Influence of the type of initial precipitating injury and at what age it occurs on course and outcome in patients with temporal lobe seizures

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1 J Neurosurg 82: , 1995 Influence of the type of initial precipitating injury and at what age it occurs on course and outcome in patients with temporal lobe seizures GARY W. MATHERN, M.D., JAMES K. PRETORIUS, M.S., AND THOMAS L. BABB, PH.D. Divisions of Neurosurgery and Clinical Neurophysiology, Department of Neurology, and the Brain Research Institute, University of California at Los Angeles School of Medicine, Los Angeles, California The type of initial precipitating injury and the age at which it occurred in 20 patients with nonlesional temporal lobe epilepsy (TLE) were related to clinical features, presurgical neuroimaging, quantified hippocampal pathologies, and seizure outcomes. Clinical data, neuroimaging records, and seizure outcomes were abstracted from medical records and confirmed with patient and family contacts. Hippocampal neuron losses and mossy fiber reactive synaptogenesis were quantified independently. Results showed that the type of initial precipitating injury and the patient s age at which it occurred were related to the clinicopathological features of TLE. An initial precipitating injury occurred in 18 patients (90%), all of whom had mesial temporal sclerosis (MTS). Patients with a prolonged initial seizure or a nonseizure initial precipitating injury before age 5 years were significantly more likely to have unilateral hippocampal atrophy (p 0.05) shown on magnetic resonance (MR) imaging, and had significantly greater inner molecular layer mossy fiber puncta densities (p 0.001) than patients with nonprolonged childhood initial precipitating injuries and/or seizures after age 5 years. Furthermore, nonseizure injuries in patients before age 5 years had significantly longer latent periods (p 0.05), and the patients did not respond to surgical treatment as well as other MTS patients. Those with an initial precipitating injury after age 5 years had MTS but showed significantly less inner molecular layer mossy fiber sprouting (p 0.05) than patients whose injuries appeared before age 5 years. Patients without an initial precipitating injury (idiopathic TLE) had significantly fewer neuron losses (p 0.05) and inner molecular layer mossy fiber puncta densities (p 0.05) and had worse outcomes following en bloc temporal lobectomy compared to patients with MTS who had experienced initial precipitating injuries. Patients with unilateral hippocampal abnormalities on MR imaging did not show significant differences in neuron losses or aberrant mossy fiber puncta densities compared to patients without asymmetry. These results support the hypothesis that the type of initial precipitating injury and the age at which the injury occurred initiates and influences the pathophysiological process that eventually develops into MTS. These data support the notion that the pathophysiology of hippocampal damage and mossy fiber sprouting after an initial precipitating injury may be a progressive process. KEY WORDS neuron loss mossy fiber synaptic reorganization epilepsy mesial temporal sclerosis hippocampal atrophy H UGHLINGS Jackson has been acknowledged as one of the first physicians to study systematically the relationships between ictal phenomena, seizure semiology, and localized pathologies in the brain. 2 As early as 1872, Jackson 28 had associated focal motor seizures to the frontal cortex. He also localized seizures associated with complex sensations and feelings to an area near the hippocampus. 27,29,38 In 1937 Gibbs, et al., 19 used the electroencephalogram to introduce the concept of psychomotor seizures as an electroclinical syndrome arising from the temporal lobe. However, little was known about the pathology or structural substrate that generated temporal lobe epilepsy (TLE). Many clinical investigators have studied TLE, but the work of Falconer and colleagues has probably contributed the most to our understanding of the anatomy and pathology of this disorder. In a series of papers from the s to the early 1970s, these investigators documented the clinical features, pathology, and seizure outcome of TLE patients following en bloc resection. 9 Many studies 1,3,5,16,37,39 have confirmed the finding that mesial temporal sclerosis (MTS) is the most common pathological finding in surgical specimens and is often associated with a childhood febrile illness. Recently, attention has shifted to other areas of TLE research, such as identifying patients at risk for developing intractable epilepsy. These studies have shown that the risk of epilepsy (that is, recurrent seizures) after an initial unprovoked seizure, is modest Rather, it is patients with a history of an initial symptomatic seizure associated with meningitis, trauma, or prolonged initial seizures, and febrile convulsions 8,10,20 who seem to comprise the groups at risk for later epilepsy. These epidemiological studies constitute a beginning and provide data concerning the J. Neurosurg. / Volume 82 / February, 1995

2 Clinical injury and epileptic pathophysiology incidence of epilepsy after a seizure. However, these studies still have not identified all patients at risk for developing intractable seizures. In light of these research trends, this retrospective surgical study was undertaken to reexamine the importance of an initial precipitating injury in determining the clinical and pathological features of TLE and MTS. We hypothesized that 1) an initial precipitating injury was necessary to generate the neuron losses and mossy fiber sprouting associated with MTS, and by comparison, patients without such an injury would not show MTS and would not have seizure control following surgery; and that 2) initial precipitating injuries with or without seizures that occur in patients before age 5 years as part of the pathogenic mechanism would show different clinicopathological findings compared to initial precipitating injuries that occurred after age 5 years. In other words, there would be clinicopathological subsyndromes of MTS based on the initial precipitating injury that would be useful in planning future research investigations and for advising prospective surgical candidates. Clinical Material and Methods Patient Population Patients with complex partial epilepsy of probable temporal lobe origin were evaluated and investigated at the University of California at Los Angeles (UCLA) from 1988 to 1992 using a standard protocol, 12 which was approved by the institution s Human Subject Protection Committee. The patients for this study were sequentially recruited; each had clinical TLE and could provide detailed clinical information and hippocampal specimens of adequate quality for analysis. 36 The present study concentrated only on those 20 patients without mass lesions. Independent variables were obtained from medical records and/or confirmed from patient and/or family interviews to define the presence or absence of an initial precipitating injury, the age of the patient when it occurred, and whether the injury involved a seizure as its mechanism. We defined initial precipitating injuries as significant medical events that occurred prior to onset of TLE. A significant medical event was an illness or cerebral injury associated with prolonged unconsciousness and/or major alterations in cognition (Table 1). Seizures were further grouped according to patients whose initial precipitating injuries involved either a prolonged (greater than 30 minutes) or complex seizure compared to nonprolonged seizures. Patients were catalogued by one author (G.W.M.), who was blinded to other clinical and pathological data, into the following groups for uniform classification: Group A: Nonseizure Initial Precipitating Injury. Patients in this group had a single significant medical illness or injury that occurred prior to age 5 years and was not associated with an observed clinical seizure at the time of the initial precipitating injury. Several different clinical diagnoses fit into this category (Table 1), and the patients had histories of hospitalization due to the injury and/or required at least 24 hours to recover neurological function. These patients may have had subclinical seizures at their initial precipitating injury but no observed sustained motor seizure activity was noted in the histories. Group B: Prolonged Seizure Initial Precipitating Injury. This group had a significant medical illness that occurred prior to age 5 years and was accompanied by a motor J. Neurosurg. / Volume 82 / February,

3 G. W. Mathern, et al. seizure. The seizure may have been prolonged such as status epilepticus associated with meningitis or encephalitis, or complex such as from febrile convulsions. The distinction from the nonseizure group was the presence of the seizure, and thus patients with a similar clinical diagnosis such as meningitis could be classified in either group. Patients may have had other seizures and a diagnosis of childhood epilepsy after their initial precipitating injury, but there was one initial significant injury recalled in the history. This group included patients with postseizure transient or permanent neurological deficits and/or developmental delay. Group C: Nonprolonged Seizure Initial Precipitating Injury. These patients had several nonsignificant brief seizures that occurred prior to age 5 years which were often associated with mild systemic childhood illness and/or fever over several months or years. These events were associated with only brief loss of consciousness, if any, and were not suggestive of status epilepticus. The patients were often diagnosed as having childhood epilepsy, and there was no postictal or interictal clinical information that suggested a neurological deficit, developmental delay, or cerebral pathology. Patients in this group and some of the patients in Group B would fit the clinical diagnosis of febrile convulsions. Group D: Older Initial Precipitating Injury. This group includes patients with any initial precipitating injury after age 5 years, a documented latent period, followed by chronic TLE. Group E: Idiopathic TLE. These patients had no known significant medical illnesses or history of seizures prior to the onset of chronic TLE. In other words, they experienced idiopathic temporal lobe seizures. The dependent variables included reliable measures about the time course of the patients seizure histories and quantified hippocampal neuron densities. The clinical variables abstracted from their medical records were: 1) onset of chronic TLE defined as the age at which the patient s typical intractable seizures were first recognized by physicians and/or family; 2) age at surgery; and 3) side of surgical resection. Neuroimaging included the interpretation of MR imaging and positron emission tomography (PET) investigations made prior to surgery. Each patient experienced a latent period, defined as the interval in years from the initial precipitating injury until the onset of intractable chronic TLE. The duration of habitual epilepsy was defined as the interval between the onset of TLE and surgery. All data were collected without knowledge of the assignment of initial precipitating injury classifications. Seizure Outcome Data Patient follow-up data were obtained using a standardized format that abstracted information from the medical record and research files. This information was collected independently of the other clinical information listed previously. Outcome was classified according to the incidence of seizures for the most recent 12-month period, and the number of years since surgery was also recorded. Hippocampal Pathological Analysis Specimens were collected in the operating room, processed for neo-timm s histochemistry using a rigorous protocol, and the results were quantified as described elsewhere. 4,6,7,36 Neuron densities were counted in a manner previously outlined. 3,5,34,36 Cell counts were performed in the hippocampal subfields based on the classification of Lorente de Nó. 33 Use of control tissue was the same as previously described, 36 and for ease of interpretation, results were presented as the percent of neuron loss relative to controls. Data Analysis Data were entered into a database on a personal computer and analyzed using a statistical program.* Differences between the groups were compared statistically using an analysis of variance (ANOVA) and further compared between individual groups (at p 0.05) using the Games Howell multiple comparisons for unequally sized samples and variances. Other statistical tests used as appropriate included chi-square and Student s t-test. The results were illustrated with commercially available graphing software. Results Profile of the Initial Precipitating Injury The 20 patients were catalogued into one of five groups as shown in Table 1. Of note, it was impressive that families could recall and provide very clear detailed histories concerning the circumstances of the initial precipitating injury. These injuries were recorded in 18 of the 20 TLE patients (90%; Groups A, B, C, and D), all of whom had MTS on pathological examination (see below); idiopathic TLE was noted in two patients (10%; Group E), neither of whom had MTS. Sixteen patients had initial precipitating injuries that occurred before age 5 years (Groups A, B, and C; 80%), and two patients experienced the injury later in life, at ages 10 and 29 years (Group D; 10%). Initial precipitating injuries with seizures were found in 11 of the 20 patients (Groups B and C; 55%), and a prolonged seizure initial precipitating injury occurred in seven patients (Group B; 35%). However, seven patients (35%) in Groups A and D had a nonseizure initial precipitating injury that involved some systemic illness or trauma that probably injured the brain. Initial Precipitating Injuries Occurring Before 5 Years of Age For Groups A, B, and C the clinical features are summarized in Table 2. The mean age of patients at the time the initial precipitating injury occurred for all three groups was 11 months, with a range of 0 to 48 months and a median of 9 months. The clinical features of these groups were similar with one exception. The length of the latent period was significantly shorter (ANOVA; p 0.05, see Table 2 and Fig. 1) for patients with nonprolonged * Super ANOVA Version 1.1 obtained from Abacus Concepts, Inc., Berkeley, California. DeltaGraph Professional purchased from DeltaPoint, Inc., Monterey, California. 222 J. Neurosurg. / Volume 82 / February, 1995

4 Clinical injury and epileptic pathophysiology seizures (Group C; 4.8 years) than for nonseizure patients (Group A; 17.3 years; at p 0.05 Games Howell). Prolonged seizure initial precipitating injuries (Group B) had latent periods that averaged 11.1 years. Initial Precipitating Injuries and Preoperative Neuroimaging The University of California at Los Angeles has used two neuroimaging modalities, MR imaging and PET (18- fluoro-2-deoxyglycose). During the time course of this study the use of MR imaging as a preoperative adjunct changed from one that excluded extrahippocampal mass lesions to one that localized hippocampal pathology. From 1988 to mid-1990, mesial temporal damage was assessed based on T 1 - and T 2 -weighted signal changes suggesting atrophy and/or damage between the two hippocampi on axial images. Nine patients were studied, four (44%) of whom had lateralized findings. From mid-1990 to 1992, a more rigorous protocol for MR imaging was introduced, consisting of coronal images oriented perpendicular to the hippocampal axis. This enhanced the anatomy of the hippocampal region, and atrophy of one hippocampus compared to the other was determined on visual qualitative inspection by the neuroradiologist. Of 11 patients studied, five (45%) showed unilateral atrophy and one (9%) showed bilateral atrophy of the hippocampus. None of the patients studied had unilateral abnormalities shown on the MR imaging opposite to the side eventually resected. Positron emission tomography findings were important criteria for determining a patient s candidacy for surgery, and localized abnormalities were found in 16 of 20 patients (80%). Unilateral abnormalities on MR imaging or PET for the groups of patients who had initial precipitating injuries are shown in Table 3. Hippocampal abnormalities were found on MR imaging significantly (p 0.05) more frequently in Groups A and B (nine of 12; 75%) who had significant initial precipitating injuries that occurred prior to 5 years of age compared to Groups C, D, and E (0 of 8; 0%) who either had nonprolonged seizure initial precipitating injuries occurring before 5 years of age (C), injuries after 5 years of age (D), or idiopathic FIG. 1. Graph showing a comparison of the onset of chronic mesial temporal lobe epilepsy in three groups of patients with different types of initial precipitating injuries that occurred prior to 5 years of age. Individual patients are shown by the open symbols and the mean and standard error of the mean are illustrated by the solid circle and bars. Nonseizure initial precipitating injuries (Group A; open circles) had the longest average latent period with a mean of months. Prolonged seizure initial precipitating injuries (Group B; open triangles) had a mean latent period of months. Nonprolonged initial precipitating injuries (Group C; open boxes) had the shortest latent periods with a mean of months. The mean lengths of the latent periods were significantly different between the three initial precipitating injury groups (p 0.05; Table 2). Notice that half (eight of 16) of the patients experienced onset of their habitual temporal lobe epilepsy (TLE) before 10 years of age (data points shown below the dashed line). TLE (E). Abnormalities appearing on PET were uniformly distributed among all groups with initial precipitating injury (see Table 3). On PET interictal hypometabolism abnormalities of the temporal lobe and hippocampus were detected significantly more often than on MR imaging (45% vs. 80% respectively; p 0.05). J. Neurosurg. / Volume 82 / February,

5 G. W. Mathern, et al. Initial Precipitating Injury and Hippocampal Pathology The quantitative amounts of fascia dentata mossy fiber puncta densities, the inner molecular layer/stratum granulosum (IML/SG) mossy fiber sprouting ratios, and hippocampal neuron losses for the categories of initial precipitating injury are shown in Table 4. There are several important findings listed in this table. 1) The inner molecular layer mossy fiber puncta densities were significantly different between the categories (ANOVA; p 0.05). Idiopathic TLE (Group E) and nonprolonged seizure initial precipitating injuries (Group C) had significantly lower inner molecular layer puncta counts compared to nonseizure initial precipitating injuries (Group A) and prolonged seizure initial precipitating injuries (Group B; at p 0.05; Games Howell). Furthermore, older initial precipitating injuries (Group D) had significantly less inner molecular layer puncta than nonseizure initial precipitating injuries (Group A; p 0.05). 2) The stratum granulosum mossy fiber puncta densities were not significantly different between the categories of initial precipitating injury (p = 0.67). 3) The IML/SG puncta ratios were significantly different between the categories (ANOVA; p 0.05), with idiopathic TLE (Group E) significantly less than nonseizure initial precipitating injuries (Group A; at p 0.05, Games Howell). 4) The averaged Ammon s horn neuron counts were significantly different between categories (ANOVA; p 0.02) with idiopathic TLE (Group E) significantly less (p 0.05) than nonseizure, prolonged seizure, and nonprolonged seizure initial precipitating injuries (Groups A, B, and C). Most of the inner molecular layer mossy fiber sprouting occurred in patients with significant nonseizure and prolonged seizure initial precipitating injuries (Groups A and B). This is illustrated in Fig. 2, in which the inner molecular layer mossy fiber puncta densities of Groups A and B are compared with Groups C, D, and E, which included either nonprolonged or older initial precipitating injuries or idiopathic TLE. The difference was highly significant (p 0.001; Student s t-test). FIG. 2. Graph showing a comparison of the amount of inner molecular layer (IML) mossy fiber (MF) puncta densities in patients with significant childhood initial precipitating injuries (Groups A and B) compared to patients with nonprolonged initial precipitating injuries (Group C), older initial precipitating injuries (Group D), and idiopathic temporal lobe epilepsy (TLE) (Group E). The average densities ( standard error of the mean) of IML MF puncta for Groups A and B were puncta/10 m 2 and the average densities for the other TLE patients were puncta/10 m 2 (see solid circles for means and standard error of the mean bars). The difference of the means between these two categories was statistically significant (p 0.001; Student s t-test). Comparison of Atrophy and Pathology in the Hippocampus Temporal lobe epilepsy patients with hippocampal signal changes (pre-1990 patients) or atrophy (post-1990 patients) were compared to patients with normal MR images. There were no significant differences in: 1) average Ammon s horn neuron counts, 2) neuron loss in any hippocampal subfield, 3) mossy fiber puncta densities in either the stratum granulosum or inner molecular layer, or 4) the IML/SG mossy fiber sprouting ratios. Seizure Outcome and Initial Precipitating Injuries The seizure outcome and average years of follow-up review for the categories of initial precipitating injury are shown in Table 5. As a whole, significant seizure relief occurred in 14 of 18 patients (77%). One patient from Group A continued to have seizures less than one year from surgery and one patient from Group B died 4 weeks postoperatively (an autopsy was performed). Groups B, C, and D showed the greatest relief from seizures (12 of 12; 100%). However, Groups A and E did not fare as well. In nonseizure initial precipitating injuries (Group A) two patients were free from seizures and the other two had rare complex partial seizures. In idiopathic TLE (Group E) both individuals continued to have seizures postoperatively with the frequency of seizures not markedly altered. The difference in seizure outcome in Groups A and E compared to Groups B, C, and D was significant (p 0.005) by chi-square analysis. 224 J. Neurosurg. / Volume 82 / February, 1995

6 Clinical injury and epileptic pathophysiology Discussion In TLE patients the presence and type of initial precipitating injury and the age of the patient when the injury occurred was significantly related to the latent period before onset of chronic seizures, the pathological findings in the hippocampus at surgery, and relief from seizures following en bloc temporal lobectomy. This retrospective surgical series found initial precipitating injuries in 90% of nonlesion TLE patients, all of whom had MTS. Initial precipitating injuries were listed in the case histories of patients who did well following en bloc temporal lobectomy. Patients with idiopathic TLE showed significantly fewer inner molecular layer mossy fiber sprouting, less neuron losses, and continued to have seizures after surgery compared to patients with initial precipitating injury. Patients with a history of a significant initial precipitating injury that occurred prior to age 5 years (Groups A and B) were more likely to have unilateral hippocampal atrophy on MR imaging and more aberrant inner molecular layer mossy fiber sprouting than other TLE patients (Groups C, D, and E). These results support the hypothesis that the type of initial precipitating injury and the age at which it occurred may determine the pathological substrate that may eventually develop into MTS and intractable TLE. In other words, the pathological substrate left after the hippocampus has been injured may not necessarily be a static insult that immediately forms an epileptogenic region. Rather, it is possible that the injured hippocampus progressively changes over time, depending on the extent and type of the initial injury, into an epileptogenic focus that pathologically shows MTS. It should be emphasized that a retrospective study can only infer these conclusions and additional prospective studies will be necessary. These results must be interpreted with caution. A human study of 20 patients is not a large series. In some groups of initial precipitating injury the numbers were small, and the data showed some biological variability. Our results will need to be confirmed in a larger prospective study. Our interpretations are based on the concept that it was the initial precipitating injury per se that was the important factor initiating the hippocampal pathological substrate. Other factors such as metabolic changes during the initial precipitating injury and the possible contribution of subclinical seizure activity during and after the injury need to be considered. Nevertheless, even with small numbers we found statistical significance, and our findings strongly support the notion that the initial precipitating injury may influence some clinical and pathological features of patients who later develop intractable TLE. The results also suggest that the pathophysiological process of MTS was not necessarily age dependent. Two of our patients had initial precipitating injuries at age 10 and 29 years and both showed MTS on pathological examination of the hippocampi. These data suggest that the reason that MTS has been associated with childhood is that children are the population more often exposed to injuries that could initiate the MTS pathophysiological process. However, the process itself may occur at any time throughout a human s life. The data from this study show interesting similarities to and differences from a paper Falconer and Taylor 18 published 25 years ago. At the time, the authors reported several clinical features associated with MTS. For example, they found that a history of a difficult birth was not an important feature in MTS (only 10% in our study). An incidence of severe illness in childhood, defined as status epilepticus, prolonged febrile convulsions, severe infections, and head injury were noted by Falconer and Taylor in 70% of their MTS patients (77% in our series). Thirty percent of their patients (35% in our study) presented with prolonged seizures, and 64% of their MTS patients (50% in our series) experienced the onset of chronic seizure before age 10 years. Similar findings were reported by Bruton 9 who retrospectively surveyed all of Falconer s surgical specimens from 1950 to The striking difference between Falconer and Taylor s paper and the present one is that MTS was found in only 47% of their first 100 cases, whereas it was found in 90% of the present surgical series. Thus, it appears that the selection criteria for surgery have improved over the past 25 years. However, despite the evolution of medical practice, with more aggressive medical treatment given at the onset of new seizures in children, the clinical character of TLE associated with MTS is still very much the same as 25 years ago. Our findings are consistent with data from animal studies 11,32,34,35,40 and suggest that the initial hippocampal injury should satisfy two objectives: 1) the injury must be sufficient to deafferent the supragranular target dendrites by destroying hilar and mossy cells, and 2) the injury cannot be so severe as to destroy too many granule cells, thereby preventing the mossy fibers from sprouting. As these mossy fibers form aberrant synaptic contacts, the reorganized circuit may be physiologically incompatible with neuronal survival. This may lead to a cycle of progressively more hippocampal neuron loss, and more mossy fiber reactive synaptogenesis until the hippocampus assumes the profile of neuron loss and mossy fiber reactive synaptogenesis that is the hallmark of MTS 6,7 and functional epileptogenesis. 1,2 This hypothesis will require further study in animal models and human subjects, but it is supported by the results of this study for the reasons indicated below. In this study, all patients who did well following temporal lobectomy had initial precipitating injuries; the two J. Neurosurg. / Volume 82 / February,

7 G. W. Mathern, et al. patients with idiopathic TLE (Group E) had no MTS and continued to have seizures following resection. This implies that a patient with idiopathic TLE may not be as good a surgical candidate as one who had an initial precipitating injury. In Falconer s series 9 histories of birth injuries, head injuries, febrile convulsions, or status epilepticus were noted in 97 (94%) of 103 MTS cases. The author noted that other possible predisposing factors may have been missed because clinical notes were incomplete, information was not known, or patients could not attend follow-up visits. It will be important to study quantitative hippocampal pathology in a larger prospective study of similar cases to confirm this notion. The identification of hippocampal atrophy on MR imaging has generated considerable interest as a means of localizing the area of hippocampal damage that is epileptogenic. 25 Our data obtained from MR imaging agree with the emerging consensus that unilateral hippocampal atrophy is a fairly specific lateralizing marker that is strongly associated with MTS. 24,26 However, our study also shows that the alternate statement is not true. Mesial temporal sclerosis as defined by neuron counts and mossy fiber neosynaptogenesis could be found in patients who did not have unilateral hippocampal atrophy on MR imaging. Our data also showed that atrophy was more likely if the patient had had an initial precipitating injury that occurred before 5 years of age and suggest that the developmental age may be an important determinant of eventual hippocampal atrophy. Hence, hippocampal atrophy may represent pathological damage at a very young age and/or alternately the subsequent failure of the immature hippocampus to grow following an injury. The human hippocampus, like the rest of the brain, grows considerably in volume over the first 2 years of life, gaining 80% of its final size. 23,30,31,41 It is possible that a focal pathological injury to the developing hippocampus during brain growth might stop the normal maturational process and prevent the increase in hippocampal volume. The remaining brain would continue to mature and grow, leaving behind the injured smaller hippocampus. The result shown on an adult MR image would be a small hippocampus. This notion suggests that the number of neurons that occupy only a fraction of the volume of the hippocampus may not be an important contributor to hippocampal atrophy but instead it is the type of injury and the patient s age at occurrence that influence the MR imaging findings. Additional studies comparing larger numbers of patients will be necessary to confirm this hypothesis. Conclusions This study has shown that a patient s initial precipitating injury is probably critical to the pathophysiological process that leads to TLE and the pathological changes observed in the hippocampus. Furthermore, the type and severity of the initial precipitating injury and the patient s age at which it occurs may be important adjuncts in determining surgical candidacy and potential relief of intractable seizures following surgery. Acknowledgment The authors wish to thank the many members of the UCLA Clinical Neurophysiology Program, who over the years have consistently collected, recorded, and maintained the patient data files and information used in this study. References 1. Babb TL: Research on the anatomy and pathology of epileptic tissue, in Luders H (ed): Epilepsy Surgery. 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8 Clinical injury and epileptic pathophysiology 23. Humphrey T: Correlations between the development of the hippocampal formation and the differentiation of the olfactory bulbs. Ala J Med Sci 3: , Jack CR, Sharbrough FW, Twomey CK, et al: Temporal lobe seizures: lateralization with MR volume measurements of the hippocampal formation. Radiology 175: , Jackson GD, Berkovic SF, Duncan JS, et al: Optimizing the diagnosis of hippocampal sclerosis using MR imaging. AJNR 14: , Jackson GD, Berkovic SF, Tress BM, et al: Hippocampal sclerosis can be reliably detected by magnetic resonance imaging. Neurology 40: , Jackson JH: On a particular variety of epilepsy ( intellectual aura ), one case with symptoms of organic disease. Brain 11: , Jackson JH: On the anatomical and physiological localisation of movements in the brain, in Taylor J (ed): Selected Writings of John Hughlings Jackson. London: Hodder & Stoughton, 1931, pp Jackson JH, Colman WS: Case of epilepsy with tasting movements and dreamy state very small patch of softening in left uncinate gyrus. Brain 21: , Jacobson M: Developmental Neurobiology, ed 3. New York: Plenum Press, 1991, pp 60 and Kretschmann HJ, Kammradt G, Krauthausen I, et al: Growth of the hippocampal formation in man. Bibl Anat 28:27 52, Leite JP, Bortolotto ZA, Cavalheiro EA: Spontaneous recurrent seizures in rats: an experimental model of partial epilepsy. Neurosci Biobehav Rev 14: , Lorente de Nó R: Studies on the structure of the cerebral cortex. II. Continuation of the study of the ammonic system. J Psychol Neurol 45: , Mathern GW, Cifuentes F, Leite JP, et al: Hippocampal EEG excitability and chronic spontaneous seizures are associated with aberrant synaptic reorganization in the rat intrahippocampal kainate model. EEG Clin Neurophysiol 87: , Mathern GW, Kupfer WR, Pretorius JK, et al: Onset and patterns of hippocampal sprouting in the rat kainate seizure model: Evidence for progressive cell loss and neo innervation in regio inferior and superior. Dendron 1:69 84, Mathern GW, Pretorius JK, Babb TL: Quantified patterns of mossy fiber sprouting and neuron densities in hippocampal and lesional seizures. J Neurosurg 82: , Nadler JV: Seizures and neuronal cell death in the hippocampus, in The Hippocampus New Vistas. New York: Alan R Liss, 1989, pp Quaerens: A prognostic and therapeutic indication in epilepsy. Practitioner 4:282, Sano K, Malamud N: Clinical significance of sclerosis of the cornu Ammonis; ictal psychic phenomena. Arch Neurol Psychiatry 70:40 53, Sundstrom LE, Mitchell J, Wheal HV: Bilateral reorganization of mossy fibers in the rat hippocampus after a unilateral intracerebroventricular kainic acid injection. Brain Res 609: , Wyss JM, van Groen T: Development of the hippocampal formation, in: The Hippocampus New Vistas. New York: Alan R Liss, 1989, pp 1 16 Manuscript received August 25, Accepted in final form June 1, This work was supported by NIH Grant NS and a Clinical Investigator Development Award (K08 NS 1603) to GWM, and the UCLA Division of Neurosurgery. Address reprint requests to: Gary W. Mathern, M.D., Division of Neurosurgery, Reed Neurological Research Center, Room 2144, UCLA Center for Health Sciences, Los Angeles, California J. Neurosurg. / Volume 82 / February,