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Keywords:

  • Epilepsy;
  • Drug treatment;
  • Children;
  • Levetiracetam;
  • Continuous spikes and waves;
  • Sleep;
  • Electrical status epilepticus;
  • Cognitive impairment

Abstract

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgments
  7. REFERENCES

Summary: Purpose: To assess the add-on efficacy of levetiracetam on the EEG, behavior, and cognition of children with continuous spikes and waves during slow sleep (CSWS).

Methods: Charts of children with behavioral and/or cognitive deterioration associated with CSWS who received levetiracetam at 50 mg/kg/day as add-on treatment were retrospectively reviewed. Awake and sleep EEG recordings and detailed neuropsychological and behavioral assessments were available at baseline and 2 months after levetiracetam initiation. In children showing clinical and/or electrophysiological improvement after 2 months, levetiracetam was continued with a new evaluation at 1 year.

Results: Twelve patients were included (9 cryptogenic and 3 symptomatic cases). Seven patients (58.3%) showed improvement of EEG record. Among these seven patients, neuropsychological evaluation was improved in three, and in the other four patients, not testable because of severe cognitive impairment, behavior was improved. Two patients improved in neuropsychological evaluation despite the lack of EEG improvement. Eight patients (66.6%) continued levetiracetam treatment after 2 months. After 1 year, four patients were still on levetiracetam, two because sustained effect on EEG and behavior and the two others because improvement in neuropsychological testing despite unchanged EEG. Levetiracetam was discontinued in the other four patients because of neuropsychological or behavioral deterioration associated with CSWS pattern, between 9 and 11 months after treatment initiation.

Conclusions: This retrospective study suggests that levetiracetam has a positive effect on the EEG, the behavior, and the cognition of patients with epilepsy and CSWS. Additional studies are warranted in order to assess the place of this drug in these epileptic conditions.

Epileptic syndromes with continuous spikes and waves during slow sleep (CSWS) represent a wide spectrum of epileptic conditions associated with cognitive dysfunction that have the EEG pattern of CSWS as common feature. This spectrum encompasses the Landau–Kleffner syndrome (LKS) and epileptic syndromes with some kind of neuropsychological deterioration together with strong activation of spike and wave discharges during nonrapid eye movement (NREM) sleep stage (1–8). There is strong evidence, in these epileptic conditions, that cognitive functioning may dramatically improve if epileptic activity is reduced with antiepileptic drugs (AED) (1, 9–12).

Levetiracetam appears to be a good candidate for pharmacological studies in epilepsies with CSWS. Studies published on the use of levetiracetam in epileptic children have shown an excellent pharmacokinetics and tolerability profile, with little deleterious effects on cognitive function and no known pharmacokinetic interactions. Levetiracetam has proved his efficacy in partial seizures. Moreover, case series suggest efficacy in some types of generalized seizures (13–18). A decrease of interictal epileptiform discharges induced by levetiracetam has been shown in the “genetic absence epilepsy rat of Strasbourg” model (19) and on neocortical slices obtained from patients treated by surgery for refractory epilepsy (20). A positive effect of levetiracetam on interictal epileptiform activity recorded by EEG has been reported in adult epileptic patients (21–23) and in children with ADHD together with improvement of attention (24). Recently, reports have suggested that levetiracetam may be useful in CSWS (25,26).

The aim of this study was to assess retrospectively the add-on efficacy of levetiracetam on the EEG, the behavior, and the cognition of a cohort of children with CSWS.

PATIENTS AND METHODS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgments
  7. REFERENCES

In our hospital, patients who are suspected to show the CSWS pattern undergo a systematic comprehensive assessment including (1) anamnesis and neurological examination; (2) neuropsychological evaluation adapted to the patients' age and compliance; (3) behavioral evaluation according to parents' and, if possible, teachers' observations as well as observations during neuropsychological testing; (4) EEG study when awake and during a complete night of sleep; and (5) cerebral magnetic resonance imaging. When a trial with an AED is being performed, efforts are made to obtain a clinical, neuropsychological, and neurophysiological evaluation after 2 months of treatment and, if the drug is continued, to obtain long-term data until at least 1 year of treatment.

According to the “Venice colloquium” guidelines, valproate is our first choice of treatment and clobazam is our second choice; the use of steroids is then considered (27). In view of the positive effects obtained in the first patients with CSWS that we treated with levetiracetam, this attitude changed so that the last patients were treated with levetiracetam before considering steroids or even before valproate or clobazam.

For the purpose of this study, we retrospectively reviewed the charts of children treated with levetiracetam who fullfilled the following two features: (i) behavioral and/or cognitive deterioration and (ii) CSWS pattern on sleep EEG, i.e., strong activation of epileptic discharges during sleep, occupying at least 85% of NREM sleep EEG (1,27). All the children included in this study received the same regimen of levetiracetam titration: 25 mg/kg/day during the first 2 weeks and then 50 mg/kg/day. Usual AED remained unchanged.

Evaluation focused first on efficacy of levetiracetam on the EEG. For this purpose, EEGs were analyzed using two different grading systems. The first grading system was called the EEG score. It was performed on awake and sleep EEG and focused on the background, the presence of slow dysrythmia, the number of epileptic foci, the presence of generalized spike wave discharges, and the presence of negative or positive myoclonia. This score was adapted from papers aimed to characterize the EEG findings in children with typical and atypical forms of rolandic epilepsy, including the modification after adjunction of an AED (28,29). Five grades were defined: grade 0 (normal EEG), grade 1 (normal background, unique focus of spikes of low amplitude), grade 2 (normal background, multiple asynchronous foci of spikes of low amplitude), grade 3 (destructured background, intermittent slow wave focus, high-amplitude spikes and waves diffusing to one hemisphere or multiple asynchronous foci of spikes of high amplitude), and grade 4 (destructured background, intermittent slow wave focus, high-amplitude spikes, and waves with diffusion to both hemispheres, eventually generalized bursts of spike and wave discharges or focal epileptic myoclonia). The second grading system was a spike and wave index (SWI) (30), determined in looking for epileptiform discharges during the first 30 minutes of NREM stages of the first and last sleep cycles. SWI was thus calculated by dividing the number of seconds presenting one or more spike and wave complexes in the two 30-minute periods divided by 3,600, multiplied by 100 to express the results in percentage. Improvement in EEG was defined as significant (+) if there was a falloff of one grade in the EEG score, impressive (++) if there was a falloff of two grades in the EEG score and very impressive (+++) if there was a two-grade decrease in the EEG score combined with a decline of more than 50% in the SWI.

The evaluation of levetiracetam treatment was secondly assessed by the effects of the drug on behavior and cognition. The tests used for the neuropsychological evaluations were the following: IQ score (WISC-III, McCarthy, Leiter), visual short-term memory (McCarthy block tapping, Corsi block tapping, NEPSY face recognition), auditory–verbal short-term memory (McCarthy, WISC-III digit span), visual long-term memory (NEPSY face recognition, Rey's Complex Figure delayed recall), auditory–verbal long-term memory (Rey's list learning and recall), visual and auditory sustained and selective attention (NEPSY, D2 scanning letters and marking targets, WISC-III code and symbol subtests, NEPSY vigilance and shifting ability to auditory targets), and visuospatial graphic organization (McCarthy, NEPSY, Rey's Complex Figure copying geometrical figures).

RESULTS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgments
  7. REFERENCES

Patients characteristics

Twelve patients (seven females and five males) aged 4–14 years were included in this study. Patients' characteristics are listed in Table 1.

Table 1. Clinical characteristics of the patients
Patient No./ age (yr)/sexEtiologyNeuropsychological profileCSWS since age (yr)IQEEG localization of interictal foci type of seizures recordedTreatment tried before LEVCurrent treatment
  1. M, male; F, female; MR, mental retardation; ADHD, attention deficit hyperactivity disorder; VPA, valproic acid; CLB, clobazam; HCT, hydrocortisone; LTG, lamotrigine; TPM, topiramate; ETS, ethosuximide; CBZ, carbamazepine.

1/9/FCryptogenicModerate MR750Right parietal Atypical absencesTPM-ETS-HCTVPA-CLB
2/14/MInv dup chromosome 15Severe MR633Left hemispheric No seizuresHCT-CLB ETSVPA-ETS
3/10/FCryptogenicSevere MR330Multifocal No seizuresHCT-CLBVPA-ETS
4/4/FCryptogenicModerate MR60Right hemispheric Focal epileptic myocloniaTPM-ETSVPA-CLB-HCT
5/11/MCryptogenicFrontal syndrome10109Right central Atypical absences Focal epileptic myocloniaVPA-LTG
6/4/MPolymicrogyriaBilateral perisylvian syndrome 70Right and left central Atypical absences
7/5/MCryptogenicFrontal syndrome5 50Right central No seizuresVPA
8/7/FPorencephalic cystOpercular syndrome and hemiplegia6 85Left hemispheric No seizuresCLB-HCTVPA
9/6/FCryptogenicFrontal syndrome5100Right hemispheric No seizuresLTGVPA
10/9/MCryptogenicLeft heminegligence with apraxia5 88Right parietal No seizuresCLB-CBZ-ETS- HCT-LTG-TPXVPA
11/10/FCryptogenicSevere MR8 30Generalized Atypical absencesCLB-HCT-ETSVPA-LTG
12/10/FCryptogenicModerate MR8 50Right hemispheric No seizuresVPA-LTG

The clinical phenotype of each patient was defined on clinical and neuropsychological examination. Three patients had a frontal syndrome, characterized by inattention, impulsiveness, mood swings, and perseveration. Six patients had moderate-to-severe mental retardation. Two patients had cerebral palsy (hemiplegic type, associated with pseudobulbar palsy in one case) and presented with regression in communication and social interactions. One patient had left heminegligence with apraxia. There was no patient with the LKS.

The etiology could be determined in three patients (both patients with cerebral palsy had antenatal vascular lesions on MRI, and one patient with severe mental retardation had a chromosomal aberration). The other cases were considered as cryptogenic.

Results of the awake and sleep EEG studies are listed in Table 2, including the EEG score and the SWI. The SWI score was equal or greater than 85% in all patients.

Table 2. EEG and neuropsychological data before and after 2 months of levetiracetam treatment
 EEG evaluationNeuropsychological evaluation after 2 months LEV
Before LEVAfter 2 months LEVGlobal evaluation
SWIEEG gradeSWIEEG gradeBehavior during testsCognitive functionBehavior reported by the parents/schoolGlobal evaluation
  1. SWI, spike and wave index during NREM sleep; LEV, levetiracetam; ND, not done; +, improved; −, worsened; =, equal; A, awake; S, sleep.

193A: 496A: 4=++=+
S: 4 S: 4 
285A: 311A: 1+++NDND++
S: 3 S: 1 
393A: 438A: 1+++NDND++
S: 4 S: 1 
495A: 492A: 1++NDND++
S: 4 S: 2 
585A: 495A: 1++++++
S: 4 S: 2 
685A: 40.5A: 1+++++++
S: 4 S: 1 
796A: 385A: 1+++++
S: 3 S: 2 
885A: 485A: 4===
S: 4 S: 4 
985A: 485A: 4=+==
S: 4 S: 4 
1085A: 285A: 2=++=+
S: 2 S: 2 
1185A: 495A: 4=NDND==
S: 4 S: 4 
1285A: 395A: 0+NDND++
S: 4 S: 3 

Seven patients had received at least three different AEDs, including a hydrocortisone cure (5 mg/kg/day during 1 month, and then slow tapering to 2 mg/kg/day during a few months) before the levetiracetam trial. These patients were considered as refractory. The other five patients were considered as nonrefractory.

Effect of levetiracetam add-on on EEG recordings, behavior, and neuropsychological evaluations

After 2 months

Levetiracetam was extremely well tolerated. Only two patients underwent transient dizziness in the first month of treatment.

A complete EEG study when awake and during a night sleep was available in all 12 patients.

Efforts were made to achieve a complete neuropsychological assessment in all patients. However, this was not always possible due to a lack of compliance of four children (patients 2, 3, 4, and 11) in whom cognitive deterioration was too severe. The neuropsychological evaluation of patient 12 was not complete enough to be analyzed. Thus, neuropsychological data before the introduction of levetiracetam and 2 months after levetiracetam introduction were available in seven patients. Visual attention could be assessed in those seven patients, graphic organization in six patients, short-term auditive memory in seven patients, long-term auditive memory in six patients, long-term visual memory in five patients, short-term visual memory in seven patients, and auditive attention in three patients.

Results are listed in Table 2. Concerning the EEG data, two patients showed a significant (+) improvement, two an impressive (++) improvement, and three a very impressive (+++) improvement, while the sleep EEG almost normalized in one case (patient 6). In summary, the EEG had improved after a 2-month levetiracetam add-on treatment in 7 of 12 (58.3%) patients.

Among these seven patients, four could not be tested because their cognitive impairment was too severe before treatment, but their behavior rated by their parents and the school teacher did improve. After 2 months of levetiracetam treatment, patient 2 was more alert, less anxious, had a better attention at school, and was sleeping better. Patient 3 was also more alert, was no more crying without any reason (it occurred more than a hundred time a day before levetiracetam), and recovered communication at school and with family members. Patient 4 was more alert, recovered communication using a few words with his parents, and had also a better tonus: she recovered the ability to sit alone and to walk a few steps. Patient 12 was less anxious and improved in learning tasks especially in reading. Among the other three children, all showed improvement in visual attention, two in short-term visual memory, two in graphic organization, one in long-term visual memory, two in long-term auditive memory and one in short-term auditive memory; auditive attention did not improve in any patient.

Among the five patients whose EEG study did not improve, two patients (patients 1 and 10) showed an improvement in their neuropsychological evaluation for the following domains: visual attention (both patients), short-term visual memory (both patients), and long-term auditive memory (patient 1). The improvement was not considered as significant by the parents and the teachers in patient 1, so that levetiracetam was discontinued. Levetiracetam was continued in patient 10. The remaining three patients were considered as either clinically unchanged (patients 9 and 11) or worsened (patient 8 who showed aggravation of his behavior) and levetiracetam was discontinued.

When the data were analyzed according to the fact that the patients were refractory or not to AEDs, positive effect of levetiracetam on EEG score and neuropsychological testing or behavior was found in three of the seven refractory patients (43%) and in four out of the five nonrefractory patients (80%).

After 1 year

In 8 of the 12 patients (66.6%), levetiracetam was continued after the 2-month evaluation. One of them did not show any EEG changes after 2 months but had an improvement in his neuropsychological evaluation and a reduction of seizure frequency. This patient is still on levetiracetam after 1 year (patient 10).

The other seven patients continued levetiracetam after 2 months because of clinical response together with EEG improvement. Among them, four patients (patients 4, 5, 6, and 7) relapsed clinically as well as electroencephalographically with the reappearance of the previous EEG and neuropsychological patterns between 9 and 11 months after levetiracetam introduction. Two patients (patients 2 and 3) sustained EEG and neuropsychological improvement after 1 year. The remaining patient (patient 12) is still on levetiracetam after 1 year but received a hydrocortisone cure 6 months after levetiracetam initiation because the positive effect of levetiracetam was considered as insufficient.

DISCUSSION

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgments
  7. REFERENCES

This is the first retrospective study evaluating levetiracetam efficacy on a series of patients with CSWS. After 2 months of add-on therapy, EEG study was improved in seven patients (58.3%) and neuropsychological evaluation and/or behavior was improved in nine patients (75%). Eight patients (66.6%) continued levetiracetam after two months. After 1 year, four of them were still on levetiracetam. In the other four patients, levetiracetam had been discontinued because of CSWS relapse.

This series expands the number of reported epileptic children with an EEG pattern of CSWS treated by levetiracetam. The effect of levetiracetam in this condition has already been observed in one case report of LKS (31) and in a study of three cases of epilepsy with CSWS (25), with positive effect on the EEG, and on neuropsychological evaluation in two patients.

Open studies evaluating AED in CSWS are rare, include few patients, and uncommonly use psychometric scales to monitor the outcome. It has been suggested at the “Venice colloquium” that valproate alone or in combination with benzodiazepines is the treatment of choice of epilepsies with CSWS (27). This suggestion is essentially based on case reports. Valproate was shown to decrease interictal epileptiform discharges in two of three patients with LKS studied by Marescaux et al. (9). In the same study, ethosuximide and clobazam were also shown as helpful in reducing CSWS (9). These results were later confirmed by several case reports (27). De Negri et al. reported a remission of CSWS in 9/15 (60%) with a 1-month intrarectal diazepam treatment (32); among these nine patients, seven showed an improvement in their neuropsychological evaluation after 6 months. When our series is compared with case control studies evaluating valproate, ethosuximide, and benzodiazepines, levetiracetam reach the same efficacy than these drugs. Clearly, further studies are needed to establish its efficacy relative to other treatments but also to a placebo, the effect of which is being estimated to reach 8% in epilepsies with CSWS (7).

Case reports have also documented the possible efficacy of sulthiame, topiramate, and intravenous immunoglobulin (33–35), but series are too small to draw conclusions about these treatments.

In epilepsies with CSWS, the efficacy of treatment is commonly evaluated with the SWI, a quantitative scoring system of the EEG calculated during NREM sleep, and with the improvement in neuropsychological function and behavior. In our study, the disappearance of the CSWS pattern assessed by the SWI was documented in only three of the nine patients (33.3%) who showed improvement in neuropsychological testing or behavior. We found that the combination of the SWI with a qualitative scoring system taking into account the global structure of the EEG, the presence of abnormal slowing, the importance of the diffusion of the epileptiform discharges, the presence of multiple asynchronous foci, and the presence of seizures during EEG recording was more closely associated with clinical improvement than the SWI alone. Indeed seven of the nine patients (77.7%) with improvement in behavior and/or neuropsychological evaluation had improved EEG score. This suggests that the evaluation of a drug effect on the EEG should not be restricted to the calculation of a SWI in epilepsies with CSWS. Other authors have already stressed on the importance of a qualitative analysis of the EEG in childhood rolandic epilepsy when risks of cognitive dysfunction or effects of AEDs are considered (28,29).

We found better efficay of levetiracetam in the nonrefractory patients compared with the group of refractory patients, which is not surprising. Another finding was the apparent escape from the treatment, observed in four patients who had responded to levetiracetam after 2 months but experienced relapse in the following months without modification of the AED regimen. A transitory effect of conventional AED on the CSWS pattern is a very frequent finding (1). This outlines the need to perform long-term observations when studying the efficacy of AED in epileptic children with CSWS.

Corticosteroids seem to have more long-lasting effects than levetiracetam. Indeed, in two case studies (9,36), corticosteroids showed a positive effect in all of the 7 cases of pharmacoresistant CSWS studied. This was confirmed by a lot of unpublished observations. Unfortunately, the long-term use of corticosteroids has several side effects that limit their use for refractory patients. This comment is also applicable to multiple subpial transections, which may be efficacious in selected cases of LKS (37,38).

Improvement in behavior and cognition with levetiracetam in the absence of improvement in the EEG in two of our patients could seem surprising. The positive effect observed could be caused by a direct action of levetiracetam on the central nervous system; indeed, levetiracetam does not exert its anticonvulsant effects by the traditionally understood impact on neuronal excitability. Levetiracetam being structurally related to nootropic agents, a class of drugs which have produced positive effects on learning and memory in animal models, it is possible that this drug could provide similar benefits in humans (39–41). Other hypotheses to consider are the placebo effect or test–retest effect. These possible confounding effects were not controlled in this retrospective study; however, it is important to note that adverse effects on cognition were not observed after levetiracetam add-on.

In conclusion, this study shows that levetiracetam lead to improvement in EEG and behavior in over half of the patients studied in this group and that the tolerance of the drug is excellent. This study also shows that a nonnegligible number of patients could escape from the treatment. A placebo-controlled study should be suitable in order to assess the place of levetiracetam in the treatment of epileptic conditions with CSWS and idiopathic epileptic syndromes with cognitive deficits.

Acknowledgments

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgments
  7. REFERENCES

Acknowledgment:  We are grateful to Isabelle Mayné for suggestions and criticisms in reviewing the manuscript.

REFERENCES

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgments
  7. REFERENCES
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