Pretreatment cognitive deficits and treatment effects on attention in childhood absence epilepsy

Abstract

Objective: To determine the neurocognitive deficits associated with newly diagnosed untreated childhood absence epilepsy (CAE), develop a model describing the factorial structure of items measuring academic achievement and 3 neuropsychological constructs, and determine short-term differential neuropsychological effects on attention among ethosuximide, valproic acid, and lamotrigine.

Methods: Subjects with newly diagnosed CAE entering a double-blind, randomized controlled clinical trial had neuropsychological testing including assessments of general intellectual functioning, attention, memory, executive function, and achievement. Attention was reassessed at the week 16-20 visit.

Results: At study entry, 36% of the cohort exhibited attention deficits despite otherwise intact neurocognitive functioning. Structural equation modeling of baseline neuropsychological data revealed a direct sequential effect among attention, memory, executive function, and academic achievement. At the week 16-20 visit, attention deficits persisted even if seizure freedom was attained. More subjects receiving valproic acid (49%) had attention deficits than subjects receiving ethosuximide (32%) or lamotrigine (24%) (p = 0.0006). Parental assessment did not reliably detect attention deficits before or after treatment (p < 0.0001).

Conclusions: Children with CAE have a high rate of pretreatment attentional deficits that persist despite seizure freedom. Rates are disproportionately higher for valproic acid treatment compared with ethosuximide or lamotrigine. Parents do not recognize these attentional deficits. These deficits present a threat to academic achievement. Vigilant cognitive and behavioral assessment of these children is warranted.

Classification of evidence: This study provides Class I evidence that valproic acid is associated with more significant attentional dysfunction than ethosuximide or lamotrigine in children with newly diagnosed CAE.

Figure 1. Structural equation model for attention impact on achievement mediated by memory and executive function

Factor loading: all prespecified CPT variables (Confidence Index, omission T-score, and commission T-score) had loadings on the Attention factor, with standardized factor loadings of 0.84 (SE = 0.061), 0.91 (SE = 0.064), and 0.26 (SE = 0.063), all at the p < 0.05 level. Both verbal memory and visual memory from the WRAML-2 assessment had significant loadings with Memory (0.70, SE = 0.053, and 0.63, SE = 0.052, respectively). WCST Perseverative response (0.447, SE = 0.064) and TONI-3 quotient (0.758, SE = 0.066) loaded with Executive Function; and Reading (0.685, SE = 0.039), Spelling (0.738, SE = 0.034), and Arithmetic (0.949, SE = 0.030) loaded with Achievement. Model characteristics: χ² = 56.41, df = 30, p = 0.0025, Comparative Fit Index = 0.975; Tucker-Lewis coefficient = 0.963; RMSEA = 0.051 (90% confidence interval: 0.030, 0.072); p (RMSEA ≤0.05) = 0.43; standardized root mean square residual = 0.051. CPT = Continuous Performance Test; RMSEA = root mean square error of approximation; SE = standard error; WCST = Wisconsin Card Sorting Test; TONI-3 = Test of Nonverbal Intelligence, 3rd edition; WRAML-2 = Wide Range Assessment of Memory and Learning, 2nd edition; WRAT-3 = Wide Range Achievement Test 3.

Figure 2. CONSORT diagram for attention randomized clinical trial

CONSORT = Consolidated Standards of Reporting Trials; CPT = Continuous Performance Test.