Specific memoryimpairment in amultiple disabledmale with fragile Xsyndrome andtemporal lobeepilepsy

Heidi Wouters*;Annick Fonteyne, Laboratory for Neuropsychology;Lieven Lagae, Department of Paediatrics;Peter Stiers, Laboratory for Neuropsychology, KU Leuven,Medical School, Leuven, Belgium.

*Correspondence to first author at Laboratorium voorNeuropsychologie, KU Leuven, Medical School, CampusGasthuisberg, Herestraat 49 – O&N Bus 504, B-3000Leuven, Belgium.E-mail: Heidi.Wouters@med.kuleuven.be

Evaluation of the cognitive repercussions of an epilepticdisorder and its treatment are important issues in clinicalfollow-up. This especially holds true for temporal lobeepilepsy (TLE) where resective surgery can be a validtreatment option. However, in patients where TLE coexistswith another neurocognitive disorder, questions can ariseabout the precise nature of the neuropsychological deficits.The aim of the present study was to evaluate memoryimpairments, found in a male aged 12 years who had the dualpathology of fragile X syndrome and refractory TLE. Memoryfunctions of this child were compared with those of a maleaged 11 years 7 months with fragile X syndrome matched forintellectual functioning as indicated by highly comparableverbal (5y 5mo vs 5y 9mo) and non-verbal (7y 2mo vs 6y1mo) cognitive age equivalents. Performance on eachneuropsychological measure was evaluated twice, separatelywith normative data based on chronological age and on verbalor non-verbal cognitive level. A specific, distinguishableprofile of task performance could be found only whencontrolling for general level of cognitive functioning. Thismade it possible to accurately evaluate neuropsychologicalabilities before and 6 months after anterior temporal loberesection even in this male with a complex neurologicalpathology.

The detrimental effect of chronic epilepsy on cognitive func-tioning is well established1 and requires treatment as earlyas possible. For children with temporal lobe epilepsy(TLE), good seizure control can be achieved through resec-tive surgery.2 Group studies on the cognitive repercussionsof this invasive treatment show that general cognitive abilityas well as learning and memory, which strongly depend onmesial temporal structures, are relatively unaffected.3,4 Inclinical practice, however, pre- and postoperative neuropsy-chological assessment needs to be performed at an individ-ual level. Here the comorbidity of intellectual disability andother neurological disorders5 makes it difficult to isolate spe-cific memory deficits known to be associated with TLE.1,6

The aim of this case report is to show how under these cir-cumstances a diagnosis of specific neuropsychological deficitsis possible by using intelligence instead of chronological age asthe basis for evaluation. Intelligence is a crucial variable in cog-nitive group studies and its control at the individual level hasbeen shown to be effective in patients with specific patholo-gy.7,8 We present the case of a 12-year-old male (Child 1) inwhom fragile X syndrome (FXS) co-existed with TLE. FXS is themost commonly recognized inherited cause of learning disabil-ity*, with associated deficits in speech, executive function,visuo-constructive abilities, and working memory.9–11 Neuro-psychological assessment was performed on this patient 5months before and 1 year after resective surgery and also on a

378 Developmental Medicine & Child Neurology 2006, 48: 378–382

Case report

See end of paper for list of abbreviations. *North American usage: mental retardation.

Case Report 379

cognitive and chronologically age-matched male (11y 7mo)with FXS only (Child 2). Their performance was compared in

order to distinguish memory deficits typically associated withTLE and neuropsychological impairments typical of FXS.

Table I: Chronological age, Verbal, and Performance IQ at 5 years of age, and median verbal and non-verbal age equivalent attime of current study obtained on Wechsler Preschool and Primary Scale of Intelligence – Revised13,14

CA (y:m) VIQ PIQ VA (y:m) PA (y:m)

Child1 (preoperative) 12:0 77 61 5:5 7:2Child 1(postoperative) 13:5 – – 7:0 8:0 Child 2 11:7 84 74 5:9 6:1

CA, chronological age; VIQ, Verbal IQ; PIQ, Performance IQ; VA, median verbal age equivalent; PA, median non-verbal age equivalent.

Figure 1: Z-score profiles for

child 1 (fragile X syndrome

[FXS] and temporal lobe

epilepsy [TLE]) and child 2

(FXS) based on (a) verbal

or (b) non-verbal cognitive

level or chronological age.

Z-score at or below –1.28

indicates impaired

performance. N, Numbers

Children’s Memory Scale

(CMS)17,18; P, Picture

Locations CMS; W, Words,

Auditory Verbal Learning

Test15,16; L, learning; S,

Stories CMS; DR, delayed

recall; D, Dot Locations

CMS; F, Memory for Faces

Nepsy19; B, Boston Naming

Test20.

FXS and TLE FXS

NP

Workingmemory

WS

WS

DF

DF

Verbalmemory

Non-verbalmemory

L

DR

L

DR

B

–4.5 –3.5 –2.5 –0.5 0.5 1.5 2.5 3.5–1.28

NP

Workingmemory

WS

W

S

DF

DF

Verbalmemory

Non-verbalmemory

L

DR

L

DR

B

–4.5 –3.5 –2.5 –0.5 0.5 1.5 2.5 3.5–1.28

Z-scores

Z-scores

a

b

Case reportChild 1 was born at term after an uncomplicated pregnancy.At the age of 4 years he started to experience complex partialseizures. A diagnosis of TLE was made and antiepileptic drugtreatment (carbamazepine and lamotrigine) started. By theage of 5 years behavioural abnormalities became evident.Subsequent genetic investigation showed a full expansion ofthe FMR-1 gene. A diagnosis of FXS was made.

Epilepsy is reported in about 20% of patients with FXS.12 Inthe case of Child 1, however, a clear underlying cause becameevident at the age of 12 years, when he was referred for epilep-sy surgery. Electroencephalographic monitoring showed ictalepileptic activity originating from the right temporal lobe,while single-photon emission computed tomography scan-ning showed ictal hyperperfusion of this region. Magneticresonance imaging (MRI) revealed right mesial temporalsclerosis, later confirmed by histopathological examination.At the age of 12 years 5 months an en bloc right anterior tem-poral lobectomy was performed, and 6 months later lamotrig-ine was discontinued. The patient has remained seizure-freeup to this day.

Child 2 was also born at term after an uncomplicatedpregnancy. At 4 years of age developmental delay and behav-ioural problems were noticed and a diagnosis of FXS wasmade. Genetic investigation showed a full expansion of theFMR-1 gene.

MethodsIn children with complex neurological disorders reducedscores on neuropsychological tasks may reflect any of the mul-tiple disabilities that they have. To overcome this diagnosticproblem we define a neuropsychological ability as specificallyimpaired if an increase in the load of the tasks on this abilityresults in a decline of task performance. Neuropsychologicalassessment, thus, not only requires specific ability relatedtasks, but also appropriate baseline tasks for comparison. In

the present study, performance on Wechsler Preschool andPrimary Scale of Intelligence – Revised (WPPSI-R)13,14 subtests,which cover a wide range of abilities without maximizing theload on any one of them, was used as a baseline level of cogni-tive ability. Raw subtest scores were individually transformedto age equivalents and the median age equivalent for each sub-scale was used as an indication of verbal and non-verbal cogni-tive level.

Learning and delayed recall for verbal and non-verbalmaterial were assessed with the Auditory Verbal Learning Test(AVLT)15,16, Stories and Dot Locations Children’s MemoryScale (CMS)17,18, and Memory for Faces Nepsy.19 In addition,CMS Numbers and CMS Picture Locations were used to evalu-ate working memory and the Boston Naming Test20 to evalu-ate name retrieval abilities.

Each raw test score was converted to a centile score twice:once using chronological age-based norms and once usingnorms based on cognitive age equivalent. The verbal ageequivalent was used for evaluation of verbal tests and thenon-verbal age equivalent for non-verbal tests. For conve-nience, centiles were converted to corresponding z-scores(mean 0 [SD 1]) and a score at or below –1.28 (10th centile)was considered impaired.

Parental informed consent was obtained for both children.During preoperative testing, Child 1 took carbamazepineand lamotrigine; postoperative he took carbamazepine only.

ResultsAs shown in Table I, the children were well matched forchronological age, verbal (VA), and non-verbal (PA) age equiva-lent at the time of first assessment and for IQ at 5 years of age.

The effect of using cognitive age equivalent or chronolog-ical age as the reference for task evaluation is presented inFigure 1. Z-score profiles of Child 1 (preoperative) and Child 2based on their VA and PA are compared in Figure 1a. Whileboth children obtained good scores on the word list task and

380 Developmental Medicine & Child Neurology 2006, 48: 378–382

Figure 2: Z-score profile for

child 1 before (pre) and

after (post) surgical

treatment, based on verbal

or non-verbal cognitive

level. Z-score at or below

–1.28 indicates impaired

performance. N, Numbers

Children’s Memory Scale

(CMS)17,18; P, Picture

Locations CMS; W, Words,

Auditory Verbal Learning

Test15,16; L, learning; S,

Stories CMS; DR, delayed

recall; D, Dot Locations

CMS; F, Memory for Faces

Nepsy19; B, Boston Naming

Test20.

Pre Post

N

PWorkingmemory

W

SWS

DF

DF

Verbalmemory

Non-verbalmemory

L

DR

L

DR

–4.5 –3.5 –2.5 –0.5 0.5 1.5 2.5 3.5–1.28

Z-scores

B

on the Boston Naming Test (z≥0.001), only Child 1 was specif-ically impaired on CMS Stories and on the four non-verbalmemory measures.

Both children had impairment of working memory, butwith a different material-specific profile. Child 1 was impairedon the non-verbal, but not on the verbal task, while the scoreof Child 2 showed the opposite pattern.

These distinctive profiles of z-scores disappeared whentask performance was evaluated based on chronological age(Fig. 1b). Both children showed severe impairments on fourmemory measures and on the working memory and nameretrieval tasks (z<–1.90). Child 1 was additionally impairedon the Memory for Faces test.

The pre- and postoperative task performance of Child 1are compared in Figure 2, using cognitive age equivalentsas baseline. This patient’s postoperative scores showed amore clear-cut delayed recall deficit. While before surgeryonly word list learning was adequate, after surgery his learn-ing scores on all four memory tasks were above the 10thcentile criterion. In contrast, all four delayed recall mea-sures were now impaired (z≤–1.33).

In addition, his working memory deficit intensified postop-eratively. His score on the non-verbal task remained very weak(z=–3.00), but now an impairment on the verbal task was alsoevident (z=–1.67).

Postoperatively this child still obtained a high score onthe Boston Naming Test.

DiscussionBoth children showed a pervasive memory and naming deficitcompared with chronological age-based normative data, mak-ing it impossible to distinguish the characteristic impair-ments associated with the genetic syndrome and epilepticdisorder. In contrast, when task evaluation was based on cog-nitive level a specific deficit in working memory became evi-dent in both children. Child 2 showed the verbal workingmemory deficit characteristic of males with FXS.9,10 In Child 1this deficit became evident after surgery, while before surgeryhe only had the non-verbal working memory deficit less con-sistently found in FXS.9–11

Specific impairment on all non-verbal memory measuresand on learning and delayed recall of complex verbal materi-al (CMS Stories) was only evident for Child 1. These impair-ments are common in TLE.1,3,6 Moreover, learning andlong-term memory are known to be relative strengths inmales with FXS.9,10 In line with this, no such impairmentswere found in Child 2.

One year after surgery all initially impaired learning scoreshad improved to a level appropriate for the level of cognitivefunctioning of Child 1. This may be due to the disappearanceof epileptic seizures and/or epileptic discharges that have adetrimental effect on transient cognitive processes, such asalertness,21 which may influence learning abilities.

Specific impairment was now evident on all measures ofdelayed recall. While recall deficits are characteristic of thismesiotemporal lobe pathology,1,6 the lack of material speci-ficity suggests a disturbed material-specific lateralization ofmesiotemporal functions. At least a part of the resected tis-sue may have had a functional role in verbal learning andmemory. Alternatively, as deviations of hippocampal vol-umes in patients with FXS have been shown,22 additionaldamage in the left hippocampus of Child 1, which could not

be visualized on MRI, could be hypothesized. Moreover, dete-rioration of verbal memory after temporal lobe surgery is fre-quently reported,6,23 regardless of the side of resection,although the reason for this is not yet fully understood.

Finally, deterioration of verbal working memory was due toan unchanged raw score on CMS Numbers which was evaluat-ed using an older norm group postoperatively (i.e. becausethe child’s verbal cognitive age equivalent was 1y 7mo higherpostoperatively).

ConclusionIn clinical practice, evaluation of strengths and weaknesses inneuropsychological functioning of patients, and their relationto neurological and imaging findings, have to be made on a reg-ular basis. The results are needed to understand the cognitiverepercussions of the disorders and constitute the basis forrehabilitation interventions. Disturbed intellectual develop-ment and the presence of multiple disorders often complicatethis evaluation process. While group studies overcome thisproblem by using matched control groups, this issue is oftenneglected in individual assessments. The present study showsthat accurate neuropsychological assessment can be per-formed under these suboptimal circumstances provided thatan appropriate baseline is chosen for task evaluation.

DOI:10.1017/S0012162206000818

Accepted for publication 18th August 2005.

Acknowledgements

We wish to thank Dr M Borghgraef and Prof Dr JP Fryns of the Centreof Human Medical Genetics, KU Leuven for making available theirclinical records. This research was supported by grant number7.0008.03 of the Fund for Scientific Research – Flanders (FWO).Lieven Lagae is holder of the UCB Chair for Cognitive Disorders inChildhood at the University of Leuven, Leuven, Belgium.

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List of abbreviations

CMS Children’s Memory Scale FXS Fragile X syndrome TLE Temporal lobe epilepsy

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