Dysplasia
A common finding in intractable pediatric temporal lobe epilepsy
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Abstract
Background: Risk factors for temporal lobe epilepsy (TLE) include history of CNS infection, family history of epilepsy, and history of febrile convulsions (FC). Pre-existing cortical dysplasia (CD) may also predispose to refractory TLE, independent of other risk factors for epilepsy.
Methods: The authors reviewed the neuropathologic features of surgical tissue from temporal lobectomies of 33 pediatric patients with refractory TLE, with and without a history of epilepsy risk factors.
Results: CD was found in 64% (21/33) of all patients with refractory TLE, including 73% (11/15) patients with a history of FC, 66% (2/3) patients with CNS infections, and 83% (5/6) patients with a family history of epilepsy. Disrupted cortical lamination, dystrophic and maloriented neurons, and balloon cells characterized the CD found in the temporal neocortex.
Conclusion: CD was seen in 21 of 33 surgical specimens from children with refractory TLE, including those with and without other epilepsy risk factors.
The etiology of temporal lobe epilepsy (TLE) is likely diverse. In some patients, there is evidence of cell loss and synaptic rearrangement in the hippocampus, either in isolation or associated with pathologic lesions of the temporal neocortex. Several lines of evidence support the hypothesis that a pre-existing lesion may predispose a subset of patients to both febrile convulsions (FC) and TLE. There is an increased occurrence of neurologic deficits or prior neurologic insults in those patients with FC that develop epilepsy.3-5⇓⇓ In a small number of patients with prolonged FC, evidence of pre-existing temporal lobe abnormalities was found on MRI scans obtained in the immediate postictal period.6 Finally, animals with developmental lesions have been shown to have a lowered fever-induced seizure threshold.7
There are several risk factors for refractory TLE. One of the most common is prior FC, present in up to 78% of patients undergoing temporal lobectomies.1,2⇓ Several human studies suggest an association between FC and hippocampal sclerosis,8,9⇓ and hippocampal swelling has been found immediately after prolonged FC in some children.6 Additionally, in young rats, a prolonged seizure caused by hyperthermia can produce long-term cellular and molecular changes in the hippocampus, suggesting a role for FC in the development of TLE.10,11⇓ Severe head trauma and CNS infection are also risk factors for epilepsy, though how the associated injury produces TLE is not well understood.12,13⇓ Family history of epilepsy has also been described as a TLE risk factor, with gene loci identified in a few families, though the pathophysiology is not well understood.14,15⇓
The current study examined temporal lobectomy specimens from children with refractory TLE with and without risk factors for epilepsy. Immunohistochemistry was used to evaluate the specimens’ neuronal organization and cytoarchitecture, testing the hypothesis that structural abnormalities predispose to refractory TLE.
Methods.
Patient selection.
All cases from 1992 to 2000 of isolated temporal lobe resection for refractory epilepsy were collected from the files of the Pediatric Regional Epilepsy Program at the Children’s Hospital of Philadelphia. Patients with multilobar resections or temporal lobe resections with extratemporal subpial transections were excluded. Thirty-three of 34 patients identified with refractory TLE were eligible for inclusion in the study. One case was excluded because the medical records did not clearly state whether there was a history of FC. An arterial–venous malformation was identified in the resected specimen from this patient.
Clinical data.
All charts were reviewed for a history and description of FC, family history of epilepsy, early risk factors for epilepsy such as prior infection, head trauma, and birth injury, neurodevelopmental disabilities, MRI studies, and postoperative seizure outcome data.
Seizure semiology varied widely but was consistent with complex partial epilepsy. All patients underwent video-EEG monitoring to capture and localize ictal onset. In addition, intracranial video-EEG using subdural electrode grids was performed in 13 patients. MRI studies, including T1- and T2-weighted images in sagittal, transverse, and coronal planes, were performed in all patients using a 1.5 T magnet.
All patients had cognitive assessments by their attending neurologist. Formal neuropsychological testing was performed in 21 of 33 patients. Patients were labeled as “mentally retarded” if their full-scale IQ (FSIQ) was ≤70 or “developmentally delayed” if their developmental quotient was <50% for age. Thirty-one of 33 patients could be classified using these criteria. Surgical outcome data with a minimum follow-up length of 6 months are reported here (n = 30). Patients were considered seizure-free if they had only an isolated postoperative seizure or a seizure with medication withdrawal.
Surgical data.
A cortical incision was made from the temporal tip to the posterior margin of the desired resection, 5 to 6 cm in a language-dominant or 6 to 7 cm in a nondominant hemisphere resection or tailored using data from intracranial EEG and functional cortical mapping. The lateral temporal cortex was removed en bloc and underwent extensive histologic examination. With sharp and blunt dissection, a broad, wedge-shaped section of hippocampus extending throughout the exposed length was then removed for examination.
Pathologic data.
Two neuropathologists personally evaluated all of the cases except for Patient 1, for whom the slides and tissue could not be relocated and the original pathology report was used. In all cases, hematoxylin/eosin-stained sections were examined. Selected sections were incubated with RMDO20 (hypophosphorylated neurofilament M, H) monoclonal antibody (provided by V. Lee, University of Pennsylvania, Philadelphia, PA) at a 1:10 dilution of tissue culture supernatants and developed with a biotinylated anti-mouse streptavidin peroxidase and 3,3′-diaminobenzadine as the chromogen. The slides were then counterstained with Mayer’s hematoxylin.
Although there is no consensus on nomenclature or the pathologic features necessary for the diagnosis of CD, the presence of features commonly seen in cortical dysplasia (CD; cortical laminar disorganization, abnormal and maloriented neurons, and balloon cells) was used to assign a diagnosis of CD in this study16,17⇓ (figure). CD was diagnosed if these features were identified in any portion of the resected lateral temporal cortex. More subjective features of CD, such as increased number of neurons in the white matter and increased number of neuronal-appearing cells in layer I of neocortex, were used only in Patient 29 owing to a marked increase in the neuronal cellularity of layers I and II.
Figure. Features of cortical dysplasia in temporal cortex. (a) Balloon cells. Hematoxylin/eosin; ×40. (b) Abnormally oriented and dystrophic processes of cytologically atypical neuron stained for neurofilament protein. RMDO20 antibody; ×20. (c) Cortical laminar disorganization: lack of the expected layered organization of neurons grouped together by size and orientation typical of six-layered neocortex. Randomly oriented neuronal processes that no longer have parallel apical dendrites extend toward the pial surface. RMDO20 antibody; ×10.
Statistical analysis.
“Jump In” software (SAS Institute, Cary, NC) was used to calculate Fisher’s exact two-tailed test and standard deviations. A p value of <0.05 was considered significant.
The study was carried out with the approval of the Institutional Review Board at the Children’s Hospital of Philadelphia.
Results.
Risk factors.
Clinical details of the febrile seizures are found in table E-1 (additional material can be found on the Neurology Web site; go to www.neurology.org). There were a total of 33 patients, of whom 15 had a prior FC (FC+), 9 had at least one FC of ≥20 minutes, and 9 had more than one FC. Six had brief generalized convulsions consistent with simple FC.18 Clinical details for children without FC (FC−) are listed in table E-2 (go to www.neurology.org). Demographic comparison of children (FC+ and FC−) is shown in the table. The groups did not differ with respect to sex distribution, side of surgical resection, mean age at onset of unprovoked seizures, and mean age at surgery. Mental retardation was more common in the FC− group (8/17; 42%) vs FC+ (1/14; 7%) (p = 0.018), and there was a trend toward a higher mean FSIQ in the FC+ group (FC+, 89.9 ± 15.5 SD; FC−, 75.5 ± 14.6 SD).
Table Comparison of patients with and without a history of febrile convulsions
Risk factors for epilepsy other than FC are also listed in tables E-1 and E-2. A history of Haemophilus influenzae meningitis was present in Patients 6 and 16, and a history consistent with viral meningitis was present in Patient 3. There were five patients with a family history of FC (four in a first-degree relative and one in both maternal and paternal second-degree relatives), all in the FC+ group. Six patients, three FC+ and three FC−, had a family history of epilepsy in a first- or second-degree relative.
Surgical outcome.
In patients with at least 6 months’ follow-up, 17 of 30 (57%) were seizure-free. The seizure freedom in the FC+ cohort was slightly higher (9/13; 69%) than in the FC− group (8/17; 43%) (p = 0.28). The proportion of seizure-free patients was lower in mentally retarded patients: 1/7 (14%) vs 14/19 (74%) without mental retardation (p = 0.02). A seizure-free outcome was reported in 4 of 5 (80%) tumor patients compared with 11 of 20 (55%) with CD (p = 0.26).
Pathology.
Using our criteria to identify CD, we found similar proportions of CD in the FC+ groups: 73% (11/15) vs 56% (10/18) in the FC− group (p = 0.47) (see the figure). CD was also commonly associated with other risk factors. Two of three children with a history of a CNS infection had CD. All five children with a family history of FC and five of six with a family history of epilepsy had CD present. There were five patients with low-grade tumors (four in FC− and one in the FC+ group) and no patients with pathology characteristic of tuberous sclerosis. Neuropathologic examination of the hippocampus was available in 19 patients (9 FC− and 10 FC+). There was evidence of neuronal loss in the hippocampus in all but one of the patients (18/19; 95%). The degree of cell loss varied from severe neuronal loss to mild loss of pyramidal cells with some gliosis. Of the 18 patients with hippocampal neuron loss, 17 patients had additional pathology such as CD (n = 13), gliosis (n = 3), and a ganglioglioma (n = 1).
Preoperative MRI did not identify patients with CD. Only three patients (Patients 11, 22, and 26) had a report of suspected CD on their preoperative MRI reports.
Discussion.
The reported occurrence of CD in TLE surgical specimens has varied between 1.3 and 77%, depending on the patient population, the criteria used to diagnose CD, and the occurrence of tumors.19-21⇓⇓ This series found a high frequency (66%; 21/33) of CD.16,20⇓ Although there is no single accepted definition of CD, this study used features commonly recognized: loss of the cortical lamination, abnormal or maloriented neurons, and balloon neurons (see the figure). Caution should be exercised in extrapolating our data to the majority of TLE patients, as those undergoing surgery are likely the most medically refractory cases and “good” surgical candidates. It is unlikely that there was a large bias in selecting children with CD for surgery as only three patients had an MRI diagnosis of CD.
Similar to previous series, 45% (15/33) of our patients undergoing temporal lobe resections had experienced a FC prior to the onset of TLE.1,8⇓ Prolonged or focal FC are more common than simple FC in patients that eventually develop TLE12,22⇓ and increase the risk of temporal lobe changes on MRI immediately following the FC.6 Consistent with these reports, 60% (9/15) of our patients with FC had at least one seizure lasting ≥20 minutes; however, the details of the fever, seizure duration, and focality are subject to recall bias in retrospective studies based on parental reports. CD was present in the majority of children with and without risk factors for TLE, including 11 of the 15 children with a history of FC. Previous studies found that children with epilepsy and a history of FC are more likely to have a family history of FC.23 Although our numbers are small, all five children with a family history of FC were in the FC+ group and all had CD. This raises the possibility that certain forms of familial FC are related to the presence of CD. Further, of the six patients with a family history of epilepsy, five had CD. This suggests a possible genetic etiology for CD. Our data suggest that CD, a pre-existing lesion, is associated with refractory pediatric TLE with or without risk factors.
CD may result from abnormal neuronal lineage and migration during the second trimester. Several reports have extended the time frame for CD lesions to insults in late gestation or even the newborn period.24,25⇓ Patients 21 and 31 had H. influenzae meningitis at 4 and 6 months, and Patient 18 had viral meningitis at 5 months. Patient 21 had gliosis, whereas Patients 18 and 31 had CD. The associations support another report of CD in patients with a history of CNS infections and refractory epilepsy.26 If a CNS infection in a patient as old as 6 months could produce CD, this would expand the time frame for neurodevelopmental injuries of this type. Alternatively, there may be a predisposition for the development of epilepsy in patients with CD that experience a second insult such as an FC or infection.
The proportion of patients who became seizure-free in our series is 58%, similar to that in other pediatric epilepsy surgery case series.27 In agreement with other studies, better outcomes were seen with low-grade tumors compared to CD. Prior studies found that a history of FC was associated with postoperative seizure freedom; there was a similar trend for better outcome in the FC+ group.2 Similar to a large case series from England, this series found a lower occurrence of seizure freedom in patients with mental retardation: 14% (1/7) vs 78% (14/19) without mental retardation (p = 0.02).28 Mental retardation may be a marker of global CNS pathology and a more extensive epileptogenic zone.
The association between a history of FC and normal IQ is intriguing. Whereas most groups found no difference in the intellectual achievement of children with and without FC, there is one report of improved memory function in children with FC, suggesting FC may improve some aspects of cognitive function.29,30⇓ The association between FC and normal IQ, however, might also be due to chance. Further studies will be necessary to replicate and better understand this relationship.
Acknowledgments
Supported by the Brown Epilepsy Fund and MRDDC training grant no. NS87413 to B.E.P.
Footnotes
Additional material related to this article can be found on the Neurology Web site. Go to www.neurology.org and scroll down the Table of Contents for the August 12 issue to find the title link for this article.
- Received October 2, 2002.
- Accepted in final form April 22, 2003.
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