Neurology -- Correspondence for Pavone et al., 56 (8) 1047-1051

Correspondence published:

Reply to letter from Ronen et al.: P Pavone, "R Bianchini, RR Trifiletti" (1 August 2001)

Neuropsychological assessment in children with absence epilepsy: G Ronen, "B Meaney, C Cunningham" (1 August 2001)

Reply to letter from Ronen et al. 1 August 2001

P Pavone
University of Catania Catania Italy,
"R Bianchini, RR Trifiletti"
Send Correspondence to journal:
Re: Reply to letter from Ronen et al.

ppavone{at}mbox.unict.it P Pavone, et al.

We agree with Ronen et al [1] that determination of cognitive deficits and long term cognitive outcome in epileptics is important. Although cognitive deficits have been described in studies with patients with epilepsy, their mechanism is unknown. Potential causes include co- morbidity related to genetic factors (i.e. intrinsic features of the epilepsy syndrome), and the effect of continued seizures and medication. Furthermore, if a mechanism is determined, it is likely to differ among epilepsy syndromes.
Our study described cognitive deficits in a population of children with a well-defined electroclinical syndrome, absence epilepsy. We did not explore the mechanisms for such deficits. There was sufficient clinical follow-up and video EEG data to determine that uncontrolled seizures were not an issue in our study patients, so we believe that uncontrolled seizures do not explain the cognitive deficits.
All our patients were taking valproate or ethosuximide, alone or in combination, at the time of the neuropsychological testing, so that it is clearly impossible to dismiss drug effects as an explanation for the cognitive deficits. Our finding of a tendency toward more severe cognitive deficits in children, who began to have seizures at an earlier age, could conceivably be explained by a more prolonged exposure to antiepileptic medication, or exposure during a critical early developmental window.
Our statement that ��it is unlikely that anticonvulsant drug effects account for the relatively specific cognitive deficits seen �� was based on the information in the literature regarding valproate and ethosuximide available to us. This statement was a working hypothesis rather than a definitive conclusion.
The more recent study of Ronen et al [1] involves a randomized double -blind crossover trial with valproate and placebo in patients with behavioral disorders and EEG abnormalities. Their patients are not epileptics. A similar type of study could not be performed in our patients as crossover to placebo would be expected to result in an increase in seizures, confounding the interpretation of results. As Ronen et al [1] have commented, and as noted in the final sentence of our paper, longitudinal follow-up of our study patients into adult life, when seizure remission off anticonvulsant drugs could be expected in the majority, might be useful. However, it is not clear to us that the findings of persistence or lack of persistence of cognitive deficits unequivocally bear on whether such cognitive deficits might be explained by drug effect. The effect of drugs on cognitive performance might outlast the exposure period.
Among our study patients, 11 of 14 were taking valproate only. Although valproate was initially introduced as an anticonvulsant, this drug has other �off-label� uses. Valproate has been used to treat patients with mood lability , to treat chorea and migraine prophylaxis . It should be possible to compare the neuropsychological profiles of patients with other conditions to those in our study. If a very similar cognitive profile is found to our study patients, then it is very likely a reflection of valproate effect rather than a reflection of �syndrome specific� deficits.
Reference:
1. Ronen, GM, Richards, JE, Cunningham C et al. Can sodium valproate improve learning in children with epileptiform bursts but without clinical seizures? Dev Med Child Neurol 2000; 42: 751-755.

Neuropsychological assessment in children with absence epilepsy 1 August 2001

G Ronen
Hamilton Health Sciences Corporation Hamilton, Ontario, Canada,
"B Meaney, C Cunningham"
Send Correspondence to journal:
Re: Neuropsychological assessment in children with absence epilepsy

roneng{at}mcmaster.ca G Ronen, et al.

Assessing cognitive deficits and long term outcome in different populations with epilepsy is immensely important. Pavone et al[1] had intended to measure such deficits in children with absence epilepsy. Their subjects showed deficits in cognition and memory compared to controls. However 14 of the 16 subjects were on valproic acid (VPA). A careful analysis indicates that the potential confounding role of VPA in this setting cannot be easily dismissed as was suggested by the authors.
Sommerback et al[2] reported an increase in errors in performing tasks, increased time in performing tasks, and lower productivity scores in epilepsy patients on VPA. Similar results were later reported. Stores et al[3] found attention problems in children with epilepsy receiving VPA. However, not all studies on this topic have been conclusive. Legarda et al[4]argued not all of the studies employed neuropsychological measures that were likely to assess subtle changes in cognition and proposed a test battery to assess cognitive changes associated with anticonvulsant therapy in childhood. Finally, while this paper was in press, a randomized, double -blind, single-crossover trial with VPA and placebo on children with learning or behavior problems associated with electrographic epileptiform discharges but without clinical seizures was reported.[5] Neuropsychological testing showed that while on VPA the children were more distractable, had increased delay in response time, and displayed lower memory scores. In addition their parents reported higher internalizing scores on the Child Behavioral Checklist while on VPA.
We believe that the potential association between VPA and cognition was not adequately addressed by the authors. In fact, this study design cannot differentiate between syndrome specific and VPA associated cognitive impairment. It would have been methodologically preferable to have conducted this study on subjects who had outgrown their absence seizures and were off all antiepileptic medications.
References
1. Pavone P, Bianchini R, Trifiletti RR, et al. Neuropsychological assessment in children with absence epilepsy. Neurology 2001;56: 1047- 1051.
2. Sommerbeck KW, Theilgaard A, Rasmussen KE, et al. Valproate Sodium: evaluation of so-called psychotropic effect. A controlled study. Epilepsia 1977; 18:159-167.
3. Stores G, Williams PL, Styles E, Zaiwalla Z. Psychological effect of sodium valproate and carbamazepine in epilepsy. Arch Dis Child 1992;67: 1330-1337.
4. Legarda SB, Booth MP, Fennel EB, Maria BL. Altered cognitive functioning in children with idiopathic epilepsy receiving valproate monotherapy. J Child Neurol 1996;11: 321-330.
5. Ronen GM, Richards JE, Cunningham C, et al. Can sodium valproate improve learning in children epileptiform bursts but without clinical seizures? Dev Med Child Neurol 2000;42: 751-755.