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Keywords:

  • Hippocampal sclerosis;
  • Extratemporal epilepsy;
  • Aetiology;
  • Dual pathology

Abstract

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgments
  7. REFERENCES

Summary: Purpose: Hippocampal sclerosis (HS) is the most common lesion underlying drug-resistant temporal lobe epilepsy. Whether HS is a developmental or acquired pathology remains unclear. Whereas HS has been causally linked to prolonged febrile convulsions in childhood, evidence also exists that it may coexist with extrahippocampal abnormalities, the concept of “dual pathology.” The aims of this study were to address whether hippocampal abnormality consistent with HS (a) occurs in children with lesional extrahippocampal epilepsy, (b) is more commonly seen in association with developmental rather than acquired extrahippocampal pathologies, and (c) whether any effect of age at seizure onset is found on the occurrence of HS in lesional extrahippocampal epilepsy.

Methods: Clinical and histopathologic data of patients having resective surgery for extrahippocampal epilepsy that included the hippocampus were investigated.

Results: Twenty-nine children were retrospectively included in this study, and 21 (72%) of 29 were found to have a hippocampal abnormality consistent with HS. No relation was noted between developmental or acquired extrahippocampal pathologies and the presence of hippocampal abnormality. Children with normal hippocampi on visual histologic assessment had a significantly younger age at seizure onset (p < 0.001). Duration of epilepsy was not correlated with the presence of hippocampal abnormality.

Conclusions: Hippocampal abnormalities are seen in similar proportions with both acquired and developmental extra-hippocampal pathologies, suggesting that these abnormalities are the result of seizures from the focus that is remote from the hippocampus. In addition, children who have their initial seizure at an early age are less likely to develop seizure-induced hippocampal injury.

The role of hippocampal sclerosis (HS) in epilepsy has been recognized for more than a hundred years. It is associated with intractable temporal lobe epilepsy and is the most common pathology identified in those patients who require surgical intervention. Sommer (1) first described the histologic features of HS in 1880 in a 25-year-old patient. He recognized a well-defined pattern of cell loss in the pyramidal layer of the hippocampus, with greater neuronal loss in CA1 and the prosubiculum (subsequently called Sommer's sector) than in the end folium (CA3 and CA4) or in the dentate gyrus. Falconer and Taylor (2) later used the term mesial temporal sclerosis, recognising that changes were frequently seen in the amygdala, uncus, and temporal lobe in association with HS. Since then, debate has occurred over whether HS is a developmental or an acquired lesion.

It is clear that HS can be acquired in animal models of limbic status epilepticus. Some data show evidence of hippocampal injury that matures into structural abnormalities similar to human mesial temporal sclerosis (3–5). Many of these animals will develop spontaneous recurrent seizures similar to human temporal lobe epilepsy. In humans, the most recognized association with HS is a prolonged febrile convulsion in childhood, and evidence for HS being acquired is accumulating in humans (2,6). In addition, magnetic resonance imaging studies have shown evidence for acute hippocampal injury associated with prolonged febrile convulsions (7–9), suggesting that a prolonged febrile convulsion could cause acute hippocampal injury leading to the subsequent development of HS.

It is likely, however, that more than one type of HS exists (10–12). HS, as described by Sommer, may represent the histologic appearance of the hippocampus at one point in a spectrum of damage that may range from severe neuronal loss in all hippocampal subzones to a minimal lesion in which loss of neurons is restricted to the end folium (13). In addition to HS recognized in children with a history of prolonged febrile convulsion, abnormality consistent with HS may be seen in patients with other lesions, including developmental anomalies in the hippocampus, the temporal lobe, or more extensively within the brain, described as dual pathology (12,14–16). The exact relations between these developmental anomalies and HS also are uncertain. It is possible that both lesions independently predate the onset of epilepsy. It is also possible that subtle areas of dysgenesis within the hippocampus itself may provide the substrate for a prolonged seizure and the subsequent development of HS (14). In pediatric surgical series, few data clarify the relations between developmental anomalies and HS. Subtle magnetic resonance imaging abnormalities, consistent with seizure-induced injury, have been identified in hippocampi that are not the primary seizure focus (9), and histologic data that show that extrahippocampal childhood seizures are associated with neuronal loss and mossy fibre sprouting within the hippocampus (17). The finding of hippocampal abnormality with postnatally acquired ischemic and encephalitic brain insults, as well as with cortical dysplasia, may be evidence against HS preexisting as a developmental lesion.

In animal models of epilepsy, susceptibility to seizure-induced hippocampal damage has been shown to be less in the immature animal than in the more mature animal (18–22). Severe seizures in the immature animal may occur without histologic evidence of hippocampal damage. Given these data, if HS is acquired after the onset of extrahippocampal seizures in humans, one might expect that it would be less common in children with early onset of seizures, particularly as the presence of HS has not consistently been shown to be related to the duration of epilepsy (17,23). Children with extrahippocampal pathologies and epilepsy, who undergo multilobar resection or hemispherectomy in which tissue from the hippocampus is obtained, provide a group in which some of the important questions regarding the relations between HS, coexisting developmental malformations, and age at onset of epilepsy may be addressed.

The aims of this study were therefore

  • 1
    To determine how frequently histologic evidence of HS is seen in children with intractable epilepsy in the context of major extrahippocampal pathologies requiring surgery.
  • 2
    To identify whether the frequency with which HS occurs is different in children with developmental extrahippocampal pathologies when compared with those with acquired extrahippocampal pathologies.
  • 3
    To investigate whether age at seizure onset influences the occurrence of HS in children with lesional extrahippocampal epilepsy.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgments
  7. REFERENCES

Clinical and pathologic data of patients having resective brain surgery, including the hippocampus, for lesional extrahippocampal epilepsies were reviewed. All children had been evaluated in the Epilepsy Surgery Programme at Great Ormond Street Hospital for Children NHS Trust, London, U.K. Routine preoperative evaluation included clinical review, documentation of seizures with video-EEG telemetry recording, ictal and interictal single-photon emission computed tomography (SPECT), magnetic resonance imaging, as well as neuropsychiatric and neuropsychological assessments. The decision to proceed to surgery was made after multidisciplinary discussion. Patient notes were reviewed for age at seizure onset, seizure semiology, duration of seizures, age at surgery, and history of febrile convulsion or status epilepticus. Seizures were classified as temporal or extratemporal in origin, based on clinical and EEG data. Clinical localization to the temporal lobe was accepted if any one of the following was present: behavioral arrest, oroalimentary automatisms, stereotyped complex automatisms with postictal confusion, psychic aura such as fear or déjà vu, an aura of a formed auditory or visual hallucination, a distinct epigastric aura, speech impairment before or immediately after the seizure, or nonspecific aura or automatisms followed by postictal confusion (24–26). Localization to the frontal lobe was considered if the seizures were brief, rapid onset or offset to the seizure occurred, nocturnal bias, bizarre behaviour or vocalization, and predilection to clustering (27–29). An occipital origin was suggested if elemental visual hallucinations, contralateral eye deviation, or ictal blindness was found (27). Laterality was based on lateral motor phenomena (e.g., limb jerking or dystonia) or lack of speech disturbance during or speech disturbance immediately after the seizure (30,31). Corroborative EEG data were available in all patients.

Histologic methods

At surgery, the temporal lobe structures including the hippocampus were resected en bloc, providing good-quality specimens for histologic analysis. Resected tissue from the extrahippocampal region and the hippocampus was rapidly fixed in 10% formalin and processed for paraffin wax histology. Sections were stained routinely with hematoxylin-eosin, hematoxylin van Gieson, luxol fast blue-cresyl violet, and for immunocytochemistry with a variety of antibodies including glial fibrillary acidic protein (GFAP), neurofilaments, and synaptophysin. The histopathology of the extrahippocampal lesion and hippocampus in each patient was visually assessed by a single observer who was unaware of the clinical data (B.H.), and cases were divided into two groups: those with abnormal hippocampal histology (ranging in severity from histologic evidence of neuronal loss in all hippocampal subzones at the more severe end of the spectrum to the finding of end-plate gliosis at the milder end of the spectrum of HS) and those with hippocampi that were histologically normal on visual assessment (13).

Data analysis

SPSS for Windows (version 11, Chicago, IL, U.S.A.) was used for the analysis. χ2 analysis was used to investigate the relation between type of pathology (i.e., developmental or acquired) and HS. To address whether the age at seizure onset was lower in patients with normal hippocampi compared with patients with HS, the data were transformed and analysed by using an independent samples t test (not assuming equal variances). The relation between duration of epilepsy and age at operation and the presence of HS, and the relation between age at seizure onset and type of pathology (developmental or acquired) were investigated by using a Mann–Whitney U test. χ2 analysis was carried out to investigate the relation between a history of febrile convulsion or status epilepticus and HS.

RESULTS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgments
  7. REFERENCES

Patient population

A cohort of 29 children who had resective surgery for lesional epilepsy that included the hippocampus between 1990 and 1999 was enrolled consecutively in the study; 27 had undergone hemispherectomy, and two had undergone multilobar resection including the temporal lobe. Fifteen male patients were in the group. Age at seizure onset ranged from day 1 of life to 7 years (median, 6 months). Age at the time of surgery ranged from 4.5 months to 17 years (median, 7 years 9 months), and duration of epilepsy ranged from 3 months to 16 years 11 months (median, 4 years 10 months). The extrahippocampal pathology associated with epilepsy requiring surgical treatment was the consequence of a vascular/ischaemic pathology in 15 children, as a result of a developmental anomaly in 12 children, and due to Rasmussen encephalitis in two children (Table 1). Developmental anomalies included hemimegalencephaly (two of 12), pachygyria (two of 12), polymicrogyria (four of 12), and other cortical dysplasias (four of 12). Vascular pathologies included Sturge–Weber Syndrome (four of 15), middle cerebral artery territory infarcts (five of 15), and more widespread vascular pathology or hemispheric encephalomalacia (six of 15). The six patients with more widespread vascular/ischaemic pathology had aetiologies that included nonaccidental injury, hemolytic uremic syndrome, and extreme prematurity with intraventricular hemorrhage. None of these children had a history of perinatal hypoxic ischemic encephalopathy.

Table 1. Patient demographics with the associated hippocampal histology
 Hippocampal sclerosis (n = 21)Normal hippocampi (n = 8)
  1. Ages and duration are expressed as range (median).

  2. SWS, Sturge–Weber syndrome.

Male105
Female113
Age at onset (mo)0.03–84 (13)0.13–6 (0.8)
Age at surgery (mo)11–192 (100)4.5–204 (19)
Duration (mo)8–187.5 (77)3–203 (15.2)
Cortical dysplasia (n = 12)75
Vascular/ischemic (n = 15)12 (3 SWS)3 (1 SWS)
Rasmussen encephalitis (n = 2)20

Hippocampal histology and lesional pathology

Histologic examination of the resected hippocampi revealed that 21 of 29 children had histologic evidence of HS, and in eight of 29, the hippocampus was histologically normal on visual assessment. Eleven of the 21 children with HS had hippocampal histology consistent with classic HS as described by Sommer (1), 10 of 21 had less severe involvement with hippocampal end-plate gliosis and sparing of neurons in the CA1 sector (Fig. 1).

image

Figure 1. The histologic findings in the hippocampus in patients in the current study. Staining is either with hematoxylin–eosin or luxol fast blue-cresyl violet. i, ii: Examples from two of the 11 patients in this study who were determined to have classic hippocampal sclerosis on visual assessment. Slides demonstrate pronounced loss of pyramidal cells in sector CA1 (*). iii, iv: Examples from two of 10 patients in this study who were found to have a minimal form of hippocampal sclerosis with evidence of neuronal loss and gliosis in the hippocampal end plate only (**). v: Example from one of the eight patients determined to have hippocampi that were classified as normal on visual inspection.

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Overall, seven (58%) of 12 patients with developmental anomalies and 12 (80%) of 15 patients with vascular/ischaemic pathology had histologic evidence of HS. No association was found between the type of extrahippocampal pathology (developmental or acquired) and the presence of HS [χ2 (1 df) = 2.03; p = 0.15]. Only one of the 29 patients was found to have a developmental anomaly within the hippocampus coexisting with HS. This patient had evidence of neuronal heterotopia within the hippocampus with an ischemic extratemporal pathology of porencephaly in the distribution of the left middle cerebral artery.

In only four of 21 patients with histologic evidence of hippocampal abnormality had preoperative imaging demonstrated this. The hippocampus in these patients was reported as either being atrophic (n = 3) or having abnormal signal (n = 1). None of the patients with normal hippocampi at histology had been documented as having abnormality noted within the hippocampus on preoperative imaging.

Early seizures and hippocampal abnormality

All children with visually normal hippocampi had onset of seizures at or younger than 6 months, and this was significantly younger than in children with HS (graph 1; t (25.16 df) = 4.41; p < 0.001). As the data were transformed for analysis, mean and confidence intervals are not reported. No significant difference was found with regard to age at surgery (Mann–Whitney U= 52; p = 0.12) or duration of epilepsy (Mann–Whitney U= 55; p = 0.16) between children with visually normal hippocampi and those with HS. Children with younger age at seizure onset were more likely to have a developmental anomaly as the extrahippocampal pathology (Mann–Whitney U= 35.5; p = 0.003).

image

Figure Graph 1. . Scatterplot of raw data for age at seizure onset (mo) related to hippocampal histology. HS, hippocampal sclerosis; HN, visually normal hippocampal histology. A reference line is inserted at age of seizure onset (6 months).

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Seizure semiology and EEG features

Localization of seizure onset was verified by ictal video-EEG findings in 20 of 29 patients in this study. In the remaining nine of 29 cases, the likely seizure onset was determined by semiology and interictal EEG findings alone. In six of nine, seizure onset consisted of focal motor jerks (with retained consciousness in all except one), in one of nine, tonic seizures with head deviation were seen, and in one of nine, semiology consisted of blinking with head nodding and deviation. From semiology, none of these seizures was determined to be of temporal onset. In one of nine, seizure semiology included an aura of strange tastes followed by oromotor automatisms. This patient had generalised bursts of discharges on interictal EEG. Seizures in this patient were determined to be of temporal onset, based on semiology.

On this basis, 16 of 21 children with HS had seizures thought to be only of extratemporal origin, four of 21 had evidence of both temporal and extratemporal seizure onset, and in one, the seizure origin could only be lateralized (Table 2). Six of the eight children with normal hippocampal histology had seizures of extratemporal origin alone, one had possible temporal lobe seizure onset in addition to extratemporal seizures, and in one, the seizures could only be lateralized. The majority of children with HS had no evidence of temporal lobe seizure onset, suggesting that, even in the context of widespread extratemporal abnormalities requiring major resective surgery, the seizure focus requiring surgical resection was remote from the abnormal hippocampus.

Table 2. Seizure-onset localization and history of febrile convulsion or status epilepticus related to hippocampal histology
Seizure onsetHippocampal sclerosis (n = 21)Normal hippocampi (n = 8)
Extratemporal seizure onset (n = 22)16 6
Extratemporal and temporal seizure onset (n = 5)41
Seizure onset unclear (n = 2)11
Febrile convulsion41
Status epilepticus53

Of the six of eight patients with normal hippocampi and extratemporal seizure onset alone, two of six were noted to have involvement of the temporal lobes ictally [centrotemporal discharges (n = 1), independent right and left temporal sharp waves (n = 1), posterior temporal discharges (n = 1)]. Ictal recording was not available in two of six. Of the 16 of 21 patients with abnormal hippocampal histology and extratemporal seizure onset alone, ictal temporal involvement was noted in three of 16 [posterior temporal discharges (n = 2), prominent centrotemporal discharges (n = 1)]. Ictal recording were not available for six of 13 patients. Therefore as ictal temporal involvement was noted in patients both with and without hippocampal abnormality, it is unlikely that the pattern of seizure spread from the extratemporal focus alone explains the hippocampal injury.

Association with febrile convulsion/status epilepticus

A history of febrile convulsion was identified in four of 21 patients with HS and in one of eight children with normal hippocampal histology (see Table 2). A history of status epilepticus (defined as a seizure or series of seizures lasting ≥30 min) was seen in five of 21 children with hippocampal abnormalities and in three of eight children with normal hippocampi. In this group of patients with extrahippocampal lesional epilepsy, no association was noted between history of febrile seizure or status epilepticus and HS [χ2 (1 df) = 0.07; p = 0.8].

DISCUSSION

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgments
  7. REFERENCES

The major findings of this study are as follows.

  • 1
    Histologic evidence of HS is commonly seen in children with intractable extrahippocampal lesional epilepsy.
  • 2
    The presence of HS is not significantly related to whether the extrahippocampal pathology is a developmental or an acquired lesion.
  • 3
    In children with extrahippocampal lesional epilepsy, those with younger age at seizure onset (younger than 6 months) are less likely to have histologic evidence of HS.

HS occurs in lesional extratemporal epilepsy but is not related to extratemporal pathology

The data in this study show that HS can occur in association with both developmental and acquired pathologies. When HS is found in association with acquired pathologies, it is possible that it occurred either at the time of the acquired insult or as a result of subsequent seizures from the lesion generated by the acquired insult. HS could also occur as a preexisting lesion in children with developmental brain anomalies, predating the onset of epilepsy. If this were the case, then one might expect that HS would coexist more commonly with hippocampal or extrahippocampal developmental anomalies or both than with acquired pathologies such as vascular/ischemic insults. This was not found in the patients in this study. In addition, only one of the 21 patients with HS had evidence of neuronal heterotopia within the hippocampus itself coexisting with HS and dentate duplication, and in this patient, the primary extratemporal pathology was ischaemic rather than developmental. Thus the common feature of the children in this study is that they have intractable epilepsy, supporting the view that HS is an acquired pathology as a consequence of injury to the hippocampus from seizures originating from the extrahippocampal focus. This view is supported by data from imaging studies that also demonstrate hippocampal abnormality in the context of extrahippocampal seizures (9).

Children with younger age at seizure onset are less likely to have HS

At least three possible mechanisms exist for this finding. It could be that HS occurs less with developmental pathologies that have earlier onset of seizures; children with younger age at initial seizure might have more aggressive epilepsy and earlier resection and thus less time in which to develop HS, or the immature hippocampus may be more resistant to seizure-induced injury than the more mature hippocampus. Children in the current study with earlier-onset seizures were more likely to have developmental anomalies as their pathology. However, HS was not shown to occur more in those children with developmental pathologies when compared with those with acquired pathologies. Many reports exist of dual pathology in the literature, showing that HS can be seen in association with extrahippocampal developmental anomalies (12,14–16). Therefore it is unlikely that the type of pathology is responsible for the lower rate of HS seen in children with younger age at seizure onset. The earlier age at seizure onset was not a reflection of earlier surgery or shorter duration of epilepsy, as neither age at surgery or duration of epilepsy was significantly associated with the presence of HS.

The preferred explanation for the findings of this study is that early age at seizure onset is protective against seizure-induced hippocampal damage. Although paediatric surgical series reporting hippocampal histology are few, other pathology studies have also noted less hippocampal abnormality in children with younger age at seizure onset (17,32,33). Kothare et al. (32) recently reported nine children who underwent functional hemispherectomy for intractable seizures related to cortical dysgenesis (eight patients) or Sturge–Weber syndrome (one patient). All had normal hippocampi. The age at seizure onset for these patients was from 4 h to 22 months (median, 2 months). None of these children had a history of febrile convulsion, although all had prolonged generalised seizures from an early age. Mathern et al. (17), in his series of 28 surgical patients, examined the hippocampi both by morphometric analysis and with neo-Timms staining. Children with extrahippocampal lesional epilepsy and repeated generalised seizures showed evidence of mild aberrant supragranular mossy fibre sprouting and synaptic reorganisation but not to the degree seen in children with hippocampal epilepsy. The former children had only moderate dentate fascia neuron loss and some loss of neurons in Ammon's horn. The children with extrahippocampal lesional epilepsy in this series (n = 11) had a mean age at seizure onset of 4.7 months (±1.2 SEM). Extrahippocampal lesional epilepsy with early-onset seizures in childhood was, therefore, not associated with changes typical of HS. This was true for children with pathologies of developmental malformations and anoxic injuries, consistent with our data and in favour of the argument that this is a true effect of age at seizure onset rather than an effect of the underlying extrahippocampal pathology. Data in the current study also reveal that children who are older than 6 months at time of initial seizure do not appear to have the same resistance to hippocampal injury, and therefore the relation between prolonged febrile convulsion and HS is conserved.

Data from this study suggest not only that less hippocampal damage is found in children with early-onset seizures but also that early-onset seizures may provide ongoing protection from seizure-induced hippocampal injury in later life, as no difference was seen in duration of epilepsy between those with HS and those with normal hippocampi. Data from studies in animal models of epilepsy show the immature hippocampus to be less susceptible to seizure-induced hippocampal injury and to the subsequent development of spontaneous seizures. In very young rat pups, seizures induced by either kainic acid or lithium-pilocarpine fail to cause hilar injury, mossy fibre sprouting, synaptic rearrangement or epileptogenesis (18–22). Even though kainic acid may cause severe seizures in immature rats, this often occurs without histologic evidence of hippocampal damage. This sparing of the immature hippocampus from seizure-induced injury may not be an all-or-none phenomenon and may be different across species. For example, immature rabbits may develop hippocampal injury after status epilepticus (34). It is, however, more difficult to cause hippocampal injury in immature animals, consistent with the findings in the current study. In addition, data from adult animal studies show that previous seizures may reduce the risk of hippocampal injury with subsequent seizures (35–37). Rats that have had kindled seizures before injection with kainic acid, despite having more generalized convulsions and faster development of severe limbic status, have minimal seizure-induced hippocampal injury when compared with rats that have not had seizures before kainic acid administration (35). No reported animal studies have addressed the question as to whether seizures in early life provide protection from seizure-induced hippocampal injury due to ongoing seizures as the animal matures into adult life.

We acknowledge that a single pathologist interpreting the brain tissue may introduce bias and that quantitative measures of assessment of hippocampal neuronal loss were not used in the current study. However, the pathologist was not aware of the clinical details of the patients, thereby reducing bias, and has many years of experience. Some hippocampi classified as normal may have had mild neuronal loss not evident on visual inspection. However, even if a proportion of those hippocampi classified as normal had a mild degree of undetected neuronal loss, this would not have been as great as in those hippocampi that were abnormal to visual inspection, and therefore this is unlikely to have had a significant impact on the findings of this study.

Our data suggest that histologic evidence of HS is common in children requiring surgery for extrahippocampal epilepsy due to both acquired and developmental pathologies and that, in these children, HS is likely to be secondary to injury from seizures originating from the extrahippocampal focus. HS was less common in children with early- rather than late-onset seizures, suggesting that early onset of seizures provides protection against seizure-induced hippocampal injury. The exact mechanisms underlying these findings require further study.

Acknowledgments

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgments
  7. REFERENCES

Acknowledgment:  Research at Great Ormond Street Hospital for Children NHS Trust benefits from R&D funding received from the NHS executive. R.C. Scott is supported by the Wellcome Trust. C.J. Riney is supported by SPARKS. We thank Professor B.G.R. Neville for his help in revising the manuscript.

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  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgments
  7. REFERENCES
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