Ten things every neurologist needs to know about neuropsychological assessments and interventions in people with epilepsy.

This paper describes 10 core features of a neuropsychological assessment with the aim of helping neurologists understand the unique contribution the evaluation can make within the wider context of diagnostic methods in epilepsy. The possibilities, limitations and cautions associated with the investigation are discussed under the following headings. (1) A neuropsychological assessment is a collaborative investigation. (2) Assessment prior to treatment allows for the accurate assessment of treatment effects. (3) The nature of an underlying lesion and its neurodevelopmental context play an important role in shaping the associated neuropsychological deficit. (4) Cognitive and behavioural impairments result from the essential comorbidities of epilepsy which can be considered as much a disorder of cognition and behaviour as of seizures. (5) Patients' subjective complaints can help us understand objective cognitive impairments and their underlying neuroanatomy, resulting in improved patient care. At other times, patient complaints reflect other factors and require careful interpretation. (6) The results from a neuropsychological assessment can be used to maximize the educational and occupational potentials of people with epilepsy. (7) Not all patients are able to engage with a neuropsychological assessment. (8) There are limitations in assessments conducted in a second language with tests that have been standardized on different populations from that of the patient. (9) Adequate intervals between assessments maximize sensitivity to meaningful change. (10) Patients should be fully informed about the purpose of the assessment and have realistic expectations of the outcome prior to referral.

Optimizing memory function in temporal lobe epilepsy.

PURPOSE: The study aimed to assess whether engagement in a memory training programme and performing internet brain training exercises improve memory function in people with temporal lobe epilepsy (TLE). METHODS: Seventy-seven people with TLE, complaining of memory difficulties, completed the study. Participants ranged in age from 19 to 67 years and 40 had left TLE. Participants were randomised to one of four conditions; Group 1: traditional memory training, Group 2: Lumosity, an on-line cognitive training programme, Group 3: traditional memory training and Lumosity, and Group 4: no training. Memory efficiency and mood were assessed at baseline and three months later. RESULTS: Group analyses indicated improved verbal recall after training (p<0.001) and improved subjective ratings (p<0.007). More participants reported a lessening of the memory burden (p<0.007) after training; differences were significant between Groups 1 and 3 compared to Group 4. Lumosity use was not associated with changes in the memory outcome measures but there was a relationship with depression ratings and the number of memory games played (p<0.01). Conventional memory training, IQ, and post-surgical status were associated with positive memory outcomes. CONCLUSIONS: The study indicates traditional memory rehabilitation techniques can help reduce the burden of memory impairment in TLE. There was no evidence that Lumosity the on-line cognitive training programme had specific advantages. Positive change was not universal and larger studies will be required to explore factors associated with successful outcomes.

Cognitive outcomes of temporal lobe epilepsy surgery in older patients.

PURPOSE: To examine the cognitive risks of temporal lobe surgery in patients aged 50 years and older. METHODS: We analysed data from 55 patients who underwent temporal lobe surgery (26 left-sided:29 right sided) from 1988 to 2012 at our centre. Pre-surgical and one year post-operative memory and naming capacity were compared to data obtained from two younger cohorts; 185 aged 18-30 and 220 aged 31-49. RESULTS: Pre-operative memory impairments were most marked for the oldest cohort and were associated with a longer duration of epilepsy. Naming capacity improved with age and better performance was associated with a later age at epilepsy onset. Post-operative declines were largest in older patients, achieving statistical significance for verbal memory, naming and subjective ratings. Left temporal lobe resections carried the greatest risk of memory and naming decline. Cognitive outcomes were unrelated to seizure outcome, VIQ or mood. CONCLUSION: Our findings indicate the cognitive risks of TLE surgery are greater for older patients. Cognitive outcomes need to be considered when assessing the efficacy of epilepsy surgery in older cohorts and pre-operative performance levels need to be taken into account.

Light therapy as a treatment for epilepsy.

From a neurobiological level to epidemiological studies, there are four strands of evidence in the scientific literature that indicate that light therapy could be an effective treatment for some people with epilepsy. (1) Sunlight is important in the endogenous production and regulation of melatonin and vitamin D, both of which influence seizure thresholds. Although melatonin influences seizure thresholds, the relationship is complex. General down-regulating effects may have different effects on seizure thresholds for people with generalised and partial epilepsy syndromes. Specific actions within the hippocampus may mean that patients with temporal lobe epilepsy are particularly susceptible to the endogenous expression of melatonin via inhibitory actions on dopaminergic activity reducing seizure thresholds. (2) If suppression of melatonin results in fewer seizures this should be evident in seasonal variations in seizure frequencies. Seizure frequencies increase in the winter and on dull overcast days. Within this larger circannual rhythm, local light conditions are also associated with variations in seizure frequencies. Controlling for seasonal patterns, complex partial seizures are significantly less likely to occur on bright sunny days, than on dull days with fewer hours of sunshine, regardless of the time of year. (3) On a wider scale, some epidemiological studies also suggest a lower prevalence of epilepsy in southern Europe compared to Scandinavia and Northern Europe. (4) Light therapy is an established medical treatment for depression. Recent research suggests that some forms of epilepsy and depression are bi-directional conditions. The mechanism of action underlying light therapy for affective disorders remains the subject of much research but is thought to involve the enhancement of the monoaminergic systems targeted by antidepressant drugs (serotonin, dopamine, and norepinephrine); systems also implicated in a number of epilepsy syndromes. In this paper, we propose the hypothesis that exposure to high intensity light may be an effective, non-invasive add-on treatment for people with temporal lobe epilepsy. Although it is more likely to be palliative than curative, it may help smooth out some of the seasonal peaks in seizure frequencies, a pattern that increases the risk of serious manifestations of the condition such as status epilepticus and sudden unexpected death in epilepsy.

Unilateral temporal lobectomy patients show lateralized topographical and episodic memory deficits in a virtual town.

A large-scale virtual reality town was used to test the topographical and episodic memory of patients with unilateral temporal lobe damage. Seventeen right and 13 left temporal lobectomy patients were compared with 16 healthy matched control subjects. After they had explored the town, subjects' topographical memory was tested by requiring them to navigate to specific locations in the town. The ability to recognize scenes from and draw maps of the virtual town was also assessed. Following the topographical memory tests, subjects followed a route around the same town but now collected objects from two different characters in two different locations. Episodic memory for various aspects of these events was then assessed by paired forced-choice recognition tests. The results showed an interaction between laterality and test type such that the right temporal lobectomy (RTL) patients were worse on tests of topographical memory, and the left temporal lobectomy (LTL) patients worse on tests of context-dependent episodic memory. Specifically, the RTL group was impaired on navigation, scene recognition and map drawing relative to control subjects. They were also impaired on recognition of objects in the episodic memory task. The LTL group was impaired relative to control subjects on their memory for contextual aspects of the events, such as who gave them the objects, the order in which objects were received and the locations in which they received them. They were also mildly impaired on topographical memory, but less so than the RTL group. These results suggest that topographical memory is predominately mediated by structures in the right medial temporal lobe, whereas the context-dependent aspects of episodic memory in this non-verbal test are more dependent on the left medial temporal lobe.

Effects of topiramate on cognitive function.

OBJECTIVE: To explore the impact of topiramate on tests of intellect and other cognitive processes. METHODS: This was a retrospective study. The neuropsychological test scores of 18 patients obtained before and after the introduction of treatment with topiramate (median dose 300 mg) were compared with changes in test performance of 18 patients who had undergone repeat neuropsychological assessments at the same time intervals. Complaints of cognitive decline precipitated referral for reassessment in five cases in the topiramate treated group. The groups were matched for age and intellectual level at the time of the first assessment. Patients were assessed using the WAIS-R, tests of verbal and non-verbal memory, language, and perceptual processing. A subgroup of patients underwent a brief reassessment after the withdrawal or substantial reduction of topiramate. RESULTS: Repeat assessments in those taking topiramate were associated with a significant deterioration in many domains, which were not seen in the comparison group. The greatest changes were for verbal IQ, verbal fluency, and verbal learning (p<0. 001). Improvements in verbal fluency (p<0.05), verbal learning (p<0. 01), and digit span (p<0.001) were recorded in those patients who had topiramate withdrawn or reduced. CONCLUSIONS: In our patient group topiramate had a negative impact on cognition which was consistent with subjective complaints of patients. Tests requiring verbal processing seemed especially sensitive to the drug. A decline in verbal intellect (VIQ), a measure which has been considered by some to be insensitive to antiepileptic drug effects, was particularly striking. Caution is warranted in the interpretation of the findings due to methodological limitations of the study design. Further investigation of mediating factors such as serum concentrations, comedication, and other potential risk factors, however, is needed to enable appropriate targeting of treatment with this effective antiepileptic agent.

Fixation-off sensitivity as a model of continuous epileptiform discharges: electroencephalographic, neuropsychological and functional MRI findings.

A case of fixation-off sensitivity (FOS) in an asymptomatic adult is presented and studied as a model for continuous epileptiform discharges. Video-electroencephalographic (EEG) revealed continuous bilateral occipital spike wave discharges during elimination of central vision, which were shown to be associated with transitory cognitive impairment demonstrated by neuropsychological testing. Functional MRI showed activation of parieto-occipital and frontal brain areas during the fixation-off discharges. This localization was confirmed with 64-channel EEG source analysis. The applied methods provided additional information on the pathophysiology of epileptiform discharges.

Postoperative hippocampal remnant shrinkage and memory decline: a dynamic process.

BACKGROUND: The severity of postoperative memory decline in unilateral temporal lobectomy patients has been associated both with the extent of hippocampal resection and MRI measures of preoperative hippocampal volume. Serial MRI of the hippocampal remnant suggest that further volume loss occurs in the immediate postoperative period. For the majority of patients, this process appears to stabilize within the first 3 months. The authors examined the relationship between the dynamic volume of the hippocampal remnant and postoperative memory decline. METHOD: Seventeen adult temporal lobectomy patients (nine, left; eight, right) underwent a full neuropsychological assessment and a volumetric MRI scan preoperatively and 3 months postoperatively. Examination of the posterior hippocampal remnant on the postoperative scan revealed volume loss in this segment compared to the identical segment preoperatively in 16 of 17 cases. Spearman's correlations were used to examine the relationship between postoperative memory decline (postoperative - preoperative memory scores) and the postoperative/preoperative hippocampal remnant volume ratio. RESULTS: The volume of the hippocampal remnant left in situ was significantly correlated with postoperative memory change. Patients with smaller remnant volumes demonstrated more postoperative memory decline than those with larger remnants. In addition, extensive hippocampal remnant shrinkage was associated with postoperative memory decline in both the right and left temporal lobectomy groups. CONCLUSIONS: The absolute volume and subsequent volume loss in the hippocampal remnant following surgery can influence postoperative memory change. These findings suggest that postoperative processes should be considered in addition to preoperative pathology and surgical factors in the prediction of postoperative memory change.

Remote memory in epilepsy.

PURPOSE: There is now a considerable amount of research relating to memory functioning in epilepsy. The majority of studies have focused on the retention of new information, and few reports have measured memory for past events. This study aims to redress this and measure the efficiency of remote memory in epilepsy. METHODS: A remote memory questionnaire was prepared and administered to three groups of patients with epilepsy and a control group without epilepsy. The questionnaire assessed knowledge of public events that occurred between 1980 and 1991, inclusive. The epilepsy groups comprised 33 patients with temporal lobe epilepsy (TLE), 33 with extratemporal epilepsy (ExTE), and 10 with primary generalized epilepsy (PGE). Thirty control subjects were tested. RESULTS: Patients with TLE performed significantly less well on the questionnaire than all other groups (p = 0.001), but no effect of laterality was recorded; patients with extratemporal or primary generalised epilepsy did not differ from controls. Performance on the questionnaire was not determined by verbal IQ, educational achievement, social class, or drug treatment, but was related to the number of generalised convulsions that had occurred since 1980. The strongest neuropsychological predictors of performance on this questionnaire were measures of verbal memory. CONCLUSIONS: The study demonstrated weak memory for past events in patients with TLE, thereby providing evidence of a broader memory disturbance in this group than has been previously highlighted. A test of remote memory, such as the one designed for this study, is easy to administer and provides clinically important information not available from conventional neuropsychological tests.

Disproportion in the distribution of gray and white matter: neuropsychological correlates.

OBJECTIVE: To examine the relationship between measures of disproportion in the regional distribution of gray and white matter and preoperative neuropsychological function in temporal lobe epilepsy patients with proved hippocampal sclerosis (HS). BACKGROUND: Subtle cerebral structural disruption, not evident on routine inspection of high-resolution MRI, is associated with poor surgical outcome in patients with histologically proved HS. Preoperative global memory dysfunction is also associated with poor postoperative seizure control. The authors hypothesize that patients with HS and abnormal regional distributions of gray and white matter would show more diffuse neuropsychological deficits preoperatively than patients with isolated HS alone. METHODS: A total of 28 adults with lateralized temporal lobe epilepsy and hippocampal volume loss measured on MRI were assessed preoperatively on neuropsychological tests of general intellect and the learning and recall of both verbal and nonverbal material. Quantitative MRI analysis of the regional distribution of gray and white matter was performed. Chi-square analyses were used to examine the relation between the presence or absence of cerebral abnormalities and preoperative performance on the neuropsychological tests. RESULTS: A total of 15 of 28 patients had extrahippocampal abnormalities on quantitative MRI analysis. Thirteen patients had global memory impairment. Bilateral memory deficits were significantly associated with both the presence of cerebral abnormalities (p < 0.02) and poor postoperative seizure control (p < 0.05). CONCLUSIONS: Disproportion in the regional distribution of gray and white matter in patients with HS may form the structural basis of global memory disturbance in a distinct group of patients with temporal lobe epilepsy.

A test of spatial memory and its clinical utility in the pre-surgical investigation of temporal lobe epilepsy patients.

Deficits in memory for figurative detail, spatial composition and the spatial location of objects in a scene have been reported postoperatively in right temporal lobectomy patients. The aim of this study was to examine whether these deficits can be used as a sign of lateralised dysfunction in pre-surgical temporal lobe epilepsy (TLE) patients. Sixty-nine patients with lateralised TLE (27 right, 42 left) were assessed on a battery of neuropsychological tests, including tests of general intellectual functioning and psychomotor speed and standardised memory tests involving the learning and recall of verbal and non-verbal material. A new task, the "Aspects of Spatial Memory Test" (AoSMT), based on the experimental tasks developed by Pigott and Milner [39] was also administered. The RTLE and LTLE groups did not differ in their overall level of intellectual function or on measures of cognitive and motor speed. On the AoSMT the LTLE group recognised significantly more figurative detail changes than the RTLE group. In addition, the RTLE group took significantly longer than the LTLE group to identify changes in orientation, figurative detail and filled/unfilled spaces. Poor scores on the AoSMT were significantly correlated with quantitative MRI measures of right hippocampal pathology. The clinical and theoretical implications of these findings are discussed.

The relationship between quantitative MRI and neuropsychological functioning in temporal lobe epilepsy.

PURPOSE: Quantitative MRI techniques provide an unparalleled opportunity to examine in vivo the relationship between the extent and laterality of hippocampal pathology and associated neuropsychological deficits. The purpose of this study was to examine the nature of the relationship between quantitative measures of hippocampal pathology and neuropsychological measures, using a multivariate approach. METHODS: We examined the relationship between two MRI measures of hippocampal structure; hippocampal volumes (HCvol) and T2 relaxation times (HCT2), and memory performance, in 80 presurgical temporal lobe epilepsy patients. RESULTS: As a group, patients with left hippocampal sclerosis (LHS) performed more poorly that those with right hippocampal sclerosis (RHS) on immediate and delayed prose recall. In the group as a whole, right hippocampal volume was significantly correlated with the delayed recall of a complex figure. None of the verbal memory test scores were significantly correlated with the right or left HCvol or HCT2 measures. However, stepwise multiple regression analyses indicated that up to a third of the variation in specific test scores could be explained by the quantitative MRI hippocampal measures in conjunction with chronological age, and age at onset of habitual epilepsy. Left hippocampal measures explained 24% of the variance in the story-recall tasks, while right hippocampal measures explained 18% of the variance in a design-learning task and 32% of the variance in a figure-recall task. CONCLUSIONS: Our results provide some support for the lateralised model of material specific memory deficits, but suggest that a number of demographic and epilepsy-related factors may interact with the extent and laterality of hippocampal pathology in shaping the nature of the associated neuropsychological deficit.

Hippocampal cell loss and gliosis: relationship to preoperative and postoperative memory function.

The authors examined the relationship between neuronal densities, glial cell densities, and the glial cell/neuron ratio in the CA1 and CA4 hippocampal subfields and preoperative and postoperative memory function in 47 patients who had undergone a temporal lobectomy (23 right, RTL; 24 left, LTL) for the relief of medically intractable epilepsy. The LTL group performed more poorly than the RTL group on a list learning and story recall task, preoperatively and postoperatively. Both the RTL and LTL groups performed more poorly on the story recall task postoperatively. In the LTL group, neuronal densities in the CA1 subfield were significantly correlated with the preoperative scores on the immediate (r = 0.53, p < 0.01) and delayed (r = 0.53, p < 0.01) recall of the story. There were no significant correlations in the LTL group between the CA1 and CA4 cell counts and Verbal IQ or scores on a measure of naming ability. None of the cell density measures in the CA1 and CA4 subfields were significantly correlated with the preoperative neuropsychological test scores in the RTL group. Postoperative decline in verbal recall was associated with the excision of a relatively intact left hippocampus, with high neuronal and low glial cell densities in the CA1 subfield. The excision of a relatively intact right hippocampus was also associated with a postoperative deterioration in verbal recall.

The role of the hippocampus in recognition memory.

Amnesic patients with focal limbic lesions in the hippocampus demonstrate normal or near normal performance on the Warrington Recognition Memory Test (WRMT) suggesting that the hippocampi may not be critical structures in these tasks. To further investigate the role of the hippocampi in recognition memory we examined WRMT performance in 99 (44 right, 55 left) patients with unilateral temporal lobe pathology identified on MRI. The patients were divided into two groups. Group 1 (n = 90) were patients with hippocampal sclerosis (40 right, 50 left). Group 2 were patients with MRI evidence of hippocampal sclerosis and cortical dysgenesis, (4 right, 5 left). Analyses of variance revealed a significant interaction between laterality and pathology group for the recognition memory for words (RMW) task. The patients with left hippocampal sclerosis and cortical dysgenesis obtained significantly lower scores than the other patient groups. There was a significant effect of pathology group on the recognition memory for faces task (RMF). The patients with hippocampal sclerosis and cortical dysgenesis obtained lower scores than the patients with hippocampal sclerosis, regardless of the laterality of their pathology. Post-operative WRMT deficits in the right and left hippocampal sclerosis groups were material specific. The clinical utility of the WRMT in the pre-surgical investigation of temporal lobe epilepsy patients and the role of the hippocampus in recognition memory are discussed in the light of these findings.

The relation between quantitative MRI measures of hippocampal structure and the intracarotid amobarbital test.

PURPOSE: The increasing sophistication of quantitative magnetic resonance imaging (MRI) techniques has generated hopes that they may eventually supersede the intracarotid amobarbital procedure (IAP) in the presurgical screening for bilateral abnormalities in prospective candidates for temporal lobe epilepsy surgery. As the first step toward this aim, the purpose of this study was to examine the relationship between these measures of structural and functional integrity. METHODS: We examined the relation between memory performance and pass/fail rates on the IAP and two MRI measures of hippocampal integrity: hippocampal volumes, adjusted for intracranial volume (HCvol) and hippocampal T2 relaxometry (HCT2), in 48 patients with medically intractable temporal lobe epilepsy, who underwent the IAP as part of their presurgical evaluation for temporal lobectomy. RESULTS: The unilateral memory scores from the IAP were not significantly correlated with the corresponding HCvol or HCT2 measures in the right- and left-temporal-lobe groups. However, the MRI measures of hippocampal asymmetry (right minus left HCvol, right minus left HCT2) were significantly correlated with our measure of functional asymmetry, the right minus left hemisphere memory score from the IAP, supporting the role of the IAP in lateralising temporal lobe dysfunction. Forty-six patients with unilateral hippocampal sclerosis and concordant EEG studies passed the IAP. Two patients failed the memory component of the IAP. In both cases, other presurgical investigations suggested bilateral abnormalities. CONCLUSIONS: We conclude that patients with unilateral hippocampal sclerosis, established by a rigorous quantitative MRI protocol, and concordant ictal and interictal EEG findings may not be at risk for postoperative amnesia, despite baseline neuropsychological deficits suggestive of bilateral disturbance.

The hippocampus: functional and structural correlations.

This paper reviews the current literature relating neuropsychological measures of the functional integrity of the hippocampus with structural indices obtained from magnetic resonance imaging (MRI) volumetric scans and the histological analysis of postoperative specimens. The first part of the discussion presents an overview of the current methods and applications of volumetric MRI of the hippocampus. The processes and contemporary standards applied to the histological analysis of resected hippocampal tissue are also described. Both of these measures of structural integrity have been studied in relation to preoperative performance on neuropsychological tests, including the intracarotid sodium amytal test, and postoperative memory functioning. The findings from these studies are reviewed. The challenges presented by these new technologies to the field of neuropsychology are discussed.