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BRAINA JOURNAL OF NEUROLOGY

Chronic temporal lobe epilepsy:a neurodevelopmental or progressivelydementing disease?C. Helmstaedter and C. E. Elger

Department of Epileptology, University Hospital of Bonn, Bonn, Germany

Correspondence to: Prof. Dr Christoph Helmstaedter,

Neuropsychology,

Department of Epileptology,

University Hospital of Bonn,Sigmund Freud Str. 25, 53105 Bonn,

Germany

E-mail: [email protected]

To what degree does the so-called initial hit of the brain versus chronic epilepsy contribute towards the memory impairment

observed in chronic temporal lobe epilepsy (TLE) patients? We examined cross-sectional comparisons of age-related regressions

of verbal learning and memory in 1156 patients with chronic TLE (age range 668 years, mean epilepsy onset 14 11 years)

versus 1000 healthy control subjects (age range 680 years) and tested the hypothesis that deviations of age regressions (i.e.

slowed rise, accelerated decline) will reveal critical phases during which epilepsy interferes with cognitive development. Patients

were recruited over a 20-year period at the Department of Epileptology, University of Bonn. Healthy subjects were drawn from

an updated normative population of the Verbaler Lern- und Merkfahigkeitstest, the German pendant to the Rey Auditory Verbal

learning Test. A significant divergence of age regressions indicates that patients fail to build up adequate learning and memoryperformance during childhood and particularly during adolescence. The learning peak (i.e. crossover into decline) is seen earlier

in patients (at about the age of 1617 years) than for controls (at about the age of 2324 years). Decline in performance with

ageing in patients and controls runs in parallel, but due to the initial distance between the groups, patients reach very poor

performance levels much earlier than controls. Patients with left and right TLEs performed worse in verbal memory than controls.

In addition, patients with left TLE performed worse than those with right TLE. However, laterality differences were evident only

in adolescent and adult patients, and not (or less so) in children and older patients. Independent of age, hippocampal sclerosis

was associated with poorer performance than other pathologies. The results indicate developmental hindrance plus a negative

interaction of cognitive impairment with mental ageing, rather than a progressively dementing decline in chronic TLE patients.

During childhood, and even more so during the decade following puberty, the critical phases for establishing episodic memory

deficits appear. This increases the risk of premature dementia later on, even in the absence of an accelerated decline. Material

specific verbal memory impairment in left TLE is a characteristic of the mature brain and seems to disappear at an older age. The

findings suggest that increased attention is to be paid to the time of epilepsy onset and thereafter. Early control of epilepsy isdemanded to counteract developmental hindrance and damage at a younger age.

Keywords: temporal lobe epilepsy; verbal memory; ageing; development; lateralization

doi:10.1093/brain/awp182 Brain 2009: 132; 28222830 | 2822

Received February 13, 2009. Revised May 18, 2009. Accepted May 23, 2009. Advance Access publication July 27, 2009

The Author (2009). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved.

For Permissions, please email: [email protected]

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IntroductionTemporal lobe epilepsy (TLE) is the most common form of chronic

focal epilepsy. Due to the localization of neuropathology in

memory-relevant brain structures, problems in episodic memory

represent the major cognitive co-morbidity of TLE. Episodic

memory is defined as the ability to acquire and later retrieve

new space- and time-related information. It is, therefore, an

essential component in establishing continuity and biographic

identity. Memory impairment in TLE reflects loss of structural

morphological integrity of the temporal lobe structures, as well

as the dynamic and potentially reversible influence of seizures

and treatment on brain function. However, we must also consider

whether epilepsy and seizures interfere with brain maturation, and

if chronic uncontrolled epilepsy causes a progressive mental

decline with ageing.

In 2002, an international multidisciplinary meeting was held to

discuss whether seizures damage the brain. The results were pub-

lished in Progress in Brain Research (Sutula and Pitkanen, 2002).

The collected evidence showed that seizures represent only a part

of the problem and that complex molecular, cellular, synaptic andsystem level dysfunctions must also be considered when question-

ing the chronic cognitive and behavioural impairments in epilepsy.

At first glance, it would appear almost certain that uncontrolled

epilepsy causes a mental decline. However, the surprising

conclusion of Tom Sutula and Asla Pitkanen was that seizures

may damage the brain only in some individuals, in some

conditions, . . . (Chapter 47, p. 513).

Lifetime-spanning studies on cognition in patients with chronic

epilepsy are not available. At best, longitudinal studies cover an

interval of up to 10 years. Studies addressing TLE were mostly

conducted on surgically treated patients (as opposed to pharma-

cologically treated patients), and although they indicate some

decline and a slight relevance of uncontrolled seizures, the results

are inconsistent and do not particularly favour the idea that

epilepsy is a progressively dementing disease (Elger et al., 2004).

A review of 20 longitudinal studies examined the cognitive out-

comes in patients with epilepsy and concluded that there is a

mild but definite relationship between seizures and mental

decline (Dodrill, 2004). However, these studies, and particularly

the older reports, comprise patients with very different epilepsy

conditions and they may well have included patients with mental

decline due to progressive aetiology. Particularly, for those patients

who today would be considered as suffering from progressive

mitochondrial or auto-immunological inflammatory brain diseases,

it is very difficult to separate the negative cognitive effects ofpathology from those of the severe seizures that are an expression

of the progressive pathology (Helmstaedter, 2007).

In contrast to longitudinal studies, cross-sectional studies can

span a wider age range. Interestingly, such studies clearly suggest

a slow cognitive decline with increased duration of epilepsy (Jokeit

and Ebner, 1999, 2002). However, there is a major methodolog-

ical problem with studies that examine the effect of epilepsy

duration on cognition. Since most epilepsies start early in life, a

longer epilepsy duration is heavily confounded by ageing, which

itself is associated with cognitive decline.

A reasonable way out of this dilemma is to compare age regres-

sions in patients with TLE against those in healthy subjects. The

concept behind this comparison states that if epilepsy systemati-

cally changes age-related cognitive development, then this should

become evident with significant deviations of the respective

regression curves from each other. If, for example, long-lasting

chronic epilepsy systematically adds to a decline, then an accel-

eration of such a decline should show a significantly steeper

regression for the patients than for the healthy subjects. First find-

ings in a relatively small sample indicated that, contrary to previ-

ous assumptions, the age regressions for healthy controls and

patients ran in parallel (Helmstaedter and Elger, 1999). At each

age, the patients performed worse than the healthy subjects and

the distance between groups remained stable over time. Thus, it

did not seem that progressive mental decline was caused by

chronic TLE. Instead, the stable distance between patients and

controls indicated that the cognitive problems in epilepsy must

evolve around the time of epilepsy onset or perhaps even earlier.

In keeping with this finding, there is indeed a long history docu-

menting the negative effects of an early onset of epilepsy on

cognition (Fitzhugh et al., 1965; Dikmen et al., 1975; Dikmenand Matthews, 1977; OLeary et al., 1983; Strauss et al., 1995;

Cormack et al., 2007).

MethodsWe extended our previous findings with adults and focused on learn-

ing and memory performance in both children and adolescents.

We evaluated memory data from a very large sample of 1156 patients

with pharmaco-resistant TLE covering a wide age range. Patients were

collected over a 20-year time period at the Department of

Epileptology, University of Bonn. From the total neuropsychological

database with approximately 6300 first presentations, we selected

patients based on neuropsychological assessment of verbal learningand memory and the diagnosis of TLE defined by MRI (temporal

lobe lesions) and/or ictal/interictal EEG. Of the 789 with available

imaging data, the MRI indicated hippocampal sclerosis/atrophy in

62% of the patients; 19% showed developmental lesions; 9%

tumours; 4% vascular lesions; and 6% had no findings. For the

remaining patients, no MRI data were available. According to the

MRI and/or EEG data, in 595 (52%) patients a left-sided TLE was

indicated; in 538 (46%) a right-sided TLE; and uncertain bilateral find-

ings were present in 23 (2%) patients. The mean age at the onset of

epilepsy was 14 11 years, with 85% of the onsets before 25 years of

age (26%, age 05; 33%, age 614; 26%, age 1524; 15%, age

25+). The mean duration of epilepsy was 1812 years.

All subjects underwent verbal memory testing using the Verbaler

Lern-und Merkfahigkeitstest (VLMT) (Helmstaedter et al., 2001),a German adaptation of the well-known Rey Auditory Verbal

Learning Test (RAVLT). Word-list learning is commonly used for

memory assessment in epilepsy patients. When applied before and

after surgery, it reliably reflects temporal lobe functioning, temporal

lobe pathology and the cognitive effects of TLE (Helmstaedter et al.,

1997a, b; Lee et al., 2002; Loring et al., 2008).

Since we standardized and published the VLMT in Germany

(Helmstaedter et al., 2001), we also have the normative data for

this memory test with, at present, 1000 healthy subjects tested

between the ages 6 and 80 years. This allowed us to compare the

age-related memory performance of patients from 6 to 70 years

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(51% males, mean age 33 12 years) against the age-related memory

performance of healthy subjects from 6 to 80 years (55% males, mean

age 3521 years) (Table 1). The VLMT requires consecutive learning

and recall of a list of 15 words (list A) over five trials; free recall of this

list after each trial is requested. After the five learning trials are com-

plete, a second word list (list B) is presented for free recall to assess the

effects of interference, Finally, unannounced recall of list A is

requested after a delay of half an hour, and a recognition trial is

performed. Recognition requires identification of the words of list A

out of an orally presented list of 50 words which comprises the words

from lists A and B as well as new distractor words. Structural analysis

of this test demonstrated that it reliably assesses verbal short-term or

working memory as well as long-term memory (Muller et al., 1997;

Helmstaedteret al., 2001). Based on the structuralfunctional correla-

tion studies, out of all possible test parameters, the total number ofcorrectly recalled words in immediate recall over the five learning

trials (learning: total trials 15) was selected because it is the most

representative of the more neocortical aspects of short-term and work-

ing memory (Elgeret al., 1997; Helmstaedteret al., 1997a, b). Of the

delayed recall scores, loss of learned words over time was chosen

because this measure provides less redundant information to learning

than absolute free delayed recall (correlation of r= 0.3 instead of

r= 0.8). This measure is the representative of the more medial

temporal-dependent aspects of long-term consolidation and retrieval

(memory: loss in delayed free recall) (Helmstaedter et al., 1997a, b;

Muller et al., 1997; Helmstaedteret al., 2001, 2002).

ResultsBy taking both linear and non-linear dependencies into account,

we performed a combined linear and non-linear regression analysis

by a modelling method called LOESS or LOWESS analysis (locally

weighted scatterplot smoothing) with a smoothing parameter

q = 0.3 (Cleveland and Devlin, 1988). This model more adequately

described the course of memory performance over the time than

standard regression methods. Instead of fitting a specification of a

function to all data in the sample, this analysis fits the regression

to localized subsets of data to build-up a function point-by-point.

The smoothing parameter q can be flexibly chosen (typically

between 0.25 and 0.5) and is the proportion of data used in

each fit. The smaller the q is, the closer the regression conforms

to the data, the larger the q is, the lesser the regression responds

to fluctuations in the data.

[Linear analyses for controls had indicated that the development

of verbal learning memory can be best explained by a quadratic

function (learning: r2 = 0.15, F= 87.1, P50.001; memory:

r2 = 0.03, F= 16.4, P50.001); whereas in patients, learning and

memory curves were best approximated by a linear and logarith-

mic function, respectively (learning: r2 = 0.031,F= 37.1,P50.001;

memory: r2 = 0.03, F= 40.1, P50.001).]

The cross-sectional development of verbal learning in relation to

age (i.e. the comparison of the age regressions of learning in

healthy subjects and TLE patients) is displayed in Fig. 1A. The

performance of both groups in 5-year increments until the age

of 30 years and 10-year increments until the age of 80 years is

displayed in Fig. 1B. The respective courses of verbal memory are

displayed in Fig. 2A and B.

Healthy controls show a course of verbal learning in relation to

age as expected from developmental psychological research(Grady and Craik, 2000; Salthouse, 2009) (Fig. 1A). There

clearly is a linear increase in the performance until about the

age of 2223 years, at which point a slow, but steady, linear

decline is present. Comparing the course of memory in healthy

subjects and patients beyond the age of 25 years shows that the

decline in learning capacity in patients runs largely parallel to that

in the controls, but at a much lower level. After the age of 50

years, the patients and controls come closer, but because of the

decreasing number of older patients, their development is difficult

to determine via the scatter plot. The results for the age groups

(Fig. 1B) show that patients and controls are closer to each other

between 60 and 70 years, mainly because of the large variance in

patient performance.The course of verbal memory (loss of learned words over time)

shows how verbal memory performance becomes optimized in

healthy subjects until young adulthood, in that retrieval efficiency

steadily improves along with the increase observed for learning

(Fig. 2A and B). The best retrieval performance (i.e. the best learn-

ing and least loss of what has been learned) is observed at the age

of 2223 years, where the mean loss approaches the zero line.

From this age onward, a decline becomes evident until age 40,

and then plateaus until the age of 70 years. After 70 years of age,

some further decline is indicated. Again, the memory courses of

healthy subjects and TLE patients over the age of 25 years run

largely parallel and the results on ageing are in keeping with our

previous findings in a selected group of patients with left mesialTLE (Helmstaedter and Elger, 1999). The results on ageing are also

in line with recent longitudinal findings on quantitative MRI in

patients with TLE and healthy subjects, which again fail to provide

evidence that chronic TLE progressively adds damage to the brain

(Helmstaedter and Elger, 1999; Liu et al., 2003, 2005).

The major finding of this study becomes evident when the

course of learning and memory development in childhood and

adolescence is compared among the groups. Here, the slopes

diverge significantly, in that a steep increase of the learning per-

formance in healthy subjects contrasts with a flattened increase in

Table 1 Distribution of patients and control subjects overage groups between 6 and 80 years

Age categories Groups Total

Controls TLE

610 134 28 162

1115 104 68 172

1620 83 107 190

2125 104 139 243

2630 92 152 244

3140 94 355 449

4150 103 208 311

5160 98 82 180

6170 136 17 153

7180 52 0 52

Total 1000 1156 2156

Until the age of 30 years, 5-year increments and in the time after 30 years,

10-year increments were choosen.

2824 | Brain 2009: 132; 28222830 C. Helmstaedter and C. E. Elger

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patients (Fig. 1A and B). When compared with healthy subjects

who increased their learning and memory performance until their

early mid-twenties, the TLE patients completely failed to build-up

their respective performance. They demonstrated only a very

moderate increase in learning capacity which came to a halt at

the age of 1617 years. Instead of further improving their perfor-

mance, the patients had already reached the point at which verbal

learning turns over into a steady decline. When the groups are

Figure 1 (A) Age regressions of verbal learning (total learning over five learning trials) in patients with chronic TLE and healthy controlsubjects (CONTR) indicate developmental hindrance rather than progressive accelerated cognitive decline in the patient group.

The figure displays a scatter plot representing all individual subjects. The two vertical lines indicate the turn over when learning starts

to decline. (B) The results on verbal learning with subjects grouped by age increments of 5 and later of 10 years. Bars represent 90% CI

for the group means. Note how the gap between patients and controls increases with the age of 1620 years and how it reaches

a maximum difference with the age of 2125 years where patients already turned into decline.


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broken down into 5- and 10-year increments, the patients and

control subjects are closest to each other at a young age

(Fig. 1B). Thereafter, the gap opens at 1620 years of age, and

then reaches the maximum difference for the 2125 years of age

groups. At that stage, healthy subjects are still improving their

performance, whereas the patients are already in significant decline.

Unlike their performance in learning, the patients performance

in memory appears to decline linearly from the very beginning

until the age of 2627 years. Memory in healthy subjects increases

linearly and peaks at age 2122 years (Fig. 2A and B). As with

learning, the age group comparison shows that the gap opens at

age 1620 years and continues until 2125 years. Accordingly, a

Figure 2 (A) Age regressions of verbal memory (loss of learned words in half hour delayed free recall) in patients with chronic TLE andhealthy control subjects (CONTR) indicate that this performance decreases in patients from the very beginning (positive values mean

greater losses). The two vertical lines indicate the time from which on memory goes over into a plateau. (B) The results on verbal

memory with subjects grouped by age increments of 5 and later of 10 years. Bars represent 90% CI for the group means. Note the

steady decline in patients, how the gap between patients and controls increases with the age of 1620 years and how it reaches a

maximum difference with the age of 2125 years.


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slow development of verbal learning and deteriorating verbal

memory is implied, but there is no hard evidence suggesting an

accelerated decline with a longer duration of epilepsy at an older

age. Finally, it should be noted that at an older age, learning and

memory performances show a different age dependence

(i.e. learning is more significantly modulated by ageing than

memory).

With regard to the findings on learning, it might be interesting

to note that separate analyses performed for memory span at the

first learning trial on list A and the single learning trial on list B

showed very similar results as observed with total learning. The

courses of memory span performance across the ages largely

mirrored those seen with learning (figures are not shown). The

rationale for adding this analysis was that memory span depends

on frontally mediated processes of working memory rather than

on medialtemporal, long-term consolidation. However, the com-

parable results are not surprising since total learning and memory

spans are highly correlated with each other (list A, r= 0.76; list B,

r= 0.56) (Muller et al., 1997).

The underlying pathology and the hemispheric lateralization ofTLE are major determinants of the verbal memory impairment in

TLE (Wieser, 2004). Since the respective subgroups were suffi-

ciently large, we also calculated subsequent analyses by taking

the presence versus absence of the hippocampal sclerosis and

the lateralizaton of the epilepsy in the left versus right hemisphere

into account.

As for the pathology, 491 (62%) of 789 patients with MRI were

diagnosed with a hippocampal sclerosis/atrophy (AHS), 298 (38%)

patients had another pathology. Comparison of the groups

indicated that verbal learning and memory performances were

worse in patients with hippocampal sclerosis than for those

patients with another pathology (learning F= 16.1, P50.000

memory F=6.9, P50.01). However, this difference was seen

only when the total groups were taken into consideration. When

the different age groups were calculated separately, the differ-

ences between patients with AHS and other pathologies were

not significant.

We compared patients with left (N =595) and right TLE

(N = 538). Both groups were impaired in verbal learning and

memory in relation to controls and, in addition, the patients

with left TLE performed worse than those with right TLE

(F=140 and 141 with P50.000 for learning and memory).

However, as indicated in Table 2, the leftright difference in

verbal learning and memory was confined to adolescence and

adulthood and the occurrence of leftright differences across the

ages was different for verbal learning and memory. In verbal

learning (total: trials 15), significant leftright differences were

observed between the age of 3150 years. In verbal memory

(loss in delayed free recall), the leftright differences were seen

between the ages of 1150 years. With an older age (450 years),the leftright differences became less pronounced and failed to

reach statistical significance.

DiscussionAge regressions of verbal learning and memory in patients with

TLE and healthy subjects were compared with the test hypothesis

that significant deviances of the age regressions would reveal

critical phases whereby epilepsy interferes with cognitive

Table 2 Differences in verbal learning (total learning) and memory (loss of learned words after delay) across the ages asdependent on the lateralization of temporal lobe epilepsy in the left versus right hemisphere

Agecategories(years)

N mean (SD) F/sig nif . Agecategories(years)

N mean (SD) F/signif.

510 VLMT learning (trials 15) R-TLE 12 40.33 (11.98) 0.001 NS 3140 R-TLE 154 46.18 (10.06) 4.45

L-TLE 16 40.19 (11.16) L-TLE 196 44.04 (8.93)

VLMT memory(loss over time) R-TLE 12 1.08 (1.56) 0.06 NS R-TLE 154 2.35 (2.19) 26.22

L-TLE 16 1.25 (1.77) L-TLE 196 3.56 (2.19)

1115 VLMT learning(trials 15) R-TLE 36 48.33 (9.36) 0.44 NS 4150 R-TLE 101 45.22 (9.37) 13.01

L-TLE 31 46.58 (12.19) L-TLE 100 40.13 (10.59)

VLMT memory (loss over t ime) R-TLE 36 1.47 (1.64) 5.40 R-TLE 101 2.39 (2.42) 10.41

L-TLE 31 2.35 (1.42) L-TLE 100 3.45 (2.20)

1620 VLMT learning(trials 15) R-TLE 47 49.06 (8.42) 0.039 5160 R-TLE 41 42.85 (9.18) 1.84 NS

L-TLE 58 49.41 (9.47) L-TLE 38 40.11 (8.73)

VLMT memory (loss over t ime) R-TLE 47 1.55 (2.09) 4.50 R-TLE 41 2.92 (2.25) 0.36 NS

L-TLE 58 2.43 (2.12) L-TLE 38 3.23 (2.30)

2125 VLMT learning (t rials 15) R-TLE 71 48.18 (9.22) 1.81 NS 6170 R-TLE 12 42.75 (9.59) 0.21 NS

L-TLE 67 46.06 (9.27) L-TLE 3 40.00 (6.55)

VLMT memory (loss over t ime) R-TLE 71 2.21 (1.97) 5.125 R-TLE 12 2.33 (2.70) 3.93 NS

L-TLE 67 3.01 (2.19) L-TLE 3 6.00 (3.60)

2630 VLMT learning (trials 15) R-TLE 64 46.30 (10.1) 0.273 NS

L-TLE 86 45.48 (9.016)VLMT Memory [loss over time] R-TLE 64 2.09 (2.39) 13.74

L-TLE 12 40.33 (11.980)

Note that left-right differences mainly appear as a characteristic of the mature and adult brain.P50.05; P50.01; P50.001; NS= not significant.


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development. Since most epilepsies start early in life, with

increasing age of patients at the time of evaluation, the impact

of the onset of epilepsy will have a decreasing contribution to

the resulting performance, whereas the contribution of the

duration of epilepsy will increase. Therefore, if deviances exist

at a young age, then one should be able to confirm either

developmental hindrance or retardation. If there are deviances at

an older age, this should be indicative of an accelerated mental

decline.

If we use this as our basis, the present results provide strong

evidence of a neurodevelopmental hindrance in chronic TLE

patients, which becomes most evident in the decade after puberty.

While the gap between patients and controls increasingly widens

at a younger age, the course of learning and memory at an older

age runs largely in parallel. However, patients at every age score

are at a much lower level than healthy subjects. Thus, no progres-

sive degenerative decline can be confirmed from these findings.

So far, this is in keeping with the results that we published in 1999

involving a selected group of patients with pure left mesial TLE

(Helmstaedter and Elger, 1999).

The age at which development comes to a halt indicates thatthe problems with learning arise in later brain maturation, which

is no longer intrinsically and ontogenetically determined, but rather

mainly extrinsically driven by experience (Segalowitz and Hiscock,

2002). Learning (i.e. the short-term and working memory aspects

of memory) highly depends on attention, executive functions and

language. Healthy subjects are able to improve their learning

capacity by increasing these more extra-temporally and mostly

frontally-associated functions. Learning, as well as memory in

terms of the access to learned materials, improves with better

behavioural organization and the extension of semantic networks

and knowledge systems. One may hypothesize that patients fail in

this particular respect.

It is remarkable that the age at which patients becomeincreasingly impaired marks the approximate endpoint of func-

tional cerebral plasticity, which helps to preserve language and

language-related memory aspects in early onset epilepsy

(Helmstaedter et al., 1997a, b, Helmstaedter, 1999). As pointed

out elsewhere in more detail (Helmstaedter and Elger, 1998;

Helmstaedter, 1999), the neocortical and mesio-limbic aspects of

verbal learning and memory seem to have different functional

plasticity. Mesial encoding functions are more bilaterally disposed,

and unilateral damage can, in part, be compensated by homolo-

gous contralateral structures quite independent of age. Unilateral

selective amygdalo-hippocampectomy demonstrates that surgical

damage often causes additional memory impairment, but will not

lead to global amnesia as long as no contralateral damage exists.Plasticity for material-specific neocortical functions is, in contrast,

time-limited, in that neocortical functions become increasingly

dependent on a single hemisphere. The critical period for contra-

lateral restitution and compensation in the presence of unilateral

damage extends to puberty (Vargha-Khadem et al., 1997;

Grunwald et al., 1998; Helmstaedter and Elger, 1998;

Helmstaedter, 1999; Liegeois et al., 2008). Accordingly, the time

course of the more medial-temporal-dependent memory aspect

among the age groups is comparably stable at an older age,

whereas learning experiences a significant modulation with

neocortical development. In the cross-sectional perspective, brain

maturation and development also seem to be important for what

is referred to as lateralization-dependent material-specific memory

impairment in TLE (Saling, 2009). First, verbal learning and

memory impairment are not confined to left TLE, i.e. patients

with right TLE perform poorly as well, although to a lesser

degree than left TLE patients. Of major interest, with regard to

the lateralization of TLE is the finding that the leftright differ-

ences in verbal learning and memory are observed in adolescent

and adult patients, but not (or less so) in children and older

patients. Thus, the impairment of verbal memory and its

material-specific affection in left TLE emerge in the mature brain

when hemispheric specialization becomes complete. At an older

age, the material specificity of the memory impairment in lateral-

ized TLE interestingly seems to disappear. Whether this reflects a

converging memory impairment pattern independent on laterali-

zation because of generally decreasing memory resources and

mental reserve capacities at an older age is an interesting

hypothesis which deserves further attention.

Hippocampal sclerosis, which was the most frequent pathology

in the evaluated group of TLE patients, had a differential impacton verbal learning and memory. The patients with hippocampal

sclerosis performed worse than those with another pathology

independent of age. Due to the cross-sectional study design, we

cannot provide answers regarding the aetiology of the observed

developmental hindrance. Do the data show additive damage,

particularly in childhood and adolescence? Do they indicate early

damage which subsequently grows into the impairment when the

affected areas should have their developmental spurts? Does

spreading epileptic activity have a distant effect on the develop-

ment of brain areas not directly involved in epilepsy? Learning and

memory are closely associated with temporal lobe structures and

are thus most critical for the study of the effects of chronic TLE on

cognition. Indeed, it is likely that the time-related changes inlearning and memory are linked to fluctuations in IQ as a function

of age. As already mentioned in the introduction, there is ample

evidence from the literature to suggest that an earlier onset of epi-

lepsy is associated with a poorer intellectual and educational out-

come (Strauss et al., 1995; Dikmen et al., 1977; Helmstaedter,

2005; Cormack et al., 2007). Evidence for the neurodevelopmen-

tal hypothesis originates from studies using quantitative brain vol-

umetric measures. These studies show that an early onset TLE, in

contrast to a late onset TLE, has substantial negative effects on

extratemporal cortical development (Hermann et al., 2002, 2003;

Weberet al., 2007; Kaaden et al., 2008).

As for the concerns about dementia in TLE, it is important to

note that although the data indicate a neurodevelopmental originof memory problems, patients are nevertheless at an increased risk

of having dementiathat is, if we use the term dementia in its

broadest sense. Even without an accelerated decline, the negative

interaction of the initially established damage with normal ageing

significantly reduces the patients reserve capacities at an older age

when processes of normal or even pathological ageing take place.

In this regard, the present data parallel those from the extraordi-

nary longitudinal Scottish Mental Survey, which indicated that

childhood IQ is a significant predictor for later dementia and mor-

tality (Whalley et al., 2000; Starret al., 2008). How later acquired


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brain damage can change the patients cognitive perspective with

ageing has been demonstrated with the effects of epilepsy surgery

on the age regression of verbal learning and memory performance

(Helmstaedteret al., 2002).

At this stage of the evaluation, the data cannot provide final

answers to the questions concerning the basic mechanisms behind

the developmental hindrance and the detailed impact of different

aetiologies, pathologies, seizure activity or medication on memory

in the lifetime cycle. The main message of this study was to pro-

vide a macro view of verbal learning and memory in TLE patients

of various ages, and to reveal that our perspective towards

patients with chronic epilepsy should change; it must shift away

from viewing epilepsy as a progressively dementing disease and

back towards showing how epilepsy, at its origin, interferes with

brain maturation and cognitive development. In the long run, this

increases the risk of premature dementia. Additional efforts are

thus needed to identify patients who are at risk and to counteract

negative cognitive development in TLE at the very beginning.

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