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Keywords:

  • Epilepsy;
  • Longitudinal;
  • Volumetric imaging;
  • Community based;
  • Seizures

Abstract

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

Summary: Purpose: Whether cerebral damage results from epileptic seizures remains a contentious issue. We report on the first longitudinal community-based quantitative magnetic resonance imaging (MRI) study to investigate the effect of seizures on the hippocampus, cerebellum, and neocortex.

Methods: One hundred seventy-nine patients with epilepsy (66 temporal lobe epilepsy, 51 extratemporal partial epilepsy, and 62 generalized epilepsy) and 90 control subjects underwent two MRI brain scans 3.5 years apart. Automated and manual measurement techniques identified changes in global and regional brain volumes and hippocampal T2 relaxation times.

Results: Baseline hippocampal volumes were significantly reduced in patients with temporal lobe epilepsy and could be attributed to an antecedent neurologic insult. Rates of hippocampal, cerebral, and cerebellar atrophy were not syndrome specific and were similar in control and patient groups. Global and regional brain atrophy was determined primarily by age. A prior neurologic insult was associated with reduced hippocampal and cerebellar volumes and an increased rate of cerebellar atrophy. Significant atrophy of the hippocampus, neocortex, or cerebellum occurred in 17% of patients compared with 6.7% of control subjects. Patients with and without significant volume reduction were comparable in terms of seizure frequency, antiepileptic drug (AED) use, and epilepsy duration, with no identifiable risk factors for the development of atrophy.

Conclusions: Overt structural cerebral damage is not an inevitable consequence of epileptic seizures. In general, brain volume reduction in epilepsy is the cumulative effect of an initial precipitating injury and age-related cerebral atrophy. Significant atrophy developed in individual patients, particularly those with temporal lobe and generalized epilepsy. Longer periods of observation may detect more subtle effects of seizures.

Chronic intractable epilepsy is associated with significant structural alterations both within and beyond the epileptogenic zone. The commonest histologic finding in human intractable temporal lobe epilepsy (TLE) is hippocampal sclerosis (HS), found in 50–70% of specimens obtained from temporal lobe resections (1,2).

Intractable TLE also may be associated with extralesional volume deficits, including the ipsilateral and contralateral temporal lobe; contralateral hippocampus; ipsilateral amygdala, entorhinal and perirhinal cortex, thalamus and caudate, and cingulate gyrus (3–7). Cross-sectional magnetic resonance imaging (MRI) studies of patients with intractable epilepsy also have reported significant cerebellar (8) and cerebral volume reduction (9). Some authors have proposed that extrahippocampal abnormalities may be capable of epileptogenesis because widespread structural deficits and cerebellar volume reduction in mesial TLE have been found to predict poor seizure outcome after temporal lobectomy (8,10).

Despite the prevalence of widespread structural abnormalities in patients with chronic epilepsy, the timing and pathogenesis of such changes remain obscure. The crucial question relates to whether the abnormalities are progressive and the cumulative effect of years of epilepsy (11); the effect of an initial precipitating insult (IPI) during a vulnerable phase of cerebral development (12); the presence of a preexisting developmental abnormality predisposing to insults and further cerebral damage (13); or a combination of these factors acting synergistically (14).

Recent longitudinal studies attempting to address this question have produced disparate results. In a study of 24 patients with newly diagnosed cryptogenic TLE, a strong correlation was found between the number of convulsive seizures and ipsilateral hippocampal volume (HV) loss over a period of 3.5 years (15). These findings were supported by a study demonstrating that the frequency of partial but not generalized seizures was correlated with ipsilateral HV loss in 12 patients with refractory TLE and unilateral HS (16). Although these hospital series suggest that HS and seizure-related hippocampal damage may evolve in the absence of an initial insult [e.g., status epilepticus (SE)] (17,18), a recent longitudinal MRI study comparing eight patients with well-controlled epilepsy with five patients with intractable partial epilepsy found no relation between seizures and either progressive or new structural hippocampal damage (19). Furthermore, group comparisons of patients with newly diagnosed partial epilepsy and age-matched controls found no differences in mean baseline HV and change in HV over a period of 1 and 3.5 years, respectively (20,21). Community-based studies of patients with newly diagnosed epilepsy have shown no effect of epilepsy syndrome, seizure recurrence or antiepileptic drug (AED) use on HV change over a 3-year period (21,22), although in 13% (22) and 8% (20) of individuals in these studies, significant hippocampal atrophy developed.

Serial imaging studies provide an opportunity for monitoring disease progression in vivo. In this study, we aimed to investigate the effect of epileptic seizures on hippocampal, cerebral grey and white matter, and cerebellar volumes, by performing a population-based longitudinal MRI study of patients with epilepsy and age-matched controls. By incorporating image registration and a range of manual, semiautomatic, and automatic segmentation techniques, we compared volume change in patients with TLE, extratemporal partial epilepsy, and generalised epilepsy and determined whether rates of cerebral damage over a 3.5-year period varied according to epilepsy syndrome. Clinical risk factors for the development of significant cerebral atrophy were investigated.

In contrast to hospital-based studies, in this community-based study, seizures were largely well controlled with medication. Only a small proportion of patients proceeded to epilepsy surgery; therefore our findings pertain largely to nonsurgical patients with epilepsy.

METHODS

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

Subjects

The initial phase of this study, performed between June 1995 and May 1997, identified 243 patients with epilepsy and 90 age- and sex-matched control subjects. Subjects were scanned on a 1.5-T GE Signa Horizon Echospeed MR scanner (GE Medical Systems, Milwaukee, WI, U.S.A.) as part of a cross-sectional study investigating the structural basis of epilepsy in the community (23).

Patients were prospectively recruited from a local population of 207,553, and case ascertainment established through the regular active surveillance of 21 local general practices within a 15-mile (24-km) radius of the National Society for Epilepsy. Patients included those with newly diagnosed seizures as well as those with chronic epilepsy. All patients were clinically assessed and investigated with an interictal EEG. Three experienced epileptologists classified patients at the time of recruitment according to epilepsy syndrome based on seizure semiology and EEG findings (24). Control subjects were healthy adult volunteers free of active neurologic or psychiatric disease who were recruited from the same community base.

The second phase of the study was performed between February 1999 and August 2001 with a follow-up MRI brain scan 3.5 years after their initial scan. All follow-up scans were performed on the same MRI scanner by using identical MRI acquisition sequences to the baseline imaging protocol. Control subjects were rescanned over the same period to control for age-related atrophy and temporal fluctuations in scanner performance. Subjects with significant cerebrovascular disease at baseline [defined as greater than two high-signal white matter lesions on either T2-weighted or fluid-attenuated inversion recovery (FLAIR) images], and patients who had undergone a neurosurgical procedure at any stage were excluded from the follow-up study. At their follow-up assessment, subjects were questioned on head injuries, alcohol consumption, drug consumption, medication (in particular, steroid use), and significant medical or psychiatric morbidity that might have occurred between the two scans that could affect cerebral structure. Patients kept a prospective record of their seizures by using seizure diaries between the two scans and were specifically questioned on episodes of status epilepticus, AED use, and AED intoxication. Clinical data including histories of IPI were supplemented with information obtained from general practice and outpatient notes, and syndromic classifications were updated. A subsequent audit of 10% of all demographic and quantitative data fields entered into a relational database showed an error rate of 0.6%.

Loss to follow-up was minimised by the tracking of individuals through the Office for National Statistics (a central U.K. health register). The study was approved by the Joint Research Ethics Committee of the National Hospital of Neurology and Neurosurgery and the Institute of Neurology, and informed consent was obtained from each subject.

MRI acquisition details of baseline and repeated scans

  • • 
    Qualitative assessment of scan pairs were performed on T1-weighted images, T2-weighted images, proton density images, and 5-mm-thick coronal FLAIR images (TR/TE/TI, 11,000/2,600/144 ms; eight echo train length), taken orthogonal to the long axis of the hippocampi.
  • • 
    Volumetric measurements were derived from a T1-weighted three-dimensional volumetric inversion recovery–prepared spoiled gradient echo (IR-SPGR) sequence (TR/TE/TI, 11,000/2,600/144 ms) with 124 contiguous coronal partitions, 1.5-mm thickness, a 24 × 18-cm field of view; matrix size, 256 × 192; and 25-degree flip angle.
  • • 
    Hippocampal T2 relaxometry measurements were performed by using 5-m-thick contiguous oblique coronal proton density images (TR/TE, 2,000/30 ms) and T2-weighted spin-echo images (TR/TE, 2,000/120 ms).

Image processing

Full details of the image-processing steps and volumetric techniques are provided in our methodologic article (25). Before volumetry, baseline and repeated T1-weighted volume datasets were corrected for signal inhomogeneity (26). The automatic segmentation software program, Exbrain, was used to extract the brain and CSF in the nonuniformity-corrected baseline scan (27). The repeated scan was coregistered and intensity matched to the segmented baseline scan by using locally developed image analysis software, MRreg (28). The optimal match was determined through maximising the cross-correlation of brain voxel intensities with a nine-parameter rigid-body transformation. The coregistered repeated scan was subsequently resampled by using sinc interpolation and a final segmentation applied.

Volumetry and relaxometry

Automatic segmentation

Exbrain was used automatically to segment coregistered image pairs, generating baseline and repeated values for total brain volume (TBV), grey matter volume (GMV), white matter volume (WMV), and intracranial volume (ICV) (27).

Hippocampal volumetry

All measurements were performed by a single trained operator (R.S.N.L.), by using the volumetry tool in MRreg. The entire length of the hippocampus was measured by using an established protocol (29). Contiguous slices of matched datasets were displayed side-by-side, with the operator blinded to the clinical status of the subject and to the chronologic order of the scan pairs. Previously drawn traces were displayed for visual reference whilet active traces were performed on the second image in the neighbouring window. The HV was automatically calculated by multiplying the sum of the cross-sectional area of each slice by the slice thickness (30).

Cerebellar volumetry

Measurements were semiautomated and performed on the matched segmented T1-weighted images by using the seed and region-growing mode in MRreg. Matched brain segmented images for each subject were displayed as described earlier. The threshold level was set to unity, with all nonbrain voxels being assigned a value of zero. Single or multiple seeds were deposited in the cerebellum. Borders between distinct anatomic structures of similar signal intensity (e.g., between cerebellum and cerebrum, and cerebellum and brainstem) were manually edited. Measurements were performed on alternate slices, as previously described (29). To account for slice skipping, the total cerebellar volume (CBV) was calculated by doubling the product of the cross-sectional area and slice thickness (31).

Hippocampal relaxometry

Hippocampal T2 (HCT2) measurements reflect the glial-to-neurone ratio in the CA1 subregion (32) and the glial cell count in the dentate gyrus (33). Baseline and repeated HCT2 measurements were performed by a single observer (P.A.B.) by using DispImage Analysis software (34). Measurements were performed on HCT2 maps that were acquired from the conventional spin-echo sequence composed of two interleaved acquisitions. The largest possible elliptical region of interest was placed in each contiguous hippocampal slice, avoiding partial volume effects from the CSF. The mean baseline and repeated HCT2 for each hippocampus were determined.

Visual comparison of image pairs

Two consultant neuroradiologists, blinded to all clinical information, compared baseline and repeated images (without registration) for qualitative change.

Statistics

Statistical analysis was performed by using SPSS for Windows, release 9 (SPSS, Inc., Chicago, IL, U.S.A.). After unblinding, the absolute change in each MRI parameter over a 3.5-year period was calculated by subtracting the baseline volume from the matched repeated volume. All volumetric measures, with the exception of ICV, were corrected for baseline ICV by using a linear regression equation derived from the control group (5). MRI evidence of HS was defined as an ICV-corrected HV <2 standard deviations (SD) below the mean control volume and a HCT2 >2 SD of the mean control HCT2 value.

Two statistical approaches were used: analysis of group means and individual subject analysis.

Group analysis

Continuous (e.g., baseline quantitative MRI data) and nominal variables were compared across the epilepsy syndromes by using Kruskal–Wallis and the χ2 test, respectively. Repeated-measures analysis of variance (ANOVA) assessed the effect of gender, initial precipitating injury, and SE on changes in MRI quantification. The model integrated cross-sectional and longitudinal data into a single framework and determined the Group × Time interaction. Patients were classified as having an IPI if they gave a clear history of an antecedent neurologic insult (e.g., a febrile seizure that was focal or >20 min in duration, a significant head injury causing loss of consciousness and posttraumatic amnesia >30 min, skull fracture, previous meningitis or encephalitis, previous convulsive SE, or a perinatal event causing significant hypoxia).

The individual contributions of different variables were assessed by using continuous variables as covariates. Dependent variables included estimated seizure frequency, number of AEDs, and alcohol intake between the two scans. The level of significance was set at p < 0.05 for all statistical analyses.

Individual analyses

This approach compared the results of a single subject against the limits of agreement defined by the control group. Individuals with significant volumetric or signal change were identified by using this method. Because grey and white matter volumes were significantly correlated in our control subjects, a Bonferroni correction was used to correct for three independent parameters (hippocampus, cerebellum, and neocortex), where 2.4 SD corresponds to an alpha level of 0.05/3 (25). Control reference ranges were established for three age epochs (<35, 35–54, and >54 years) because age is significantly correlated with the rate of cerebral atrophy (35).

RESULTS

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

Demographic data

One hundred seventy-nine patients with epilepsy and 90 control subjects were rescanned after 3.5 years. Causes of attrition are provided in Table 1. The demographic details of the patients and control group are indicated in Table 2. The proportions of male to female subjects were similar in the four groups. TLE patients had a comparably longer interscan interval (H = 11.67; p = 0.009), and control subjects consumed significantly greater amounts of alcohol (H = 19.52; p < 0.001). Histories of perinatal injuries, febrile seizures, numbers of convulsive seizures, previous meningitis and encephalitis, duration of epilepsy, and proportions of new and chronic cases were comparable between patient groups. One (1.5%) TLE patient and one (2%) patient with extratemporal partial epilepsy had a stroke between the two scans. No patients contracted meningitis between the two scans. TLE patients had their first afebrile seizure later (H = 7.19; p = 0.028), were older 2= 9.80; p < 0.001), and had received treatment with a greater number of AEDs (H = 13.43; p = 0.001) than patients with generalized epilepsy and those with extratemporal partial epilepsy. TLE patients with and without HS were more likely to have sustained a prior IPI (χ2= 12.45; p = 0.002 and χ2= 10.34; p = 0.006, respectively).

Table 1. Causes of attrition among patients
Causes
  1. aTen of the 23 patients had isolated seizures with no further recurrence.

  2. Untraceable refers to patients who could not be traced by the Office for National Statistics, as they were no longer registered with a general practice.

Death11 (4.5%) 
Infirmity 5 (2.1%) 
Untraceable 7 (2.9%) 
Emigration 4 (1.6%) 
Pregnancy 1 (0.4%) 
Inability to tolerate scan 2 (0.8%) 
Neurosurgical intervention11 (4.5%) 
Refusal23 (9.5%)a
Table 2. Demographic and clinical characteristics
CharacteristicControlsTLEExtratemporalGeneralized
  1. ISI, interscan interval; SE, status epilepticus; median age, median age at baseline; median no. of AEDs, median number of antiepileptic drugs taken between the two scans.

  2. *Defined as epilepsy for 5 years, with a seizure in the 12 months prior to baseline scan.

  3. aOne control subject was taking carbamazepine after a cutaneous varicella zoster infection.

Number 90   66   51   62   
Median age in yr (range) 35 (14–77)38 (17–71)31 (14–74)31 (15–74)
Gender, males (%)49 (54%) 29 (45%) 32 (62%) 27 (44%) 
 Females (%)41 (46%) 36 (55%) 20 (38%) 35 (56%) 
Median ISI in mo (range) 42 (40–48)48 (38–54)42 (39–44)42 (21–52)
Patients with new-onset seizures (%)19 (29.2%)17 (32.7%)26 (41.9%)
Patients with chronic epilepsy (%)* 46 (70.8%)35 (67.3%)36 (58.1%)
Median no. of convulsive seizures (range) 1 (0–492) 0 (0–294) 1 (0–250)
Median no. of focal seizures (range)  38 (0–3,690)   0 (0–1,340)
Median age at seizure onset (yr)21.518   15   
Median no. of AEDs (range) 0 (0–1)a2 (0–6) 2 (0–7) 1 (0–6) 
Median no. of alcoholic units consumed per week (range)7.5 (0–72) 2 (0–70)1 (0–28) 2 (0–160)
Patients with history of febrile seizures6 (9.2%)3 (5.8%)3 (4.8%)
Patients with history of SE4 (6.2%)4 (7.7%)2 (3.2%)
Patients with history of SE between scans2 (3.1%)1 (1.9%)1 (1.6%)
Patients with history of meningitis/encephalitis5 (7.7%)5 (9.6%)3 (4.8%)
Patients with history of perinatal injury4 (6.2%) 6 (11.5%)3 (4.8%)
Patients with significant head injuries between scans 1 (1.1%)2 (3%)  2 (3.9%)4 (6.5%)
Cross-sectional findings at baseline

Fourteen patients (21%) with TLE had HS at baseline (Table 3). Patients with TLE had a significantly smaller mean ICV-corrected HV and increased HCT2 measurement compared with other patient groups and controls (χ2= 23.70; p < 0.001 and F= 8.19; p = 0.042, respectively). After exclusion of HS patients, TLE patients had smaller mean ICV-corrected baseline HVs than did controls 2= 11.82; p = 0.008), although HCT2 values were no longer significantly increased. The difference in mean corrected baseline HV between the cohorts remained significant after covarying for baseline age and ICV-corrected TBV. No significant difference was found in ICV-corrected TBV, GMV, WMV, or CBV between the four groups at baseline.

Table 3. Quantitative dataThumbnail image of
Longitudinal findings

Baseline and repeated quantitative measures and their percentage changes for each subject group are listed in Table 3.

Group analysis of quantitative changes

Hippocampal volume (Fig. 1A). Repeated measures of ANOVA showed a significant reduction in hippocampal volume over time (F= 23.91; p < 0.0001), a significant difference between the four cohorts (F= 10.96; p < 0.0001), but no Time × Group interaction. The main effects on the rate of HV loss were age at baseline (F= 19.26; p < 0.0001) and change in TBV (F= 84.01; p < 0.0001).

image

Figure 1. Longitudinal changes in magnetic resonance imaging parameters for each subject group. The mean baseline and repeated values are shown for (A) combined hippocampal volume, (B) mean hippocampal T2 relaxation times, (C) total cerebellar volume, (D) total brain volume, (E) grey matter volume, and (F) white matter volume. All brain volumes were corrected for baseline intracranial volume.

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The mean baseline ICV-corrected HV of the 56 patients with a history of IPI was significantly reduced compared with the 123 patients without such a history (F= 8.10; p < 0.005). A similar observation was seen when considering TLE patients only (F= 7.43; p = 0.008), which persisted on exclusion of patients with HS. The observed volume reductions remained significant after correcting for baseline TBV, suggesting that the impact of the insult on initial HV was independent of the effect on the whole brain. A history of an antecedent neurologic insult did not significantly affect the rate of HV loss either in all patients or in those with TLE (F= 0.033; p = 0.86) (Fig. 2A).

image

Figure 2. The effect of antecedent neurologic insults on longitudinal volume changes. Mean baseline and repeated volumes are shown for (A) combined hippocampal volume and (B) cerebellar volume.

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The change in hippocampal volume over the 3.5-year period was comparable between control and patient groups (F= 0.72; p = 0.54). Of the 33 patients with cryptogenic TLE, the epileptic focus was clearly lateralised in 19 cases. No correlation was observed between the number of convulsive seizures, documented partial seizures, and change in ipsilateral HV loss. Only patients with extratemporal partial epilepsy showed a correlation between the degree of HV loss and the number of convulsive seizures between scans (F= 6.00; p = 0.018).

Hippocampal T2 relaxometry (Fig. 1B). Hippocampal T2 relaxation time was significantly different between the subject groups (F= 13.45; p < 0.0001). A nonsignificant Group × Time interaction was observed (F= 2.25; p = 0.084), with HCT2 relaxation times decreasing with age in controls and extratemporal partial epilepsy patients, and increasing in patients with TLE and generalized epilepsy.

Exclusion of the 14 patients with HS at baseline resulted in a change in the group effect, with a decrease in HCT2 in patients with TLE below that of patients with extratemporal partial epilepsy. Patients with a history of an IPI had a significantly higher baseline HCT2 compared with those without such a history (F= 14.25; p < 0.0001). TLE patients with a history of an IPI were associated with a significantly increased HCT2, which persisted after exclusion of HS patients. Prior neurologic insults, number of AEDs, and estimated number of convulsive and partial seizures did not influence change in HCT2.

Total cerebellar volume (Fig. 1C). Patients with epilepsy had smaller corrected baseline CBVs than did control subjects, although the difference was not significant (F= 1.63; p = 0.184). A significant reduction in CBV was observed in all groups over the 3.5-year period (F= 20.06; p < 0.0001). The rate of cerebellar volume loss was not significantly different between the four subject groups (F= 1.66; p = 0.18). The main effect on the rate of cerebellar atrophy was age (F= 4.33; p = 0.038) and change in TBV (F = 86.85; p < 0.0001), suggesting that a proportionate degree of generalized cerebral atrophy was usually present. The estimated number of convulsive seizures, phenytoin (PHT) use, and alcohol consumption between scans did not predict the degree of cerebellar volume loss over time.

A history of an IPI was associated with an overall reduction in CBV (F= 5.35; p = 0.021) and a significantly increased rate of cerebellar atrophy (−1.86% in 3.5 years compared with −0.65%; F= 4.63; p < 0.033), which could not be attributed to age, alcohol intake, recurrent head injuries, or AED use between scans (Fig. 2B).

Total brain volume (Fig. 1D). Total brain volume decreased significantly over the study period (F= 49.50; p < 0.0001). The loss in TBV was similar between the controls and patient groups (F= 1.56; p = 0.20). The main effect on the loss of TBV with time was age (F= 11.02; p = 0.001). The estimated number of convulsive seizures predicted TBV loss in patients with extratemporal partial epilepsy (F= 5.52; p = 0.023). The Time × Matter (grey and white) interaction was not significant (F= 0.009; p = 0.93), suggesting that both GMV and WMV loss were contributing similarly to the observed loss in TBV. A history of an IPI did not have a significant effect on the overall TBV (F= 3.03; p = 0.083) or the rate of cerebral atrophy (F= 1.62; p = 0.21).

Cerebral grey matter volume (Fig. 1E). Total grey matter decreased significantly with time (F= 9.78; p = 0.002), but no difference was found between the cohorts and no Time × Group interaction. Once baseline age was accounted for, the change in GMV with time was no longer significant. Frequency of convulsive seizures predicted GMV loss in patients with extratemporal partial epilepsy (F= 5.71; p = 0.021) but not in the other epilepsy syndromes.

Cerebral white matter volume (Fig. 1F). A highly significant reduction in WMV was observed with time (F= 39.68; p < 0.0001). No difference was noted between the cohorts and no Time × Group interaction. Baseline age was the main determinant of the observed change in WMV (F= 16.46; p < 0.0001).

Gender, seizure type, duration of epilepsy and a history of status epilepticus, did not have an effect on any of the quantitative changes measured.

Analysis of quantitative changes in individual subjects

Six of the 90 (6.7%) control subjects had significant quantitative changes that could not be attributed to confounding factors. Twelve patients (19.4%) with generalized epilepsy, 15 (22.7%) with TLE, and five (9.8%) with extratemporal partial epilepsy had changes in at least one MRI parameter that could not be attributed to confounding factors such as alcohol abuse or progressive structural lesions. Patients were more likely to develop significant atrophy than were controls 2= 6.20; p = 0.008). In only one (1.5%) patient with TLE did significant hippocampal atrophy develop over the study period. Significant hippocampal atrophy was seen in seven (11.3%) patients with generalized epilepsy and one (1.9%) patient with extratemporal partial epilepsy.

Details of individuals with inexplicable quantitative changes exceeding the control reference range are given in Table 4. None of these significant volume changes was detected on visual assessment. Episodes of SE, head injuries, seizure recurrence, history of an IPI, numbers of AEDs, duration of epilepsy, and numbers of convulsive seizures were comparable between patients with and without the development of significant atrophy. Patients in whom atrophy developed were significantly older than their counterparts without atrophy (mean baseline age, 37.8 years, compared with 35 years, respectively; Mann–Whitney U 1625; p = 0.006).

Table 4. Individual control subjects and patients showing significant quantitative changes over 3.5-year period
SubjectHVHCT2CBVTBVGMVWMVCommentAED
  1. AED, Antiepileptic drugs taken during follow-up period; TLE, temporal lobe epilepsy; CPS, complex partial seizures; SGS, secondarily generalized seizures; SPS, simple partial seizures; NCSE, nonconvulsive status epilepticus.

  2. CBZ, carbamazepine; VPA, sodium valproate; ESM, ethosuximide; LTG, lamotrigine; GBP, gabapentin; PHT, phenytoin; PB, phenobarbitone; PRM, primidone; CLB, clobazam; NTZ, nitrazepam; TPM, topiramate; TIAG, tiagabine. GTCS, generalized tonic-clonic seizures. IGE, idiopathic generalized epilepsy; CAE, childhood absence epilepsy; JAE, juvenile absence epilepsy.

Controls (n = 90)
 C1 [UPWARDS ARROW] 2.6SDD 
 C2 [DOWNWARDS ARROW] 3.1SDD 
 C3 [UPWARDS ARROW] 3.4SDD 
 C4 [UPWARDS ARROW] 3.0SDD 
 C5[DOWNWARDS ARROW] 3.4SDD [DOWNWARDS ARROW] 2.7 SDD 
 C6 [DOWNWARDS ARROW] 3.2 SDD[DOWNWARDS ARROW] 3.6 SDD 
TLE (n = 65)
 T1[DOWNWARDS ARROW] 4.2SDD Right cryptogenic TLE. Episode of NCSE fortnight before baseline scan. Frequent SPSCBZ, VPA
 T2–3 Mean [DOWNWARDS ARROW] 3.3SDD(1) Cryptogenic TLE. Severe head injury before baseline. No further seizures.VPA
 T4–5 Mean [UPWARDS ARROW] 2.7SDD (2) Cryptogenic TLE. 82 CPSCBZ, CLB, PHT, VPA
 (1) Cryptogenic TLE. >1,800 SPS between scansPHT
 T6–7Mean [UPWARDS ARROW] 2.4SDD (2) Cryptogenic TLE. ∼80 CPSCBZ, LTG, GBP
 (1) Left cryptogenic TLE. ∼180 SGSTPM, CBZ, PHT, NTZ
 (2) Left cryptogenic TLE. 3 SGSCBZ, VPA
 T8 [UPWARDS ARROW] 2.4 SDD Cryptogenic TLE. Only 1 further CPSNIL
 T9 [DOWNWARDS ARROW] 3.0 SDD Symptomatic TLE. 139 CPS, 6 SGSCBZ, GBP, CLB, TPM
 T10–14 Mean [DOWNWARDS ARROW] 3.5SDD Range (2.4–4.8SDD) 3 Symptomatic, 2 cryptogenic TLE. Seizure frequency ranged from 0–94 SGS and 0–410 CPSNumber of AEDs from 1–5
 T15 [DOWNWARDS ARROW]2.5SDD[DOWNWARDS ARROW]2.6SDD Cryptogenic TLE. 410 CPSVPA, GBP, LTG, CBZ
Extra-temporal (n = 52)
 E1 [DOWNWARDS ARROW]3.4SDD FLE. Cluster of SGS before baseline scan, then seizure freeVPA
 E2–4Mean [UPWARDS ARROW] 2.8SDD, Range (2.5–3.1) 3 FLE. Seizure frequency ranged from 0–294 SGSNumber of AEDs from 1–4
 E5 [DOWNWARDS ARROW]2.8SDD[DOWNWARDS ARROW]3.0SDD Cryptogenic partial epilepsyVPA, PHT, PB
 Generalized (n = 62)
 G1–4Mean [DOWNWARDS ARROW] 3.0SDD, Range (2.4-3.6) All had IGE. Mean seizure frequency ranged from 0 to 210 GTCSAll taking VPA
 G5–6Mean [DOWNWARDS ARROW] 2.8SDD (1) Cryptogenic generalised epilepsy No seizuresNIL
 (2) Cryptogenic generalised epilepsy 88 GTCSPRM, VPA, LTG, GBP
 G7[DOWNWARDS ARROW] 2.4SDD [DOWNWARDS ARROW]2.6SDD[DOWNWARDS ARROW] 4.5SDD[DOWNWARDS ARROW] 2.9SDD JAE. No GTCS. >1,000 absencesVPA, ESM
 G8[DOWNWARDS ARROW] 2.5SDD [DOWNWARDS ARROW] 4.4SDD[DOWNWARDS ARROW] 3.3SDD IGE. >100 absencesCBZ
 G9[DOWNWARDS ARROW] 3.4SDD [DOWNWARDS ARROW] 2.5SDD Cryptogenic generalised epilepsy. 4 GTCS between scansLTG, VPA
 G10 [DOWNWARDS ARROW] 3.5SDD IGE. 84 GTCSTPM, ESM, LTG, GBP, TIAG
 G11 [UPWARDS ARROW] 2.4SDD[UPWARDS ARROW] 3.3SDD[DOWNWARDS ARROW] 2.6SDDIGE. No history of overt seizuresCBZ
 G12 [UPWARDS ARROW] 2.0SDD CAE. >100 absencesVPA

In none of the 14 patients with HS at baseline did significant hippocampal atrophy or a significant increase in HCT2 develop. In no individuals did HS develop de novo, as defined in the Statistics section.

DISCUSSION

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

Two key questions are addressed in this longitudinal MRI study: (a) whether epilepsy is associated with MRI-detectable cerebral damage over a 3.5-year period, and (b) whether particular clinical risk factors increase individual susceptibility to damage. The main findings were that (a) patients with TLE had significantly reduced HVs and longer HCT2 times than controls, patients with extratemporal partial epilepsy, and generalized epilepsy at baseline; (b) loss of hippocampal and neocortical volume was comparable between patient groups and controls and therefore not syndrome dependent; (c) a history of an IPI was associated with an overall reduction in hippocampal and cerebellar volume, and an increased rate of cerebellar atrophy; (d) convulsive seizures were correlated with change in HV, TBV, and GMV in patients with extratemporal partial epilepsy; (e) in a greater proportion of individuals with epilepsy significant hippocampal and neocortical volume loss developed compared with that in control subjects.

Methodologic issues and limitations of the study

As a population-based study that included patients with newly diagnosed and chronic epilepsies, our patient groups were inevitably heterogeneous, reflecting a diverse range of aetiologies with variable susceptibility to damage. This diversity may have influenced our ability to detect group differences between the epilepsy syndromes but allowed us to explore a wider range of individual variation and is more relevant to the population developing epilepsy than would that in a selected clinic population. Our individual analysis identified significant volume and signal change in a greater number of patients with epilepsy than in control subjects. Although volume changes were more commonly observed in individuals with TLE and generalised epilepsy, this finding was not statistically significant.

Our study is based on the assumption that brain damage is detectable by using a serial MRI approach. Although prospective MRI studies have demonstrated the rapid development of hippocampal damage over several months (18,36,37), it is possible that seizure-induced damage is subtle and not readily picked up by current imaging techniques. Coregistration of serial scans allowed us to improve the variability of repeated measurements and thus reduce change due to measurement error. Some evidence indicates that pathologically proven HS may exist in the absence of a significantly reduced HV (38) or increased HCT2 (32). Consequently, our stringent definition of HS may underestimate the development of HS in patients undergoing either significant HV reduction or HCT2 increase alone. The proportions of patients in whom HS develops de novo may also vary according to whether HS is defined on quantitative MRI or visual criteria, although visual comparison in this study did not observe the development of HS in any patient.

Hippocampal damage in temporal lobe epilepsy

Cross-sectional studies have shown significant ipsilateral HV reduction in patients with frequent seizures and prolonged duration of TLE (39). It has thus been proposed that volume reductions reflect either (a) the cumulative neurobiologic effect of repeated seizures or (b) a bias toward the accumulation of refractory cases after a severe precipitating injury. Our study confirmed that patients with TLE had significantly reduced HVs at baseline. Analysis of longitudinal data revealed similar rates of hippocampal volume reduction in patients with TLE, extratemporal focal epilepsy, and control subjects. No correlation was observed with numbers of convulsive or partial seizures. Patients with histories of neurologic insults showed significant overall reductions in HV, suggesting that for the majority of TLE patients, structural damage is likely to be related to an IPI, with subsequent volume loss being influenced by age rather than by seizures.

In our study, subject groups demonstrated differential changes in HCT2 relaxometry. Patients with TLE and generalised epilepsy demonstrated a nonsignificant increase in HCT2. Studies incorporating absolute cell counts have shown that an increased HCT2 signal reflects the severity of dentate gliosis, with many astrocytes showing glial fibrillary acidic protein (GFAP)-positive properties indicative of recently occurring or ongoing abnormal processes (33). In our patients with TLE, change in HCT2 was not correlated with seizure frequency, AED exposure, or drug intoxication. The reason for the observed decrease in HCT2 relaxometry in control subjects and patients with extratemporal partial epilepsy is not clear. Phantom-based quality assurance data of repeated HCT2 measures at our institution have shown no consistent long-term drift, and subjects were aligned to the same external landmark on each scan occasion. It is possible that HCT2 values may decrease with age with a disproportionate loss of glial to neuron cells in the dentate gyrus.

In contrast to a recent follow-up study of 12 patients with HS (15), in none of the 14 patients with HS at baseline in our study did significant HV loss or increase in HCT2 relaxation time develop over the period studied. Only a relatively low number of patients had HS at baseline, and this is likely to reflect both the broad spectrum of disease severity seen in population-based studies and the exclusion of children with HS seen with seizures before age 14 years. The lack of detectable disease progression in patients with HS could be a manifestation of the “floor effect,” in which the initial insult may have been so severe as to damage the hippocampus to such an extent that no further damage could be observed over the study period (40). In accordance with Salmenperä's study (22), we did not observe the development of HS (using our morphometric criteria) in any patient with a normal scan at baseline.

Although progressive hippocampal atrophy occurred infrequently among our epilepsy population and was influenced primarily by the age of the patient; a complementary voxel-based neocortical interrogation of the same study population (41) has shown that TLE is associated with the development of subtle neocortical atrophy. Temporal lobe atrophy was observed in 17% of patients with chronic TLE and HS, suggesting that neuronal damage may extend beyond the hippocampus to involve the ipsilateral temporal lobe, particularly in the presence of severe hippocampal damage from an initial brain injury.

Cerebellar and neocortical damage in epilepsy

Cerebellar atrophy in epilepsy has previously been considered a consequence of either prolonged PHT therapy (42), seizure-mediated cellular damage through cerebrocerebellar diaschisis (43), hypoxic damage (44), or SE (45). In this study, patients with epilepsy had a reduced cerebellar volume at baseline compared with controls, although this was not significant. Our observation that cerebellar volume loss over time was comparable in patients and controls suggests that these mechanisms cannot wholly explain the volume loss observed in patients with epilepsy, and that at least part of the CBV loss is likely to occur independent of a history of seizures or AED therapy. The association of an IPI with an overall reduction in CBV and increased cerebellar atrophy suggests a putative link between cerebral insults and epilepsy-related cerebellar atrophy. This is consistent with suggestions that cerebellar damage may occur after brain trauma (46), and that loss of inhibitory function in patients with a structurally damaged cerebellum may worsen prognosis for good seizure control (8). Although patients with epilepsy had reduced total brain volumes at baseline and accelerated rates of cerebral atrophy, particularly patients with TLE (Fig. 1D), these findings were not statistically significant.

Initial precipitating insults

A major insult can cause ipsilateral hippocampal damage and damage to other structures, particularly on the side of the seizure focus (36). In their clinicopathologic study (47), Mathern et al. showed that IPIs were important in the pathogenesis of HS, and that HS occurred in patients with extratemporal partial epilepsy only if a prior IPI had occurred. In TLE patients, HS was strongly associated with IPIs involving seizures. Our results showed that a history of an IPI was associated with a significant reduction in hippocampal volume. This observation persisted after exclusion of patients with HS, suggesting that the reduced brain volumes did not simply reflect the greater number of patients with HS in those with a history of IPIs. A significant increase in the rate of cerebellar atrophy was seen in patients with a history of IPIs, which could not be attributed to other potential confounders (e.g., alcohol consumption, age, AED use, or a history of recurrent head injuries between the two scans).

Our results corroborate previous suggestions that, in addition to causing measurable volume changes, an insult may prime the brain, making it more vulnerable to the effect of seizures (48). Experimental studies in rats demonstrated progressive cortical and subcortical neuronal loss for ≤1 year after traumatic brain injury (49,50) and suggested that a chronically progressive degenerative process may be initiated by the injury. Putative mechanisms for the progressive tissue loss observed after brain injury include the consequences of the primary insult (i.e., wallerian degeneration) and progressive secondary injury mechanisms including apoptotic cell death, inflammation,and excitotoxicity in white matter tracts. Consistent with this hypothesis is the finding by Kim and colleagues (51) that those with temporal lobe complex partial seizures associated with an overt structural lesion show less neuronal loss than do those with a history of complicated febrile seizures or an IPI.

Seizures

Regression analyses showed that only patients with extratemporal partial epilepsy had a significant correlation between frequency of convulsive seizures and change in HV, TBV, and GMV. No correlation was found between seizure frequency and ipsilateral HV loss in cryptogenic TLE, suggesting that regional volume loss seen in association with convulsive seizures is not necessarily localized to the site of seizure generation but may be remote from the epileptic focus. Methodologic differences that may explain the discrepancy between our results and Briellmann's (15) finding that numbers of generalized tonic–clonic seizures are inversely correlated with ipsilateral HV loss, include differences in the populations studied, scanner consistency, blinding procedures, and use of age-matched controls (52).

Despite the prospective documentation of seizures, an accurate seizure count, particularly of focal seizures, was not always attainable because patients were not always aware of their seizures. Nonetheless, it would seem implausible that inaccuracy of seizure recall should affect our observations significantly, because the change in HV in the four groups was strikingly comparable (Fig. 1A). Mathern and colleagues (47) showed that longer durations of TLE were associated with decreased neuron densities in all hippocampal subfields, an observation independent of IPI-induced neuronal loss, although a long time course (>30 years) was required to demonstrate the negative correlation. Thus the authors proposed that the substantial hippocampal neuronal loss observed in HS was likely to be the result of an IPI rather than the effect of repeated limbic seizures. Their suggestion that limbic seizures slowly “damaged” the brain over several decades may contribute to the lack of correlation observed between seizures and hippocampal atrophy in our study.

None of the four patients with SE between the two scans experienced significant brain volume losses or HCT2 changes over the 3.5-year period. Opinion regarding cerebral damage after SE is divided. Although a number of case reports described the development of HS after an acute process (37), Salmenperä and colleagues (40) showed that progressive HV reduction was not an invariable consequence of promptly treated SE.

Gender

A previous cross-sectional study showed that men with TLE demonstrated greater brain atrophy compared with women with TLE. Because the number of convulsive seizures contributed significantly to these abnormalities in men but not in women, the authors postulated that men were more vulnerable to seizure-induced brain volume loss, although the initial damage was likely to be gender independent (53). In our study, we found no gender effect with regard to either initial volume loss or ongoing susceptibility to brain damage. Changes were comparable in men and women for all MRI parameters studied.

Exposure to antiepileptic drugs

Our data did not provide evidence for increased cerebral damage with prolonged exposure to AEDs. Although patients with TLE had been exposed to significantly more AEDs than had patients with extratemporal partial epilepsy and generalized epilepsy, the rate of volume loss was comparable in the three patient groups. A recent study comparing HV changes in newly diagnosed patients treated with carbamazepine, vigabatrin, and tiagabine monotherapy found no difference after 3 years of follow-up (22).

The role of PHT in the pathogenesis of cerebellar atrophy has not been resolved in previous retrospective studies. PHT treatment is frequently compounded by the cumulative effect of hypoxia in the context of repeated convulsive seizures. In the present study, we found no association between treatment with PHT—either long-term use or acute intoxication—and whole cerebellar volume. It is possible that seizures or PHT use might exert a selective regional effect, and a more detailed study of the cerebellar hemispheres and lobules of the vermis may be warranted.

Future work

The observation that hippocampal and cerebral atrophy in individual patients is not always related to high seizure numbers, in this and other studies (15), implies that factors other than overt seizures have a significant role. In our study, the predominant factors influencing volume loss were a history of an antecedent neurologic insult and age. We therefore believe that it is important to control for these variables when assessing the contribution of seizures on the brain. Although our findings did not support a syndrome-specific effect for regional volume loss, the patient population in our community-based study was heterogeneous, and follow-up of more homogeneous patient groups over a longer time might identify particular characteristics, such as genotype, that place individuals at an increased risk of epilepsy-related damage.

Current efforts to increase reproducibility and reduce operator intervention by automation [for example, by automatic propagation of manually drawn baseline segmentation to coregistered follow-up scans (54)] may provide more sensitive measures in the future, although their current performance does not surpass that of the methods used here. The serial use of new MRI contrasts such as magnetization transfer ratio imaging (55) may identify more subtle changes. Serial MR spectroscopic studies also may be of value in assessing functional changes that are not detected on structural imaging.

Conclusion

In summary, our longitudinal study of 179 patients with epilepsy showed that progressive regional or global cerebral damage is not an inevitable consequence of epileptic seizures. The significantly reduced baseline HV observed in patients with TLE was attributed largely to an antecedent neurologic insult. Subsequent hippocampal and neocortical atrophy was determined primarily by age and was, in the majority of cases, independent of a diagnosis of epilepsy. In a greater number of patients (23% of TLE patients), significantly more volume loss developed over a period of 3.5 years, than it did control subjects. This appeared independent of seizure frequency and AED use and may have occurred in response to an underlying epileptic process. A suggestion exists that an early neurologic insult may prime the brain and enhance age-related cerebellar atrophy. Further studies are required to characterise these neurologic insults because measures such as the prompt treatment of prolonged febrile seizures may modulate the impact of such insults on the brain and reduce subsequent atrophy.

Acknowledgments

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

Acknowledgment:  This work was supported by the Wellcome Trust (55742), the National Society for Epilepsy, and the UCLH NHS Trust Neuroepidemiology Unit. We thank Drs. J. Stevens and B. Kendall for their expert neuroradiologic interpretations, and Dr. A.D. Everitt and Miss K. Birnie for collection of baseline data. We also thank all patients and control subjects who participated in this study.

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  1. Top of page
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  3. METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgments
  7. REFERENCES
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