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Keywords:

  • Memory;
  • Mesial temporal sclerosis;
  • Temporal lobe epilepsy;
  • Neuropsychology;
  • Cognition

Summary

  1. Top of page
  2. Summary
  3. Patients and Methods
  4. Results
  5. Discussion
  6. Acknowledgment
  7. Disclosure
  8. References

Purpose

Material-specific memory impairment is used as a lateralizing tool in the evaluation of temporal lobe epilepsy. Lateralizing ability of material-specific memory deficits in temporal lobe epilepsy remains controversial.

Methods

We studied memory impairment profiles of verbal and nonverbal memory deficits with eight memory subtests of four neuropsychological instruments (two verbal and two nonverbal) in 87 right-handed patients with epilepsy associated with unilateral mesial temporal sclerosis (MTS; 44 right – R, 43 left – L) and 42 controls, with an IQ >70, at least 8 years of education, and without comorbidities.

Key Findings

Selective verbal memory impairment was noted in 11 of 43 or 25.6% of left MTS cases, with 82.2% specificity, whereas selective nonverbal memory impairment was noted in 11 of 42 or 26.2% of right MTS cases, with 92% specificity. Nonlateralizing profiles of memory performance were seen in the remaining 65 of 87 patients. Approximately half (46/87 or 52.9%) of the patients had intact memory function in both modalities, equally distributed between patients with right MTS (23/44) and left MTS (23/43). Global impairment of both memory types was seen in 12 of 87 or 13.8% of patients, equally distributed between the two groups (7/43 left and 5/44 right).

Significance

Lateralizing profiles of selective verbal and nonverbal memory deficits are highly specific for left and right MTS, although infrequently encountered in our patients. Nonlateralizing profiles predominated in this population. These findings suggest hemispheric asymmetry memory function, with complex functional interaction of the hippocampi, and possible compensatory mechanisms in the setting of a unilateral lesion.

Memory impairment is a well-recognized feature of temporal lobe epilepsy (TLE) (Bell et al., 2011). The devastating effect of mesial temporal structures resection on memory function led to widespread use of neuropsychological testing in patients undergoing temporal lobe resections to treat medically refractory epilepsy (Sherman et al., 2011).

Intensive neuropsychological testing led to the development of the material-specific theory of memory function, with verbal memory function associated with dominant mesial temporal lobe structures, and nonverbal or visual-spatial memory function associated with nondominant mesial temporal structures (Loring et al., 1988). Although rather robust evidence is noted for association of verbal memory and left temporal structures in preoperative patients, evidence of an association between right temporal lobe structures and nonverbal memory remains less clear (Kim et al., 2004; Grammaldo et al., 2006; Keary et al., 2007).

Many of the studies that support material-specific model of memory function were limited by methodologic constraints of the time. Widespread use of structural magnetic resonance imaging (MRI) has further challenged the model (Kennepohl et al., 2007; Baxendale & Thompson, 2010).

To gain a better insight of the use of neuropsychological memory testing as a lateralizing tool, we evaluated the frequency of material-specific profile of memory impairment in a sample patients with TLE associated with unilateral mesial temporal sclerosis (MTS). We also evaluated sensitivity and specificity of verbal and nonverbal selective memory impairment in this patient population.

We evaluated the occurrence of material-specific profile of memory impairment in patients with TLE associated with MRI-defined unilateral MTS.

Patients and Methods

  1. Top of page
  2. Summary
  3. Patients and Methods
  4. Results
  5. Discussion
  6. Acknowledgment
  7. Disclosure
  8. References

Patient selection

We retrospectively analyzed a consecutive series of patients with TLE secondary to unilateral MTS, followed in the epilepsy outpatient clinic in a university-based epilepsy surgery referral center in São Paulo, Brazil. All patients underwent comprehensive neuropsychological testing including four memory tests in the period between January 1999 and May 2009. Diagnosis of TLE was established on epileptic seizure occurrence, with features suggestive of temporal lobe origin, interictal epileptiform discharges in the temporal regions, and brain MRI findings of unilateral hippocampal volume loss on T1-weighted images and/or increased signal on T2-weighted or fluid-attenuated inversion recovery (FLAIR) images, without other MRI lesions, except for fewer than five small calcified lesions suggestive of inactive neurocysticercosis, located outside the temporal lobes or minor microleucoencephalopathic changes on T2 or FLAIR sequences.

Inclusion criteria

Right-handed patients, between 17 and 55 years of age, with 8 or more years of education and full scale or estimated IQ > 70.

Exclusion criteria

Clinical, other neurologic or active psychiatric disease, including anxiety and depression, previous or current ethanol abuse, comorbidity with nonepileptic psychogenic seizures, or any other condition (or treatment thereof) that could interfere with neuropsychological test performance. Assessment of depression and anxiety was performed on a clinical basis. Patients who were medicated for anxiety or depression were not excluded if symptoms were considered under control. For example, patients with a current diagnosis of clinical depression or with active psychotic symptoms were not included in the study.

Control group

A control group of healthy controls (patients' friends or relatives) fulfilling the same inclusion and exclusion criteria.

Ethics committee approval

All subjects signed the informed consent term, approved by the institutional review board, research protocol 977/03. Patients who had undergone neuropsychological testing before 2003, signed the term retrospectively.

Demographic and epilepsy features data

Information regarding gender, age at neuropsychological testing, education years, age at epilepsy onset, epilepsy duration, and antiepileptic drug (AED) use were obtained for patients and, where appropriate, controls, during interview, or through chart review.

AED use was characterized by the number of current total and sedative AEDs (barbiturates, benzodiazepines, and topiramate). AED loads were calculated with the formula:

  • display math

The numerator represents total daily AED dose and the denominator represents a standard AED dose (Deckers et al., 1997). Adopted standard AED doses were: Phenobarbital = 100, phenytoin = 300, carbamazepine = 600, oxcarbazepine = 900, valproate = 750, clobazam = 15, clonazepam = 2, topiramate = 200, primidone = 250, lamotrigine = 200, gabapentin = 900.

Neuropsychological test battery

All subjects underwent comprehensive neuropsychological testing. Patients were not tested if they had presented a seizure within the previous 24 h.

Verbal Memory was evaluated with the Rey Auditory Verbal Learning Test (RAVLT; Rey, 1999) and the Logical Memory Test (WMS-R; Spreen & Strauss, 1998). For RAVLT we considered the number of recalled items on immediate recall after the initial five consecutive encoding trials, and a postinterference delayed recall (30 min).

Nonverbal Memory was evaluated with the Rey Visual Design Learning Test (RVDLT; Rey, 1999) and the Rey-Osterrieth Complex Figure (ROCF) (Rey, 1942). The same scoring system as used for RAVLT was used for RVDLT.

Memory test scoring

Mean scores for performance in all tests for all three groups (right and left MTS and controls) were calculated, and were compared among groups.

Definition of cutoff scores for verbal and nonverbal memory tests

Cutoff scores were obtained for each of the eight subtests (RAVLT immediate and delayed recall, Logical Memory Immediate and Delayed Recall, RVDLT immediate and delayed recall, and ROCF immediate and delayed recall), after obtaining receiver operating curves (ROCs), comparing patients (right and left) with controls, determining a cutoff score that yielded a sensitivity of at least 0.8, with the best corresponding specificity.

Immediate memory measurements may reflect impairment in encoding and attention, whereas delayed memory deficits may reflect impaired retrieval and storage mechanisms. Because patients with MTS-associated epilepsy display impaired performance in both memory aspects, we used both scores to calculate verbal and nonverbal memory scores. Although scores may reflect distinct underlying neurobiologic process, we used different measures to reflect a compound memory score in verbal and nonverbal modalities. Verbal memory was considered impaired if patient's performance was below cutoff scores in two or more of the four verbal memory tests; likewise, nonverbal memory was considered impaired if patient's performance was below cutoff score in two or more of the four nonverbal memory tests.

Definition of memory performance profiles

Profiles of memory testing performance were classified, according to performance in verbal and nonverbal memory tests, as:

  • Profile 1: Selective verbal memory impairment—impaired verbal memory and preserved nonverbal memory.
  • Profile 2: Selective nonverbal memory impairment—impaired nonverbal memory, with preserved verbal memory.
  • Profile 3: Intact memory—preserved verbal and nonverbal memory.
  • Profile 4: Globally impaired memory—impaired verbal and nonverbal performances.

Sensitivity, specificity, and positive and negative predictive values. Test for robustness

Sensitivity, specificity, and positive and negative predictive values were calculated for left MTS and selective verbal memory impairment (Profile 1), as well as for right MTS and selective nonverbal memory impairment (Profile 2).

To assess robustness of this approach, we also calculated these values for different impairment classification rules. We redefined impairment in a selective memory domain in two additional rules: a less stringent and a more stringent criterion. The less stringent criterion was defined as decreased scores in one or more tests in that memory modality (including patients with mild impairment). The more stringent criterion was defined as decreased scores in three or four memory tests in that memory modality (including patients with more severe impairment).

Pathology

Hospital records were reviewed for pathology records of mesial temporal lobe structures.

Statistical analysis

Mean scores and standard deviations for each memory test were calculated for patients and controls with SPSS 13.0 for Windows (IBM, Armonk, NY, U.S.A.) using analysis of variance (ANOVA) followed by multiple comparisons (Bonferroni), when normal distribution or variance equality hypotheses were accepted (Shapiro-Wilk), or with nonparametric Kruskal-Wallis, followed by multiple comparisons (Dunn) if normal distribution was rejected, with a significance level of p < 0.05. Performance of right and left MTS patients (classified in the different memory performance profiles) were compared as categorical variables, using Pearson's chi-square or Fisher's exact test (when one of the expected values were below five), with a significance level p < 0.05.

Results

  1. Top of page
  2. Summary
  3. Patients and Methods
  4. Results
  5. Discussion
  6. Acknowledgment
  7. Disclosure
  8. References

We studied 87 patients (44 right and 43 left MTS) and 42 normal controls.

Demographic and epilepsy features data

Gender distribution, age, education did not differ among groups and controls (Table 1). Right and left MTS groups did not differ in age at epilepsy onset, epilepsy duration, AED and sedative AED number, and total and sedative AED load (Table 1).

Table 1. Demographic, epilepsy, and AED treatment data in right and left MTS and controls
GroupLeft MTSRight MTSControlsp-Value
  1. MTS, mesial temporal sclerosis; N, number of subjects; SD, standard deviation; AED, antiepileptic drug; NS, not significant.

N434442 
Gender    
Women (%)21 (55.8)20 (45.5)24 (57.1)0.8 (NS)
Age    
Mean (SD)37.6 (10.5)37.5 (9.3)38.8 (10.8)0.8 (NS)
Median3838.539
Education (years)    
Mean (SD)11.0 (3.4)11.2 (2.6)11.2 (2.1)0.9 (NS)
Median111111

Age at onset

 Mean (SD)

9.4 (7.4)9.5 (8.6)0.9 (NS)

Epilepsy duration

 Mean (SD)

29.2 (10.4)29.4 (13.0)0.9 (NS)

AED number

 Mean (SD)

2.5 (0.9)2.3 (0.8)0.4 (NS)

Sedative AEDs number

 Mean (SD)

1.1 (0.7)0.9 (0.6)0.42 (NS)

AED load

 Mean (SD)

3.7 (1.6)3.6 (1.6)0.7 (NS)

Sedative AED load

 Mean (SD)

1.6 (1.1)1.3 (1.0)0.2 (NS)

Verbal memory performance

Data regarding performance of all groups on verbal memory testing are presented in Table 2. Left MTS group performed significantly worse than right MTS and controls in immediate and delayed RAVLT recall. On RAVLT recognition, left MTS performed significantly worse than controls, but the performance of right and left MTS groups did not differ. Both right and left MTS groups performed significantly worse than controls on immediate and delayed Logical Memory test recall, but the performance of left and right MTS groups did not differ.

Table 2. Between-group comparison: verbal and nonverbal memory testing
TestsLMTS N = 43 Mean (SD)RMTS N = 44 Mean (SD)Controls N = 42 Mean (SD)p-Value
  1. C, control; MTS, mesial temporal sclerosis; N, number of subjects; SD, standard deviation; RMTS, right mesial temporal sclerosis; LMTS, left mesial temporal sclerosis; RAVLT = Rey Auditory Verbal Learning Test; RVDLT, Rey Visual Design Learning Test; NS, not significant.

RAVLT immediate recall7.2 (3.1)8.7 (3.1)9.0 (3.1)

C vs. LMTS = 0.02

RMTS vs. LMTS = 0.03

RAVLT delayed recall6.2 (3.3)8.6 (3.2)9.2 (3.2)

C vs. LMTS < 0.001

RMTS vs. LMTS = 0.002

RAVLT recognition12.9 (1.6)13.4 (1.7)13.8 (1.6)C vs. LMTS = 0.02
Logical memory (immediate)18.6 (6.5)19.2 (6.6)26.4 (11.2)

C vs. LMTS < 0.001

C vs. RMTS < 0.001

Logical memory (delayed)12.5 (6.3)13.8 (7.3)19.1 (8.2)

C vs. LMTS = 0.001

C vs. RMTS = 0.007

RVDLT immediate recall8.2 (3.1)7.5 (3.3)8.5 (3.8)NS
RVDLT delayed recall8.1 (3.3)7.2 (3.4)8.1 (4.1)NS
RVDLT recognition13.2 (1.9)12.9 (1.7)13.5 (2.3)NS
Rey-Osterrieth Complex Figure immediate14.8 (6.4)13.6 (6.7)17.5 (7.7)NS
Rey-Osterrieth Complex Figure delayed13.1 (5.6)12.7 (6.5)16.5 (7.3)C vs. RMTS = 0.02

Cutoff scores were 5 points for immediate and 4 points for RAVLT delayed recall, and 13 points for immediate and 7 points for Logical Memory delayed recall.

When groups were compared by individual global performance on verbal memory tests, there was a significantly higher proportion of left MTS patients with verbal memory impairment (18/43 or 41.9%) compared with controls (4/34 or 11.8%, p = 0.03). Although there was a higher proportion of left MTS patients with verbal memory impairment compared to right MTS patients (left MTS 18/43 or 41.9% vs. 10/44 or 22.7%), this difference did not reach statistical significance (p = 0.29).

Nonverbal memory performance

Data regarding group performance on nonverbal memory testing are presented in Table 2. Left and right MTS groups performed significantly worse than controls in the delayed recall of the ROCF. Right MTS patients performed worse than left MTS patients and controls on ROCF immediate recall, but this difference did not reach statistical significance (p = 0.057).

Cutoff scores were five points for immediate and five points for delayed RVDLT recall, and six points for immediate and eight points for delayed recall of the ROCF. Group performances did not differ on RVDLT. Groups did not differ when compared by individual global performance on nonverbal memory tests. There was no statistically significant difference between the proportion of patients with impaired nonverbal memory in the right and left MTS groups (9/43 or 20.9% vs. 16/44 or 36.4%, p = 0.23).

Analysis of memory performance profiles

Distribution of left and right MTS according to performance profiles of memory testing is presented in Table 3. Approximately half (46/87 or 52.9%) of the patients presented intact verbal and nonverbal memory (Profile 3), with similar distribution in left and right MTS groups. Only 12 of 87, or 13.8%, of the patients presented global memory impairment (Profile 4), equally distributed between left and right MTS groups. Regarding lateralizing profiles, a significantly greater proportion of patients with selective nonverbal memory impairment (Profile 2) was seen among right MTS patients (Profile 2: right MTS 11/44 or 25% vs. left MTS 2/43 or 4.6%. p = 0.02). A greater proportion of patients with selective verbal memory impairment was seen among left MTS patients. This difference did not reach statistical significance (Profile 1: left MTS 11/43 or 25.6% vs. right MTS 5/44 or 11.4%, p = 0.15).

Table 3. Left and right MTS groups: memory performance profiles
GroupsProfile 1 N = 16Profile 2 N = 13Profile 3 N = 46Profile 4 N = 12
  1. MTS, mesial temporal sclerosis; N, number of subjects; Profile 1, selective verbal memory impairment; Profile 2, selective nonverbal memory impairment; Profile 3, intact memory; Profile 4, global memory impairment.

Left MTS

N = 43

112237

Right MTS

N = 44

511235
p0.150.020.90.7

Profile 1 (selective verbal memory impairment)

This profile showed a low sensitivity (32.4%), but high specificity for left MTS (82.2%). Positive predictive value for left MTS in patients performing in Profile 1 was 68.8%, with a negative predictive value of 50%.

Redefining cutoffs using a more stringent criterion yielded better specificity (89.5%), positive predictive values (84.6%), sensitivity (36.7%), and similar negative predictive values (47.2%).

Using a less stringent criterion yielded better specificity (94.9%), positive (75%) and negative (52.9%) predictive values, and decreased sensitivity (15.4%).

Profile 2 (selective nonverbal memory impairment)

This profile showed low sensitivity (32.4%), but high specificity for right MTS (92%). Positive predictive value for right MTS in patients performing in Profile 2 (selective nonverbal memory impairment) was 84.6%, with a negative predictive value of 50%.

Redefining cutoffs using a more stringent criterion yielded slightly decreased specificity (86.4%), positive predictive values (70%), sensitivity (29.2%), and slightly higher negative predictive values (52%).

Using a less stringent criterion yielded similar specificity (91.7%), decreased positive predictive values (62.5%), sensitivity (11.9%), and negative predictive values (47.2%).

Pathology reports

Sixty-one of 87 patients (70.1%) underwent epilepsy surgery. Pathology reports with mesial temporal lobe structure evaluation were available for 44 of (72.1%) 61 of operated patients. MTS was confirmed in 42 (95.4%) of 44 patients. In two patients (4.5%), no histologic abnormalities were reported. In two patients, associated hippocampal microdysgenesis was noted.

Discussion

  1. Top of page
  2. Summary
  3. Patients and Methods
  4. Results
  5. Discussion
  6. Acknowledgment
  7. Disclosure
  8. References

Memory skills, or ability to register, encode, and retrieve previously presented information are fundamental neurobiologic processes that may be impaired in TLE. Although widely used as a lateralizing tool to localize seizure focus, the material-specific model of memory impairment in epilepsy is limited by methodologic constraints of the original studies, especially regarding lack of appropriate neuroimaging evaluation (Baxendale & Thompson, 2010). Lack of consistent findings that indicate an association between nonverbal memory impairment and right TLE has further challenged the material-specific memory impairment model (Kennepohl et al., 2007; Baxendale & Thompson, 2010).

Most previous studies that evaluated the lateralizing ability of memory testing studied heterogeneous patient samples, which included cases of nonlesional TLE, epilepsy due to other etiologies (such as tumors and malformations of cortical development), or extratemporal epilepsy cases (Jones-Gotman, 1986; Loring et al., 1989; Hermann et al., 1995; Baxendale et al., 1998; Baxendale & Thompson, 2010). In this study, we included a relatively homogeneous sample of patients with MRI-diagnosed MTS. Dual-pathology and bilateral MTS cases were not included. Our sample consisted of patients with longstanding (approximately 30-year) TLE associated with hippocampal sclerosis, with balanced gender distribution. Both patient groups were comparable in terms of age at disease onset, epilepsy duration, and AED use.

The patient sample in this study consists of a rather homogeneous patient group, harboring a lesion in a pivotal structure for memory function. The patient sample relative homogeneity may allow us to more clearly discern differences in memory performance of patients with hippocampal lesions in the language dominant and nondominant hemispheres. Because we used cutoff scores derived from a demographically matched control group, our findings cannot be extrapolated to different patient populations.

A different approach could be taken, comparing cognitive performance of patients with MTS to that of patients with lateralized nonlesional TLE. This approach would also present limitations, since patients with MTS would have to be matched to non-MTS patients, regarding interictal and ictal electroencephalography (EEG) findings. In addition, nonlesional TLE cases may include both patients with neocortical TLE (without apparent lesions on imaging studies), as well as patients with subtler hippocampal lesions, such as endfolium sclerosis, not easily detected by MRI.

To avoid age-related memory decline as a confounding factor, we did not include patients older than age 55. In addition, we excluded patients with mental retardation. All patients had at least 8 years of education. These inclusion criteria were chosen to minimize impaired global cognition or inadequate schooling on test performance. When compared to controls, we found that patient groups displayed similar performance in tests measuring attention, abstract reasoning, semantic memory, and visual-spatial skills (data not shown). Impairment in selective cognitive domains (verbal and nonverbal memory, confrontation naming, processing speed, inhibitory control, response selection and global cognitive function) were noted between patients and controls, as well as between right and left MTS patients.

Approximately 12% of controls performed on the impaired range on verbal memory testing. This could be interpreted as indicative of cognitive impairment in a subgroup of controls. However, we do not believe this is the case. Although a minimum of eight education years was required as an inclusion criterion, some apparently normal functioning people in urban populations in large Latin American cities may perform in the impaired range on formal testing, as a consequence of inadequate schooling. Because controls were recruited from the same social and educational background as that for the patient population, it is reasonable to consider that the performance of controls represents an adequate comparison for the patient population. This notion is further strengthened by lack of difference on performance in tests measuring reasoning abilities and semantic memory between patients and controls.

The finding of impaired abilities on selective cognitive domains in the patients compared to controls indicates differences in cognitive abilities related to the disease process, and, possibly, at least in part, to medication effect. We also tried to minimize the negative impact on cognition of a recent seizure by not testing patients who reported having had a seizure within the previous 24 hours.

Medication effects can negatively impact on cognitive function. Although medication effects are more likely to negatively affect attention and executive functions, memory and language abilities may also be influenced negatively by antiepileptic drugs. Patients in both study groups (right and left MTS patients), were receiving a comparable number of drugs, with roughly equivalent total and sedative drug loads; therefore, it is unlikely that difference in performance on neuropsychological testing between right and left MTS is due to a drug effect. Measured differences between right and left MTS patients more likely reflect underlying neurobiologic differences related to hemispheric function specialization of memory functions.

Most studies that evaluated performance on verbal and nonverbal memory tests have used only one test to evaluate verbal and nonverbal memory (Naugle et al., 1994; Hermann et al., 1995; Loring et al., 2000; Sawrie et al., 2001; Raspall et al., 2005).

We evaluated verbal and nonverbal memory with two instruments for each type of memory modality, and used two scores for each instrument to assess memory impairment. In addition, we established appropriate cutoff scores to distinguish patients from controls, who were adequately matched to our patient population. Only one other study that evaluated memory function in epilepsy used a control group (Naugle et al., 1994). Other studies relied on standardized data for controls (Loring et al., 1988, 1989; Naugle et al., 1994; Piguet et al., 1994; Hermann et al., 1995; Loring et al., 2000; Sawrie et al., 2001; Raspall et al., 2005; Grammaldo et al., 2006; Keary et al., 2007). These studies merely compared performance of patients with right and left sided lesions or “epileptic focus.”

Rather than comparing group performances, we used individual patient performance in verbal and nonverbal memory tests to compare groups. We also combined performance in verbal and nonverbal memory test to determine memory performance profiles. This approach has allowed us to discern that patients with mesial TLE do not constitute a homogeneous sample in memory performance.

Approximately half of MTS patients display preserved memory function on neuropsychological testing by our criteria. A minority of patients showed global memory impairment, involving verbal and nonverbal memory. These patterns were seen in equal proportions in right and left MTS cases.

Lateralizing profiles of memory impairment were noted in approximately one third of patients. Selective impairment of nonverbal memory was noted in 25% of right MTS patients. This pattern showed high specificity and positive predictive power for right MTS, albeit with low sensitivity. Selective impairment of verbal memory was noted in approximately 25% of the left MTS cases. This pattern was also seen in 11% of the right MTS patients. This pattern showed moderate positive predictive power and high specificity for left MTS.

With testing for robustness of the memory impairment classification system using less and more stringent criteria for selective memory impairment, we found different results for verbal and nonverbal memory. Although for nonverbal memory more or less stringent criteria did not improve sensitivity, specificity, or negative and positive predictive values for right MTS, the use of more stringent criteria to define verbal memory impairment improved sensitivity, specificity, and positive predictive values for left MTS. However, regardless of stringency of criteria for memory impairment, we consistently found low sensitivity, high specificity, and positive predictive values for selective memory impairment and dominant or nondominant hemisphere MTS.

The memory tests used in this study have not been standardized for Brazilian Portuguese or for Brazilian population. We cannot, therefore, compare our cutoff scores to published standardized data.

Our findings indicate that lateralizing profiles of memory impairment occur in approximately one fourth of patients with MTS patients. When encountered, selective verbal and nonverbal memory impairment appear to be very specific, respectively, for left and right MTS. These findings lend further support to the material-specific model of memory processing (Loring et al., 1988; Golby et al., 2001).

The finding of preserved memory in approximately half of our patient sample is intriguing. It may indicate redundancy in memory function between both hippocampi, thereby protecting certain individuals from material-specific memory impairment resulting from a unilateral hippocampal lesion. Alternatively, one could speculate that neuronal plasticity, especially in the setting of an early lesion, may allow preservation of memory function in both modalities with unilateral hippocampal damage. Memory reserve has been traditionally assessed with the intracarotid amytal test, and, more recently, with memory functional MRI (fMRI) paradigms (Bonnici et al., 2013). Greater activation of contralateral mesial temporal lobe structures on fMRI memory paradigms correlates with better postoperative episodic memory performance in patients with TLE, especially left TLE (Köylü et al., 2008). One may also speculate that age at epilepsy onset (or at the precipitating initial insult) may be related to memory impairment. This question should be investigated in future studies.

It is also unclear why a subgroup of individuals with unilateral hippocampal damage presents global impairment of memory functions, involving both memory modalities. It is tempting to speculate that these patients may display bilateral hippocampal dysfunction, not necessarily related to a lesion. One hypothesis, which remains to be proven, is that hippocampal function may be disrupted an effect at-distance of contralateral abnormal electrical activity. In addition, studies with TLE patients have disclosed widespread changes in cortical thickness, white matter pathways, thalamus, and callosal and cerebellar networks, both ipsilateral and contralateral to the epileptogenic focus, that are associated with impaired cognitive profiles (Dabbs et al., 2009; Bell et al., 2011).

The findings of patterns of selective involvement of verbal and nonverbal memory function, with high specificity, respectively, for left and right hippocampal lesions are in agreement with the findings of fMRI studies that indicate differential patterns of hippocampal activation in response to verbal and nonverbal stimuli (Golby et al., 2001). These findings also corroborate in the clinical setting that memory function displays hemispheric subspecialization in memory function, which should not be understood as exclusively lateralized but rather as displaying complex and asymmetric patterns of interaction.

fMRI studies that evaluated preoperative and postoperative word and face encoding paradigms showed that greater asymmetry of activation was the best predictor for postoperative verbal and nonverbal memory decline. Activation asymmetry, language lateralization, and neuropsychological test performance were better predictors of postoperative memory decline for left compared to right TLE. Verbal and nonverbal preoperative memory utilizes both the diseased and the normal hippocampi. In addition, the ipsilateral posterior hippocampus may contribute to memory reserve (Bonelli et al. 2010).

Our findings indicate that neuropsychological testing has low sensitivity for lesion lateralization in patients with MTS. Neuropsychological testing of memory function in patients with MTS, much more than a mere lateralizing tool, should be viewed as an important instrument in assessing hippocampal function in patients with TLE. Neuropsychological testing performance may be a useful tool, in conjunction with fMRI memory paradigms, to evaluate memory reserve and risk of memory decline following epilepsy surgery.

The recognition of different patterns of memory function in patients with hippocampal sclerosis also opens new avenues for the understanding of neuronal networks involved in memory processes. It also poses relevant clinical questions involving the role of neuronal plasticity in early hippocampal lesions, as well as possible differential effects of epilepsy surgery on memory function, in relation to preoperative patterns of memory performance profiles.

We conclude that patients with epilepsy associated with unilateral hippocampal sclerosis present with different profiles of memory impairment. Lateralizing profiles of selective verbal and nonverbal memory deficits are highly specific for left and right MTS, although infrequently encountered in our patients. Nonlateralizing profiles predominated in this population. These findings suggest hemispheric asymmetry memory function, with complex functional interaction of the hippocampi and limbic structures, and possible compensatory mechanisms in the setting of a unilateral lesion.

Acknowledgment

  1. Top of page
  2. Summary
  3. Patients and Methods
  4. Results
  5. Discussion
  6. Acknowledgment
  7. Disclosure
  8. References

Funding by FAPESP (Cinapce Program grant number 2005/56464-9).

Disclosure

  1. Top of page
  2. Summary
  3. Patients and Methods
  4. Results
  5. Discussion
  6. Acknowledgment
  7. Disclosure
  8. References

None of the authors has any conflict of interest to disclose. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.

References

  1. Top of page
  2. Summary
  3. Patients and Methods
  4. Results
  5. Discussion
  6. Acknowledgment
  7. Disclosure
  8. References
  • Baxendale SA, Thompson PJ. (2010) Beyond localization: the role of traditional neuropsychological tests in an age of imaging. Epilepsia 51:22252230.
  • Baxendale SA, van Paesschen W, Thompson PJ, Connelly A, Duncan JS, Harkness WF, Shorvon SD. (1998) The relationship between quantitative MRI and neuropsychological functioning in temporal lobe epilepsy. Epilepsia 39:158166.
  • Bell B, Lin JJ, Seidenberg M, Hermann B. (2011) The neurobiology of cognitive disorders in temporal lobe epilepsy. Nat Rev Neurol 7:154164.
  • Bonelli SB, Powell RH, Yogarajah M, Samson RS, Symms MR, Thompson PJ, Koepp MJ, Duncan JS. (2010) Imaging memory in temporal lobe epilepsy: predicting the effects of temporal lobe resection. Brain 133(Pt. 4):11861199.
  • Bonnici HM, Sidhu M, Chadwick MJ, Duncan JS, Maguire EA. (2013) Assessing hippocampal functional reserve in temporal lobe epilepsy: a multi-voxel pattern analysis of fMRI data. Epilepsy Res 105:140149.
  • Dabbs K, Jones J, Seidenberg M, Hermann B. (2009) Neuroanatomical correlates of cognitive phenotypes in temporal lobe epilepsy. Epilepsy Behav 15:445451.
  • Deckers CL, Hekster YA, Keyser A, Meinardi H, Renier WO. (1997) Reappraisal of polyterapy in epilepsy: a critical review of drug load and adverse effects. Epilepsia 38:570575.
  • Golby AJ, Poldrack RA, Brewer JB, Spencer D, Desmond JE, Aron AP, Gabrielli JD. (2001) Material-specific lateralization in the medial temporal lobe and prefrontal cortex during memory encoding. Brain 124:18411845.
  • Grammaldo LG, Giampà T, Quarato PP, Picardi A, Mascia A, Sparano A, Meldolesi GN, Sebastiano F, Esposito V, Di Gennaro G. (2006) Lateralizing value of memory tests in drug-resistant temporal lobe epilepsy. Eur J Neurol 13:371376.
  • Hermann BP, Connell B, Barr WB, Wyler AR. (1995) The utility of the Warrington Recognition Memory Test for temporal lobe epilepsy: pre- and postoperative results. J Epilepsy 8:139145.
  • Jones-Gotman M. (1986) Right hippocampal excision impairs learning and recall of a list of abstracts designs. Neuropsychologia 24:659670.
  • Keary TA, Frazier TW, Busch RM, Kubu CS, Iampietro M. (2007) Multivariate neuropsychological prediction of seizure lateralization in temporal epilepsy surgical cases. Epilepsia 48:14381446.
  • Kennepohl S, Sziklas V, Garver KE, Wagner DD, Jones-Gotman M. (2007) Memory and the medial temporal lobe: hemispheric specialization reconsidered. Neuroimage 36:969978.
  • Kim H, Yi S, Son EI, Kim J. (2004) Lateralization of epileptic foci by neuropsychological testing in mesial temporal lobe epilepsy. Neuropsychology 18:141151.
  • Köylü B, Walser G, Ischebeck A, Ortler M, Benke T. (2008) Functional imaging of semantic memory predicts postoperative episodic memory functions in chronic temporal lobe epilepsy. Brain Res 1223:7381.
  • Loring DW, Lee GP, Martin RC, Meador KJ. (1988) Material-specific learning in patients with partial complex seizures of temporal lobe origin: convergent validation of memory constructs. J Epilepsy 1:5359.
  • Loring DW, Lee GP, Meador KJ. (1989) Verbal and visual memory index discrepancies from the Wechsler Memory Scale—Revised: Cautions in interpretation. Psychol Assess 1:198202.
  • Loring DW, Hermann BP, Lee GP, Drane DL, Meador KJ. (2000) The Memory Assessment Scales and lateralized temporal lobe epilepsy. J Clin Psychol 56:563570.
  • Naugle RI, Chelune GJ, Schuster J, Luders HO, Comair Y. (1994) Recognition memory for words and faces before and after temporal lobectomy. Assessment 1:373381.
  • Piguet O, Saling MM, O'Shea MF, Berkovic SF, Bladin PF. (1994) Rey figure distortions reflect nonverbal recall differences between right and left foci in unilateral temporal lobe epilepsy. Arch Clin Neuropsychol 9:451460.
  • Raspall T, Doñate M, Boget T, Carreño M, Donaire A, Agudo R, Bargalló N, Rumià J, Setoain X, Pintor L, Salamero M. (2005) Neuropshychological tests with lateralizing value in patients with temporal lobe epilepsy: reconsidering material-specific theory. Seizure 14:569576.
  • Rey A. (1942) L'examen psychologique dans les cas d'encéphalopathie traumatique. Arch Psychol 28:112.
  • Rey A. (1999) Teste de cópia e de reprodução de memória de figuras geométricas complexas: manual. Casa do Psicólogo, São Paulo.
  • Sawrie SM, Martin RC, Gilliam F, Knowlton R, Faught E, Kuzniecky R. (2001) Verbal retention lateralizes patients with temporal lobe epilepsy and bilateral hippocampal atrophy. Epilepsia 42:651659.
  • Sherman EM, Wiebe S, Fay-McClymont TB, Tellez-Zenteno J, Metcalfe A, Hernandez-Ronquillo L, Hader WJ, Jetté N. (2011) Neuropsychological outcomes after epilepsy surgery: systematic review and pooled estimates. Epilepsia 52:857869.
  • Spreen O, Strauss E. (1998) A compendium of neuropsychological tests. 2nd ed. Oxford University Press, New York.