Epilepsy; Temporal Lobe JM Stern, University of California Los Angeles, Los Angeles, CA, USA HG Wieser, Neurologische Klinik, Universita¨tsspital, Zu¨rich, Switzerland r 2014 Elsevier Inc. All rights reserved. This article is a revision of the previous edition article by Heinz Gregor Wieser, volume 2, pp 251–256, r 2003, Elsevier Inc.
Introduction Aretaeus of Cappadocia (second century AD) knew that epilepsy comprises different types of seizures, including complex behavioral episodes. Galen (also second century AD) differentiated epilepsy from other convulsions and also coined the term ‘aura.’ Tissot (1865) gave precise descriptions of various epileptic auras, including visual and acoustic hallucinations and sudden deambulation. Calmeil (1824) differentiated petit mal from other seizure types and characterized petit mal seizures (e´tourdissement) by disorientation, stereotyped behavior, verbal perseverations, deambulation, and a silly laughter. This description contains all core elements of what was later called the focal dyscognitive seizures, including loss of consciousness. In 1825, Bouchet and Cazauvieilh presented important autopsy data with pathologies in the Ammon’s horn. John Hughlings Jackson (1889) described the symptomatology of ‘dreamy states’ and of other variants of ‘uncinate fits,’ which in 1938 were called psychomotor seizures by Gibbs et al. and in 1941 were called ‘temporal lobe seizures’ by Jasper and Kershman. Jackson’s concept of uncinate fits as ‘a particular variety of epilepsy’ was based on the postmortem finding of temporal lobe lesions associated with olfactory hallucinations, dreamy states, elaborated automatisms, and amnesia. Jackson and Stewart (1899) provided the early definitive description of such seizures: At the onset [there is] a crude sensation of smell or one of taste, or there are movements of chewing or smacking the lips [sometimes there is spitting]. In some cases there is warning by what is known as the epigastric sensation, a systemic sensation which especially appertains to the digestive system.yMany of the symptoms depend, of course, on discharge widespread beyond y of what I call the uncinate region.
The era of epilepsy surgery verified this pioneering concept with the reproduction of many of these particular signs and symptoms by electrical stimulation and improved correlation analyses of clinical with electroencephalographic (EEG) and pathological findings.
Epileptic Seizures and Syndromes of the Temporal Lobe A variety of conditions associated with focal seizures of presumed temporal lobe origin have been termed temporal lobe epilepsy. Differing criteria, such as ictal behavior, location of the lesion or the epileptogenic focus, and interictal or rarely ictal EEG findings, were used. From the convention of describing clinical seizure type, EEG seizure type, EEG interictal
expression, anatomical substrate, etiology, and age, the 1981 International League against Epilepsy (ILAE) International Classification of Epileptic Seizures retained only clinical seizure type and interictal and ictal EEG expressions. The 1989 International Classification of Epilepsies and Epileptic Syndromes recognized two types of temporal lobe epilepsy or seizures – hippocampal (mesiobasal limbic or primary rhinencephalic psychomotor) epilepsy and lateral temporal seizures – and defined them purely on an anatomical basis. In the more recent Diagnostic Scheme of the ILAE Task Force on Classification and Terminology, a five-level or five-axes system was proposed. In this system, seizures of temporal lobe origin can be described as focal sensory seizures with elementary or with experiential sensory symptoms or as focal motor seizures with typical (temporal lobe) automatisms or with hyperkinetic automatisms. Gelastic seizures are also listed under epileptic seizure types. Furthermore, under the category continuous seizure type are listed the aura continua and limbic status epilepticus (psychomotor status). Under the axis epilepsy syndromes and related conditions, familial temporal lobe epilepsies and symptomatic (or probably symptomatic) focal epilepsies are listed. Familial temporal lobe epilepsy may be either mesial or lateral, and each is apparently due to different genetic etiologies. Specifically, familial lateral temporal lobe epilepsy has been associated with mutation in the LGI-1 gene. A key clinical distinction between the mesial and lateral forms is the common occurrence of auditory auras in familial lateral temporal lobe epilepsy. Symptomatic focal epilepsies list limbic epilepsies with (i) mesial temporal lobe epilepsy (MTLE) with hippocampal sclerosis, (ii) MTLE defined by specific etiologies, and (iii) other types defined by location and etiology. Problems occur because the term temporal lobe epilepsy has also been used to refer to conditions in which (i) the primary epileptogenic region is outside the temporal lobe but discharges preferentially propagate to the temporal lobe to produce typical seizures, (ii) an old and initially epileptogenic lesion leads to the development of an active temporal lobe focus in the sense of an independent secondary focus while the primary epileptogenic lesion has lost its epileptogenic properties (sometimes called secondary temporalization), and (iii) the epileptogenic region is in the lateral temporal lobe and gives rise only to neocortical-type seizures. Pure descriptive terms, such as psychomotor epilepsy, have obvious limitations because psychomotor seizures can originate outside the temporal lobes. Given the lack of a unanimously accepted terminology, many epileptologists prefer an etiological approach and categorize epilepsy as (i) MTLE associated with hippocampal sclerosis, (ii) ‘lesional’ temporal lobe epilepsy (defined by lesions in the temporal lobe other
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Epilepsy; Temporal Lobe
than hippocampal sclerosis), and (iii) neocortical temporal lobe epilepsy.
Mesial Temporal Lobe Epilepsy In recent years, strong arguments have been presented for the existence of a collection of MTLE syndromes. These are common and often drug resistant but surgically remediable. They consist of relatively homogeneous clinical features, and have several characteristic sets of findings in paraclinical tests (including histology, magnetic resonance imaging (MRI), positron emission tomography (PET), and EEG), and have excellent outcome following mesial temporal lobe resection. The syndromes apparently differ in genetic and environmental factors, natural history, pathogenesis, and prognosis. Most important, however, is the often association with hippocampal sclerosis.
developing epilepsy varied from 2% to 7%, but only 2.4% of children with no prior neurological disease develop subsequent epilepsy in later life. There are relationships between a history of childhood febrile seizures and hippocampal sclerosis demonstrated by hippocampal volume loss on volumetric MRI and between a history of childhood febrile seizures and hippocampal neuronal loss histopathologically. A significant association between the severity of hippocampal sclerosis and younger age of onset of epilepsy but no definite relationship of hippocampal sclerosis to the duration of epilepsy have been found, implying that hippocampal sclerosis is not the consequence of long-standing seizures but that there is an agespecific sensitivity of the hippocampus to whatever causes hippocampal sclerosis. The prevalence of a positive family history of febrile seizures is higher in patients with late seizure recurrence and in patients with temporal lobe epilepsy treated surgically. It is assumed that the tendency for febrile seizures is genetically determined and inherited in a multifactorial way.
Epidemiology Focal dyscognitive seizures (which has replaced the term complex partial seizures) are a common seizure manifestation, especially when anterior temporal lobe pathology is present. However, not all patients with focal dyscognitive seizures have MTLE. Precise epidemiological information on MTLE is not available because data necessary to identify the syndromes usually are not available in large databases, and the medically refractory variant of this syndrome is more often identified than the variant that responds to medications with seizure freedom. It is likely that MTLE is the most common form of human epilepsy.
Clinical Course Patients with MTLE experience a high rate of treatment failure with antiepileptic drugs (AEDs) and their epilepsy may actually progress. Response to AED treatment in the first few months correlates positively with a good outcome, whereas very young seizure onset (o2 years of age), a high frequency of seizures, a known etiology, a history of status epilepticus, and a history of febrile seizures are associated with a lower likelihood of remission. In MTLE, aggravation of seizure problems is often associated with an accentuation of personality and behavior problems and a decline in memory.
Pathophysiology and Genetics The majority of focal epilepsies begin in early life. Childhood febrile seizures, particularly when complex (i.e., prolonged or focal), are an important factor in the development of temporal lobe epilepsy associated with mesial temporal sclerosis, although this issue remains controversial. In surgical series, the rate of febrile seizures ranges from 9% to 50%, and in a neuropathology study Margerison and Corsellis found hippocampal sclerosis in 22 of 26 cases thought to have temporal lobe epilepsy on clinical grounds, although such series are likely significantly biased by case selection. In prospective cohort studies of children with febrile seizures, the risk of
Mesial Temporal Sclerosis The term mesial temporal sclerosis has been used more or less synonymously with Ammon’s horn sclerosis and hippocampal sclerosis, although these terms imply different degrees of anatomical involvement. The term mesial temporal sclerosis has advantages because it better accounts for the fact that the amygdala, during examination, often shows equally severe pathology consisting of neuronal loss and gliosis to that of the hippocampus. The most characteristic pathological substrate of MTLE is hippocampal sclerosis with marked loss of neurons in the cornu ammonis (CA) fields CA1 and hilar region, some loss in endfolium (CA3/CA4), and relative sparing of the CA2 region. The subicular complex, entorhinal cortex, and the temporal gyri are relatively resistant to cell loss. Hippocampal sclerosis is associated with other characteristic features, such as mossy fiber sprouting and selective loss of somatostatin and neuropeptide Y-containing neurons. It is found in up to 70% of patients with medically refractory temporal lobe epilepsy undergoing surgery. The association between epilepsy and a sclerotic hippocampus was described as early as 1825, but at that time hippocampal sclerosis was believed to be an effect rather than a cause of epilepsy. Whether hippocampal sclerosis is the cause or the consequence of seizures in MTLE is still controversial. Today, the vulnerability of Sommer’s sector CA1 and the hilus of the dentate and sector CA3 is explained by the richness of certain glutamate receptors, N-methyl-D-aspartate (NMDA) in the case of CA1 and kainate receptors in the case of the hilus of the dentate gyrus and sector CA3. Activation by glutamate or aspartate causes an excessive influx of Ca2 þ ions into the postsynaptic pyramidal neurons that may damage them irreversibly. Since the pyramidal cells of the CA3 do not contain the calcium-buffering protein calbindin and those of the CA1 sector contain only small concentrations of it, they are particularly vulnerable. Calbindin is present in the pyramidal cells of CA2 and the granule cells of the dentate gyrus. Chromogranin A, another calcium-binding protein, shows a
Epilepsy; Temporal Lobe
distribution that matches the profile of hippocampal sclerosis very well (i.e., it is absent in the vulnerable sectors CA1 and CA3 and present in the resistant sector CA2 and in the granule cells of the dentate gyrus and their axons, the mossy fibers). g-Aminobutyric acid (GABA)ergic neurons are also protected against Ca2 þ -induced damage by either calbindin or parvalbumin, and the sparing of subiculum can be explained by the much lesser content of NMDA receptors. Hippocampal sclerosis is most commonly found in patients with a history of febrile seizures or status epilepticus in childhood, but it also has a lesser but significant correlation with birth trauma. A common denominator of many studies is that there might be a particular time frame (approximately 3 months to 5 years) during which noxious events are particularly harmful. Presumably, only a few NMDA receptors are developed in the hippocampus in newborns. However, the pathology of MTLE is not completely uniform. Gliosis might involve anterior mesial temporal lobe structures in addition to the hippocampus, and it might consist of ‘dual pathology’ (i.e., cortical microdysgenesis and cortical dysplasia, as well as hamartomas, small tumors, and cavernomas, can be found in addition to hippocampal sclerosis). Moreover, hippocampal sclerosis is often a bilateral condition, although frequently with a unilateral preponderance. The events that initiate the process of hippocampal sclerosis are unknown, 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.
Clinical Characteristics Typically, onset of seizures occurs at the end of the first decade. First attacks might present as focal or secondarily generalized seizures. Initially, response to AEDs is good, but seizures often recur in adolescence or early adulthood and tend to become refractory to AEDs. Seizures in MTLE are typically characterized by auras evolving into dyscognitive seizures with initial arrest (motionless stare), followed by oroalimentary and manual automatisms. Vegetative–autonomous signs and symptoms are prominent. Auras occur frequently in isolation and typically consist of epigastric-rising sensations associated with olfactory, gustatory, and psychic phenomena (fear, dreamy states, de´ja`-vu, de´ja`-ve´cu, de´ja` entendu, and other kinds of recollections) and alterations of self-perception (in time and space) as well as changes in the emotional and affective sphere. Dystonic posturing of one extremity can occur and is a valid lateralizing sign indicating contralateral ictal onset. Automatisms may be ictal or postictal, de novo or reactive. Ictal automatisms frequently consist of oroalimentary symptoms, such as lip smacking and swallowing, and gestural (e.g., picking), fumbling, and purposeless movements. Consciousness is typically gradually lost or at least clouded. Marked reactive automatisms might be seen in the postictal phase. Typical for the behavior of seizures in MTLE is varying degrees of postictal confusion with amnesia for the ictal event and persisting postictal memory deficit. Postictal aphasia with
dominant temporal lobe seizures is also typical. Secondary generalization can occur, particularly in children; it is relatively infrequent in adults receiving AEDs. The ictal behavior of seizures involving the limbic system is particularly rich. The overall clinical gestalt of mesiobasal limbic seizures can be described within three groups: absence like; predominance of psychomotor symptoms and automatisms; and predominance of psychosensory and/or pure psychic intellectual, cognitive, and emotional (i.e., experiential) symptoms. Many symptoms depend on a characteristic seizure discharge constellation (i.e., the type of propagation along preferential pathways) and appear within a characteristic ‘march’ of symptoms. Most ictal hallucinations are experiential phenomena in the sense of being recollections of past experiences. Psychic symptoms can be described as (i) intellectual and (ii) affective-emotional phenomena. Jackson’s description of the dreamy state (e´tat de reˆve) includes recollections in the sense of de´ja` vu, de´ja`-entendu, and de´ja`-ve´cu; unfamiliarity/unreality (jamais vu, jamais entendu, and jamais ve´cu); forced thinking; and the rapid recollection of the past (panoramic vision). Emotional auras are rarely reported. The most common is fear often associated with restlessness and irritability. Sadness and pleasure, elation, exhilaration, satisfaction, and the ‘eureka feeling’ are well documented. Some aura symptoms may not have counterparts in normal human experience and cannot be described. A ‘strange feeling’ without further elaboration is in fact very often reported. Ictal autonomic phenomena can be classified as 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 are used. According to the effector systems, one can distinguish between cardiovascular, respiratory, pupillary, sudo- and pilo-motor, salivation, gastrointestinal, and genitourinary.
Seizure Distribution Seizures typically occur randomly, with a common frequency of a few per month. There is no marked circadian preponderance of seizure occurrence, but drowsiness and light sleep (nonrapid eye movement sleep stage 1 facilitate seizures). Sleep deprivation and stress usually also exacerbate seizures. In female patients with MTLE, seizures might be exacerbated by menstrual cycle phases during which the ratio of estrogen to progesterone is increased. The neurological examination of patients with MTLE is frequently normal. Detailed neuropsychological examination, however, reveals various degrees of material-specific learning and memory deficits. Usually, they are more pronounced with left MTLE and may be associated with subtle speech problems if the dominant hemisphere is predominantly involved. Endocrine functions usually remain normal, but some women may report irregularities of the menstrual cycle or hyposexuality. Often, however, it is difficult to attribute these changes to the epileptic process per se and to differentiate from possible side effects of AEDs.
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Patients with MTLE may be at greater risk to develop certain personality and behavior disorders. Depression is common in MTLE and more likely to occur than in other medical conditions with similar forms of disability. It is apparently a manifestation of the limbic system dysfunction. Waxman and Geschwind described an interictal behavioral and personality syndrome of TLE consisting of irritability, lower stress tolerance, ‘stickiness’ and sometimes hypergraphia, ‘hyperreligiosity,’ as well as hyposexuality, with altered self-perception as a kind of ‘sensory-limbic hyperconnection’ syndrome due to kindling-like mechanisms. Psychosis-like states in the sense of schizophrenia-like psychosis are also associated with MTLE, but this is uncommon and remains poorly characterized.
Paraclinical Findings in Mesial Temporal Lobe Epilepsy In MTLE, characteristic and typical interictal and ictal EEG findings can be found. Interictal EEG typically consists of sharp waves with or without slow waves and with a maximum of their field in basal anterior electrodes (such as sphenoidal or true temporal electrodes). Ictal scalp EEG findings typically consist of regular theta rhythms of approximately 5 s1 with a crescendo-like increase in amplitude and spatial extent across the scalp. Seizure onset might be characterized by regional or generalized attenuation of background EEG rhythms with disappearance of interictal spikes. Direct recording from the hippocampal formation often shows a hypersynchronous hippocampal discharge pattern followed by a low-amplitude, high-frequency recruiting rhythm of more than 20 s1. The other frequent seizure-onset pattern of hippocampal seizures is the low-voltage fast discharge. These two patterns may both predict hippocampal tissue loss of different type and distribution. High-resolution, thin-section, T1-weighted MRI demonstrates hippocampal atrophy in a high percentage of patients with MTLE, and T2-weighted imaging techniques visualize hippocampal sclerosis with increased signal and blurring of the internal architecture. Quantitative MR volumetry reveals asymmetries. Magnetic resonance spectroscopy (MRS), particularly protonMRS (1H-MRS), indicates neuronal loss and hippocampal sclerosis by measuring reduced N-acetyl-L-aspartate (NAA) and increases in the choline: NAA ratio. Interictal 18F-fluorodesoxyglucose PET reveals widespread temporal hypometabolism and involves the ipsilateral thalamus and other subcortical structures. Flumazenil PET has demonstrated reduced benzodiazepine receptor binding and 11 C-carfentanil PET an upregulation of mu-opioid receptor binding in mainly the ipsilateral temporal lobe. Single-photon emission tomography (SPECT) studies have shown reduced blood flow interictally in the temporal lobe ipsilateral to the epileptogenic mesial temporal lobe. Ictal SPECT in MTLE has shown temporal hyperperfusion during seizures, mesial hyperperfusion and lateral temporal lobe hypoperfusion in the immediate postictal period, and hypoperfusion in the entire temporal lobe in the later postictal seizure phase. With 123I-iomazenil SPECT, reduced benzodiazepine receptor binding in the area of the focus can be demonstrated.
Differential Diagnosis Both benign childhood epilepsy with centrotemporal spikes and MTLE can begin in childhood with generalized seizures. However, the partial seizures of benign childhood epilepsy with centrotemporal spikes usually have early sensory and/or motor lateralized symptoms localized around the mouth and/ or the upper extremity. Interictal EEG spikes are also different in these two syndromes: The broad centrotemporal EEG spike is located more posteriorly and superiorly and has a characteristic transverse dipole, whereas in MTLE the spike or spikewave discharges are located more anteriorly and basally with a characteristic oblique dipole direction. Differentiation from temporal lobe epilepsy due to other lesions in or close to the mesial temporal lobe is usually easy by MRI. Focal seizures of extratemporal origin often have an aura consisting of symptoms identifying the involved primary epileptogenic area.
Treatment No single AED is considered the treatment of choice in MTLE because none has evidence for superior efficacy. Response to treatment is usually satisfactory in the beginning. Later, however, a substantial percentage of patients become refractory to AEDs. Surgical therapy in medically refractory patients with MTLE is highly effective and renders approximately 80% of patients seizure free. Most centers have modified temporal lobe surgery in MTLE with the goal of resecting mesial temporal lobe structures more radically and minimizing lateral temporal lobe resection.
Prognosis Without surgery, the prognosis of medically refractory patients with MTLE is relatively poor. Both severity and frequency of seizures often increase, and memory may decline, resulting in severe psychosocial disturbances. Early surgical intervention (i.e., relief of disabling seizures before the negative consequences of MTLE interfere critically with vocational and social development) results in the best psychosocial outcome and should be envisaged in this surgically remediable epileptic syndrome. Several groups have reported good surgical results in children with temporal lobe epilepsy.
Lesional Temporal Lobe Epilepsy In the 1928–73-period Montreal series of surgically excised epileptogenic temporal lobes, discrete focal lesions such as gliomas and gangliogliomas, meningocerebral cicatrix and remote contusions, vascular malformations of brain and/or pia, hamartomas, and other lesions were found in 202 of 857 specimens. Even higher percentages of lesions have been found in other histopathological studies of mesial temporal lobe resections. Neuroectodermal tumors, predominantly low-grade gliomas and gangliogliomas, are frequently encountered. Whereas focal dysplasia was precisely described as early as 1971, dysembryoplastic neuroepithelial tumors and several types of cortical dysgenesis have been recognized with progressively increasing frequency only in recent years.
Epilepsy; Temporal Lobe
Lateral Neocortical Temporal Lobe Seizures In comparison to seizures originating in the mesial temporal lobe structures, seizures originating in the lateral neocortical temporal lobe structures are much less common and 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 exist and have been well documented. Such seizures spread to the ipsilateral mesial temporal structures. 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. There are no absolute symptoms and signs indicative of lateral temporal seizure onset, but ictal aphasia, auditory, visual, and vestibular hallucinations, as well as early motor symptoms with contralateral tonic–clonic manifestations and head–eye deviation are more frequently seen in neocortical lateral than in mesiobasal seizures.
See also: Epilepsy, Diagnosis of. Epilepsy, Psychiatric Comorbidities of. Epilepsy; Surgery. Epilepsy Treatment Strategies. Epileptic Seizures. Epileptic Syndromes and Diseases
Further Reading Babb TL and Brown WJ (1987) Pathological findings in epilepsy. In: Engel J (ed.) Surgical Treatment of the Epilepsies, pp. 511–540. New York: Raven Press.
Bonilha L, Martz GU, Glazier SS, and Edwards JC (2012) Subtypes of medial temporal lobe epilepsy: Influence on temporal lobectomy outcomes? Epilepsia 53: 1–6. Engel Jr J (2001) A proposed diagnostic scheme for people with epileptic seizures and with epilepsy: Report of the ILAE Task Force on Classification and Terminology. Epilepsia 42: 796–803. Engel Jr J, Williamson PD, and Wieser HG (2008) Mesial temporal lobe epilepsy with hippocampal sclerosis. In: Engel Jr, J and Pedley TA (eds.) Epilepsy: A Comprehensive Textbook, 2nd edn., pp. 2479–2486. Philadelphia: Lippincott Williams & Wilkins. Falconer MA, Serafetinides EA, and Corsellis JA (1964) Etiology and pathogenesis of temporal lobe epilepsy. Archives of Neurology 10: 233–248. Gloor P (1991) Mesial temporal sclerosis: Historical background and an overview from modern perspective. In: Lu¨ders H (ed.) Epilepsy Surgery, pp. 689–703. New York: Raven Press. Jackson JH and Stewart P (1899) Epileptic attacks with a warning of crude sensation of smell and with intellectual aura (dreamy state) in a patient who had symptoms pointing to gross organic disease of the right temporo-sphenoidal lobe. Brain 22: 334–549. Kahane P and Bartolomei F (2010) Temporal lobe epilepsy and hippocampal sclerosis: Lessons from depth EEG recordings. Epilepsia 51(supplement 1): 59–62. Wieser HG (2000) Temporal lobe epilepsies. Handbook of Clinical Neurology, vol. 73, pp. 53–96. Amsterdam: Elsevier. Wieser HG, Engel Jr J, and Williamson PD (1993) Surgically remediable temporal lobe syndromes. In: Engel J (ed.) Surgical Treatment of the Epilepsies, 2nd edn., pp. 49–63. New York: Raven Press. Williamson PD, Siegel AM, and Roberts DW (2000) Neocortical epilepsies. Advances in Neurology 2000: 84.
Relevant Website http://epilepsyfoundation.org/aboutepilepsy/syndromes/temporallobeepilepsy.cfm Epilepsy Foundation.