers: alveus, stratum oriens, stratum pyramidale, stratum radiatum, stratum lacunosum, and stratum moleculare.
A striking feature of the connectivity of the hippocampal formation is that it has its cortical connections only through the entorhinal cortex, which itself, however, is a link in numerous multisensory corticocortical networks.
The intrinsic wiring of the hippocampal formation is mainly unidirectional. The predominantly superficial layers of the entorhinal cortex give rise to a powerful excitatory projection, called the perforant path (which “perforates” the subiculum to reach the hippocampus).
The perforant path is composed of glutaminergic fibers to the dentate gyrus. The axons of the granule cells of the dentate gyrus, the mossy fibers, have a large content of zinc (McLardy 1962). Mossy fibers project to CA3 and CA4. Axons of CA3-CA4 enter the alveus and then the fimbria, but they first emit the Schaffer collaterals, which reach the apical dendrites of CA1 in the strata radiatum and lacunosum. The axons of CA1, by entering the alveus, produce collaterals that reach the subiculum. The subiculum emits by glutaminergic fibers the principal efferent pathways, which follow the fimbria, the crus, the body of the fornix, and then the postcommissural fornix (behind the anterior commissure) to reach the anterior thalamic nuclei, either directly or via the mamillary bodies.
The entorhinal cortex receives inputs from the sensory association areas of the temporal lobe, conveying visual, auditory, somatosensory, gustatory, nociceptive, and olfactory signals (Van Hoesen and Pandya 1975;Insausti et al 1987a; 1987b). These inputs are distributed along the rostrocaudal extent of the entorhinal cortex, with the olfactory inputs occupying the most rostral part.
Fibers from layer II and III that form the origin of the perforant path exhibit a further differentiation. Whereas fibers from layer II distribute almost exclusively to the dentate gyrus and CA3, fibers from layer III project exclusively to CA1 and the subiculum.
Thus, the perforant path is the main afferent to the hippocampus. A second path, the alvear path, was described by Cajal (Cajal 1911). Although the core elements of this neuronal chain (ie, entorhinal area, gyrus dentatus, Cornu Ammonis, and subiculum) are of disparate anatomy, they constitute a single functional unit and are, therefore, rightly grouped into the “hippocampal formation” (Powell and Hines 1975; Squire 1986).

Nuclei amygdalae

The amygdalae are located directly above the temporobasal cortex and ventrorostral to the tip of the temporal horn of the lateral ventricle. Usually one differentiates 3 main nuclear groups: the phylogenetically older corticomedial, the younger basolateral, and a central group. In essence, the corticomedial group receives afferences from various areas of the olfactory cortex, in particular from the periamygdalar cortex, whereas the basolateral group receives its afferences from the inferotemporal neocortex (Brodman area 20).

In the rhesus monkey, nearly all cortical areas of the temporal lobe, major parts of the frontal lobe, and the insular cortex project to the amygdala (Ben-Ari 1981). These projections have a differential distribution within the amygdala. Some parts of some amygdaloid nuclei receive several cortical sensory projections. The lateral part of the central nucleus, the laterobasal nucleus, and the dorsomedial part of the lateral nucleus are areas where substantial convergence of cortical input occurs. It is well-documented that visual, auditory, olfactory, and, to some extent, taste information reaches the amygdala. Somatic sensory input is less clear, but there is reason to believe that all 5 modalities have some convergence in the dorsomedial part of the lateral nucleus. For example, the dorsomedial part of the lateral nucleus receives projections from the orbitofrontal area, which responds to olfactory stimulation, and this part is also the major amygdaloid projection zone of the cortical taste area. In addition, there are posterior insular cortex projections to this area carrying visceral and probably other somatic information. Moreover, auditory input from the temporal polar cortex projects powerfully to this region. Visual projections are directed primarily to the dorsolateral part of the lateral nucleus.
Efferent fibers from the amygdala are the stria terminalis and, to a lesser degree, the ventrofugal bundle with overlapping targeting areas in the medial and rostral hypothalamus (nuclei ventromedialis and dorsomedialis hypothalami, regio praeoptica), regio septalis (nuclei lateralis septi, “bed nucleus” of the stria terminalis, diagonal band), as well as the posterior part of the magnocellular nuclei dorsomedialis thalami. The latter connects the amygdala with the orbitofrontal cortex and constitutes a part of the second, ie, “basolateral limbic circuit,” formulated by Yakovlev and reemphasized by Livingston and Escobar (Yakovlev 1948;Livingston and Escobar 1971).
Functional anatomy of the hippocampal formation. Hippocampal slice work, both in animals and in humans, has been a cornerstone of the investigation of the basic mechanism of epileptogenesis and has clarified the functional anatomy of the hippocampal formation, which is quickly summarized. The trisynaptic pathway is tightly restricted in the rostrocaudal dimension so that separate lamellae can be identified. According to this plan, the hippocampal formation is organized in a series of functional lamellae arranged perpendicularly to the longitudinal axis of the hippocampal formation and operating independently of each other. Because of this lamellar organization, thin slices can be cut that preserve at least some important functions of the hippocampus during maintenance in vitro. Hippocampal slice studies have demonstrated that hippocampal CA3, but not CA1, pyramidal cells become pacemakers for interictal spiking. This disparity can be accounted for by certain intrinsic membrane conductances in CA3 pyramidal cells along with recurrent excitatory connections between CA3 pyramidal cells, both lacking in CA1. On the other hand, ictal events develop in CA1, but not in CA3 (Lothman 1991). The dentate gyrus serves as a critical control point for the regulation of epileptogenesis. Biochemical operations and morphology of dentate granule cells are altered as a function of epilepsy. The granule cells at this location undergo an enduring decrease of calbindin (a calcium-binding protein) in kindled animals (Baimbridge et al 1985).

Functional loops between the basal ganglia and the temporal lobe

With a view towards some of the well-known symptoms of temporal lobe seizures, such as déjà vu, jamai vu, macropsia, micropsia, delusions of familiarity, depersonalization, and the recently rediscovered contralateral tonic or dystonic posturing (Magnus et al 1954; Ajmone-Marsan and Ralston 1957; Kotagal et al 1989; Newton et al 1992), the connections of the temporal lobes with the basal ganglia are important.

The basal ganglia (ie, the caudate, the putamen, and the ventral striatum), are known to receive inputs from the frontal, parietal, and temporal lobes. The output from the basal ganglia via the thalamus addresses the frontal motor and the prefrontal cortex. Basal ganglia loops with the cortex have been thought to “funnel“ or collect information from diverse cortical areas to direct motor output and the executive functions of the frontal lobe. Evidence has been provided that the output nuclei of the basal ganglia, the substantia nigra pars reticulata, projects via the thalamus to the inferotemporal cortex (area TE), ie, targets at least 1 visual area in the inferotemporal cortex (Middleton and Strick 1996), which is critically involved in recognition and discrimination of visual objects.
This might explain why dysfunction of the basal ganglia loop with the inferotemporal cortex leads to alterations in visual perception, including visual hallucinations. Mishkin and colleagues have proposed that visuomotor associations including “habit memories“ involve the “visual striatum,“ ie, the tail of the caudate, and caudal or ventral portions of the putamen (Bachevalier and Mishkin 1994; Brown et al 1995; Malkova et al 1995). These findings explain that damage to basal ganglia impair visual perception. They also explain visual hallucinations produced by lesions in substantia nigra pars reticularis or brainstem compression (“peduncular hallucinosis,“ seeing fully-formed images of people or animals), and possibly also visual hallucinations seen as a major side effect of the use of L-dopa or other dopaminergic agents.
Moreover, these findings may account for the dystonic posturing, which is an important lateralizing sign and which occurs in 15% to 70% of patients with mesial temporal lobe seizures (Kotagal et al 1989; Fakhoury and Abou-Khalil 1995). Indeed, ictal SPECT studies have equated this dystonic posturing with increased blood flow in the basal ganglia ipsilateral to the seizure onset (Newton et al 1992).


The most common pathologic substrate of mesial temporal lobe epilepsy is hippocampal sclerosis (Bratz 1899; Babb and Brown 1987). The 2 most common pathologic terms that have been used synonymously with hippocampal sclerosis are mesial temporal sclerosis and Ammon’s horn sclerosis, although these terms imply different degrees of anatomical involvement (Falconer et al 1964; Margerison and Corsellis 1966; Armstrong and Bruton 1987). However, other specific types of hippocampal pathology are associated with mesial temporal lobe seizures, such as tumors, dysembryoplastic neuroepithelial tumors, and other dysgenetic malformations. The term mesial temporal sclerosis has advantages because it more appropriately takes into account that the amygdala, when being examined, shows often equally severe pathology consisting of neuronal loss and gliosis than the hippocampus (Gloor 1991).

Hippocampal sclerosis

The term hippocampal sclerosis should only be used for the specific type of hippocampal cell loss with marked loss of neurons in the CA1 and hilar region and some loss in endfolium (CA3/CA4) but relative sparing of the CA2 region. The subicular complex, entorhinal cortex, and other transitional cortex and temporal gyri are relatively resistant to cell loss. Hippocampal sclerosis is associated with other characteristic features, such as mossy fiber sprouting (Sutula et al 1989) and selective loss of somatostatin and neuropeptide Y-containing neurons (De Lanerolle et al 1992). It is found in up to 70% of patients with medically refractory temporal lobe who undergo surgery epilepsy(Babb and Brown 1987). In epilepsy specimens, the granule cell layer is often wider and somehow disorganized (Houser 1990). Dispersed granule cells may extend into the surrounding molecular layer and sometimes show a bilaminar pattern.

However, pathology of mesial temporal lobe epilepsy is not completely uniform; other cerebral diseases can also cause hippocampal damage but usually show a different pattern with variable accentuation of special subfields, mostly involving CA2 region. Gliosis might involve anterior mesial temporal lobe structures in addition to the hippocampus and might consist of “dual pathology.” Moreover, in autopsy specimens from patients with intractable seizures, hippocampal sclerosis is very often a bilateral condition, although frequently with a unilateral preponderance (Margerison and Corsellis 1966). Blümcke and colleagues have recently proposed a new clinicopathological classification system for mesial temporal sclerosis (Blumcke et al 2007).
The events that initiate the process of hippocampal sclerosis are not known in detail, but there is no doubt that the epileptogenicity of this disorder results from loss of specific neurons in the hippocampus and synaptic reorganization of surviving cellular elements with resulting hypersynchronization and hyperexcitability (Engel et al 1998). Mathern and colleagues showed that patients with initial precipitating injuries had hippocampal sclerosis, whereas those with idiopathic temporal lobe epilepsy showed fewer neuron losses and worse post-resection seizure relief (Mathern et al 1995a; 1995c). Patients with nonseizure initial precipitating injuries were on average older at injury, had a longer latent period, and showed fewer neuron losses in Ammon’s horn, CA1, and prosubiculum than those with seizure-associated initial precipitating injuries. Initial precipitating injury patients with repetitive, nonprolonged seizures showed the shortest latent period, earliest age of temporal lobe epilepsy onset, and less CA2 damage than the other initial precipitating injury groups. CA1 and prosubiculum neuron losses were greater in patients with temporal lobe epilepsy for longer than 22 years. Initial precipitating injuries after age 4 years were associated with latent periods shorter than 10 years compared with variable and longer latent periods of initial precipitating injuries before 4 years of age. The results of Mathern and colleagues indicate that in surgically-treated temporal lobe epilepsy, hippocampal (Mathern et al 1995a;1995c). Most of the hippocampal damage found at surgery and the clinical time course of the habitual temporal lobe epilepsy are influenced by the pathogenic initial precipitating injury mechanism.

sclerosis and good seizure outcomes are associated with initial precipitating injuries

Mody and Heinemann found that dentate granule cells in the kindled animal are more sensitive to agonists that activate the N-methyl-D-aspartate (NMDA) type of glutamate receptors compared to nonkindled animals (Mody and Heinemann 1987). Binding studies indicate that dentate granule cells have abundant receptors for NMDA
(Bekenstein et al 1990) and that their expression and operation are altered after kindling (Yeh et al 1989). These findings are very interesting in light of experimental results showing that maximal dentate activation and changes that take place in maximal dentate activation can be opposed by NMDA antagonists (Stringer and Lothman 1990).
Morphological changes of dentate granule cells as a consequence of epilepsy were initially reported by Tauck and Nadler, who demonstrated sprouting of the axons (mossy fiber sprouting) in animals (Tauck and Nadler 1985). Several laboratories have documented that it occurs also in the human epileptic brain (Sutula et al 1988; 1989; Mathern et al 1995b; Proper 2001). It is reasonable to assume that mossy-fiber sprouting contributes significantly to epileptogenesis by providing recurrent excitation of adjacent cells.
Parent and Lowenstein as well as Scharfman reviewed seizure-induced neurogenesis (Parent and Lowenstein 2002; Scharfman 2004). Several lines of evidence implicate newly generated neurons in structural and functional network abnormalities in the epileptic hippocampal formation of adult rodents. These abnormalities include aberrant mossy-fiber reorganization, persistence of immature dentate granule cell structure (eg, basal dendrites), and the abnormal migration of newborn neurons to ectopic sites in the dentate gyrus. Taken together, these findings suggest a pro-epileptogenic role of seizure- or injury-induced neurogenesis in the epileptic hippocampal formation. Conversely, neurogenesis also might contribute to network homeostasis; Jakubs and colleagues found that new neurons born into the pathological environment differed with respect to synaptic drive and short-term plasticity of both excitatory and inhibitory afferents (Jakubs et al 2006). The new granule cells formed in the epileptic brain exhibited functional connectivity consistent with reduced excitability. By this means, adult neurogenesis might contribute to network homeostasis in the epileptic temporal lobe (Kempermann 2006).
Recurrent seizures in infancy may interrupt synapse maturation and produce persistent decreases in molecular markers for glutamatergic synapses—particularly components of the NMDA receptor complex implicated in learning and memory (Swann et al 2007).

“Lesional“ temporal lobe epilepsy

This is defined by lesions in the temporal lobe other than hippocampal sclerosis. In the Montreal series (1928-1973) of surgically excised epileptogenic temporal lobes, Mathieson studied 857 of 878 patients and found in 202 patients the following discrete focal lesions: gliomas and gangliogliomas (105), meningocerebral cicatrix and remote contusion (39), vascular malformations of brain or pia (19), hamartomas (14), residuum of cerebral abscess (10), tumors other than gliomas (10), tuberous sclerosis and formes frustes (4), and residuum of old infarct (1) (Mathieson 1975). Even higher percentages of lesions were found in a neuropathological study enrolling 247 patients with mesial temporal lobe resections (Plate et al 1993). Neoplasms and microscopic clusters of oligodendroglia-like foci of 30 to 100 cells (interpreted as precursor lesions for neuroepithelial tumors) were found in 126 patients. Thus, neuroectodermal tumors, predominantly low-grade gliomas and gangliogliomas, are frequently encountered. Although focal dysplasia was already precisely described as early as 1971 (Taylor et al 1971), dysembryoplastic neuroepithelial tumors
(Daumas-Duport et al 1988; Daumas-Duport 1993) and several types of cortical dysgenesis have only been increasingly recognized in more recent years, mainly as a result of improved in vivo diagnosis due to the advent of high resolution MRI. However, at present, microdysgenesis is still not visible on neuroimaging and remains a pathological diagnosis. It is, thus, likely that several subtle forms of migrational disorders are underdiagnosed in most series (Palmini et al 1991a; 1991b; 1991c).

A useful classification scheme for cortical dysgenesis presenting with epilepsy in general was proposed by Raymond and colleagues (Raymond et al 1996). These authors also list “dysgenesis of the archicortex (duplication or dispersion of the dentate fascia, ie, most probably some forms of hippocampal sclerosis).” The latter, ie, the disorganization of the dentate gyrus in temporal lobe epilepsy has increasingly attracted researchers (Houser 1990; Houser et al 1992; Mello et al 1992). Of 34 temporal lobe specimens from patients with temporal lobe epilepsy, Mello and colleagues found the granule cells normally arranged in 44%, generally dispersed in 38%, and displayed in a bilaminar arrangement in 18% (Mello et al 1992). Varying degrees of hippocampal sclerosis were observed in all cases. The pathogenesis of these abnormalities is controversial. Arguments for both, pre-and postnatal mechanisms have been put forward as well as evidence for being both the cause and the effect of epilepsy. Some arguments are in favor of a migrational defect: the occurrence of granule cells in the molecular layer suggests that they have migrated beyond their target position; the presence of granule cells in the hilus of the dentate gyrus suggest that some cells have not completed their normal migration; their elongated form is reminiscent of developing forms; and their alignment in vertically-oriented rows is similar to the radial arrangement of migrating cells (Houser et al 1992). Mathern and colleagues quantified hippocampal mossy-fiber synaptic reorganization and neuron losses to determine the pathological features associated with epileptogenic fascia dentata, differentiating patients with temporal lobe epilepsy and mesial temporal sclerosis with seizure genesis in the hippocampus, or temporal mass lesions with seizures that were probably extrahippocampal (Mathern et al 1995b). They found that inner molecular layer mossy-fiber puncta densities and neuron losses are greater in patients with mesial temporal sclerosis than in those with lesions and concluded that mossy-fiber sprouting contributes to the pathophysiology of hippocampal seizures. However, some patients with extrahippocampal lesions had mossy-fiber sprouting similar to mesial temporal sclerosis patients, suggesting that hippocampi in lesion patients may be capable of epileptogenesis from synaptic reorganization as well.
Several subtypes of MTLE-HS might exist, including at least a primary form, possibly a secondary form, and a familial form (Kobayashi et al 2003; Ferreira et al 2004).

Neuronal loss and gliosis

Neuronal loss and gliosis are typical pathological findings in mesial temporal lobe epilepsy but do not, per se, prove an active seizure disorder. There are studies showing autopsy specimens of hippocampal pathology without ante mortem seizures (Vogt and Vogt 1937; Corsellis 1957; Meencke and Veith 1991). In other words, not every damaged hippocampus is epileptogenic, and not every severe seizure history causes hippocampal sclerosis.

Dual pathology

If hippocampal sclerosis is associated with other pathology of the temporal lobe, we speak of a dual pathology (Levesque et al 1991). Cortical microdysgenesis and cortical dysplasia (ie, alterations of neuronal migration) as well as hamartomas, small tumors, and cavernomas may be found in addition to hippocampal sclerosis. Diagnoses such as microdysgenesis, heterotopia, and hamartomas depend heavily on the pathological criteria to define an area as abnormal. It is also not clear what pathology then is responsible for seizure genesis. Numerous studies have retrospectively analyzed the neuropathological findings in patients with temporal lobe epilepsy, including such with proven seizure onset in the hippocampal formation (Spielmeyer 1927; Stauder 1936; Mathieson 1975; Corsellis and Bruton 1983; Duncan and Sagar 1987;McMillan et al 1987; Bruton 1988; Estes et al 1988; Plate et al 1993; Wolf et al 1993; Mathern et al 1995a;Blumcke et al 2007). Salanova and colleagues studied the occurrence of dual pathology in their series of 240 patients with temporal lobe epilepsy who underwent temporal resections following a comprehensive pre-surgical evaluation (Salanova et al 2004). Thirty-seven (15.4%) of these had hippocampal sclerosis or temporal lobe gliosis in association with another lesion (dual pathology). Eighteen of 37 patients with dual pathology had heterotopia of the temporal lobe; 9 had cortical dysplasia; 4 had cavernous angiomas or arteriovenous malformations; 1 had a dysembryoplastic neuroepithelial tumor; 1 had a contusion; and 4 patients had cerebral infarctions in childhood. Abnormal head MRI was found in 68.5% of the patients, abnormal positron emission tomography scans in 91.3%, and abnormal ictal SPECT in 96%. The intracarotid amobarbital procedure showed impaired memory of the epileptogenic side in 72% of the patients. Twenty patients had left-sided and 17 had right-sided en bloc temporal resections, including the lesion and mesial temporal structures. Twenty six (70.2%) became seizure-free; 8 (21.6%) had rare seizures; 2 (5.4%) had worthwhile seizure reduction, and 1 (2.7%) had no improvement (range of follow-up 1 to 16 years, mean = 7.4 years). The dual pathology was almost exclusively seen in patients whose lesions were congenital or occurred early in life.

Besides pathological findings, some clinical features help to define MTLE-HS, such as early insults, severe
febrile convulsions, age and modes of onset, higher incidence of seizures within a family, clinical course, development of drug-resistance, and material-specific memory deficits (So et al 1989a; 1989b; Cendes et al 1993a; 1993b; French et al 1993; Hudson et al 1993; Williamson et al 1993; Selwa et al 1994; Mathern et al 1995c).

Differential diagnosis

Some patients with familial mesial temporal lobe epilepsy are documented to have intractable seizures with hippocampal sclerosis; in these patients, the genetic defect may cause mesial temporal lobe epilepsy, which then leads to hippocampal sclerosis with or without febrile seizures (Cendes et al 1998; Kobayashi et al 2002). There is no evidence to suggest that familial partial epilepsies with variable foci, partial epilepsies with auditory features, or temporal lobe variants of benign childhood epilepsy with centrotemporal spikes ever evolve into MTLE-HS.
Both benign childhood epilepsy with centrotemporal spikes and mesial temporal lobe epilepsy can begin in childhood with generalized seizures. However, the partial seizures of benign childhood epilepsy with centrotemporal spikes usually have sensory- or motor-lateralized symptoms localized around the mouth or the upper extremities. Interictal EEG spikes are also different in these 2 syndromes: The broad centrotemporal EEG spike is located more posteriorly and superiorly and has a characteristic transverse dipole; whereas in mesial temporal lobe epilepsy, the spike or spike-wave discharges are located more anteriorly and basally with a characteristic oblique dipole direction. Differentiation from temporal lobe epilepsy due to other lesions in or near the mesial temporal lobe is usually easy by MRI. Clinical signs and symptoms might be similar, although in mesial temporal lobe epilepsy, age of seizure onset is usually earlier, and there is often a history of complicated febrile seizures as well as an increased incidence of family members with seizures.
Complex partial seizures of extratemporal origin often have an aura consisting of symptoms pointing more closely to the involved primary epileptogenic area.
The so-called “cryptogenic” temporal lobe epilepsy denotes temporal lobe epilepsies without a pathological substrate. It is difficult to estimate the incidence of this epilepsy category. Available figures from surgical series are heavily biased, as are the figures of the familial temporal lobe epilepsy syndrome with a benign course (Berkovic et al 1994). Although in Mathieson’s surgical series no histopathological abnormality was found in 173 (20%) of 857 resected temporal lobes (Mathieson 1975), Plate and colleagues’ Zurich study found no pathology in only 2% of 224 available mesial temporal lobe tissue specimens (Plate et al 1993). Because the surgical outcome of patients without pathology is usually worse compared to those with histological abnormalities, it must be considered that in patients without histopathological abnormalities and who did not become seizure-free following temporal lobe resection, the temporal lobe was not the origin of the seizures. Therefore, this category might disappear in surgical series with more sophisticated diagnosis in the near future.
Lateral neocortical temporal lobe seizures are much rarer, and they usually show a morphological lesion invading the lateral temporal cortex alone or in combination with the insula. However, seizures of lateral temporal origin and without a gross morphological lesion do exist and have been documented by stereoelectroencephalography (Wieser and Muller 1987). Such seizures, as a rule, spread to the ipsilateral mesial temporal structures, which may act as a kind of “amplifier” sustaining and prolonging the seizure discharges. Clinical signs and symptoms supportive of seizures arising from the lateral temporal neocortex commonly derive from epileptic discharges involving cortex of more than one lobe. No absolute specific symptoms and signs are indicative for lateral temporal seizure onset, but the following symptoms are more frequently encountered in lateral neocortical temporal seizures: ictal aphasia, if the dominant hemisphere is involved; auditory hallucinations, if the posterior insula (Heschl gyrus) and the superior temporal gyrus are involved (Wieser 1980; Wieser and Williamson 1993); vestibular hallucinations, which have been documented with posterior-temporal-parietal discharges (Wieser 1987a). Visual hallucinations, in particular macropsia and micropsia, as well as teleopsia, plagiopsia, dysplatopsia, achromatopsia, or erythropsia and xanthopsia, loss or enhancement of 3-dimensional apperception, polyopia, palinopsia, and quick-motion as well as slow-motion, can occur with discharges in the temporo-parieto-occipital junction and inferotemporal cortex.
Motor symptoms with contralateral tonic or clonic manifestations and head or eye deviation are more frequently seen in neocortical lateral than in mesiobasal seizures, whereas dystonic posturing occurs more frequently (in about 40% of patients) with documented mesial temporal lobe onset seizures.
Insular seizure onset has been found in 6 of 50 consecutively SEEG-explored patients by Isnard and colleagues (Isnard et al 2004). This group reported a relatively typical ictal semiology beginning with a sensation of laryngeal constriction and paresthesiae, often unpleasant, affecting large cutaneous territories, most often at the onset of a complex partial seizure. It was eventually followed by dysarthric speech and focal motor convulsive symptoms. The insular origin of these symptoms was supported by the data from functional cortical mapping of the insula by using direct cortical stimulations.
Seizures of frontal lobe origin usually have features (eg, brief and clustered, no postictal disturbances, nocturnal predilection, hyperkinetic automatisms) that help to distinguish them from temporal onset seizures. However, the differential diagnosis might be difficult without invasive recordings if frontal lobe onset seizures invade one or both temporal lobes (Jasper et al 1995).

Diagnostic workup

Diagnosis of MTLE-HS requires a constellation of signs and symptoms and cannot be made on the basis of a single criterion. Today hippocampal atrophy and hippocampal sclerosis can be reliably diagnosed in vivo with MRI (Berkovic et al 1991; Williamson et al 1993; Kuzniecky and Jackson 1995). MRI distinguishes MTLE-HS (Risinger et al 1989; Ebersole and Pacia 1996). It strongly depends on semi-invasive and invasive EEG, although there are relatively typical scalp EEG findings in mesial temporal lobe epilepsy.

from MTLE due to other lesions. The diagnosis of hippocampal and parahippocampal seizures, however, relies on typical ictal onset location and pattern

EEG. Interictal regional slowing in patients with temporal lobe epilepsy not associated with a mass lesion is topographically related to the epileptogenic area and, therefore, has a reliable lateralizing, and possibly localizing, value. Its presence is irrelevant to the severity or chronicity of the epilepsy as well as to lateral deactivation secondary to neuronal loss in the mesial temporal structures. Although slow EEG activity is generally considered a nonspecific sign of functional disturbance, interictal regional slowing in temporal lobe epilepsy should be conceptualized as a distinct electrographic phenomenon that is directly related to the epileptogenic abnormality. There is a strong correlation between interictal regional slowing and lateral temporal hypometabolism (Koutroumanidis et al 1998). In hippocampal background EEGs recorded from patients with temporal lobe epilepsy, both delta and theta spectral components are present. Zaveri and colleagues found group differences in spectral measures of background hippocampal signals recorded from patients with mesial temporal sclerosis compared to patients with the so-called “paradoxical temporal lobe epilepsy,” which is characterized by minimal cell loss and comparatively poorer surgical outcome, suggesting that substrate differences in cellular composition and connectivity are reflected in hippocampal background EEGs (Zaveri et al 2001).
Interictal typical epileptiform graphoelements in scalp EEG are grouped, blunt sharp-waves with or without slow waves that recur with a frequency of about 1 per second. They show a characteristic distribution with a maximum of their field in basal anterior electrodes (such as sphenoidal or true temporal electrodes). They may be unilateral, bilateral-dependent, or bilateral-independent (Wieser 1983; 1987b; Wieser et al 1993).
Ictal scalp EEG findings typically consist of fairly regular theta-rhythms of about 5 per second with crescendo-like increase of the amplitude paralleled by a slowing of the discharge rhythms.
Seizure onset in scalp EEG might be characterized by regional temporal or generalized attenuation of background EEG rhythms with disappearance of interictal “spikes.”
Direct recording from the temporal lobe, including the hippocampal formation, often shows that hippocampal spikes remain localized. However, they might propagate to the amygdala or lateral and anterior temporal areas.
Hippocampal seizure onset often is with the so-called “hypersynchronous hippocampal discharge pattern” (Engel 1990; Wieser et al 1993). The other frequent seizure onset pattern of hippocampal seizures is the low-voltage, high-frequency discharge.

followed by a low-voltage, fast-recruiting rhythm of more than 20 per second

These 2 patterns may both predict hippocampal tissue loss but of different degrees and distribution (Townsend and Engel 1991; Spencer et al 1992a; 1992b; Velasco et al 2000). Out of 478 seizures recorded in 68 patients with temporal lobe seizures who were undergoing diagnostic monitoring with depth electrodes, Velasco and colleagues found that the seizure onsets in 78% of these patients were either hypersynchronous onsets beginning with low-frequency, high-amplitude spikes, or low-voltage fast onsets increasing in amplitude as the seizures progressed (Velasco et al 2000). Nearly twice as many patients were having hypersynchronous seizure onsets as those having low-voltage, fast onsets. Patients with hypersynchronous seizure onsets had a significantly greater probability of having (1) focal rather than regional seizure onsets, (2) seizures spreading more slowly to the contralateral mesial temporal lobe, and (3) cell counts in resected hippocampal tissue showing greater neuronal loss. These results provide evidence that the most frequent electrographic abnormality associated with mesial temporal seizures is local hypersynchrony, a condition associated with major neuronal loss in the hippocampus. Low-voltage, fast seizure onsets more frequently represent widely distributed discharges, which interact with and spread more rapidly to surrounding neocortical areas.
Bartolomei and colleagues studied the pre-ictal synchronicity in limbic networks and found that the time interval that precedes the rapid discharge was characterized by significant cross-correlation values, indicating strong interactions among mesial temporal structures as compared to those seen during background activity (Bartolomei et al 2004). Interactions between the hippocampus and entorhinal cortex were predominant in 83% of patients. Interactions between the entorhinal cortex and amygdala were observed in 50% and between the amygdala and hippocampus in 58% of patients.
Analysis of coupling directionality indicated that most of the couplings were driven either by the hippocampus or by the entorhinal cortex. During rapid discharges, there was a significant decrease of cross-correlation values. At high-frequency tonic discharge seizure onset, significant interactions between the hippocampus and entorhinal cortex were observed. The entorhinal cortex was found to be the leader structure in most of the seizures with tonic discharge in the mesial structures, whereas the hippocampus was the leader in “type 1 transition” (similar to the hypersynchronous seizure onset pattern) in which the emergence of pre-ictal spiking was followed by a rapid discharge.
In 63% of patients, volumetric measurements of entorhinal cortex demonstrated atrophy ipsilateral to the epileptic side. A significant correlation between the strength of entorhinal cortex-hippocampus coupling and the degree of atrophy was found. In patients with a normal entorhinal cortex volume, the entorhinal cortex was never the leader structure in entorhinal cortex-hippocampus coupling (Bartolomei et al 2005). Although with SEEG we have found that amygdala onset seizures are relatively infrequent, ie, constitute about 3% to 5% of psychomotor seizures (Wieser 1983), Gotman and Levtova reported in their phase-coherence study that the amygdala was leading in 21% of focal-mesial and 53% of regional temporal lobe seizures, and the hippocampus was leading in 48.5% of focal mesial and in 27% of regional temporal lobe seizures (Gotman and Levtova 1996). In the remaining seizures, discharges were synchronous in these 2 structures.
Bartolomei and colleagues also confirmed a strong unidirectional or bidirectional coupling between the amygdala and hippocampus in seizures of mesial temporal origin (Bartolomei et al 2001). In this seizure subtype, there was no significant coupling between medial and lateral structures at the beginning of the seizures. 

Seizure propagation

Seizure spread is very important in accounting for intermediate and late clinical signs and symptoms. In MTLE-HS the “symptomatogenic zone” might include insular and lateral neocortical temporal cortices. In general, the following aspects are important:

Compared to seizures in other brain areas, seizure spread is slow in MTLE-HS. Seizure spread is not random, but follows preferred propagation pathways, which reflect at least to some degree the physiological connectivity of brain areas. A characteristic spread is into the posterior cingulate gyrus. The mode of transhemispheric propagation is not entirely clear; it might be transcallosal after the ipsilateral frontal lobe is “ictally” activated. Spread to the ipsilateral neocortical temporal lobe might be seen as often as spread to the contralateral mesial temporal lobe structures without involvement of the ipsilateral neocortical temporal lobe. At present, there are no good estimates on the frequency of these 2 scenarios. Very often ipsilateral frontal or orbitofrontal cortices are invaded ictally (but this observation is based on depth recordings with the sampling error) (Lieb et al 1986; Wieser 1988). About 30% of hippocampal onset seizures appear first in the contralateral hippocampus prior to the ipsilateral or contralateral temporal neocortex. There is some evidence, however, that ipsilateral frontal or orbitofrontal ictal involvement is not a necessary condition for seizure spread to the contralateral mesial temporal lobe. Contralateral propagation usually is accompanied by a marked disturbance or loss of consciousness. The mean interhippocampal seizure propagation time is around 15 seconds (Wieser and Siegel 1991). A long interhippocampal seizure propagation time is predictive of surgical success (Lieb et al 1986) and was inversely correlated with cell counts in the CA4 region (Spencer et al 1992c).
Localized hippocampal discharges might occur without any noticeable clinical accompaniments or consist of “minor” symptoms only. Isolated hippocampal discharges in the language-dominant hemisphere might express themselves in a marked decline of performance of tachistoscopically presented lexical decision tasks, and isolated discharges of the right hippocampus were shown to lead to a decline of performance in a tachistoscopic matching task of facial expressions (Wieser et al 1985).
A regional but unilateral mesial temporal lobe involvement of the discharges usually is experienced as a clearly recognized aura by the patient (Wieser 1991). Lack of aura experience strongly correlates with indicators of bitemporal dysfunction such as bitemporal interictal sharp waves and bitemporal ictal propagation in scalp EEG, as well as absence of lateralized MRI sclerosis in patients with mesial temporal lobe epilepsy (Schulz et al 2001).
In children with mesial temporal lobe epilepsy in the scalp EEG, ictal seizure discharges might be more wide-spread and consist of irregular, high-voltage, spike and slow-wave patterns (Glaser and Golub 1955).
Discharges confined to the hippocampus produce no scalp EEG rhythms. The regular 5-to 9-Hz subtemporal and temporal scalp EEG pattern requires the synchronous recruitment of adjacent inferolateral temporal neocortex.
Ebersole and Pacia defined 7 patterns of early seizure discharges, grouped patients according to their seizure pattern, and correlated these with the site of seizure onset determined by intracranial EEG (Ebersole and Pacia 1996; Pacia and Ebersole 1997). Categorization by seizure pattern was also compared with brain MRI findings and intracarotid amobarbital (Wada) testing. These authors found that an initial, regular 5- to 9-Hz inferotemporal rhythm was most specific for hippocampal-onset seizures. Less commonly, a similar vertex or parasagittal positive rhythm or a combination of these rhythms was recorded. Discharges confined to the mesiobasal temporal cortex produce a vertex dominant rhythm due to the net vertical orientation of dipolar sources located there. A focal or regional, low voltage, fast-rhythm (20 to 40 Hz) is often associated with widespread background flattening. Seizures originating in the temporal neocortex were most often associated with irregular, polymorphic, 2- to 5-Hz lateralized activity. Seizures without a clear lateralized EEG discharge were most commonly of temporal neocortical origin. The authors conclude that the initial pattern of ictal discharge on scalp EEG can assist in distinguishing seizures of temporal neocortical onset from those of hippocampal onset. Visual and quantitative sublobar source analyses of scalp ictal EEGs can predict surgical outcome in most cases after anterior mesial temporal lobe resection (Assaf and Ebersole 1999) and can complement noninvasive presurgical evaluation.

Fast frequency oscillations and ripples

Localizing information by EEG is usually provided by the region of onset of the seizure, by the predominance of the discharge during the seizure, and by postictal slow waves. Fast frequencies (15 to 30 Hz) are much more frequent during seizures of focal onset than during seizures of widespread onset. High frequency oscillations (80 to 200 Hz) appear to characterize small epileptogenic zones (Gotman et al 1995). Hippocampal fast ripples (200 to 500 Hz) have been associated with seizure onset in both human and experimental epilepsy. In rat hippocampal slices in vitro, the correlation between the action potentials of bursting pyramidal cells and local field potential oscillations suggests that synchronous onset of action potential bursts and similar intrinsic firing patterns among local neurons are both necessary conditions for fast-ripple oscillations. Blockade of ionotropic glutamate receptors desynchronized onset of action potential bursts in individual pyramidal cells and abolished fast ripples (Dzhala and Staley 2004). Thus, it seems that fast ripples are the product of pathological neuronal hypersynchronization associated with seizure-generating areas (Staba et al 2004; Schindler et al 2006). In a study by Jirsch and colleagues, no discrete high frequency activity was present in poorly localized seizures, whereas it was found in regions of primary epileptogenesis and rarely in regions of secondary spread (Jirsch et al 2006). Absent high-frequency activity seems to indicate poor localization, whereas the presence of focal high-frequency activity near the time of seizure onset may signify proximity to the epileptogenic focus in mesial temporal lobe and neocortical seizures. High-frequency events in the local field potential of CA1 cells, which are similar to ripples, play a role in the rapid storage of new memories (Cheng and Frank 2008).

Ictal onset slow potential shifts. With foramen ovale electrodes and a special recording technique, including a subgaleally implanted reference electrode, we have recorded ictal DC shifts (Stodieck and Wieser 1987). In a study by Vanhatalo and colleagues, all seizures were associated with negative DC shifts at temporal derivations (30 to 150 µV relative to vertex), beginning at the electrical seizure onset and lasting for the whole seizure (Vanhatalo et al 2003). In 8 seizures (5 patients) with documented mesial temporal lobe onset, the polarity of the DC shift was initially positive, followed by a negative shift after lateral spread of seizure activity. In all cases, the side of the EEG shift agreed with other diagnostic tests and, at times, was more clearly lateralized than the conventional scalp EEG. Mader and colleagues studied 32 seizures recorded with hippocampal depth and subdural electrodes with the low frequency filter “opened” (LLF=0.1 Hz, HLF=70 Hz, 3 dB/octave) and identified a slow potential shift at the onset of the seizure of longer than 1.5 seconds in duration (1.5 sec to 11.5 sec; 62% longer than 5 sec) and more than 100 µV in amplitude in 84% of the seizures (Mader et al 2005). The maximum shift ranged from 139 µV to 2305 µV. Thus, a slow potential shift at the onset of depth-recorded seizures is likely to be a useful visual aid for localizing electrographic seizure onset.
Magnetic resonance imaging. High-resolution, thin-section T1-weighted MRI demonstrates hippocampal atrophy in a high percentage of patients with mesial temporal lobe epilepsy (Kuzniecky and Jackson 1995), and T2-weighted imaging techniques visualize hippocampal sclerosis by increased signals. Quantitative MR volumetry may reveal asymmetries and is useful to answers questions about the posterior extent of hippocampal abnormalities (Cascino et al 1991). Progressive volume loss in the mesial temporal lobe in relation to duration of epilepsy is not limited to the hippocampus but also affects the entorhinal cortex and the amygdala (Bernasconi et al 2005). Entorhinal cortex atrophy ipsilateral to the seizure focus appears to be specific to mesial temporal lobe structural damage associated with temporal lobe epilepsy (Bernasconi et al 2003). Furthermore, thalamic atrophy ipsilateral to the seizure focus is found in temporal lobe epilepsy but not in other forms of focal epilepsy or idiopathic generalized epilepsies. In temporal lobe epilepsy, thalamic atrophy is correlated with duration of disease. Patients with a history of prolonged febrile seizures had smaller thalamic volumes ipsilateral to the seizure focus than those without (Natsume et al 2003). In conclusion, hippocampal atrophy proven by MRI volumetrics is highly predictive of significant neuronal cell loss and an excellent indicator of success (Luby et al 1995).

Diffusion tensor imaging

Diffusion tensor imaging of the hippocampal formation revealed that patients with temporal lobe epilepsy had significantly increased diffusivity and decreased fractional anisotropy in the hippocampal formation ipsilateral to the seizure focus, as compared with values in the contralateral hippocampal formation. When compared with healthy subjects, patients had significantly higher mean diffusivity in the ipsilateral hippocampal formation (Assaf et al 2003; Yu et al 2006).

Thivard and colleagues performed diffusion tensor imaging and statistical parametric mapping of the entire brain in 35 well-defined mesial temporal lobe epilepsy patients and in 36 healthy volunteers (Thivard et al 2005). They identified 3 abnormal areas: an increased diffusivity was detected in the epileptic hippocampus and the ipsilateral temporal structures associated with a decreased anisotropy along the temporal lobe; a decreased diffusivity was found in the contralateral nonsclerotic hippocampus, the amygdala, and the temporal pole; and finally, a decreased anisotropy was noted ipsilaterally in posterior extratemporal regions. Duration of epilepsy, age at onset, and frequency of generalized tonic-clonic seizures or partial complex seizures did not correlate with the presence of diffusion abnormalities. Region of interest analysis in the hippocampus and parahippocampus demonstrated a correlation between lower ipsilateral diffusivity values and occurrence of epigastric aura as well as between higher anisotropy values in both hemispheres and history of febrile seizures. Rodrigo and colleagues performed uncinate fasciculus fiber tracking and compared its fractional anisotropy values between patients and controls, separately for the right and left uncinate fasciculus (Rodrigo et al 2007). The left-minus-right fractional anisotropy uncinate fasciculus asymmetry index was computed to test for intergroup differences. Asymmetries were found in the control group with right-greater-than-left fractional anisotropy. This asymmetrical pattern was lost in the patient group. Right fractional anisotropy values were lower in patients with right hippocampal sclerosis versus controls. These findings may be related to the preferential pathway of seizure spread from the mesial temporal lobe to frontal and insulo-perisylvian areas.

Magnetic resonance spectroscopy

Magnetic resonance spectroscopy, in particular proton-MRS (1H-MRS) has proven to be able to indicate neuronal loss and hippocampal sclerosis by measuring reduced N-Acetyl-L-aspartate (NAA) and increases in the choline/NAA ratio (Matthews et al 1990; Laxer et al 1993;Wieser et al 1996). However, NAA (and Cr) abnormalities in temporal lobe epilepsy do not result solely from neuronal loss and gliosis but can be reversible after postsurgical control of seizures. This implies that the NAA and Cr abnormalities in patients with temporal lobe epilepsy, at least in part, are dynamic markers of both local and remote physiologic dysfunction associated with ongoing seizures (Cendes et al 1997). Li and colleagues found that in patients with localization-related epilepsy, 40% to 50% have neuronal metabolic dysfunction that extends beyond the epileptogenic zone defined by clinical-EEG or the structural abnormality defined by MRI (Li et al 2000a). Serles and coworkers extended these observations of postoperative NAA recovery of seizure-free patients by characterizing the time course of recovery as an exponential function with a half-time of approximately 6 months (Serles et al 2001). The reversal of neuronal metabolic dysfunction remote from the epileptic focus may underlie the clinical observation of improvement of cognitive dysfunction after successful epilepsy surgery. Li and colleagues confirmed a linear correlation between the midtemporal NAA/Cr relative asymmetry ratio and surgical outcome (Li et al 2000b).

Positron emission tomography

Functional deficits can be demonstrated in patients suffering from mesial temporal lobe epilepsy using 18F-fluorodesoxyglucose (FDG) PET. Interictal hypometabolism is, as a rule, wide-spread and involves the ipsilateral lateral temporal lobe as well as ipsilateral thalamus and other subcortical structures (Engel et al 1991; Hajek et al 1993; Henry et al 1993). The extent and degree of hypometabolism correlates with outcome. Extratemporal cortical hypometabolism outside the seizure focus, in particular hypometabolism in the contralateral cerebral cortex, is associated with a poorer postoperative seizure outcome in temporal lobe epilepsy (Choi et al 2003). According to a study by Vinton and colleagues, the extent of resection of the region of hypometabolism on the preoperative FDG-PET is predictive of outcome following surgery for nonlesional temporal lobe epilepsy independent of the presence of hippocampal sclerosis and total brain volume of hypometabolism (Vinton et al 2007).

Salanova and coworkers correlated the volumetric head MRI and FDG-PET scan findings with the history, intracarotid amobarbital procedure, pathology, and outcome in 38 patients with medically refractory temporal lobe epilepsy treated surgically and found that FDG-PET scans and head MRIs were complementary: 95% of patients had either MRI-hippocampal sclerosis (MRI-HS) or temporal hypometabolism (Salanova et al 1998).
Kim and colleagues found that bilaterality of the EEG findings correlated with bilateral temporal hypometabolism on 18F-FDG PET (Kim et al 2006). Symmetric or asymmetric interictal bitemporal hypometabolism may signal bilateral independent seizure onset in approximately half the patients. Patients with temporal lobe epilepsy and bitemporal hypometabolisms but without bilateral MRI changes may still be operated on successfully, but surgical suitability should be proven by comprehensive intracranial EEG studies and Wada tests (Koutroumanidis et al 2000).
Flumazenil-PET has demonstrated reduced benzodiazepine receptor binding (Savic et al 1996), and 11C-carfentanil-PET an upregulation of mu-opioid receptor binding, in mainly the ipsilateral temporal lobe (Frost 2001); but 18F-cyclofoxy studies (cyclofoxy binds to mu and kappa) and 11C-diprenorphine-studies (diprenorphine binds to mu, kappa, and delta receptors) did not give conclusive results.

Single photon emission tomography

SPECT studies have shown reduced blood flow interictally in the temporal lobe ipsilateral to the epileptogenic mesial temporal lobe and ictal SPECT in mesial temporal lobe epilepsy temporal hyperperfusion during the seizures, mesial hyperperfusion and lateral temporal lobe hypoperfusion in the immediate postictal period, and hypoperfusion in the entire temporal lobe in later postictal seizure phases (Berkovic et al 1993). 99mTC-hexamethylpropyleneamineoxime (HMPAO) and 99mTc-L,L-ethyl cysteinate dimer (ECD) have advantages over 123I-labeled amines (HIPDM and IMP) because there is no redistribution in the brain. With 123I-Iomazenil SPECT, reduced benzodiazepine receptor binding in the area of the focus can be demonstrated (Haldemann et al 1992; Wieser 1994). SPECT with MAO-B-inhibitors (such as Ro 43-0463) might be able to visualize gliosis (Buck and Wieser 2007).

Memory: presurgical evaluation methods

Animal and human lesion studies have revealed the importance of the hippocampal formation and the amygdala for learning and memory. More precisely, encoding of new information has been associated with the hippocampal formation, and, in particular, with the perirhinal and entorhinal cortices (Squire and Butters 1984; Squire 1986; Squire and Zola-Morgan 1991; Mishkin 1993).

Disorders of learning and memory are clearly associated with temporal lobe dysfunction and have been studied in temporal lobe epilepsy before and after temporal lobe surgery (Milner 1966; 1975; Birri et al 1982; Rausch and Crandall 1982; Ojemann and Dodrill 1985; Gonser et al 1986; Jones-Gotman 1986a; 1986b; Henke et al 1999; 2003). Early investigators noted severe mnestic deficits following either bilateral mesial temporal resections or unilateral resections in the presence of occult lesions in the contralateral temporal lobe (Scoville and Milner 1957; Penfield and Milner 1958; Penfield and Mathieson 1974). These observations gave rise to the functional reserve model of hippocampal function in which postsurgical memory deficits were believed to be mediated by the capacity of the contralateral temporal lobe structures to support memory. However, material-specific learning and memory deficits, found in most patients with temporal lobe epilepsy (Milner 1975), might be specifically related to the involved temporal lobe; and at least certain types of pre-existing bilateral mesiobasal lesions, such as cysts, do not necessarily lead to an amnestic syndrome (Henke and Wieser 1996). When the language-dominant hemisphere is involved, memory deficits are usually more pronounced, and verbal memory, in particular, is insufficient. Verbal memory impairment has been found to correlate with hippocampal pyramidal cell loss (Sass et al 1990). However, there is no doubt that dysfunction of structures other than the mesiobasal temporal structures (in particular, the diencephalic and probably also the thalamic structures) (Hurley et al 1995), also can produce severe memory deficits. For example, Kapur and colleagues have described anterograde, but not retrograde memory loss following combined mamillary body and medial thalamic lesions (Kapur et al 1996). Furthermore, there is evidence that the mesial temporal structures play an important role in the recognition of emotion in facial expressions (Adolphs et al 1994) and in complex musical abilities, particularly in the recognition of musical consonances and dissonances (Wieser and Mazzola 1986).
Pre- and postoperative comparison of performances of patients with temporal lobe epilepsy have contributed quite a lot to the understanding of temporal lobe functions (Jones-Gotman et al 1997). There are, however, some limitations because most patients with a long history of temporal lobe seizures (1) have a preoperative memory deficit, and the degree of this deficit influences postoperative outcome; (2) take high-dosed AEDs with known side-effects regarding higher cognitive functions preoperatively and reduce or discontinue AEDs postoperatively; (3) become seizure-free and, thus, escape the negative consequences of seizures on cognitive performance and motivation. Also, in lesional cases and in patients with resective surgery, compensatory mechanisms (ie, plasticity) play an important role.
Thus, although substantial evidence has been accumulated that the temporal lobe and, particularly, its mesiobasal and basal structures are very important for memory, the exact role of the hippocampal formation is still a matter of research. Hippocampal N-acetyl-aspartate and T2 relaxation time, functional MRI, (O15)-H2O PET-studies, selective memory temporal lobe-Amytal tests (which allow the temporary inactivation of restricted mesial temporal areas), and intrahippocampal cognitive-evoked potential studies have revealed some interesting results. In conclusion, these studies suggest that the hippocampal region is activated by nonverbal stimuli if the material is visually complex, if spatial relations are stressed in the instruction, and if the stimuli are novel. Moreover, there is evidence that the hippocampus and the parahippocampal gyrus are critical for the establishment and storage of associations between components of a learning event rather than items in isolation (Henke et al 1999). The combined measurements of hippocampal N-acetyl-aspartate and T2 relaxation time can be used to examine the degree of ipsi- and contralateral hippocampal dysfunction or injuries and their relationship to memory performance (Namer et al 1999).

Selective memory temporal lobe Amobarbital tests

The temporary inactivation of the structures intended to be definitively resected is most probably the best way to predict possible deficits associated with the resection. The so-called intracarotidal Amobarbital test, pioneered by Wada (Wada 1949), was first used for language lateralization and for prediction of postoperative memory outcome. Although in temporal lobe surgery, it predicts at least a certain degree of severe global memory deficits, it has considerable limitations to exactly predict the risks with regard to the type and degree of material-specific memory deficits in amygdalohippocampectomy. The selective inactivation of the territory of the anterior choroidal artery (or of the P2 segment of the posterior cerebral artery in the case of a so-called “posterior” test; or of the anterior choroidal artery and posterior communicating artery in the case of the technique with temporary balloon occlusion distal to the origin of the anterior choroidal artery) has improved the validity of this test (Wieser et al 1997). Nevertheless, the variability of the vascular supply and the fact that these arteries provide, as a rule, only a restricted territory of interest (the anterior choroidal artery supplies the amygdala and the anterior part of the hippocampus; and the posterior cerebral artery supplies the more posterior hippocampus) still present problems. In addition, the appropriate interpretation of the task-performance asks for co-injection of a SPECT tracer and concomitant EEG recording from the structures of interest. Selective temporal lobe memory Amobarbital tests in candidates for amygdalohippocampectomy have generally confirmed the material-specific memory role of anterior mesiotemporal structures. With a dual verbal- and nonverbal-coding recurrent memory task (so-called DOKO) with nonverbal motor responding (button-press), the prediction of postoperative memory performance is rather good for the verbal memory but underestimates postoperative nonverbal (figural) memory performance.

Event-related potentials. In temporal lobe epilepsy patients, intracranial ERPs show alterations (increase in latency and decrease of amplitude) that correlate well with the Wechsler Memory Scale, and the hippocampal P300 correlates well with neuronal cell density. The recently described N400 recorded from the anterior fusiform gyrus is thought to reflect access of semantic memory, whereas the P300 is thought to reflect rules-based mapping of stimuli onto discrete covert or overt responses, ie, encoding processes (Nobre et al 1994; McCarthy et al 1995; Nobre and McCarthy 1995). Late potentials around 500 to 900 msec account for the patient’s engagement in recollection processing, and ERPs differentiate priming and recognition to familiar and unfamiliar faces (Begleiter et al 1995; Paller et al 1995). Several authors have described limbic correlates of the scalp P300 elicited in visual and auditory oddball paradigms using depth electrodes in epileptic patients (Halgren et al 1980; 1995; Stapelton and Halgren 1987; Loring et al 1988; Grunwald et al 1995) and to the scalp N400 in word recognition paradigms (Smith et al 1986). Therefore, it can be assumed that the careful study of ERPs recorded from mesiobasal temporal structures in temporal lobe epilepsy patients has the potential to clarify the role of these structures in the various kinds of memory and to quantify preoperative deficits. Indeed, Grunwald and colleagues reported that the amplitude of the intrahippocampal N400 elicited in a word recognition paradigm is an excellent predictor of postoperative memory performance in patients suffering from temporal lobe epilepsy (Grunwald et al 1995).

Syndromes and diseases in which the seizure type occurs

Hippocampal and parahippocampal seizures are the hallmark of mesial temporal lobe epilepsy. At the Istanbul ILAE Meeting, the Commission on Neurosurgery discussed in depth whether mesial temporal lobe epilepsy with hippocampal sclerosis is a syndrome. More participants were in favor of considering MTLE-HS a subtype of a greater syndrome of mesial temporal lobe epilepsy rather than a distinct syndrome, implying that mesial temporal lobe epilepsy, regardless of the cause, represents a sufficient cluster of signs and symptoms to make up a syndromic diagnostic entity. There was no consensus, however, and arguments against this position depended on the actual or potential features that make MTLE-HS unique—such as its progressive nature, genetic predisposition, and initial precipitating incidents—whereas the other subtypes due to specific static or neoplastic etiologies could be considered diseases. It was generally agreed that there were several subtypes of MTLE-HS, including at least a primary form, possibly a secondary form, and a familial form. A major point is that MTLE-HS appears to involve areas of structural and functional disturbances that are much more extensive than the hippocampus and maybe even the mesial temporal area (Wieser 2004). Seizures originating in the amygdala are relatively rare and usually invade the hippocampus (Wieser 2000; Wieser et al 2000).

Prognosis and complications

It was calculated that 6% of patients presenting with a single seizure will eventually develop MTLE-HS. Some patients who have MTLE-HS have seizures that are easily controlled by medication, but only those with severe forms are well characterized because they are the ones that commonly present at tertiary epilepsy centers. Today it is not clear whether the benign and severe forms of mesial temporal lobe epilepsy represent 2 different pathophysiological conditions or a spectrum of a single pathophysiological condition. Patients with dual pathology may have hippocampal sclerosis that is a nonspecific result of the primary epileptogenic lesion and not in itself epileptogenic, they may have hippocampal sclerosis that is secondary to the primary epileptogenic lesion but also epileptogenic. Chassoux and colleagues analyzed the distribution of the epileptogenic zone according to stereo-EEG with intralesional recordings in 4 patients evaluated for intractable partial epilepsy associated with focal unilateral polymicrogyria, involving the posterior temporal region in 2, the perisylvian area in 1, and the temporoparietal junction in the other (Chassoux et al 2008). Although intralesional recordings demonstrated intrinsic epileptogenicity in polymicrogyria, these authors concluded that unilateral focal polymicrogyria belongs to a large epileptogenic network extending beyond the MRI lesion.
Several studies have concluded that patients who have mesial temporal lobe epilepsy with MRI-identified hippocampal sclerosis are more likely to have intractable seizures than patients with other MRI-identified lesions. A large study, from a tertiary center in Paris found that only 11% of patients with hippocampal sclerosis and only 3% with dual pathology had been seizure-free in the past year (Semah et al 1998), whereas another study, from a primary center in Glasgow, also found hippocampal sclerosis to be associated with the most intractable seizures but reported that 46% of these patients had been seizure-free in the past year (Stephen et al 2001). The difference between these observations in the tertiary and primary centers confirm a view that there is a relatively high incidence of benign MTLE-HS, although it is unclear how many of these patients appearing at the primary center were in their “silent” period and would eventually develop refractory epileptic seizures. A characteristic interictal behavioral feature of MTLE-HS is material-specific memory deficit, but this can also be seen with mesial temporal lobe epilepsy due to other mesial temporal lesions. Many other psychiatric and psychological problems, especially depression, have been reported to be more prevalent in MTLE-HS.
Latent and silent periods between the initial precipitating incidents and onset of habitual seizures have been described as characteristic features of MTLE-HS. But there are patients without identifiable initial precipitating incidents, and some have habitual seizures that begin immediately after the initial precipitating incidents. A silent period occurring between the first habitual seizure and the onset of intractability exists in a high percentage of patients (Berg et al 2003). The silent period, indicating that seizures are initially easily controlled for some time before they become medically refractory, strongly suggests that the pathological substrate is progressive. Progressive behavioral changes, particularly increasing memory deficit, and an increased appearance of contralateral EEG spikes over time are other observations in the same direction.

Treatment options

Antiepileptic drug (AED) therapy. Carbamazepine is considered the treatment of first choice in mesial temporal lobe epilepsy, and response is usually satisfactory in the beginning. Later, however, a substantial percentage obviously becomes refractory to available AEDs, including classic first-line AEDs such as carbamazepine, phenytoin, valproate, and primidone, as well as new AEDs, such as topiramate and levetiracetam.
Surgery. Surgical therapy in medically refractory patients with mesial temporal lobe epilepsy is highly effective and renders about 80% of patients seizure-free (Engel 1993; Wieser et al 2003; Cohen-Gadol et al 2006). Most centers have modified temporal lobe surgery in mesial temporal lobe epilepsy with the goal to resect mesial temporal lobe structures more radically and to minimize lateral temporal lobe resection. Selective amygdalohippocampectomy with the trans-Sylvian approach (Wieser and Yasargil 1982; Yasargil et al 1985;1993; Yonekawa et al 1996) or the subtemporal approach (Hori et al 2007) and the so-called Spencer operation (resection of mesial temporal structures, of temporal pole, and of only a small amount of anterior lateral temporal cortex) have been strongly advocated in mesial temporal lobe epilepsy (Crandall 1987). There is evidence that sparing of the lateral temporal lobe cortex has advantages in terms of neuropsychological outcome and that originally hypometabolic lateral temporal lobe structures show a trend for normalization of their metabolism. In well-chosen candidates for amygdalohippocampectomy who already have unilateral material-specific memory and learning deficits, no additional clinical relevant deficits occur postoperatively, and the contralateral material-specific memory performance usually increases (Wieser 1992). Paglioli and colleagues reported data suggesting that postoperative verbal memory scores may even improve in patients who undergo selective resection of a sclerotic hippocampus in the dominant temporal lobe (Paglioli et al 2006). Similar findings were reported with classical anterior temporal lobe resections (Rausch and Crandall 1982). Patients without pre-existing memory deficits, particularly those not becoming seizure-free following left temporal lobe resections, usually worsen in their verbal memory. For a better prediction of the postoperative memory and learning in patients considered to be at risk, selective temporal lobe memory Amobarbital tests are used at our site.
Without surgery, the prognosis of medically refractory patients with mesial temporal lobe epilepsy is relatively poor. Both severity and frequency of seizures may increase, and memory may decline, possibly resulting in severe psychosocial disturbances. Early surgical intervention (ie, relief of disabling seizures before the negative consequences of mesial temporal lobe epilepsy interfere critically with vocational and social development) results in best psychosocial outcome (Khan and Wieser 1992) and should be envisaged in this prototype of a surgically remediable epileptic syndrome. Several groups have also reported good surgical results in children with temporal lobe epilepsy (Meyer et al 1986; Munari 1995). Surgery-related major complication rates are low, with reports of below 1% from most centers (Wieser et al 2003).
The response to epilepsy surgery during the first follow-up year is a reliable indicator of the long-term postoperative outcome. Discontinuation of antiepileptic drugs after successful epilepsy surgery is possible in a high percentage (Schiller et al 2000; Wieser and Hane 2003; 2004; Kim et al 2005). Seizure recurrence after planned discontinuation of AEDs in seizure-free patients after epilepsy surgery, however, is relatively high. The recurrence rate in adults in 4 studies was 33%, with maximum follow-up ranging from 1 to 5 years. In one study of children with temporal lobe epilepsy, the recurrence rate was 20%; more than 90% of adult patients with seizure recurrence regained seizure control with reinstitution of previous AED therapy (Schmidt et al 2004). Seizure freedom without aura at 1 year or more is a reasonable indication for the attempt at AED discontinuation. Younger age at the time of surgery and a shorter disease duration seem to affect successful AED discontinuation for a long-term period.


Often, hippocampal and parahippocampal seizures can not be detected by scalp EEG. If precise localization is necessary (ie, if selective mesial resection is planned), besides stereotactic depth EEG, the semi-invasive foramen ovale electrode technology proved very helpful in recording from the mesial temporal lobes (Wieser and Moser, 1988; Wieser and Morris 1996). Other techniques are subdural recordings with strips and grids.
Intraoperative electrocorticography can be and is used by many centers to tailor the extent of the resection (Oliveira et al 2006; Holmes and Chatrian 2007).

Associated disorders

mesial temporal lobe epilepsy
mesial temporal lobe epilepsy with hippocampal sclerosis

Related summaries

Familial mesial temporal lobe epilepsy
Mesial temporal lobe epilepsy

Differential diagnosis

intractable seizures with hippocampal sclerosis
benign childhood epilepsy with centrotemporal spikes
complex partial seizures of extratemporal origin
cryptogenic temporal lobe epilepsy
lateral neocortical temporal lobe seizures
insular seizures
seizures of frontal lobe origin


For more specific demographic information, see the Epidemiology, Etiology, and Pathogenesis and pathophysiology sections of this clinical summary.


0-01 month
01-23 months
02-05 years
06-12 years
13-18 years
19-44 years
45-64 years
65+ years

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