Cerebellar atrophy in temporal lobe epilepsy

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Epilepsy & Behavior 7 (2005) 279–287 www.elsevier.com/locate/yebeh

Cerebellar atrophy in temporal lobe epilepsy Bruce P. Hermann a,*, Katherine Bayless a, Russ Hansen a, Joy Parrish b, Michael Seidenberg b b

a Department of Neurology, University of Wisconsin, Madison, WI 53792, USA Department of Psychology, Rosalind Franklin School of Medicine and Science, North Chicago, IL, USA

Received 11 April 2005; revised 26 May 2005; accepted 27 May 2005 Available online 26 July 2005

Abstract Purpose. The goal of this work was to determine the presence and degree of cerebellar atrophy in chronic temporal lobe epilepsy, its clinical seizure correlates, and its association with general cortical atrophy. Methods. Study participants were 78 persons with temporal lobe epilepsy and 63 age- and gender-matched healthy controls. All subjects underwent high-resolution MRI with manual tracing of the cerebellum. Clinical seizure features and history were obtained by structured interview and review of medical records. Results. The epilepsy group exhibited significant abnormality in cerebellar volume, with mean reductions ranging from 4 to 6.6% depending on adjustments. Significantly more individual subjects with epilepsy exhibited cerebellar atrophy compared with controls across all operational definitions or thresholds of abnormality including z 6 2.0 (13% TLE, 3.4% controls) and z 6 1.5 (22% TLE, 3.4% controls). Clinical seizure features reflecting both neurodevelopmental (history of initial precipitating injuries) and severity of course (longer duration, increased number of lifetime generalized tonic–clonic seizures) factors were associated with cerebellar atrophy. Atrophy of the cerebellum could be observed independent of more general (cerebral) atrophic processes. Conclusions. The presence of cerebellar atrophy is a reflection of the extratemporal abnormalities that can be observed in localization-related temporal lobe epilepsy, which may be due, at least in part, to factors associated with epilepsy chronicity.  2005 Elsevier Inc. All rights reserved. Keywords: Cerebellar atrophy; Temporal lobe epilepsy; Quantitative magnetic resonance imaging

1. Introduction Cerebellar atrophy, a neuropathological abnormality not uncommonly noted among patients with chronic epilepsy, was carefully described and characterized prior to the introduction of phenytoin. Cerebellar atrophy was reported in neuropathological investigations of institutionalized epilepsy patients dating back to 1825 [1], and the profound loss of Purkinje cells, preservation of basket cells, granule cell damage, and associated (BergmannÕs) gliosis were characterized by neuropathologists early in the last century [2]. While occasional *

Corresponding author. Fax: +1 608 265 0172. E-mail address: [email protected] (B.P. Hermann).

1525-5050/$ - see front matter  2005 Elsevier Inc. All rights reserved. doi:10.1016/j.yebeh.2005.05.022

investigators viewed this neuropathology as unassociated with epilepsy [3], it was more generally believed to be a direct consequence of chronic epilepsy, although opinions varied regarding the exact mechanism of effect [1,4– 6]. Following the development [7,8] and release [9,10] of phenytoin, it soon became evident that acute intoxication was associated with signs of cerebellar dysfunction [11]. Withdrawal or reduction of phenytoin often, but not always, resulted in resolution of symptoms. Reports appeared noting that some chronically treated patients exhibited persisting signs of cerebellar dysfunction, leading to interest in the role of phenytoin in the etiology of cerebellar atrophy [12–14]. Further supporting the view that treatment factors could contribute to or cause


B.P. Hermann et al. / Epilepsy & Behavior 7 (2005) 279–287

cerebellar atrophy were observations that this neuropathology could be induced in animals by phenytoin toxicity [15–17], as well as findings that cerebellar atrophy could be observed in humans without epilepsy [18–21] or in humans with very well-controlled epilepsy [13,22], following exposure to acute or chronic toxic doses of phenytoin. Dam and colleagues refocused interest on the role of frequent and severe seizures and the contribution of seizure-induced hypoxia in the etiology of cerebellar atrophy, marshalling both animal and human data to support this view [23–27]. Further suggestion of direct seizure-related mechanisms came from investigations of patients with frequent partial seizures in whom hypoxia was uncommon, yet who exhibited cerebellar atrophy [28,29]. Considered less often were the potential effects of initial etiological insults and early neurodevelopmental factors in the etiology of epilepsy-related cerebellar atrophy [29,30]. Debate regarding the relative contribution of drugs (phenytoin), seizures, and other factors continues to the present [31]. Through the years, cerebellar atrophy has been investigated not only by histopathological analysis, but by evolving neuroimaging techniques including pneumoencephalography [14,32,33], computed tomography (CT) [13,21,22,34,35], and magnetic resonance imaging (MRI) [18,19,29,36,37]. The availability of quantitative MRI volumetric techniques offers to characterize more precisely the presence, degree, distribution, and predictors of cerebellar atrophy in patients with chronic epilepsy. As summarized in Table 1, six quantitative MRI volumetric investigations have addressed the problem of cerebellar atrophy in epilepsy [38–44]. As is true of the larger literature, there is variability across these studies with respect to the populations studied, with only two investigations focusing specifically on temporal lobe epilepsy. Only one investigation examined children with epilepsy [41], and the abnormalities in cerebellar volume identified in that investigation indicate that neurodevelopmental factors are contributors to cerebellar atrophy. This emerging quantitative MRI literature contains investigations with varying image acquisition and volumetric processing procedures, as well as nonoverlapping primary outcome measures [e.g., comparison of group means, derivation of percentage reduction in cerebellar volume, determination of the degree of cerebellar atrophy (mild, moderate, severe)], making it difficult at times to compare results across studies and populations. The clinical seizure variables examined as predictors of cerebellar atrophy are variable across studies, with only one factor (duration of epilepsy) consistently examined. Few of the investigated clinical epilepsy variables are reliably associated with cerebellar atrophy across studies, but variations in methodology likely contribute to this problem.

The purpose of this investigation is threefold. The first aim is to characterize the presence and degree of cerebellar atrophy using various definitions of cerebellar atrophy to determine the rate and reliability of findings across various definitions of pathology. This is undertaken with respect to both group data (mean percentage volume loss) and individual data (proportion of subjects exhibiting cerebellar atrophy of varying severity). The second aim is to identify which of a number of clinical epilepsy factors are associated with cerebellar pathology. The clinical factors of interest here reflect the etiology, course, and treatment of epilepsy and were selected especially to reflect potential adverse neurodevelopmental as well as progressive effects of epilepsy on the cerebellum. The latter analyses control for the known effects of normal aging on brain structure to identify the unique impact of duration of disorder on cerebellar structure. The final aim is to determine the degree to which atrophy of the cerebellum occurs independent of atrophy of the cerebrum. These issues are examined in a large cohort of subjects with localization-related temporal lobe epilepsy and healthy age- and gender-matched controls spanning a very broad age range (14–60 years).

2. Methods 2.1. Subjects Participants included 78 patients with a diagnosis of temporal lobe epilepsy and 63 healthy controls. The subject selection process has been described in detail previously [45]. Briefly, initial selection criteria for epilepsy subjects included: (1) chronological age from 14 to 60 years, (2) localization-related temporal lobe epilepsy, (3) no MRI abnormality other than atrophy on clinical reading, and (4) no other neurological disorder. Epileptologists reviewed patientsÕ medical records including seizure semiology and previous EEG and neuroimaging reports, and rated each patient as having seizures of definite, probable, or possible temporal lobe origin. Definite temporal lobe epilepsy was defined by continuous video/ EEG monitoring of spontaneous seizures demonstrating temporal lobe seizure onset; probable temporal lobe epilepsy was determined by review of clinical semiology with features reported to reliably identify complex partial seizures of temporal lobe origin versus onset in other regions (e.g., frontal lobe) in conjunction with interictal EEGs, neuroimaging findings, and developmental and clinical history. Only patients meeting criteria for definite and probable temporal lobe epilepsy proceeded to recruitment for study participation, patients with possible temporal lobe epilepsy were excluded. Selection criteria for healthy controls included: (1) chronological age from 14 to 60, (2) either a friend or family member of the patient, (3) no current substance

B.P. Hermann et al. / Epilepsy & Behavior 7 (2005) 279–287


Table 1 Quantitative MRI investigations of cerebellar atrophy (CA) in epilepsy Study


MRI technique

Volumetric results

Predictive variables

Cognitive variables

Bohnen et al. (1998) [40]

54 patients with medically refractory partial epilepsy

Slice thickness 1.5–1.6 mm Semiautomated tracing on every brain image slice of cerebellum

Subjects without localized cerebral lesions had smaller cerebellar volumes than those with lesions (P < 0.05)

Significant Monthly seizure frequency Nonsignificant Age Age at onset Duration of epilepsy


Lawson et al. (2000) [41]a

231 children with epilepsy (10 determined on the basis of a median split of the distribution), frequency of complex partial seizures during the past year (none, yearly, monthly, weekly)], and treatment factors [i.e., years of phenytoin therapy, number of antiepilepsy medications]. Estimated lifetime number of generalized tonic–clonic (GTC) seizures was associated with cerebellar atrophy. Specifically, 52.9% of subjects with increased lifetime GTC seizures exhibited cerebellar atrophy versus 21.6% of subjects with fewer lifetime GTC seizures (P = 0.021). History of an initial precipitating injury was significantly associated with cerebellar atrophy (P = 0.05) in that 43.2% with positive histories, compared with 20% with negative histories, had cerebellar atrophy. The total number of current antiepilepsy medications (P = 0.076) and chronological age (P = 0.062) revealed trends that were not statistically significantly related to cerebellar atrophy. Not related to the presence of cerebellar atrophy were the frequency of complex partial seizures during the past year (yearly/none vs. weekly/monthly) (P = 0.94), gender (P = 0.09), age of onset of recurrent seizures (P = 0.50), or percentage of duration of epilepsy taking phenytoin (P = 0.51). There was no difference in cerebellar volume between patients with ictally confirmed left versus right temporal lobe onset. 3.3. Progression and cerebellar atrophy Determining whether increasing duration of epilepsy is associated with progressive adverse effects on brain structure requires consideration of the effects of normal age-related changes because increasing duration of epilepsy is invariably linked to increasing chronological age (r = 0.58, P < 0.001 in this epilepsy sample). One direct approach to address this issue is to examine the correlations of age with ICV-adjusted cerebellar volume in the control versus epilepsy groups. Greater than normal age-related changes in the epilepsy group compared with controls would infer an added impact or burden of chronic epilepsy on brain structure over time. There is a modestly stronger relationship between age and loss of cerebellar volume in the epilepsy group (Spearman r = 0.39, P = 0.001) compared with healthy controls (Spearman r = 0.22, P = 0.09) group. A more direct approach is provided in Fig. 3, where mean-adjusted

Fig. 3. Duration of epilepsy and adjusted (ICV, age, gender) cerebellar volume.

(age, gender, ICV) cerebellar volumes are examined as a function of decades with epilepsy. ANCOVA was significant (P = 0.025), with evident decreasing adjusted cerebellar volume as a function of duration of epilepsy. 3.4. Specificity of cerebellar atrophy The question of how closely cerebellar atrophy and cerebral atrophy are linked was examined in two ways. First, the correlation between total cerebellum and total cerebrum tissue among healthy controls is very robust (Spearman r = 0.69, P < 0.001), but substantially lower (though still significant) among the epilepsy subjects (Spearman r = 0.32, P = 0.008). This differential association of cerebral and cerebellar volumes in the controls versus epilepsy subjects suggests a dissociation of atrophic processes. Second, and perhaps more directly, epilepsy subjects can be identified who exhibit atrophy of the cerebrum and/or cerebellum using ICV-corrected z scores. Again, using a z score of 6 1.0, there is no significant relationship between atrophy of the cerebellum and cerebrum [v2 (1) = 0.58, P = 0.45], indicating that atrophy in these structures can occur independently.

4. Discussion The results of this investigation demonstrate the following: (1) There is a significant reduction in total cerebellar volume among subjects with chronic temporal lobe epilepsy compared with healthy controls that is evident regardless of analytic technique or definition of abnormality, (2) In the context of this overall group effect, there is variability across individuals with epilepsy regarding the presence of cerebellar atrophy, (3) Clinical factors associated with both the cause and the course of the disorder are related to cerebellar atrophy, (4) Cerebellar atrophy can occur independently of more general atrophic processes (e.g., atrophy of the cerebrum). These findings are discussed in greater detail in the material to follow.

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4.1. Cerebellar atrophy in chronic temporal lobe epilepsy This study compared a large cohort of subjects with temporal lobe epilepsy representing a broad age spectrum (ages 14–60) with age- and gender-matched healthy controls who were friends and relatives of the patients. While there are rare occasional reports denying an association between chronic epilepsy and cerebellar atrophy [34], every quantitative MRI investigation has reported smaller cerebellar size in the epilepsy groups examined. Significant atrophy of the cerebellum was evident in the epilepsy subjects studied here, with a 6.7% loss in raw uncorrected cerebellar volume (P < 0.001), and approximately 4% loss when cerebellar volume was conservatively adjusted for total intracranial volume (P = 0.016). No matter how the cerebellar data were analyzed or the covariates used, mean cerebellum volumes were consistently significantly smaller in the epilepsy subjects. The general vulnerability of the cerebellum in chronic epilepsy has long been recognized in neuropathological studies. Spielmeyer reported that AmmonÕs horn sclerosis and cerebellar atrophy were the most common abnormalities in chronic epilepsy [2]. Margerison and Corsellis reported in an examination of the brains of 55 temporal lobe epilepsy patients that damage to the hippocampus (65%) was followed by pathology in the cerebellum (45%), amygdala, (27%), thalamus (25%), and cerebral cortex (22%) [52]. In the context of this overall vulnerability, there was considerable variation in cerebellar volumes across epilepsy subjects. The incorporation of a large age- and gender-matched control group provided the normative data by which it was possible to identify individual epilepsy subjects exhibiting significant cerebellar atrophy. By use of different operational definitions of abnormality, from 33.8% (z 6 1.0) to 13% (z 6 2.0) of subjects with chronic temporal lobe epilepsy exhibited significant volumetric loss in the cerebellum (Fig. 1). Thus, in the context of the robust mean group effect described above, there was considerable individual variability in the expression of this volumetric abnormality, suggesting that particular features of the disorder may underlie this comorbid neuropathology. 4.2. Predictors of cerebellar atrophy It is reasonable to suspect that features of the subjectsÕ epilepsy predispose to extratemporal volumetric abnormalities, including cerebellar atrophy. To identify the predictors of cerebellar atrophy, temporal lobe epilepsy subjects with versus without cerebellar atrophy were derived (Fig. 2) using operational criteria. They were then compared across a range of clinical seizure variables reflecting factors associated with the cause, course, and treatment of the epilepsy. The results of


these analyses suggested that cerebellar atrophy was associated with both etiological factors (i.e., presence of a significant initial precipitating event) and features associated with the severity of the disorder (i.e., number of lifetime GTC seizures, duration of disorder). This overall pattern of findings appears consistent with a model that involves both neurodevelopmental and course factors. As such, the neurodevelopmental effect is conceptually consistent with findings of cerebellar atrophy in children with epilepsy [41], and the course findings (i.e., lifetime generalized seizures) are consistent with other cross-sectional studies, reporting that features of the severity of the epilepsy are associated with cerebellar atrophy [41–44]. Given concern regarding the possibility of progressive adverse effects of chronic temporal lobe epilepsy on brain structure, we specifically attempted to determine whether the simple duration of disorder was associated with progressive cerebellar atrophy. While, on the one hand, duration of disorder provides little information regarding the severity of the disorder, it does serve as a potentially cumulative marker of years of medication treatment, interictal EEG abnormalities, clinical seizure activity, and other clinical features. However, in that there are normal age-related changes in brain structure, the effects of duration of epilepsy on cerebellar volume need to be adjusted for normal age-related changes that were evident in both the epilepsy sample (Spearman r = 0.39) and healthy controls (Spearman r = 0.22). Cerebellar volumes were subsequently adjusted for chronological age, ICV, and gender and compared as a function of decades with epilepsy (Fig. 3). Increasing duration was associated with reduction in cerebellar volume, with a stepwise decline in adjusted volume with increasing decades of disorder. Thus, these cross-sectional data appear consistent with the hypothesis that greater than age-related changes may be present in the cerebellum in patients with very chronic epilepsy. One important issue to be addressed by quantitative MR procedures concerns the specific location of the volumetric loss in the cerebellum with increasing duration of disorder. We are currently acquiring volumes of the specific cerebellar lobes to determine where and to what degree this volume loss predominates and the degree to which lateralized temporal lobe epilepsy influences the pattern of cerebellar abnormalities. Interestingly, there were a number of factors that were not associated with cerebellar atrophy, including treatment factors (e.g., phenytoin use and duration) and other variables potentially reflective of the severity of the disorder (e.g., frequency of CPS over the past year). The limitations associated with retrospectively obtained clinical information are appreciated, especially in regard to medication history and seizure frequency counts.


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4.3. Specificity of cerebellar atrophy One issue addressed was the independence of cerebellar atrophy from atrophy in other regions, specifically, the cerebrum. The results suggest a dissociation of atrophy of the cerebellum and cerebrum. For instance, among the controls there was a significant correlation between cerebral and cerebellar volumes (r = 0.69), an association that appeared disrupted and substantially reduced in the epilepsy patients (r = 0.32). Most directly, identification of patients exhibiting atrophy of the cerebrum and/or cerebellum using operational criteria revealed that there was no significant association between atrophy in these two structures. 4.4. Clinical consequences of cerebellar atrophy The lack of information regarding the cognitive and behavioral consequences of cerebellar atrophy in epilepsy is noteworthy [31], particularly in light of increasing interest in the contributions of the cerebellum to higher cognitive functions and emotional-behavioral status [53–56]. We have demonstrated elsewhere that performance on tasks known to be mediated by the cerebellum (e.g., trace classic conditioning of the eyeblink response) is impaired in chronic temporal lobe epilepsy and that the normal cerebellum volume–conditioning relationship observed in healthy controls is disrupted in epilepsy patients [57]. In that cerebellar atrophy may be caused by a mix of developmental, progressive, and treatment factors, the impact of cerebellar atrophy in epilepsy on cerebellum-mediated cognitive tasks may differ compared with the effects reported in patient groups with acute cerebellar lesions or chronic disease where the cerebellum is affected [58]. Given the reported association of cerebellar atrophy and emotional disorders in other clinical groups [56], examination of this relationship in persons with epilepsy would be of interest. 4.5. Limitations and conclusions Several limitations in this investigation should be recognized. First, cross-sectional data cannot infer causality, and this caution is especially important when attempting to understand the effects of chronic epilepsy on changes in brain structure. Prospective data are required to conclusively answer this question. Attempts to examine duration effects in a cross-sectional fashion may also be especially sensitive to cohort effects. That is, individuals with considerably longer durations of epilepsy are older and had access to a limited array of available medications, with phenytoin prominent among them, compared with younger subjects with a shorter duration of epilepsy who have the benefit of a broader range of available medications. Second, this investigation and other quantitative MRI investigations rely on

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