Memory in children with epilepsy: a systematic review.

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Contents lists available at ScienceDirect

Seizure journal homepage: www.elsevier.com/locate/yseiz

Memory in children with epilepsy: A systematic review Leanne Menlove *, Colin Reilly Research Department, Young Epilepsy, St. Piers Lane, Lingfield, Surrey RH7 6PW, United Kingdom

A R T I C L E I N F O

A B S T R A C T

Article history: Received 2 July 2014 Received in revised form 28 September 2014 Accepted 4 October 2014

Purpose: Research suggests an increased risk for cognitive impairment in childhood epilepsy with memory being one area of cognition most likely to be affected. Understanding the prevalence and predictors of memory difficulties may help improve awareness of the difficulties and allow efficacious supports to be put in place. Method: A systematic review was carried out using the search terms ‘memory’, ‘children’ and ‘epilepsy’ in the database PUBMED. Eighty-eight studies met inclusion criteria. The review focuses on comparisons of memory scores of children with epilepsy and controls, and comparison of memory scores of children with epilepsy to normative scores. Predictors of memory impairment and the effect of surgery on memory functioning are also reviewed. Results: The majority (78%) of studies reviewed revealed that children with epilepsy scored lower than controls and normative scores on measures of memory. Post-surgery, memory scores were reported to improve in 50% of studies. Predictors of memory impairment included a greater number of AEDs used, younger age of onset, increased seizure frequency and longer duration of epilepsy. Conclusion: Children with epilepsy have a high frequency of memory impairments. However, the exact prevalence of difficulties is not clear due to the lack of population-based data. Most studies have not controlled for IQ and thus it is unclear if difficulties are always related to global cognitive difficulties. There is need for future population-based studies and studies focussing on the neurobiology of memory problems in children with epilepsy. ß 2014 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.

Keywords: Memory Epilepsy Children Predictors

1. Introduction Cognitive impairments are often associated with childhood epilepsy and can be a crucial complication of the condition contributing to negative psychosocial outcomes.1 Cognitive outcome in childhood epilepsy is likely to be related to underlying aetiology, abnormal brain structure and epileptic activity,2,3 with the contributions of each likely to be interrelated.4 Cognitive impairments in childhood epilepsy can be global, affecting overall cognitive ability/IQ with a high association with global cognitive impairment and intellectual disability (IQ > 70).5,6 Cognitive difficulties can also be specific, affecting particular aspects of cognitive functioning in the absence of, or of a greater magnitude than, the global difficulties. One of the areas of cognition where specific difficulties have frequently been noted is memory. Memory is a crucial part of cognitive functioning, allowing

* Corresponding author. Tel.: +44 1342 832243x490. E-mail addresses: [email protected] (L. Menlove), [email protected] (C. Reilly).

flexibility and adaptation of information from our ever changing environment.7 Understanding of the mechanisms responsible for the cognitive problems, including memory difficulties, often associated with childhood epilepsy lags far behind that of knowledge of the mechanism of epilepsy.8 Epilepsy interferes with the developmental trajectory of brain networks underlying cognition9 and it would appear that the underlying aetiology of a child’s epilepsy is involved in the mechanism of permanent deficits in cognition.8 This underlying aetiology contributes to the generation of seizures as well as lasting changes in neural circuits affecting the brains’ ability to process and store information. These impairments likely result from temporary disruption of neural activity patterns and can become permanent if seizures or epileptiform activity are more frequent. How changes in neural circuitry contribute to memory or other cognitive processes is not clear. It is also not clear if different aetiologies, different types of seizures or different medications affect cognitive processes in a different manner. Impairments in memory can have a detrimental impact on quality of life in childhood epilepsy10 and memory impairments are associated with difficulties in academic achievement in

http://dx.doi.org/10.1016/j.seizure.2014.10.002 1059-1311/ß 2014 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.

Please cite this article in press as: Menlove L, Reilly C. Memory in children with epilepsy: A systematic review. Seizure: Eur J Epilepsy (2014), http://dx.doi.org/10.1016/j.seizure.2014.10.002

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childhood epilepsy, even after IQ has been controlled for.11 Therefore, understanding the prevalence of difficulties in memory and possible predictors of such difficulties is essential with respect to improving quality of life and everyday functioning in the condition. An important consideration in treatment of epileptic seizures is the impact of such treatment on cognitive and behavioural impairments. It is important to balance the need to treat seizures with the need to minimise cognitive and behavioural side effects. Therefore, it is important to know if treatments, such as AEDs and surgery affect memory functioning. The purpose of this paper is to review studies on memory in childhood epilepsy with a focus on prevalence of difficulties in comparison to controls and normative scores on standardised tests of memory. The review also focuses on the impact of epilepsy surgery on memory performance. The final part of the review focuses on predictors of memory in childhood epilepsy.

2. Material and methods

2.2. Search and selection process The electronic database PubMed was searched from 8th August 1993 to 8th August 2013 using the following search terms in the ‘Title/Abstract’; ‘memory’, ‘children’ and ‘epilepsy’. Only English language articles were considered for this review. Eligibility and selection of relevant articles were first assessed by screening results based on title/abstract review and removing duplicates. The full texts were then screened according to predefined inclusion and exclusion criteria outlined below. The search and selection process was performed together by two reviewers (HS, LM). 2.3. Criteria for inclusion and exclusion To meet the criteria for inclusion in this review studies had to refer to children (aged 0–18 years), contain more than 10 participants and include standardised measures of memory. Review articles were excluded. Of the 282 search results a total of 88 studies met criteria for inclusion (refer to Supplement 1 for overview of studies used in review). 2.4. Data extraction and analysis

The PRISMA guidelines were followed for this systematic review methodology.12

The analysis within this review focused on extracting the following data from all relevant studies: (1) memory performance

Identification

2.1. Methods

Records identified through searching databases (n= 282)

Records after duplicates removed

Included

Eligibility

Screening

(n=282)

Records screened based on title/abstract review (n=282)

Full text articles assessed for eligibility (n=112)

Records excluded (n=170 ) 170 titles/abstracts did not meet inclusion criteria. Reasons for exclusion included not being in the English language, being review articles, having less than 10 children with epilepsy, and not having standardised measures of memory.

Full text articles excluded (n=24 ) When reviewing full texts, a further 24 did not meet inclusion criteria. Reasons for exclusion included not being in the English language, being review articles, having less than 10 children with epilepsy, and not having standardised measures of memory.

Studies included in qualitative synthesis (n =88)

Fig. 1. Flow diagram of methodology.


Author

Sample size

Age range

Gender

Epilepsy type

Measures of memorya

CWE controls

2013

Widjaja et al.13

CWE: 40 Cont: 25

Mean age: 13.5 years

CWE: (M) 17 (F) 23 Cont: (M) 14 (F) 11

CAVLT, CMS

CWE = Controls

2013

Verrotti et al.14

6–11 years

CWE < Controls

Pinabiaux et al.15

TLE

RBMT

CWE < Controls

2013

Oitment et al.16

CWE: (M) 5, (F) 4 Siblings: (M) 5, (F) 3 Cont: (M) 8 (F) 8 CWE: (M) 18 (F) 7 CONT: CWE: (M) 18 (F) 7 CWE: (M) 39, (F) 36 Cont: (M) 29, (F) 28 CWE: (M) 17, (F) 19 Cont: (M) 9, (F) 23 M:F = 2.6:1

WISC-IV, NEPSY-II

2013

CWE: 9 Siblings: 8 Cont: 18 CWE: 25 Cont: 50 CWE: 119 Cont: 57 CWE: 36 Cont: 28 CWE: 18 Cont: 18 CWE: 106 Cont: 106 CWE: 188 Cont: 41 CWE: 15 Cont: 15 CWE: 28

Non-lesional localisation-related epilepsy RE

EWIS

PMQ, WMS, DNMS, CMS

CWE < Controls

TLE

WCST, WRAML

CWE < Controls

BRE

CANTAB

CWE < Controls

CWE: (M) 60, (F) 46

Epilepsy

WISC-IV

CWE < Controls

Epilepsy

WISC-R

CWE < Controls

CAE

CBTT, WISC-III

CWE = Controls

6–17 years

CWE (M) 100, (F) 88 Cont: (M) 25, (F) 16 CWE: (M) 8, (F) 7 Cont: (M) 8, (F) 7 (M) 12, (F) 16

WISC-R, VADS

CWE < Controls

CWE: 17 Cont: 15 ADHD: 15 CWE: 44 Cont: 22 CWE: 20 Cont: 41 CWE: 82 Cont: 51

8–14 years

(M) 47, (F) 0

CEOP (n = 17) SOE (n = 11) Epilepsy

N-Back tasks (for working memory)

CWE < Controls

11–14 years

CWE: (M) 19 (F) 25, Cont: (M) 13, (F) 9 (M) 30, (F) 31

TLE

WMS

CWE < Controls

IGE

EMQ, WISC-IV, WMTB-C, WRAML2, CMS

CWE < Controls

CAE CPS

TOMAL, CVLT, Doors and people test, WISC

CWE < Controls

CWE: 31 Cont: 31 CWE: 13 Cont: 13 CWE: 219 Cont: 131 CWE: 16 T1D: 14 Cont: 15

6–16 years

Cont: (M) 26, (F) 25 CPS: (M) 25, (F) 17 CAE: (M) 14, (F) 17 CWE: (F) 18, (M) 13 Cont: NR CWE: (M) 6, (F) 7 Cont (M) 8, (F) 5 CWE; (M) 107, (F) 112 Cont: (M) 63, (F) 68 CWE: (M) 5, (F) 11 T1D: (M) 5, (F) 9 Cont: (M) 3, (F) 12

Epilepsy (well controlled)

Back matching working memory tasks

CWE < Controls

‘Uncomplicated’ epilepsy

NEPSY

CWE < Controls

Epilepsy

Verbal memory and learning instruments (not outlined in study) WRAML WCST

CWE < Controls

CWE: 155 Cont: 277 CWE: 40 Cont: 18 CWE: 25 Cont: 25 CWE: 20 Cont: 40 CWE: 21 Cont: 25 CWE: 20 Cont: 30 CWE: 52 Cont: 48

6–18 years

Cont: (M) 127, (F) 150 CWE:(M) 121 (F) 156 CWE: (M) 22, (F) 18 Cont: (M) 14, (F) 4 CWE: (M) 11, (F) 14 Cont: (M) 11, (F) 14 CWE: (M) 11, (F) 9 Cont: (M) 20, (F) 20 CWE: (M) 10, (F) 11 Cont: (M) 17, (F) 8 CWE: (M) 6, (F) 14 Cont: (M) 12, (F) 18 CWE: (M) 29, (F) 23 Cont: (M) 17, (F) 21

Epilepsy

EpiTrack Junior Test

CWE < Controls

RSFE

WMS and CMS

CWE < Controls

BRE

KET-KID

CWE < Controls

Early TLE.

Story recall, Recall of word lists

CWE < Controls

IGE (n = 9) BRE (n = 12) Epilepsy

Visual one-backmatching working memory task was performed WPPSI-R, NEPSY

CWE = Controls CWE < Controls

NOE

CMS

CWE = Controls

2012

17

Rzezak et al.

18

2012

Vintan et al.

2012

Sherman et al.19

2012

Nicolai et al.20

2012

21

D’Agati et al.

2012

Polat et al.22

2012

Bechtel et al.23

2012

Cormack et al.24

2012

Gascoigne et al.25

2012

Kernan et al.26

2011

Myatchin and Lagae27

2010

Rantanen et al.28

2010

Dunn et al.29 30

2010

Conant et al.

2010

Helmstaedter et al.31

2010

Everts et al.32

2009

Danielsson and Peterman

2009

Jambaque et al.34

2009

Myatchin et al.35

2008

Selassie et al.

37

Hermann et al.

5–18 years 8–16 years 6–14 years Mean age: 11 6–18 years 9–15 years

6–16 years 6–16 years

3–6 years 6–14 years 6–11 years

7–18 years 4–8 years 11–15 years 6–16 years 6–7 years 8–18 years

years

CAE

CWE = Controls

3

2008

36

33

8–18 years

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Table 1 Children with epilepsy versus children without epilepsy on measures of memory.

Sample size

Age range

Gender

Epilepsy type

Measures of memorya

CWE controls

2008

Vago et al.38

7–13 years

CVLT-CV

CWE < Controls

Kaczmarek et al.39

CWE: (M) 16, (F) 8 Cont: (M) 11, (F) 5. NR

BRE

2007

CE

VCFT

CWE < Controls

2007

Siren et al.40

CWE: 24 Cont: 16 CWE: 89 Cont: 95 CWE: 11 Cont: 10 CWE: 25 Cont: 25 CWE: 21 Cont: 21 CWE: 28 CWE: 22 Cont: 22 CWE: 31 Cont: 31 CWE: 80 Cont: 80 CWE: 24 Cont: 20 CWE: 42 Cont: 30 CWE: 176 Cont: 113 CWE: 37 CWE: 55 CWE: 24

CAE (n = 10) JAE (n = 1) TLE

WISC-R WPPSI-R WISC-III, WCST, WRAOML

CWE = Controls

7–16 years

CWE: (M) 5, (F) 5 Cont: (M) 5, (F) 5 NR

CWE < Controls

6–16 years

(M) 7, (F) 14

IGE

WASI

CWE = Controls


NR CWE: (M) 12, (F) 10 Cont: (M) 12, (F) 10 CWE: (M) 12, (F) 19 Cont: (M) 12, (F) 1 CWE: (M) 36, (F) 44 Cont:(M) 36, (F) 44 CWE: (M) 10, (F) 14 Cont: (M) 8, (F) 12 NR

BRE BCECTS

WRAML WISC-III, TUKI

CWE < Controls CWE < Controls

Epilepsy

CMS

CWE = Controls

FE

WISC-R, VSR

CWE < Controls

IE CE Epilepsy

WISC-R, CVLT

CWE < Controls

WISC-RN, Learning locations

CWE < Controls

CWE: (M) 93, (F) 83 Cont: (M) 71, (F) 42 (M) 17, (F) 20 (M) 22, (F) 33 (M) 17, (F) 7

Epilepsy.

FePsy: Recognition of words and figures.

CWE < Controls

RE Epilepsy NDPE

DNMS, CMS, WMS, ROCF, WIS VLMT, AVLT WISC-R, AVLT, DCS-R

CWE = Controls CWE < Controls CWE < Controls

41

2007

Guimaraes et al.

2007

Davidson et al.42

2007 2006

Northcott et al.43 Volkl-Kernstock et al.44

2006

Borden et al.45

2006

Jocic-Jakubi and Jovic46

2005

Henkin et al.47

2005

Oostrom et al.

48

49


6–16 years 7–16 years 10–17 years 7–16 years 6–12 years

2005

Aldenkamp et al.

2004 2002 2002

Kadis et al.50 Gleissner et al.51 Lendt et al.52

2002

Schouten et al.53

CWE: 69 Cont: 66

5–16 years

CWE: (M) 33, (F) 36 Cont: (M) 30, (F) 36

Epilepsy

Word Span Location learning

2001 2001

Aldenkamp et al.54 Pavone et al.55

6–13 6–16 years

FePsy: Recognition of words and figures WISC-R, TOMAL

Williams et al.56 Lendt et al.57

CWE: (M) 1, (F) 11 CWE: (M) 6, (F) 10 Cont:(M) 6, (F) 10 CWE: (M) 28, (F) 37 (M) 21, (F) 29

AE AE

2001 1999

TLE TLE

CVLT-C VLMT, DCS-R

CWE = Controls CWE = Controls

1999

Seidel and Mitchell.58

TLE

WRAOML

CWE < Controls

1998

Hershey et al.59

CWE: 21 CWE: 16 Cont: 16 CWE: 65 CWE: 20 Cont: 30 CWE: 10 Cont: 14 CWE: 28 Cont: 19

CWE = Controls CWE < Controls (on high demand tasks) CWE < Controls CWE < Controls

TLE

SDR, DMNS, Story Recall Task, Pattern Recall Task, Verbal Span, Spatial Span

1994 1993

Beardsworth and Zaidel60 Jambaque et al.61

CWE < Controls on simple spatial span CWE = Controls verbal span CWE < Controls CWE < Controls

7–18 years. 6–17 years 6–15 years

8–13 years 10–16 years 6–12 years 7–16 years

CWE: (M) 6, (F) 4 Cont: (M) 8, (F) 6 CWE: (M) 18, (F) 10 Cont: (M) 18, (F) 10

CWE: 29 NR (M) 11, (F) 18 TLE BMCFT, WISC CWE: 60 7–15 years CWE: (M) 25, (F) 35 PE SMB, WISC-R Cont: 60 Cont: (M) 25, (F) 35 Memory tests – AVLT: Auditory Verbal Learning Test, BMCFT: Beardsworth Memory for Children Faces Test, CANTAB: Cambridge Neuropsychological Test Automated Battery, CAVLT: Children’s Auditory Verbal Learning Test, CBTT: Corsi Block Tapping Test, CMS: Children’s Memory Scale, DCS-R: Diagnosticum fur Cerebralschaden (German figural memory test), DNMS: Denman Neuropsychology Memory Scale, EMQ: Everyday Memory Questionnaire, FePsy: Computerised Neuropsychological Testing, KET-KID: Kognitiver Entwicklungstest fu¨r das Kindergartenalter (Cognitive Developmental Scale for Preschool Children), NEPSY: A Developmental NEuroPSYchological Assessment, PMQ: Parent Memory Questionnaire, RBMT: Rivermead Behavioural Memory Test, ROCF: Rey–Osterrieth Complex Figure, SDR: Spatial Delayed Response, SMB: The Signoret Memory Battery, TOMAL: Test Of Memory and Learning, TUKI: Tu¨binger Luria Christensen Neuropsychological Test Set for Children, VADS: Visual Aural Digit Span Test, VCFT: Verbal and Categorical Fluency Test, VLMT: Verbal Learning Memory Test, VSR: Verbal Selective Reminding, WASI: Wechsler Abbreviated Scale of Intelligence, WCST: Wisconsin Card Sorting Test, WISC: Wechsler Intelligence Scale for Children, WMBT-C: Working Memory Battery for Children, WMS: Wechsler Memory Scale, WPPSI-R: Wechsler Preschool and Primary Scale of Intelligence-Revised, WRAOML/WRAML: Wide Range Assessment of Memory and Learning. Epilepsy Syndromes – AE: Absence Epilepsy, BCECTS: Benign Childhood Epilepsy with Centro-Temporal Spikes, BRE: Benign Rolandic Epilepsy, CAE: Childhood Absence Epilepsy, CE: Cryptogenic Epilepsy, CEOP: Childhood Epilepsy with Occipital Paroxysms, CPS: Complex Partial Seizures, EWIS: Epilepsy With Intractable Seizures, FE: Focal Epilepsy, FLE: Frontal Lobe Epilepsy, IE: Idiopathic Epilepsy, IGE: Idiopathic Generalised Epilepsy, JAE: Juvenile Absence Epilepsy, NDPE: Newly Diagnosed Partial Epilepsy, NOE: New Onset Epilepsy, PE: Partial Epilepsy, RE: Rolandic Epilepsy, RSFE: Refractory Symptomatic Focal Epilepsy, SOE: Symptomatic Occipital Epilepsy, TLE: Temporal Lobe Epilepsy. a Refer to Supplement 2 for memory tests and subscales.

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Table 1 (Continued )

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Table 2 Comparison of children with epilepsy (CWE) with normative scores (norms). Year

Author

Sample size

Age range

Gender

Measures of memorya

Comparative to normative scores

2013 2013

Hrabok et al.10 Pinabiaux et al.15


CWE < norms CWE < norms

Longo et al.62 Braakman et al.63 Vintan et al.18

8–17 years 6–16 years 6–14 years

(M) 90, (F) 89 CWE: (M) 18 (F) 7 CONT: CWE: (M) 18 (F) 7 (M) 10, (F) 9 (M) 46, (F) 25 M:F = 2.6:1

CVLT-C RMBT

2013 2012 2012

WCST RAVLT, ROCF CANTAB

CWE < norms CWE < norms CWE < norms

2012

Sherman et al.19

CWE 90 CWE: 25 Cont: 50 CWE: 66 CWE: 71 CWE: 18 Cont: 18 CWE: 106 Cont: 106 CWE: 23 CWE: 82 Cont: 51

Mean age: 11 years

CWE: (M) 60, (F) 46

WMI

CWE < norms


AVLT, ROCF TOMAL, CVLT

CWE = norms CWE < norms

CWE: 66

6–18 years

(M) 13, (F) 10 Cont: (M) 26, (F) 25 CPS: (M) 25, (F) 17 CAE: (M) 14, (F) 17 (M) 28, (F) 38

CWE < norms

CWE: 13 Cont: 13 CWE: 65 CWE: 43 CWE: 155 Cont: 277 CWE: 40 Cont: 18 CWE: 51 CWE: 11 Cont: 10 CWE: 25 Cont: 25 CWE: 20

3–6 years old

BNT, EOWPVT, CMS, WMS NEPSY CMS, WMS III TEMA EpiTrack Junior Test

CWE < norms CWE = norms CWE < norms

WMS, CMS

CWE < norms

ROCF, CAVLT STIM (visual and spatial memory tasks) WISC III, WCST


WISC, ROCF, RBMT, SMB WRAML


NEPSY DMNS, WMS III


WRAML WRAML, ROCF

CWE < norms CAE = normsb, FLE < normsc, TLE < normsd CWE < norms CWE < norms

64

2012 2012

Kwon et al. Kernan et al.26

2011

Smith and Lah.65 28

2010

Rantanen et al.

2010 2010 2010

Engle and Smith66 Piccinelli et al.67 Helmstaedter et al.31

2010

Everts et al.32

2009 2007

68

Smith et al. Siren et al.40

2007

Guimaraes et al.41

2007

Jambaque et al.

69

43

2007

Northcott et al.

2007 2006

Bender et al.70 Smith et al.71

2005 2004

Northcott et al.72 Nolan et al.73

2004 2004

Fastenau et al.74 Lindgren et al.75

2003 2002 2002

Mabbott and Smith.76 Culhane-Shelburne et al.77 Schouten et al.53

2001

Pavone et al.55

2001 1998

Williams et al.56 Hershey et al.59

1998 1998 1994

Williams et al.78 Szabo et al.79 Beardsworth and Zaidel60

CWE: 42 Cont: 40 CWE: 19 CWE: 27 Cont: 15 CWE: 28 CWE: 70

CWE: 1 73 CWE: 32 Cont: 25 CWE: 44 CWE: 27 CWE: 69 Cont: 66 CWE: 16 Cont: 16 CWE: 65 CWE: 28 Cont: 19 CWE: 79 CWE: 14 CWE: 29

7–16 years

CWE: (M) 6, (F) 7 Cont (M) 8, (F) 5 (M) 32, (F) 33 (M) 21, (F) 22 Cont: (M) 127, (F) 150 CWE:(M) 121 (F) 156 CWE: (M) 22, (F) 18 Cont: (M) 14, (F) 4 CWE: (M) 26, (F) 25 CWE: (M) 5, (F) 5 Cont: (M) 5, (F) 5 NR

7–14 years

(M) 13, (F) 7

6–12 years

CWE: (M) 26, (F) 16 Cont: (M) 16, (F) 24 (M) 11, (F) 8 CWE: (M) 13, (F) 14 Cont: (M) 6, (F) 9 NR (M) 35, (F) 35

6–16 years 5–17 years 6–18 years 7–18 years 6–17 years 4–15 years

3–12 years 8–17 years 3–15 years 6–18 years

8–15 years 7–15 years 5–19 years 8–18 years 5–16 years 6–16 years 8–13 years 7–16 years 6–15 years 7–12 years NR

(M) 101, (F) 72 CWE: (M) 17, (F) 15 Cont: (M) 13, (F) 13 (M) 18, (F) 26 (M) 15, (F) 12 CWE: (M) 33, (F) 36 Cont: (M) 30, (F) 36 CWE: (M) 6, (F) 10 Cont:(M) 6, (F) 10 CWE: (M) 28, (F) 37 CWE: (M) 18, (F) 10 Cont: (M) 18, (F) 10 CWE: (M) 42, (F) 37 (M) 7, (F) 7 (M) 11, (F) 18

WRAML RAVLT, ROCF

CWE < norms

CWE < norms

CAVLT CVLT, WRAML Word Span, Location Learning WISC-R, TOMAL

CWE = norms CWE = norms CWE = norms

CVLT-C SDR, DMS,

CWE = norms CWE = normse, CWE < normsf CWE = norms CWE = norms CWE < norms

WCST, WRAML CAVLT-2 BMCFT, WISC

CWE < norms

Memory tests – AVLT: Auditory Verbal Learning Test, BMCFT: Beardsworth Memory for Children Faces Test, BNT: Boston Naming Test, CANTAB: Cambridge Neuropsychological Test Automated Battery, CAVLT: Children’s Auditory Verbal Learning Test, CMS: Children’s Memory Scale, CVLT-CV: California Verbal Learning TestChildren’s Version, DNMS: Denman Neuropsychology Memory Scale, DMS: Delayed Match to Sample, EOWPVT: Expressive One Word Picture Vocabulary Test, NEPSY: A Developmental NEuroPSYchological Assessment, RAVLT: Rey-Auditory Verbal Learning Task, RBMT: Rivermead Behavioural Memory Test, ROCF: Rey–Osterrieth Complex Figure, SDR: Spatial Delayed response, SMB: The Signoret Memory Battery, TOMAL: Test Of Memory and Learning, WCST: Wisconsin Card Sorting Test, WISC: Wechsler Intelligence Scale for Children, WISC-R: Wechsler Intelligence Scale for Children, WMI: Working Memory Index, WMS: Wechsler Memory Scale, WRAML: Wide Range Assessment of Memory and Learning. a Refer to Supplement 2 for memory tests and subscales. b On verbal tests. c In two verbal tests. d Across all 5 verbal memory tests. e on short-delay memory tasks. f On spatial tasks with high memory loads or long delays.


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in children with epilepsy compared to controls, (2) memory performance in children with epilepsy compared to normative scores, (3) memory performance in children with epilepsy pre and post-surgery, (4) predictor variables for memory in children with epilepsy (Fig. 1). 3. Results Children in the included studies ranged from 3 to 18 years with a similar number of males and females in most of the studies. With respect to types of epilepsy a wide range of categorisations have been used, making comparisons between studies based on epilepsy syndromes or aetiology difficult. Table 1 compares memory scores in studies of children with epilepsy and ‘control’ groups. In 38/49 (78%) studies children with epilepsy scored lower than control children. However, in 12/49 (24%)

studies,13,21,30,35,37,40,42,45,50,53,57,59 memory scores for children with epilepsy were no different than children without epilepsy. Table 2 illustrates the scores of children with epilepsy on standardised assessment instruments in comparison to normative scores on these instruments. With the exception of seven (21%) studies,53,56,64,76–79 children with epilepsy scored below normative scores on measures of memory. With the exception of Kernan et al.,26 comparison of children with epilepsy versus controls or normative controls have not controlled for IQ, making it difficult to ascertain whether memory difficulties are over and above global cognitive impairments. The results of Kernan et al.’s study indicate that children with epilepsy showed poorer performance on verbal memory tasks relative to controls after controlling for IQ.26 Studies which have focussed on comparisons between memory scores in children with epilepsy before and after surgery are displayed in Table 3. The impact of epilepsy surgery on memory

Table 3 Comparing memory in children with epilepsy pre and post-surgery. Year

Author

Sample size

Age range

Gender

Epilepsy type

Measures of memorya

Pre versus post surgery

2013

Oitment et al.16


Epilepsy

PMQ, WMS, DMNS, CMS WISC-III or WISC-IV, WPPSI

Post-surgery = Pre surgery

Viggedal et al.80

CWE: (M) 39, (F) 36 Cont: (M) 29, (F) 28 (M) 7, (F) 10

EWIS

2012

CWE: 119 Cont: 57 CWE: 17

2007

Jambaque et al.69

CWE: 20

7–14 years

(M) 13, (F) 7

TLE

SMB, ROCF, WISC-III

2006

Smith et al.71

CWE: 27 Cont: 15

6–17 years

CWE: (M) 13, (F) 14 Cont: (M) 6, (F) 9

Epilepsy

WMS-III, DMNS

2005

Lee et al.81

CWE: 132

5–16 years

(M) 69, (F) 63

Epilepsy

2005

Gleissner et al.

CWE: 30

7–17 years

(M) 11, (F) 19

TLE

CMS, WRAML, CVLT-C, ROCF VLMT, AVLT, DCS-R

2003

Mabbott and Smith76

CWE: 44

5–19 years

(M) 18, (F) 26

FE

CAVLT

2002 2002

Gleissner et al.51 Kuehn et al.83

CWE: 55 CWE: 26


(M) 22, (F) 33 (M) 16 (F) 10

TLE RE

2002

Lendt et al.52

CWE: 24

6–15 years

(M) 17, (F) 7

FLE, TLE

VLMT, AVLT WPPSI-R, WISC-III, WAIS-R, WAIS-III, WRAML WISC-R, AVLT, DCS-R

2002

Smith et al.84

CWE: 51

6–18 years

(M) 26, (F) 25

IE

CMS, DMNS, ROCF

1999

Lendt et al.57

(M) 21, (F) 29

TLE

VLMT, DCS-R

1998

Szabo et al.

CWE: 20 Cont: 30 CWE: 14

10–16 years

79

7–12 years

(M) 7, (F) 7

TLE

CAVLT-2

1994

Beardsworth and Zaidel60

CWE: 29

NR

(M) 11, (F) 18

TLE

BMCFT WISC-R

82

Post-surgery > Pre surgery in half of the subjects but < in half (verbal memory) Post-surgery < Pre surgery (figurative memory) Post-surgery > Pre surgery (working memory) Post-surgery > Pre surgery (verbal episodic memory, naming test performance, working memory) Post-surgery = Pre surgery (story recall and face recognition) Post-surgery > Pre surgery (verbal memory) Right resection: Post surgery > Pre surgery (visual memory) Left resection = Post surgery = Pre surgery (visual memory) Verbal memory and design recall, Post surgery = Pre surgery, Face recognition, Post surgery > Pre surgery Post-surgery = Pre surgery Post-surgery = Pre surgery

Post-surgery > Pre surgery (short-term memory, longterm memory) Surgical Group = Non-Surgical Group Post-surgery = Pre surgery Post-Surgery < Pre surgery in verbal memory Post-Surgery = Pre Surgery in other memory areas. RTLE: Post surgery > Pre surgery LTLE: Post surgery = Pre surgery

Memory Tests – AVLT: Auditory Verbal Learning Test, BMCFT: Beardsworth Memory for Children Faces Test, CAVLT: Children’s Auditory Verbal Learning Test, CMS: Children’s Memory Scale, CVLT-C: California Verbal Learning Test-Children’s version, DCS-R: Diagnosticum fur Cerebralschaden (German figural memory test), DMNS: Denman Neuropsychology Memory Scale, NBMT-CV: Nine Box Maze Test-Children’s Version, PMQ: Parent Memory Questionnaire, ROCF: Rey–Osterrieth Complex Figure, SMB: Signoret Memory Battery, TREFE: Test de Reconnaissance des Expression Faciales pour Enfants, VLMT: Verbal Learning and Memory Test, WISC-III: Wechsler Intelligence Scale for Children (3rd edition), WISC-IV: Wechsler Intelligence Scale for Children (4th edition), WMS: Wechsler Memory Scale, WPPSI-R: Wechsler Preschool and Primary Scale of Intelligence-Revised, WRAOML/WRAML: Wide Range Assessment of Memory and Learning. Epilepsy Syndromes – EWIS: Epilepsy With Intractable Seizures, FLE: Frontal Lobe Epilepsy, IE: Idiopathic Epilepsy, TLE: Temporal Lobe Epilepsy, FE: Focal Epilepsy. a Refer to Supplement 2 for memory tests and subscales.


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performance results are mixed. Seven studies out of 14 (50%) suggest that at least some aspects of memory are better postsurgery,52,60,69,76,80–82 whereas seven (50%) suggest memory performance remains the same after surgery.16,51,57,71,76,79,83 One study suggests that figurative memory was worse after surgery80 and another that verbal memory scores declined after surgery.79 When looking at different types of memory, one study found that surgery had no effect on verbal memory and design recall tasks but that face recognition improved in children with epilepsy after surgery.75 Table 4 shows significant predictors of memory scores in children with epilepsy. A total of eight predictor variables have been considered across the studies, although only five were assessed in more than five studies; AEDs (25 studies), age of onset (21 studies) seizure frequency (16 studies), duration of epilepsy (9 studies) and age (8 studies). In relation to AEDs, 19 of 25 (76%) studies show no impact of AEDs on memory performance. Of those that did show an effect, the impact on memory performance was negative.19,31,36,58,86 In relation to age of onset, eleven (52%) studies show no impact and seven studies (33%) suggest that risk of memory difficulties is greater for children with younger age of epilepsy onset.19,29,46,55,85,87,90 Increased seizure frequency was associated with worse performance in five of 16 (31%) studies,26,46,49,54,84 with the rest of the studies showing no significant effect of seizure frequency on memory performance. Longer

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duration of epilepsy was associated with an increased risk of memory impairment in two of eight (25%) studies where it was reported.19,73 Five of eight (63%) studies which looked at chronological age found younger age to be a significant predictor of memory impairment.38,61,82,88,89 Gender differences in memory task performance were found in two of five (40%) studies. Girls performed better than boys on delayed recall of stories and the learning phase of word list tasks, whereas boys performed significantly better on visual memory tasks than girls.61,68 One study assessed the effect of comorbidity on episodic and semantic memory. The types of comorbidities included in this study were academic difficulties, depression, aggressive behaviour, attention deficit/hyperactivity disorder, anxiety and Asperger’s disorder. It was found that the presence of comorbidity had no effect on memory performance.65 4. Discussion The purpose of this review was to examine studies which have focussed on the performance of children with epilepsy on measures of memory. The majority of studies reported lower memory scores in children with epilepsy compared to controls without epilepsy. Most studies also report that children with epilepsy score below normative scores on memory performance tasks. The difficulties in memory experienced by children with

Table 4 Predictor variables for memory in children with epilepsy. Year 2013 2013 2013 2012 2012 2012 2012 2012 2012 2011 2010 2010 2010 2010 2010 2010 2009 2009 2008 2008 2008 2007 2007 2007 2006 2006 2006 2006 2005 2005 2005 2005 2004 2003 2002 2002 2002 2001 2001 2001 1999 1999 1993

Author 15

Pinabiaux et al. Longo et al.62 Oitment et al.16 Braakman et al.63 Vintan et al.18 Sherman et al.19 Gonzalez et al.85 Polat et al.22 Kernan et al.26 Smith and Lah.65 Engle and Smith66 Dunn et al.29 Brandl et al.86 Piccinelli et al.67 Helmstaedter et al.31 Everts et al.32 Danielsson and Peterman33 Smith et al.68 Selassie et al.36 Van Mil et al.87 Vago et al.38 Siren et al.40 Jambaque et al.69 Bender et al.70 Borden et al.45 Northcott et al.88 Jocic-Jakubi and Jovic46 Scarpa et al.89 Oostrom et al.48 Gleissner82 Aldenkamp et al.49 Germano et al.90 Nolan et al.73 Hernandez et al.91 Smith et al.84 Gleissner et al.51 Lendt et al.52 Aldenkamp et al.54 Pavone et al.55 Williams et al.56 Camfield et al.92 Seidel and Mitchell.58 Jambaque et al.61

Gender

Age

Seizure frequency

AED usage

Age of onset

Duration of epilepsy

Comorbidities

NR NR NR NR NR NR NR NR NR NR NR X NR NR NR NR NR U NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR X NR X NR NR NR NR Nr NR U

x NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR X NR NR U NR NR X NR U NR U NR U NR NR NR NR NR NR NR NR NR NR NR NR U

NR NR X X NR X NR X U X NR NR NR NR NR NR NR NR X X NR NR NR X NR NR U NR X NR U X NR NR U NR NR U NR NR NR NR X

NR X X X NR U X X NR X X NR U NR U NR X NR U X NR U NR X NR X NR NR X NR NR X NR NR X X NR NR X X X U X

NR X X X U U U NR U NR X U NR NR NR X NR X U U NR NR X X X NR U NR NR NR NR U NR NR X NR NR NR U NR NR NR X

NR NR NR X NR U NR NR NR NR NR NR NR NR NR X NR X NR X NR NR NR NR NR NR NR NR NR NR NR NR U NR X X NR NR NR X NR NR NR

NR NR NR NR NR NR NR NR Nr U NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR

U: interaction found; X: no interaction found; NR: not reported as a predictor.


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epilepsy span a wide range of memory instruments and thus indicate impairment across a wide range of aspects of memory. The wide range of assessment instruments used and diversity in samples makes it difficult to comment authoritatively on whether or not particular aspects of memory are more likely to be affected or whether particular syndromes are more likely to be associated with particular impairments. Some studies have noted particular aspects of memory to be more at risk. It was found that children with epilepsy scored lower than normative scores on measures of spatial tasks with high memory load or long delays, but not on short delay memory tasks which were within the normal range.59 Lindgren et al.75 reported that the percentage of children with epilepsy scoring below average on various memory tasks were: immediate memory (31%), auditory-verbal memory and learning (65%), visuospatial memory and learning (4%) and delayed recall (15%). In terms of epilepsy type/ syndrome the wide range of epilepsy types/syndromes reported and difference in how epilepsy is categorised makes comparisons across studies difficult. One study that involved a comparison of epilepsy types did note a difference. Nolan et al.73 noted that scores for children with absence epilepsy on measures of verbal memory, did not significantly differ from the normative scores, however children with frontal and temporal lobe epilepsy scored lower than normative scores for these verbal memory tests. Kernan et al.26 reported that children with absence epilepsy and children with complex partial seizures did not differ on measures of memory. Studies of memory functioning did not find that performance declined after epilepsy surgery compared with performance before surgery, with the exception of two studies79,80 where some, but not all aspects of memory showed a decline. Viggedal et al.80 found that post surgery figurative memory scores were lower for children with epilepsy. However, working memory improved after surgery in 73% of participants and verbal memory improved in half of the subjects but declined in the other half.80 Szabo et al.79 found that verbal memory scores were worse after surgery for children with temporal lobe epilepsy who initially performed above the median preoperatively and tended to decrease in children who had left, rather than right, temporal lobe resection. No change after surgery was found in children with temporal lobe epilepsy who had temporal lobe resection (TLR) in two studies.51,57 Short term and long term memory were found to improve in children with temporal lobe epilepsy after surgery in one study.52 These results suggest that aspects of memory may be affected differently after surgery in children with temporal lobe epilepsy. Seven studies found an improved post surgery performance.52,60,69,76,80,81,83 However, some studies reported no difference before and after surgery. For example, face recognition and story recall did not change after surgery in one study.71 Oitment et al.16 reported no change in memory scores after surgery in children with epilepsy, even in the 56% of patients who became seizure free after surgery. Although a better cognitive outcome might be expected with seizure freedom, underlying neurological impairment may influence cognition, not the seizures themselves.93 One study noted group differences with respect to memory performance and laterality of epilepsy pre and post surgery. Children with left temporal lobe epilepsy did not change after surgery, whereas right temporal lobe epilepsy patients’ scores improved post surgery.60 The improvement in memory in some studies post-surgery could be due to the larger potential for cerebral plasticity in children.57,82 However, studies with longer follow up periods and comprehensive memory batteries are needed. Epilepsy surgery has known benefits for seizure frequency, but there is significant individual variation with respect to memory and other cognitive functions. Additionally other clinical factors should also be considered when predicting memory outcome after surgery, for example age,

gender, side of excision, site, time of surgery, duration of epilepsy and extent of brain affected. In line with this, younger age and early surgery have been found to predict good memory outcome in children with temporal lobe epilepsy,57,69,82 whereas longer duration of epilepsy and left-sided surgery were associated with memory impairment.82 However, one study found that none of these factors significantly predicted memory outcome after surgery.93 Therefore, further research on the role of clinical factors in predicting memory outcome after surgery is needed. With regard to predictors of memory performance in childhood epilepsy there is a lack of consensus from the data with respect to significant predictors. This is likely to be due to the wide variation of memory measures used, definitions of epilepsy and definitions of predictors. Factors such as earlier age of onset, increased seizure frequency, longer duration of epilepsy and greater number of AEDs used have been found to be related to memory impairments in some, but not all studies. These factors have previously been reported to be associated with global cognitive difficulties5,94 and therefore, it is not clear if their impact on memory is over and above that of their impact on global cognitive functioning. However, Kernan et al.26 noted that children with absence epilepsy and complex partial seizures both demonstrated mild verbal memory deficits that were not associated with deficits in generalised cognitive functioning. It is somewhat surprising that more studies have not focussed on possible contributions from comorbid behavioural and psychiatric conditions, such as ADHD given the close relationship between memory and attention and high risk for ADHD in childhood epilepsy.95 When interpreting the findings of this review, it is important to consider limitations of the research studies. Firstly, there is a lack of population-based data. The majority of participants are recruited from hospital-based samples which limits the generalisability of results to all children with epilepsy. Studies have used a wide range of instruments and epilepsy has been defined and categorised in varying ways. Predictor variables have differed across studies, making comparison between studies difficult. Reporting group means can be potentially misleading as on an individual level performance may vary significantly. Not all studies provided means and standard deviations, therefore it was not feasible to calculate effect sizes. Furthermore, the statistical methods used in studies differed and teasing out the independent contributors of factors was not always feasible.

5. Conclusion Children with epilepsy appear to be at significant risk for memory impairment. It is not clear if this impairment is over and above global cognitive impairment as most studies have not controlled for IQ or compared memory with different aspects of cognitive functioning. The noted memory impairments point to the need for comprehensive neuropsychological assessment to identify the extent and nature of the difficulties. Further research is needed to identify consistent predictor variables of memory impairment in children with epilepsy. Population-based studies using comprehensive memory batteries and clearly defined syndromes/types of epilepsy are also needed to garner estimates of the prevalence and nature of the problem as well as identifying contributory factors. There are no published studies on interventions to support the memory of children with epilepsy and thus there is a need to see what support and interventions may be useful in this population. There is also a need to explore the neurobiology of memory impairments in childhood epilepsy to better understand the role of contributor factors such as underlying brain dysfunction and seizures.


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Conflict of interest None declared. Acknowledgment We would like to thank Hannah Scrivener for help with the literature search. Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.seizure.2014.10.002. References 1. Chin RF, Cumberland PM, Pujar SS, Peckham C, Ross EM, Scott RC. Outcomes of childhood epilepsy at age 33 years: a population-based birth-cohort study. Epilepsia 2011;52:1513–21. 2. Chan S, Baldeweg T, Cross JH. A role for sleep disruption in cognitive impairment in children with epilepsy. Epilepsy Behav 2011;20(3):435–40. 3. Hermann B, Meador KJ, Gaillard WD, Cramer JA. Cognition across the lifespan: antiepileptic drugs, epilepsy, or both? Epilepsy Behav 2010;17(1):1–5. http:// dx.doi.org/10.1016/j.yebeh.2009.10.019. 4. Berg AT, Frobish SN, Levy D, Testa SR, Beckerman FMB, et al. Special education needs of children with newly diagnosed epilepsy. Dev Med Child Neurol 2005;47(11):749–53. 5. Berg AT, Langfitt JT, Testa FM, Levy SR, DiMario F, Westerveld M, et al. Global cognitive function in children with epilepsy: a community based study. Epilepsia 2008;49:608–14. 6. Murphy CC, Trevathan E, Yeargin-Allsopp M. Prevalence of epilepsy and epileptic seizures in 10-year-old children: results from the Metropolitan Atlanta Developmental Disabilities Study. Epilepsia 1995;36(9):866–72. 7. Smith EE, Jonides J, Koeppe RA. Dissociating verbal and spatial working memory using PET. Cereb Cortex 1996;6:11–20. 8. Kleen JK, Scott RC, Lenck-Santini PP, Holmes GL. Cognitive and behavioural comorbidities of epilepsy. In: Noebels JL, Avoli M, Rogawski MMA, Olsen RW, Delgado-Escueta AV, editors. Jasper’s basic mechanisms of the epilepsies. 4th ed. Bethedsa: Internet; 2012. 9. Ibrahim GM, Morgan BR, Lee W, Smith ML, Donner EJ, Wang F, et al. Impaired development of intrinsic connectivity networks in children with medically intractable localization-related epilepsy. Hum Brain Mapp 2014. http:// dx.doi.org/10.1002/hbm.22580 [Epub ahead of print]. 10. Hrabok M, Sherman EMS, Bello-Espinosa L, Hader W. Memory and healthrelated quality of life in severe pediatric epilepsy. Pediatrics 2013;131(2): 525–32. 11. Harrison S, Cross H, Harkness W, Vargha-Khadem F. Pre-operative educational status of children with focal epilepsy. Epilepsy Behav 2013;28:328. 12. Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med 2009;6(6):e1000097. http://dx.doi.org/10.1371/journal.pmed1000097. 13. Widjaja E, Skocic J, Go C, Snead OC, Mabbott D, Smith ML. Abnormal white matter correlates with neuropsychological impairment in children with localization-related epilepsy. Epilepsia 2013;54(6):1–16. 14. Verrotti A, Matricardi S, Di Giacomo DL, Rapino D, Chiarelli F, Coppola G. Neuropsychological impairment in children with rolandic epilepsy and in their siblings. Epilepsy Behav 2013;28:108–12. 15. Pinabiaux C, Bulteau C, Fohlen M, Dorfmuller G, Chiron C, Pannier LH, et al. Impaired emotional memory recognition after early temporal lobe epilepsy surgery: the fearful face exception? Cortex 2013;49:1386–93. 16. Oitment C, Vriezan E, Smith ML. Everyday memory in children after respective epilepsy surgery. Epilepsy Behav 2013;28:141–6. 17. Rzezak P, Guimaraes CA, Fuentes D, Guerreiro MM, Valente KD. Memory in children with temporal lobe epilepsy is at least partially explained by executive dysfunction. Epilepsy Behav 2012;25:577–84. 18. Vintan MA, Cristea PS, Benga I, Muresanu DF. A neuropsychological assessment, using computerized battery tests (CANTAB), in children with benign rolandic epilepsy before AED therapy. J Med Life 2012;5:114–9. 19. Sherman EMS, Brooks BL, Fay-McClymont TB, MacAllister WS. Detecting epilepsy-related cognitive problems in clinically referred children with epilepsy: is the WISC-IV a useful tool? Epilepsia 2012;53(6):1060–6. 20. Nicolai J, Ebus S, Biemans DP, Arends J, Hendriksen J, Vles JS, et al. The cognitive effects of interictal epileptiform EEG discharges and short nonconvulsive epileptic seizures. Epilepsia 2012;53(6):1051–9. 21. D’Agati E, Cerminara C, Caserelli L, Pitzianti M, Curatolo P. Attention and executive functions profile in childhood absence epilepsy. Brain Dev 2012;34:812–7. 22. Polat M, Gokben S, Tosun A, Serdaroglu G, Tekgul H. Neurocognitive evaluation in children with occipital lobe epilepsy. Seizure 2012;21:241–4.

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