Fiber ball white matter modeling in focal epilepsy.

Multicompartment diffusion magnetic resonance imaging (MRI) approaches are increasingly being applied to estimate intra-axonal and extra-axonal diffusion characteristics in the human brain. Fiber ball imaging (FBI) and its extension fiber ball white matter modeling (FBWM) are such recently described multicompartment approaches. However, these particular approaches have yet to be applied in clinical cohorts. The modeling of several diffusion parameters with interpretable biological meaning may offer the development of new, noninvasive biomarkers of pharmacoresistance in epilepsy. In the present study, we used FBI and FBWM to evaluate intra-axonal and extra-axonal diffusion properties of white matter tracts in patients with longstanding focal epilepsy. FBI/FBWM diffusion parameters were calculated along the length of 50 white matter tract bundles and statistically compared between patients with refractory epilepsy, nonrefractory epilepsy and controls. We report that patients with chronic epilepsy had a widespread distribution of extra-axonal diffusivity relative to controls, particularly in circumscribed regions along white matter tracts projecting to cerebral cortex from thalamic, striatal, brainstem, and peduncular regions. Patients with refractory epilepsy had significantly greater markers of extra-axonal diffusivity compared to those with nonrefractory epilepsy. The extra-axonal diffusivity alterations in patients with epilepsy observed in the present study could be markers of neuroinflammatory processes or a reflection of reduced axonal density, both of which have been histologically demonstrated in focal epilepsy. FBI is a clinically feasible MRI approach that provides the basis for more interpretive conclusions about the microstructural environment of the brain and may represent a unique biomarker of pharmacoresistance in epilepsy.

Altered structural connectome in non-lesional newly diagnosed focal epilepsy: Relation to pharmacoresistance.

Despite an expanding literature on brain alterations in patients with longstanding epilepsy, few neuroimaging studies investigate patients with newly diagnosed focal epilepsy (NDfE). Understanding brain network impairments at diagnosis is necessary to elucidate whether or not brain abnormalities are principally due to the chronicity of the disorder and to develop prognostic markers of treatment outcome. Most adults with NDfE do not have MRI-identifiable lesions and the reasons for seizure onset and refractoriness are unknown. We applied structural connectomics to T1-weighted and multi-shell diffusion MRI data with generalized q-sampling image reconstruction using Network Based Statistics (NBS). We scanned 27 patients within an average of 3.7 (SD = 2.9) months of diagnosis and anti-epileptic drug treatment outcomes were collected 24 months after diagnosis. Seven patients were excluded due to lesional NDfE and outcome data was available in 17 patients. Compared to 29 healthy controls, patients with non-lesional NDfE had connectomes with significantly decreased quantitative anisotropy in edges connecting right temporal, frontal and thalamic nodes and increased diffusivity in edges between bilateral temporal, frontal, occipital and parietal nodes. Compared to controls, patients with persistent seizures showed the largest effect size (|d|>=1) for decreased anisotropy in right parietal edges and increased diffusivity in edges between left thalamus and left parietal nodes. Compared to controls, patients who were rendered seizure-free showed the largest effect size for decreased anisotropy in the edge connecting the left thalamus and right temporal nodes and increased diffusivity in edges connecting right frontal nodes. As demonstrated by large effect sizes, connectomes with decreased anisotropy (edge between right frontal and left insular nodes) and increased diffusivity (edge between right thalamus and left parietal nodes) were found in patients with persistent seizures compared to patients who became seizure-free. Patients who had persistent seizures showed larger effect sizes in all network metrics than patients who became seizure-free when compared to each other and compared to controls. Furthermore, patients with focal-to-bilateral tonic-clonic seizures (FBTCS, N = 11) had decreased quantitative anisotropy in a bilateral network involving edges between temporal, parietal and frontal nodes with greater effect sizes than those of patients without FBTCS (N = 9). NBS findings between patients and controls indicated that structural network changes are not necessarily a consequence of longstanding refractory epilepsy and instead are present at the time of diagnosis. Computed effect sizes suggest that there may be structural network MRI-markers of future pharmacoresistance and seizure severity in patients with a new diagnosis of focal epilepsy.

Severe statin-induced autoimmune myopathy successfully treated with intravenous immunoglobulin.

Statin-induced autoimmune necrotising myopathy causes a severe progressive muscle weakness even when the statins are discontinued. First-line treatment is usually with high dose steroids followed by immunosuppressants, but this is often ineffective and there is a high risk of side effects. We describe a diabetic patient who had a very severe statin-induced autoimmune myopathy. He made a full recovery with regular intravenous immunoglobulin (IVIg) infusion in relatively low dose (55 g the first day followed by 50 g/day the second and third day, subsequently he was given 50 g/day for 3 days every 6 weeks). His symptoms relapsed when the IVIgs were discontinued for 28 weeks but remitted again following recommencement of IVIg infusions (50 g/day for 3 days every 7 weeks). Our case suggests IVIgs are an effective and well tolerated alternative to steroids and immunosuppressants.

Comparison of manual and automated fiber quantification tractography in patients with temporal lobe epilepsy.

OBJECTIVE: To investigate the agreement between manually and automatically generated tracts from diffusion tensor imaging (DTI) in patients with temporal lobe epilepsy (TLE). Whole and along-the-tract diffusivity metrics and correlations with patient clinical characteristics were analyzed with respect to tractography approach. METHODS: We recruited 40 healthy controls and 24 patients with TLE who underwent conventional T1-weighted imaging and 60-direction DTI. An automated (Automated Fiber Quantification, AFQ) and manual (TrackVis) deterministic tractography approach was used to identify the uncinate fasciculus (UF) and parahippocampal white matter bundle (PHWM). Tract diffusion scalar metrics were analyzed with respect to agreement across automated and manual approaches (Dice Coefficient and Spearman correlations), to side of onset of epilepsy and patient clinical characteristics, including duration of epilepsy, age of onset and presence of hippocampal sclerosis. RESULTS: Across approaches the analysis of tract morphology similarity revealed Dice coefficients at moderate to good agreement (0.54 - 0.6) and significant correlations between diffusion values (Spearman's Rho=0.4-0.9). However, within bilateral PHWM, AFQ yielded significantly lower FA (left: Z = 4.4, p<0.001; right: Z = 5.1, p<0.001) and higher MD values (left: Z=-4.7, p<0.001; right: Z=-3.7, p<0.001) compared to the manual approach. Whole tract DTI metrics determined using AFQ were significantly correlated with patient characteristics, including age of epilepsy onset in FA (R = 0.6, p = 0.02) and MD of the ipsilateral PHWM (R=-0.6, p = 0.02), while duration of epilepsy corrected for age correlated with MD in ipsilateral PHWM (R = 0.7, p<0.01). Correlations between clinical metrics and diffusion values extracted using the manual whole tract technique did not survive correction for multiple comparisons. Both manual and automated along-the-tract analyses demonstrated significant correlations with patient clinical characteristics such as age of onset and epilepsy duration. The strongest and most widespread localized ipsi- and contralateral diffusivity alterations were observed in patients with left TLE and patients with HS compared to controls, while patients with right TLE and patients without HS did not show these strong effects. CONCLUSIONS: Manual and AFQ tractography approaches revealed significant correlations in the reconstruction of tract morphology and extracted whole and along-tract diffusivity values. However, as non-identical methods they differed in the respective yield of significant results across clinical correlations and group-wise statistics. Given the absence of excellent agreement between manual and AFQ techniques as demonstrated in the present study, caution should be considered when using AFQ particularly when used without reference to benchmark manual measures.

The long-term outcomes of epilepsy surgery.

OBJECTIVE: Despite modern anti-epileptic drug treatment, approximately 30% of epilepsies remain medically refractory and for these patients, epilepsy surgery may be a treatment option. There have been numerous studies demonstrating good outcome of epilepsy surgery in the short to median term however, there are a limited number of studies looking at the long-term outcomes. The aim of this study was to ascertain the long-term outcome of resective epilepsy surgery in a large neurosurgery hospital in the U.K. METHODS: This a retrospective analysis of prospectively collected data. We used the 2001 International League Against Epilepsy (ILAE) classification system to classify seizure freedom and Kaplan-Meier survival analysis to estimate the probability of seizure freedom. RESULTS: We included 284 patients who underwent epilepsy surgery (178 anterior temporal lobe resections, 37 selective amygdalohippocampectomies, 33 temporal lesionectomies, 36 extratemporal lesionectomies), and had a prospective median follow-up of 5 years (range 1-27). Kaplan-Meier estimates showed that 47% (95% CI 40-58) remained seizure free (apart from simple partial seizures) at 5 years and 38% (95% CI 31-45) at 10 years after surgery. 74% (95% CI 69-80) had a greater than 50% seizure reduction at 5 years and 70% (95% CI 64-77) at 10 years. Patients who had an amygdalohippocampectomy were more likely to have seizure recurrence than patients who had an anterior temporal lobe resection (p = 0.006) and temporal lesionectomy (p = 0.029). There was no significant difference between extra temporal and temporal lesionectomies. Hippocampal sclerosis was associated with a good outcome but declined in relative frequency over the years. CONCLUSION: The vast majority of patients who were not seizure free experienced at least a substantial and long-lasting reduction in seizure frequency. A positive long-term outcome after epilepsy surgery is possible for many patients and especially those with hippocampal sclerosis or those who had anterior temporal lobe resections.

A voxel-based asymmetry study of the relationship between hemispheric asymmetry and language dominance in Wada tested patients.

Determining the anatomical basis of hemispheric language dominance (HLD) remains an important scientific endeavor. The Wada test remains the gold standard test for HLD and provides a unique opportunity to determine the relationship between HLD and hemispheric structural asymmetries on MRI. In this study, we applied a whole-brain voxel-based asymmetry (VBA) approach to determine the relationship between interhemispheric structural asymmetries and HLD in a large consecutive sample of Wada tested patients. Of 135 patients, 114 (84.4%) had left HLD, 10 (7.4%) right HLD, and 11 (8.2%) bilateral language representation. Fifty-four controls were also studied. Right-handed controls and right-handed patients with left HLD had comparable structural brain asymmetries in cortical, subcortical, and cerebellar regions that have previously been documented in healthy people. However, these patients and controls differed in structural asymmetry of the mesial temporal lobe and a circumscribed region in the superior temporal gyrus, suggesting that only asymmetries of these regions were due to brain alterations caused by epilepsy. Additional comparisons between patients with left and right HLD, matched for type and location of epilepsy, revealed that structural asymmetries of insula, pars triangularis, inferior temporal gyrus, orbitofrontal cortex, ventral temporo-occipital cortex, mesial somatosensory cortex, and mesial cerebellum were significantly associated with the side of HLD. Patients with right HLD and bilateral language representation were significantly less right-handed. These results suggest that structural asymmetries of an insular-fronto-temporal network may be related to HLD.

Facial Onset Sensory and Motor Neuronopathy: Further Evidence for a TDP-43 Proteinopathy.

Three patients with the clinical and investigation features of facial onset sensory and motor neuronopathy (FOSMN) syndrome are presented, one of whom came to a post-mortem examination. This showed TDP-43-positive inclusions in the bulbar and spinal motor neurones as well as in the trigeminal nerve nuclei, consistent with a neurodegenerative pathogenesis. These data support the idea that at least some FOSMN cases fall within the spectrum of the TDP-43 proteinopathies, and represent a focal form of this pathology.

CANOMAD responding to weekly treatment with intravenous immunoglobulin (IVIg).

A 48-year-old man presented with numbness in fingers and diplopia 1 week after a flu-like illness. He made a full recovery but 8 years later developed progressive and disabling sensory ataxia. He had superimposed acute flare-ups with numbness, double vision and ptosis, all following infections. A blood test showed antidisialosyl antibodies including GD1b, GD3, GT1b and GQ1b in keeping with the diagnosis of chronic ataxic neuropathy, ophthalmoplegia, IgM paraprotein, cold agglutinins and antidisialosyl antibodies (CANOMAD). Initial treatment with monthly courses of intravenous immunoglobulin (IVIg) 0.4 g/kg/day for 5 days every 4 weeks helped temporarily but there were marked disabling fluctuations of symptoms. With IVIg 0.6 g/kg/day weekly his symptoms are stable. He remains mobile and has no eye symptoms without need for any other medication. This case demonstrates that weekly IVIg infusions instead of one 5-day course monthly may be able to avoid fluctuations of symptoms in CANOMAD.

Self-reported feelings of anger and aggression towards others in patients on levetiracetam: data from the UK antiepileptic drug register.

OBJECTIVES: To ascertain the frequency of self-reported anger and depression in levetiracetam (LEV). DESIGN: We compared patients with epilepsy (PWE) taking LEV with PWE taking other antiepileptic drugs (AEDs). SETTING: All PWE and controls submitted information to the UK AED register. PARTICIPANTS: We analysed the data of 418 PWE and 41 control participants. 158 participants took LEV in monotherapy or as part of polypharmacotherapy, 260 PWE took other AED. PRIMARY AND SECONDARY OUTCOME MEASURES: All PWE and controls completed the Liverpool Adverse Event Profile (LAEP) which includes items on anger and depression quantified on a four-point Likert scale, with 1 indicating that there was never a problem; 2, rarely a problem; 3, sometimes a problem and 4, always or often a problem. RESULTS: 49% of PWE on LEV and 39% on AED other than LEV reported anger as sometimes or always being a problem (p=0.042). 48% of PWE on LEV and 45% on AED other than LEV reported depression as sometimes or always being a problem (p=0.584). 7% of control participants reported anger as sometimes being a problem and 93% reported anger as never or rarely being a problem. Depression was never a problem in 75% of controls and rarely a problem in 25%. CONCLUSIONS: Anger and depression were more frequently reported as a problem by PWE than by control participants. Our observational register of self-reported symptoms suggested anger being more often a problem in patients taking LEV than in PWE taking other AED. PWE should be informed about this potential problem of LEV.

An unusual presentation of an epidermoid brain tumour: a tale of two specialties.

A 33-year-old right-handed lady was referred to the psychiatry and neurology services by her general practitioner. Previously, she was under psychiatric care for bipolar affective disorder. Recently, her mood had deteriorated prompting the re-referral to the psychiatrists. In addition she had strange attacks. These strange attacks seemed to her like 'sensory overload' or that the 'brain just stops'. Other sensations throughout the attacks included feeling like she is in a 'fish bowl' and surrounding sights and sounds were distorted. She could not speak. After the attack she was hot and flustered, suffered memory loss and was tearful. Both the psychiatrist and the neurologist considered the possibility of these attacks being psychiatric in aetiology. However, the alternative possibility of a coexistence to epilepsy and depression was investigated and MRI demonstrated an epidermoid tumour with the supratentorial portion displacing the left temporal lobe.

Self reported adverse effects of mono and polytherapy for epilepsy.

PURPOSE: Adverse effects of anti epileptic drugs (AEDs) can significantly affect the life of people with epilepsy. We used a register to determine if polytherapy with AED has more adverse effects than monotherapy. METHODS: We established a register for people with epilepsy (www.UKAED.info). Participants were requested to complete the Liverpool Adverse Event Profile (LAEP) to quantify adverse effects. We also recorded type of epilepsy, seizure control and AED including drug doses. Five hundred and seventy six complete data sets were available, monotherapy (n=186), polytherapy (n=325) and control subjects not taking AED (n=65). RESULTS: The mean LAEP scores in polytherapy (45.56, confidence interval (CI)=44.36-46.76) were significantly higher than the mean LAEP scores in monotherapy (42.29, CI=40.65-44.02) and the mean LAEP scores in controls (33.25, CI=31.05-35.44). Tiredness, memory problems and difficulty concentrating were the most common symptoms in patients taking AED and were consistently higher in polytherapy than in monotherapy. Tiredness was reported as always or sometimes being a problem in (polytherapy/monotherapy/controls) 82.5%/75.6%/64.6%, memory problems in 76%/63.2%/29.2% and difficulty concentrating in 68%/63.9%/30.8%. The proportion of seizure-free patients was significantly lower in the polytherapy group (17%) than in the monotherapy group (55%). Depression rates between the monotherapy and polytherapy groups were similar. Drug dosages were higher in polytherapy, however this did not reach statistical significance. CONCLUSION: Patients on polytherapy had significantly higher LAEP scores than patients on monotherapy. This should be carefully discussed with the patient before a second AED is added.

Protracted neuroborreliosis--an unusual cause of encephalomyelitis.

A 58-year-old lady with waxing and waning of non-specific symptoms including fatigue, dizziness, hearing loss and unsteady gait for 15 months, became acutely confused 12 h prior to presentation. On admission to a district hospital she was feverish and unresponsive. Her travel history consisted of visits to Argentina, Chile and the Outer Hebrides. CT of the brain was normal. Lumbar puncture demonstrated a lymphocytic pleocytosis of 500 cells, protein of 1 g/l, a low glucose ratio with negative cytology and viral PCR (including herpes simplex 1 and 2). MRI revealed multiple abnormal areas of high signal on T2 fluid attenuated inversion recovery sequencing within the cerebellum, temporal lobes and periventricular areas. Western blotting of serum and cerebrospinal fluid for Borrelia burgdoferi were both positive. She was treated with cefuroxime and aciclovir and within 24 h she was alert and responsive. She received 4 weeks of cefuroxime in total and made a good recovery.

Dilemmas in the interpretation of diagnostic accuracy studies on presurgical workup for epilepsy surgery.

We conducted a systematic review to determine which noninvasive technologies should be used in the workup for epilepsy surgery to identify structural or functional abnormalities to help locate the site of seizure onset. The review focused on patients where there was insufficient confidence, in either the decision to go to surgery or the site at which surgery should be conducted, after the initial clinical examination. The majority of the studies identified were single-gate diagnostic accuracy studies; none were randomized controlled trials, and only one reported the effect of the test results on the decision making process. It became apparent that the data derived from diagnostic accuracy studies could not be used to answer the review question. This article focuses on the methods used to extract data from the diagnostic accuracy studies, the difficulties interpreting the resulting data, why such studies are not an appropriate study design in this setting, and how the evidence-base can be improved.

The duration of temporal lobe epilepsy and seizure outcome after epilepsy surgery.

UNLABELLED: To assess the effect of the duration of epilepsy on the outcome of epilepsy surgery in non-lesional medically refractory temporal lobe epilepsy we reviewed the outcome of 76 patients. METHODS: All patients had anterior temporal resections for "non-lesional" temporal epilepsy (excluding any patient with tumours or vascular malformations but including patients with hippocampal sclerosis). Outcome at one year was assessed using Engel's scale. RESULTS: 67% had a good outcome (Engel I or II). The mean duration of epilepsy was 23.0 years (range 2.9-46.9 years). Overall, there was no significant difference between patients with good outcome (mean duration 22.4 years) and poor outcome (mean duration 24.2 years) (p=0.49). The proportion of patients with good outcome was slightly higher in the shorter duration groups. (Duration less than 10 years 75%, 10-19 years 71%, 20-29 years 65%, 30-39 years 62%, and 40-49 years 60% good outcome, p=0.95). CONCLUSION: We found no significant associations between outcome and duration of epilepsy.

Persistent seizures following left temporal lobe surgery are associated with posterior and bilateral structural and functional brain abnormalities.

PURPOSE: To perform a quantitative MRI and retrospective electrophysiological study to investigate whether persistent post-surgical seizures may be due to brain structural and functional abnormalities in temporal lobe cortex beyond the margins of resection and/or bilateral abnormalities in patients with temporal lobe epilepsy (TLE). METHODS: In 22 patients with left TLE and histopathological evidence of hippocampal sclerosis, we compared pre-surgical brain morphology between patients surgically remedied (Engel's I) and patients with persistent post-surgical seizures (PPS, Engel's II-IV) using voxel-based morphometry (VBM). Routine pre-surgical EEG and invasive and non-invasive telemetry investigations were additionally compared between patient groups. RESULTS: Results indicated widespread structural and functional abnormalities in patients with PPS relative to surgically remedied patients. In particular, patients with PPS had significantly reduced volume of the ipsilateral posterior medial temporal lobe and contralateral medial temporal lobe relative to surgically remedied patients. Furthermore, successful surgery was associated with clear anterior (89%) and unilateral (100%) temporal lobe EEG abnormalities, whilst PPS were associated with widespread ipsilateral (91%) and bilateral (82%) temporal lobe abnormalities. DISCUSSION: We suggest that these preliminary data support the hypothesis that PPS after temporal lobe surgery are due to functionally connected epileptogenic cortex remaining in the ipsilateral posterior temporal lobe and/or in temporal lobe contralateral to resection.

Nonconvulsive status epilepticus: Epilepsy Research Foundation workshop reports.

In April 2004, a group of physicians with an interest in nonconvulsive status epilepticus representing a spectrum of opinion met in Oxford, sponsored by the Epilepsy Research Foundation (a charitable organization), to discuss and debate the definition, diagnosis and treatment of nonconvulsive status epilepticus. We felt that such a meeting would be useful, as nonconvulsive status epilepticus is a subject that provokes strong reactions, perhaps largely due to the relative lack of evidence and the surfeit of opinion. The meeting was arranged such that there were formal talks followed by a discussion led by one of the attendees. We present here the extended abstracts of the main talks with the points raised by the discussants. Despite disagreements on certain issues there was much in the way of consensus. First, it was agreed that nonconvulsive status epilepticus is a term that covers a range of disparate conditions with varying prognoses and treatments. The agreed definition was thus suitably vague, A<>. Secondly, it was agreed that even within a specific condition (e.g. complex partial status epilepticus), the prognosis and treatment depends upon the context in which the condition occurs (e.g. in the critically ill, in coma, in the A<> and in people with prior epilepsy). Perhaps, most importantly it was agreed that we lacked good clinical data, and the challenge was to design good studies for a condition that is underrecognised and often difficult to diagnose.

Comparison of standard and optimized voxel-based morphometry for analysis of brain changes associated with temporal lobe epilepsy.

We compared statistical parametric maps (SPMs) of group-wise regional gray matter differences between temporal lobe epilepsy (TLE) patients with unilateral hippocampal atrophy (HA) determined by manual volumetric analysis relative to a healthy control population using standard and optimized voxel-based morphometry (VBM). We also investigated the impact of customized neuroanatomical templates on SPMs. Standard and optimized VBM analyses of gray matter concentration (GMC) and gray matter volume (GMV) correctly identified HA, regardless of the template used for normalization. The distribution of hippocampal and extrahippocampal abnormalities differed according to the technique (standard v optimized; GMC v GMV), but was not dependent on template type (default v customized) within each technique. In particular, hippocampal GMC reduction was confined to subregions of hippocampus, whereas GMV reduction was observed in the hippocampal head, body, and tail. Unlike standard and optimized GMC reduction, symmetrical GMV reduction was observed in bilateral thalamus, lenticular nuclei, cerebellum, and ipsilateral entorhinal cortex, perirhinal cortex, and fusiform gyrus in both left and right HA patients. These results show that group-wise SPMs of GMC (i.e., regional distribution of gray matter) and GMV (i.e., volume per se) reduction can identify focal atrophy that has been quantified with manual region of interest techniques, although effects are attenuated in analyses of GMC. Unlike SPMs of GMC, analyses of GMV revealed similar extrahippocampal abnormalities as previous region-of-interest volumetric and histopathological studies of intractable TLE. We suggest that in studies of neurological disorders, optimized VBM analyses of GMV may reveal subtle neuroanatomical changes that are not identified in analyses of GMC.

How accurate are witness descriptions of epileptic seizures?

PROBLEM: The diagnosis of epilepsy largely relies on the seizure description by a witness. Our aim was to assess the accuracy of seizure descriptions. METHODS: Twenty volunteers (10 medical students, 4 junior doctors working on a neurological ward and 6 non-medical students) viewed a video of a partial then secondary, i.e. generalised seizure, and were then asked to provide a written account of the event. The seizure had eight key features. Volunteers scored one mark for each described key feature. One mark was deducted for each false observation. RESULTS: The mean positive score was 3.5 (range 1 to 6). Unresponsiveness and lateralising features were often missed. The mean negative score was -0.8 (range 0 to -3). Erroneously described features included 'patient rolled over', 'agitated' or 'arms flopped about' as part of the tonic clonic seizure. Left and right were sometimes confused. The mean total score was 2.7 (range -2 to 6). A medical and a non-medical student achieved the highest scores, a doctor the lowest score. CONCLUSIONS: The accuracy of seizure descriptions by witnesses was generally low and there were wide variations.

Voxel-based morphometric comparison of hippocampal and extrahippocampal abnormalities in patients with left and right hippocampal atrophy.

We used voxel-based morphometry (VBM), an automatic whole-brain MR image analysis technique, to investigate gray matter abnormalities in patients with temporal lobe epilepsy (TLE), in whom hippocampal atrophy (HA) was demonstrated by application of the Cavalieri method of modern design stereology. VBM results (P < 0.05, corrected) indicated preferential gray matter concentration (GMC) reduction in anterior hippocampus in patients with left HA and posterior hippocampus in patients with right HA. GMC reduction was also found in right dorsal prefrontal cortex in left and right HA patients. Prefrontal atrophy may be due to epileptiform excitotoxic discharges from the reciprocally connected pathological hippocampus, and may be the underlying biological cause for executive dysfunction in patients with TLE. GMC excess in ipsilateral parahippocampal, cerebellar, and pericallosal regions was common to both left and right HA groups relative to controls, and is hypothesized to reflect diminished gray-white matter demarcation, underlying white matter atrophy, or structural displacement due to cerebrospinal fluid expansion. However, bilateral temporal lobe GMC excess was observed in left HA patients, while ipsilateral temporal lobe GMC excess was observed in right HA patients. This work demonstrates methodological consistency between automated VBM and manual stereological analysis of the hippocampus in group comparisons, indicates widespread extrahippocampal gray matter abnormalities in unilateral HA, and suggests that there may be inherent differences in the effect of TLE on temporal lobe structures depending on the side of HA.