Cognitive characteristics of PTEN hamartoma tumor syndromes.

PURPOSE: We sought to characterize cognition in individuals with germline PTEN mutations (n = 23) as well as in PTEN mutation-negative individuals with classic Cowden syndrome or Bannayan-Riley-Ruvalcaba syndrome (n = 2). METHODS: Twenty-five individuals completed a comprehensive neuropsychological evaluation. One sample t-tests and effect sizes were used to examine differences in participant test scores compared with normal controls. Composite scores were created for each patient within each of the cognitive domains assessed and classified as above average, average, or below average according to normative standards. χ(2) analyses compared these classifications to expected proportions in normal control samples. RESULTS: The mean intelligence quotient was in the average range, and the range of intellectual functioning was very wide (from extremely low to very superior). However, in a large subset of patients, scores were lower than expected on measures of motor functioning, executive functioning, and memory recall, suggesting disruption of frontal circuits in these participants. CONCLUSION: This is the first study to characterize cognition in individuals with PTEN mutations and associated syndromes using a comprehensive neuropsychological battery. Contrary to previous reports suggesting an association with intellectual disability, the mean intelligence quotient was average, and there was a broad range of intellectual abilities. Specific evidence of disruption of frontal circuits may have implications for treatment compliance and cancer surveillance, and further investigation is warranted.

Word-finding difficulties confound performance on verbal cognitive measures in adults with intractable left temporal lobe epilepsy.

This study sought to determine if word-finding difficulties (WFDs), which are common in adults with dominant temporal lobe epilepsy (TLE), are related to performance on verbal cognitive measures, including memory. One hundred six individuals with left TLE and pathologically confirmed mesial temporal sclerosis completed comprehensive preoperative neuropsychological evaluations. Patients were divided into two groups based on the degree of benefit received from phonemic cueing on a confrontation naming task. Cognitive performance was then compared between patients with greater and fewer WFDs. Patients with greater WFDs demonstrated poorer performance on many verbal cognitive measures compared to those with fewer WFDs. In contrast, there were no significant differences between groups on any of the nonverbal cognitive measures. Chi-square analyses indicated that below average verbal memory performance occurred at a significantly higher rate for patients with greater WFDs (42-46%) as compared to patients with fewer WFDs (18-24%). Results showed that WFDs confound performance on verbal cognitive measures in adult patients with left TLE, particularly on measures with high demands for lexical retrieval. This suggests that when patients have word-retrieval difficulties, measures of verbal memory and verbal intelligence may be underestimated and potentially lead to misinterpretation of test performance and misinformation regarding risk of declines after surgical resection.

Working memory and intelligence are associated with victoria symptom validity test hard item performance in patients with intractable epilepsy.

Loring et al. (Journal of clinical and experimental neuropsychology, 2005:27;610­617) observed relationships between VSVT hard item performance and IQ and memory indices in epilepsy surgical candidates, with a potential confound of low FSIQ on VSVT performance. The present study replicated the Loring et al. study in a larger sample and extended their findings by examining the relationships among VSVT performance, FSIQ, and working memory. A total of 404 patients with medically intractable epilepsy completed a comprehensive neuropsychological assessment. Differences in WAIS-III and WMS-III performance were examined as a function of VSVT hard score categories as determined by Grote et al. (2000)--that is, valid, > 20/24; questionable, 18­20; or invalid, < 18. Quantile regression models were constructed to compare the strength of the relationship between FSIQ and VSVT at various points of the FSIQ distribution. Linear regression analyses examined working memory as a potential mediator between FSIQ and VSVT performance. The invalid group performed more poorly than the valid and questionable groups on multiple measures of intelligence and memory. The strength of the relationship between FSIQ and VSVT hard item performance decreased as FSIQ increased, and working memory mediated this relationship. Results suggest VSVT hard item scores may be impacted by working memory difficulties and/or low intellectual functioning.

Mapping anterior temporal lobe language areas with fMRI: a multicenter normative study.

Removal of the anterior temporal lobe (ATL) is an effective surgical treatment for intractable temporal lobe epilepsy but carries a risk of language and verbal memory deficits. Preoperative localization of functional zones in the ATL might help reduce these risks, yet fMRI protocols in current widespread use produce very little activation in this region. Based on recent evidence suggesting a role for the ATL in semantic integration, we designed an fMRI protocol comparing comprehension of brief narratives (Story task) with a semantically shallow control task involving serial arithmetic (Math task). The Story > Math contrast elicited strong activation throughout the ATL, lateral temporal lobe, and medial temporal lobe bilaterally in an initial cohort of 18 healthy participants. The task protocol was then implemented at 6 other imaging centers using identical methods. Data from a second cohort of participants scanned at these centers closely replicated the results from the initial cohort. The Story-Math protocol provides a reliable method for activation of surgical regions of interest in the ATL. The bilateral activation supports previous claims that conceptual processing involves both temporal lobes. Used in combination with language lateralization measures, reliable ATL activation maps may be useful for predicting cognitive outcome in ATL surgery, though the validity of this approach needs to be established in a prospective surgical series.

Seizure semiology and aging.

The incidence of epilepsy is high in older individuals. However, epilepsy in the elderly may be underdiagnosed and undertreated because of diagnostic difficulties. The main goal of this study was to determine whether seizure semiology differs between older and younger adults with epilepsy in the outpatient setting. Fifty patients with focal epilepsy aged 55 years and older and 50 patients aged between 18 and 45 years were included. Review of medical records contained detailed seizure description. There were no differences in seizure semiology between groups, except that subtle perceptions of transient confusion were seen in older patients but not in younger patients (P=0.0028). Older patients had less generalized motor seizures, but the differences between groups did not reach significance (P=0.01). Older patients may present with subtle symptoms of seizures characterized by brief periods of confusion, which may contribute to greater difficulty diagnosing seizures in the elderly.

Effect of apolipoprotein ε4 allele on hippocampal and brain volume in intractable temporal lobe epilepsy.

This study investigated the relationship between the apolipoprotein (APOE) ε4 allele and brain volumes in patients with medically intractable temporal lobe epilepsy (TLE). MRI-based volumetric analyses of the hippocampi, cerebral hemispheres, and whole brain were conducted in 59 patients with TLE (31 with left TLE, 28 with right TLE) with hippocampal sclerosis (HS). There were no differences in hippocampal, hemispheric, or whole brain volumes as a function of ε4 status even after correcting for hemispheric and total brain volumes. However, APOE ε4 carriers showed a trend toward having a smaller discrepancy between ipsilateral and contralateral hippocampal volumes than patients without this allele, and post hoc analyses suggest there may be an increased incidence of bilateral HS in ε4 carriers. In summary, APOE ε4 is not associated with significant hippocampal, hemispheric, or whole brain atrophy in patients with medically intractable TLE. However, ε4 carriers may be more likely to have bilateral HS, with an apparent dose-dependent effect.

Clinical utility of the Boston Naming Test in predicting ultimate side of surgery in patients with medically intractable temporal lobe epilepsy: A double cross-validation study.

The Boston Naming Test (BNT) is often used in the evaluation of surgical epilepsy patients to assess left temporal lobe function. In 2005, Busch et al. demonstrated the diagnostic utility of the BNT in predicting ultimate side of surgery in patients with temporal lobe epilepsy. BNT raw score significantly predicted ultimate side of surgery, moderated by Full Scale IQ (FSIQ), age at seizure onset, and duration of epilepsy. The final regression equation correctly predicted side of surgery in 69.5% of the sample. The current study demonstrated excellent cross-validation of this equation in an independent sample of 104 patients who eventually underwent temporal lobectomies, correctly predicting side of surgery in 67.3% of patients. The combination of the two samples resulted in a new, more-stable regression equation that correctly predicted side of surgery in 68.8% of the combined sample. These results further support the clinical utility of the BNT in predicting side of surgery.

Comparison of personality traits in patients with frontal and temporal lobe epilepsies.

The current study sought to characterize and compare personality traits of patients with temporal lobe epilepsy (TLE) and frontal lobe epilepsy (FLE). Ninety-seven adults with medically intractable epilepsy (TLE n=58, FLE n=39) completed the Personality Assessment Inventory (PAI) as part of routine preoperative investigations. Not surprisingly, both epilepsy groups endorsed significantly more symptoms across PAI clinical scales than the normative sample, most notably on scales assessing Depression and Somatic Complaints. Direct comparison of personality profiles of people with FLE and TLE revealed that FLE was associated with relative elevations on scales assessing emotional lability and relationship difficulties (i.e., Mania, Borderline Features, Antisocial, Stress, and Nonsupport). Although effect sizes were moderate to large, the clinical significance of these differences was questionable (<1 SD). However, results of a logistic regression suggested that the Borderline Features and Anxiety scales have incremental validity in predicting seizure site (FLE vs TLE) above education and duration of recurrent seizures. These results suggest that patients with FLE may exhibit more behavioral traits associated with frontal dysfunction than patients with TLE.

APOE epsilon4 is associated with postictal confusion in patients with medically refractory temporal lobe epilepsy.

This study examined the relationship between the APOE epsilon4 allele and postictal confusion in patients with medically intractable temporal lobe epilepsy (TLE). Patients with at least one epsilon4 allele (n=22) were three times more likely to exhibit postictal confusion (68%) than the 63 patients without epsilon4 (43%). These preliminary results demonstrate that APOE epsilon4 is associated with an increased risk of postictal confusion in patients with medically intractable TLE, suggesting possible dysfunction in neuronal recovery mechanisms.

Relationship between presurgical memory performance on the Wechsler Memory Scale-III and memory change following temporal resection for treatment of intractable epilepsy.

Previous research demonstrated a relationship between preoperative memory measured by the Wechsler Memory Scale-Revised (WMS-R) and postsurgical memory change in patients who underwent left (LATL), but not right (RATL) anterior temporal lobectomy. The current study replicated previous efforts using the Wechsler Memory Scale-Third Edition (WMS-III) in a larger sample. The WMS-III was administered to 161 patients with medically intractable epilepsy prior to and approximately 6 months following LATL or RATL. Correlations between presurgical memory on WMS-III indices and memory change following surgery were calculated for each group. Significant negative relationships were found between pre- and postsurgical memory scores in patients who underwent LATL on all WMS-III measures (r=-0.31 to -0.43). Significant negative correlations were observed in patients who underwent RATL only on visual memory measures (r=-0.24 to -0.44). Findings support previous conclusions using the WMS-R showing that patients who undergo LATL with higher presurgical memory ability are at greater risk for memory decline following temporal resection than patients with lower presurgical memory scores.

Poor presurgical performance on both verbal and visual memory measures is associated with low risk for memory decline following left temporal lobectomy for intractable epilepsy.

Studies have shown a lower risk for verbal memory decline following dominant anterior temporal lobectomy (ATL) among patients with poor, presurgical verbal memory scores. It is unclear however, if the risk of decline is increased in patients who also have reduced visual memory. Objective and subjective memory outcome following left ATL was examined in twelve patients with reduced presurgical visual and verbal memory scores. Only one patient demonstrated a meaningful decline in memory scores, with a decline in visual memory following surgery. Presurgically, this patient demonstrated poor memory bilaterally on Wada testing and small discrepancy in hippocampal volumes. She was also one of two patients who continued to have seizures post-surgery. This preliminary study suggests that patients with unilateral, left TLE and poor verbal and visual memory are unlikely to show meaningful memory declines following left ATL, particularly if they demonstrate expected patterns on Wada testing, hippocampal volume discrepancy (left < right), and postsurgical seizure-freedom.

Assessment of depression in epilepsy: the utility of common and disease-specific self-report depression measures.

OBJECTIVES: Depression is common in epilepsy, with rates ranging from 20 to 55% in most samples and reports as high as 70% in patients with intractable epilepsy. However, some contend that depression may be over- and/or under-reported and treated in this population. This may be due to the use of common self-report depression measures that fail to take into account the overlap of disease and depressive symptoms and also the host of side effects associated with antiepileptic medication, which may also be construed as depression. METHODS: The present study examined the utility of common self-report depression measures and those designed specifically for the medically ill, including a proposed new measure, to determine which may be more appropriate for use among people with epilepsy. RESULTS: We found that common self-report depression measures are useful for screening depression in epilepsy, particularly with a raised cutoff for one, with sensitivities ranging from .91 to .96. A measure designed for the medically ill obtained the greatest specificity of .91, suggesting its use as a diagnostic tool with a slightly raised cutoff. The positive likelihood ratio of this latter measure was 8.76 with an overall classification accuracy of 88%. CONCLUSIONS: Assessment of depression in epilepsy can be improved when utilizing self-report measures that better differentiate disease symptoms from neurovegetative symptoms of depression (e.g. fatigue, sleep disturbance). This was demonstrated in the present study. Clinical implications are discussed.

Estimating risk of word-finding problems in adults undergoing epilepsy surgery.

OBJECTIVE: This retrospective, observational study examined the frequency and magnitude of change in naming ability as a function of side/site of epilepsy surgery and identified predictive factors to assist clinicians in identifying patients at low, moderate, or high risk of postoperative naming decline. METHODS: A total of 875 adults with pharmacoresistant epilepsy (454 left/421 right; 763 temporal/87 frontal/25 posterior quadrant) met inclusion criteria and completed the Boston Naming Test before and after surgery. Clinically meaningful change in naming ability was assessed using reliable change indices for epilepsy. Demographic, cognitive, and seizure variables were examined to determine factors most predictive of naming decline and to develop a decision tree to assist with clinical decision-making. RESULTS: Naming decline was rare in right-sided resections and did not exceed the level expected by chance (5% overall; 90% confidence interval [CI] ± 2%). Naming decline occurred in 41% (CI ± 5%) of patients after left temporal resection (TLR) compared to 10%-12% (CI ± 10%-19%) in other left-sided surgical groups. A sizable proportion of left TLR patients (17%; CI ± 4%) showed substantial declines in naming (>11 points). Decline following left TLR was related to later age at seizure onset, older age at surgery, and higher preoperative naming ability. These factors correctly predicted naming decline in 68% of patients and were associated with degree of decline following left TLR. A decision tree is provided to assist clinicians in identifying patients at low, moderate, or high risk for postoperative naming declines. CONCLUSIONS: In addition to discussions regarding risk for memory decline following left TLR, patients should be counseled about potential decline in word-finding ability.

Executive functioning and depressed mood before and after unilateral frontal lobe resection for intractable epilepsy.

Executive dysfunction occurs in a variety of patients who have sustained damage to the frontal lobes. In individuals with frontal lobe epilepsy (FLE) or after unilateral frontal lobe resection (FLR), a unique neuropsychological profile linking executive functions (EF) with the frontal lobe has been elusive, with conflicting findings in the literature. Some studies show greater risk of executive impairment with left-sided FLE or FLR, while others report greater risk for right-sided patients. Some studies report no relationship between FLE and EF impairment, while others show EF impairment regardless of side of seizure foci or surgery. In patients with temporal lobe epilepsy, executive dysfunction is associated with depressed mood possibly reflecting disruption of cortical-limbic pathways and/or frontal-striatal circuitry. Although not previously examined, depression level may affect executive functioning in those with FLE or FLR. We hypothesized that FLE patients with poor mood state would show greater executive dysfunction than FLE patients without poor mood state. The relationship among EF, side of surgery and depressed mood before and 8 months after unilateral FLR was evaluated in 64 patients using validated measures of EF and mood state (Beck Depression Inventory-II). Results indicated that individuals with depressed mood before surgery had greater difficulty on a task of mental flexibility compared to patients without preoperative depressed mood. Further, individuals with depressed mood before surgery had significant increases in perseverative responding and completed fewer categories on a card-sorting task after surgery compared to patients without preoperative depressed mood. Regression analyses showed that among side of surgery, seizure freedom status after surgery and depression status, only pre-surgical depression status explained a significant amount of variance in executive functioning performance after surgery. Results suggest that clinically elevated depressive symptoms before surgery are a risk factor for moderate declines in EF after surgery. Results may be attributable to reduced cognitive reserve in patients with depressive symptoms, or may reflect a common cause attributable to damage to unilateral dorsal and ventral lateral frontal lobe.

Memory performance in older adults before and after temporal lobectomy for pharmacoresistant epilepsy.

Little is known about the effects of epilepsy surgery on memory in older adults. The purpose of this study was to determine if older adults exhibit greater memory decline than younger adults after anterior temporal lobectomy (ATL). Patients 55 years and older at time of surgery (23 left, 14 right ATL, range 55-66 years) were compared to patients age 25-35 years (44 left, 33 right ATL) to assess differences in preoperative to postoperative change in WMS-III index scores. Repeated-measures ANOVAs and ANCOVAs revealed that older patients did not demonstrate greater decline than younger patients across any of the memory indices. Rather, in the left ATL group, older patients showed less decline than younger patients on the Auditory Delayed Memory Index. Similarly, in the right ATL group, older patients showed less decline than younger patients on the Visual Delayed Memory Index. These patterns were also apparent in frequency of individual change. Results provide preliminary evidence that older adults who are good candidates for ATL are not at greater risk for memory decline when measured at 7 months postoperatively.

Pre-surgical mood predicts memory decline after anterior temporal lobe resection for epilepsy.

This study examined pre-surgical depressed mood as a predictor of post-surgical memory change in adults who underwent temporal lobe resections (TLRs; n = 211). Patients completed the Wechsler Memory Scale-III and Beck Depression Inventory-Second Edition (BDI-II) before and after TLR (left = 110, right = 101) and were divided into two groups (clinically elevated depressive symptoms or not depressed) based on BDI-II score. Left-TLR patients with poorer pre-surgical mood had greater verbal memory declines after surgery compared with nondepressed left- or right-TLR patients and right-TLR patients with poor mood. Further, pre-surgical BDI-II score demonstrated incremental validity in predicting post-surgical memory change in left-TLR patients beyond pre-surgical memory scores. Differences in seizure outcome and post-surgical mood change could not account for memory decline. Results suggest that elevated pre-surgical depressive symptomatology is a risk factor for post-surgical memory decline and indicate that mood should be considered when advising patients about cognitive risks associated with temporal lobectomy. Results are discussed in terms of poor pre-surgical mood as an indicator of reduced cognitive reserve.

The Family Pictures subtest of the WMS-III: relationship to verbal and visual memory following temporal lobectomy for intractable epilepsy.

This study examined the extent to which the Family Pictures (FP) subtest of the Wechsler Memory Scale-Third Edition (WMS-III) is related to verbal memory measures and right mesial temporal integrity. Epilepsy patients who underwent temporal lobectomy did not differ in the extent to which FP scores changed from before to after surgery, although postoperative FP performance was worse in those who underwent right temporal lobectomy than in those who underwent left temporal lobectomy. FP was most strongly related to the Logical Memory subtest from the WMS-III. Results suggest that FP measures both verbal and visual memory and is minimally sensitive to lateralization of temporal lobectomy.

Review of normative data for common screening measures used to evaluate cognitive functioning in elderly individuals.

When conducting neuropsychological evaluations of the elderly, it is important to compare patients' test scores to appropriate normative data to maximize diagnostic and descriptive accuracy. Many sets of normative data are now available for screening measures that assess cognitive functioning in the elderly. This article systematically reviewed available norms for 6 widely used screening measures of cognitive functioning in elderly patients. Details regarding the sample characteristics and data collection methods are provided for each set of norms, thereby providing a useful reference for clinicians.