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Topiramate in childhood epileptic encephalopathy with continuous spike-waves during sleep: A retrospective study of 21 cases
e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y x x x ( 2 0 1 6 ) 1 e6
Official Journal of the European Paediatric Neurology Society
Original article
Topiramate in childhood epileptic encephalopathy with continuous spike-waves during sleep: A retrospective study of 21 cases P. Vrielynck*, P. Marique, S. Ghariani, F. Lienard, V. de Borchgrave, K. van Rijckevorsel, C. Bonnier William Lennox Neurological Hospital, Reference Center for Refractory Epilepsy, Universite Catholique de Louvain, Ottignies, Belgium
article info
abstract
Article history:
Objective: Encephalopathy with continuous spike-wave during sleep (CSWS) is a particu-
Received 9 January 2016
larly difficult-to-treat childhood epileptic syndrome. This study sought to present the EEG
Received in revised form
improvement and clinical efficacy of topiramate (TPM), a broad spectrum antiepileptic drug
28 August 2016
(AED), in a series of 21 children with CSWS encephalopathy.
Accepted 29 August 2016
Methods: We retrospectively reviewed the EEG results and clinical data of children with CSWS followed-up in our institution and treated with TPM. Sleep EEGs were performed 0e3
Keywords:
months prior to TPM introduction and then at 3 and 12 months. The exclusion criteria were
CSWS
(1) introduction of another AED and (2) withdrawal of a potentially aggravating AED during
ESES
the first 3 months of treatment. In addition to spike index (SI), the severity of EEG abnor-
Topiramate
malities was rated using an original scale that also considered the spatial extent of
Epilepsy
interictal epileptiform discharges.
Childhood
Results: 21 patients were included (18 males, 4-14y, three symptomatic cases). At 3 months, sleep EEG was improved in 14 and normalized in four (TPM doses: 2e5.5 mg/kg/day). Among these 18 patients, 16 manifested cognitive or behavioural improvement. In a subgroup of seven patients with frequent seizures, five became seizure-free and one had over 75% decrease in seizure frequency. At the one-year follow-up, 20 children were still on TPM and 10 exhibited persistent EEG improvement without any other AED being introduced, most of them with clinical benefits. Conclusion: TPM can decrease EEG abnormalities in epileptic encephalopathy with CSWS, achieving clinical improvement in the majority of patients. However, relapse may occur in the long-term in nearly half of cases. Otherwise, TPM has proven particularly useful in reducing seizure frequency in refractory cases. © 2016 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.
e de Clerlande 6, BE-1340 Ottignies, Belgium. * Corresponding author. Centre Hospitalier Neurologique William Lennox, Alle E-mail address: [email protected] (P. Vrielynck). http://dx.doi.org/10.1016/j.ejpn.2016.08.015 1090-3798/© 2016 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved. Please cite this article in press as: Vrielynck P, et al., Topiramate in childhood epileptic encephalopathy with continuous spike-waves during sleep: A retrospective study of 21 cases, European Journal of Paediatric Neurology (2016), http://dx.doi.org/10.1016/ j.ejpn.2016.08.015
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Encephalopathy with continuous spike waves during sleep (CSWS) is an epileptic syndrome affecting children, characterized by cognitive or behavioural degradation associated with a particular age-dependant electroencephalography (EEG) pattern, with or without clinical seizures. There is currently no consensus on the definition of this EEG pattern.1 Classically, diagnosis requires observation of diffuse epileptiform discharges with a spike index (SI) superior to 85% during sleep.2 Yet this definition is probably too restrictive, potentially reflecting only the “tip of the iceberg”.3 Several authors have, in fact, widened their definition to include an SI inferior to 85%, and no SI cut-off has so far been specified in the International League Against Epilepsy (ILAE) definition of 1989.4,5 The causes of encephalopathy with CSWS include early structural lesions in about 40% of cases and genetic factors, most frequently GRIN2A mutation, though the aetiology remains undetermined for a significant proportion of patients.6,7 Decreases in interictal epileptiform discharges (IED) have been linked to clinical improvement.8 In the absence of any randomized controlled trial (RCT) data, there are currently no evidence-based therapeutic guidelines available. The treatments usually considered are: (1) standard antiepileptic drugs (AEDs) like valproate (VPA), levetiracetam (LEV), sulthiame (STM); (2) benzodiazepines; (3) corticosteroids.9 Nevertheless, many children are drugresistant. There is also no methodological consensus on EEG abnormality quantification and treatment efficacy evaluation. Topiramate (TPM) is a “broad spectrum” AED with multiple mechanisms of action, including carbonic anhydrase inhibition, sodium channel blockage, GABAergic activity, and decrease in glutamate-mediated excitation via the AMPA/ kainate receptor.10 TPM has been proven effective in RCTs as add-on therapy in the following epileptic syndromes of childhood: symptomatic focal epilepsy, idiopathic generalized epilepsy with tonic-clonic seizures, and Lennox-Gastaut syndrome.10 Open studies have also suggested TPM efficacy in West syndrome and Dravet syndrome.11,12 Until now, the efficacy of TPM has never been specifically studied in CSWS encephalopathy. Positive results have been suggested in some large case series of refractory childhood epilepsies.11,13 This retrospective study sought to evaluate, over the long and short term, EEG findings and clinical response to TPM in a series of 21 children with CSWS encephalopathy.
imaging (MRI), and IQ scores. The exclusion criteria were: (1) introduction of another AED and (2) withdrawal of a potentially aggravating AED, such as carbamazepine (CBZ) or oxcarbazepine (OXC), during the first 3 months of TPM treatment. The dosages and titration of the TPM varied depending on the clinician's choice. SI was defined as the percentage of 1-second periods of EEG containing at least one spike-wave, as described by Aeby et al.14 Overnight EEG was monitored during the first hour of sleep by three neurologists (VdB, FL, and PV). In addition to SI, the severity of EEG abnormalities was rated a posteriori using an original gradation scale, also taking into account the spatial extent of the IEDs, as described in Fig. 1. This scale was based on a score resulting from two numbers between 0 and 4 multiplied together, the first being the SI, the second reflecting the spatial distribution of IEDs. The scale included six grades, from 0 (no EEG abnormality) to 5 (continuous generalized IEDs during more than 80% of sleep). Some examples of sleep EEG recordings with their corresponding grade are shown in Supplementary Materials. EEG improvement was defined as a decrease by at least one grade. All children were hospitalized in our institution during topiramate treatment. They benefitted from multidisciplinary care with speech therapy, occupational therapy, education and for some of them neuropsychological and psychomotor therapy. IQ was performed 1e11 months before TPM introduction (mean 2,7 months). IQ scales used were WISC-III, Hiskey Nebraska or KABC. Clinical evaluation was based on neuropsychological, psychological, and speech therapist qualitative reports and/or quantitative assessments, as well as remarks from the family and clinicians taken from the medical files. The clinical data was reviewed independently by a neuropsychologist (PM) and paediatric neurologist (CB), neither of whom were directly involved in the children's treatment, both blinded to the EEG results. At 3 months, the cognitive and behavioural aspects were considered separately. At 1 year, only the clinical global tendency was considered. Clinical outcome was defined as improvement, no significant change, or aggravation. Evolution was considered positive if majority of therapists described improvement, stable if only a slight progress was noted or quantified evaluation showed no change, and negative if therapists described no improvement or regression, or quantified evaluation showed degradation. The number of seizures was taken from family and nursing reports.
2.
3.
Results
3.1.
Patients (Table 1)
1.
Introduction
Methods
We retrospectively reviewed EEG and clinical data from children with epileptic encephalopathy associated with CSWS followed-up in our institution and treated with TPM. The following inclusion criteria applied: (1) cognitive or behavioural degradation in relation with abundant epileptic activity on sleep EEG; (2) bilateral IED significantly increased during sleep, with an SI of at least 50%; (3) sleep EEG performed 0e3 months before TPM initiation, and then at 3 and 12 months; (4) availability of clinical history, brain magnetic resonance
From 1999 onwards, 32 children had been treated with TPM in our institution for CSWS and cognitive or behavioural disturbance. We did not include 11 as they did not fulfil inclusion criteria, primarily due to lack of EEG data. Data from 21 patients was analysed, which included 18 boys aged 4y4m to 14y with global IQs of between 44 and 121. MRI was normal in all but three children. GRIN2A mutation was found in one case.
Please cite this article in press as: Vrielynck P, et al., Topiramate in childhood epileptic encephalopathy with continuous spike-waves during sleep: A retrospective study of 21 cases, European Journal of Paediatric Neurology (2016), http://dx.doi.org/10.1016/ j.ejpn.2016.08.015
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Fig. 1 e Spatial extension score depends on cerebral regions involved by IED. Focal ¼ a limited part of one hemisphere; hemispheric ¼ a major part of one hemisphere; diffuse ¼ major parts of both hemispheres; generalized ¼ all cerebral regions. Frequency of IED score is based on SI.
Table 1 e VPA ¼ valproate, CBZ ¼ carbamazepine, LTG ¼ lamotrigine, LEV ¼ levetiracetam, CLB ¼ clobazam, CLN ¼ clonazepam, HCT ¼ hydrocortisone, cort ¼ corticosteroids. Patient number Sex 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21
m m m m m f m m m m m m m f m m m f m m m
Age
Age at onset
IQ
MRI
Past AED
Seizures in the last year
9y7m 9y3m 8y4m 6y9m 4y4m 11y10m 14y0m 7y6m 8y8m 9y3m 8y3m 5y7m 6y9m 7y10m 5y10m 11y5m 4y10m 4y2m 10y3m 5y10m 6y6m
7y 8y 6y1/2 5y 3y 11y 13y 7y 6y 4y1/2 5y1/2 4y 5y 6y1/2 4y1/2 10y1/2 3y1/2 3y 7y 4y 3y
61 54 52 48 NA 57 53 72 56 83 63 41 94 94 57 121 71 75 41 44 46
normal normal normal normal thalamic haemorrhage normal periventricular leucomalacia normal normal normal normal nodular heterotopia normal normal normal normal normal normal normal normal normal (GRIN2A mutation)
VPA,LTG VPA,LTG VPA,LTG,CLB,CLN,cort VPA,LTG,CBZ CBZ,HCT,VPA CBZ,VPA,LTG,CLB VPA,CLB VPA VPA VPA,LTG,CBZ CBZ,VPA VPA,LTG VPA VPA VPA VPA e VPA VPA,CBZ VPA LEV,CLB
0 0 >monthly 1 1 >10 0 1 0 3 >monthly weekly 0 7 3 monthly 0 monthly 4 0 0
All except one were refractory to standard AEDs like VPA or benzodiazepine. Two were unsuccessfully treated with corticosteroids. On TPM initiation, all children received one or two AEDs, except for Patient 2. Seizures were reported in 13 children in the year before TPM initiation. A subgroup of seven children had had more than six seizures in the previous year (Patients 3, 6, 11, 12, 14, 16, and 18).
3.2.
Short-term results (Table 2)
At 3 months, at least one concomitant AED had been discontinued in seven patients, five of which continuing to receive TPM as monotherapy. Sleep EEG grade improved in 18/21 children (86%) with a mean TPM dose of 3.5 mg/kg/day (range: 2e5.5). Sleep EEG normalized in four (19%). Of these 18 patients exhibiting EEG improvement, 16 also demonstrated cognitive or behavioural improvement. The sleep EEG remained unchanged in two children and worsened in one. In these three, no clinical improvement was noted. Clinical variables (age at onset, duration of CSWS, IQ, and gender) did not influence the outcome. All the better responders, i.e. those exhibiting EEG normalization, had normal MRIs.
Seizure outcome was very good in the subgroup of seven patients with frequent seizures: five became seizure free and one benefitted from an over 75% decrease in seizure frequency.
3.3.
Long-term results (Table 3)
At the 1 year follow-up, 20 children were still receiving TPM. A new AED was added in six patients due to worse EEG results. Among the 18 children who initially showed EEG improvement, this persisted without any other AED being introduced in 10 (Patients 1, 2, 7, 9, 10, 12, 14, 18, 20 and 21). In these patients, the mean TPM dose was 4.4 mg/kg/d (range: 2.3e5.5); nine exhibited cognitive or behavioural improvement in comparison with their initial status and one was considered clinically stable. Thus, EEG grade remained improved over the long term in 10/21 children (48%), the majority of whom exhibited clear clinical benefit. Of the 13 children who had had seizures, seven continued to receive TPM with no other AED until 1 year later, at which point three were seizure-free, two exhibited a reduction in seizure frequency >75%, one was stable and one suffered from increased seizure frequency.
Please cite this article in press as: Vrielynck P, et al., Topiramate in childhood epileptic encephalopathy with continuous spike-waves during sleep: A retrospective study of 21 cases, European Journal of Paediatric Neurology (2016), http://dx.doi.org/10.1016/ j.ejpn.2016.08.015
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Table 2 e Diff ¼ diffuse, F ¼ frontal, C ¼ central, T ¼ temporal, P ¼ parietal, ant ¼ anterior, post ¼ posterior, pred ¼ predominance. Clinical outcome: « þ » ¼ improvement, « ¼ » ¼ no change, « - » ¼ worsening. EEG before TPM SI (%)
Localisation
Grade
80 80 90 50 95 90 80 80 80 75 70 80 80 75 75 80 60 80 80 90 65
generalized generalized generalized generalized generalized generalized diff ant pred L diff pred R generalized diff pred R CT generalized bilat T pred L bilat CT pred R generalized generalized bilat CT pred L R CT þ L PT bilat PT pred R diff ant pred L diff pred CT diff post
5 5 5 4 5 5 4 4 5 3 4 3 3 4 4 3 2 3 4 4 3
TPM dose (mg/kg/d)
AED after 3 months TPM
5.5 3.3 4 4 5 3.1 2 2.5 5 3.4 2.8 5 3.8 4 4.3 2.7 2 2 2.8 3 3
VPA þ LTG 0 ESM þ CLB LTG VPA LTG 0 VPA þ CLB 0 LTG VPA VPA VPA 0 VPA VPA 0 VPA VPA VPA CLB
EEG after 3 months TPM
Clinical outcome
SI (%)
Localisation
Grade
Cognition
Behavior
0 0 80 40 80 70 20 75 0 65 60 45 0 60 70 80 15 65 55 45 55
NA NA LT diff pred R generalized diffuse, ant L FC generalized NA bilat CT pred R CP pred L L CT þ R CP NA diff ant diff post pred R bilat CTP pred R bilat C L TP þ R T diff ant pred L bilat CT RT
0 0 2 2 5 3 1 5 0 2 2 2 0 3 3 3 1 2 3 2 1
¼ þ þ þ e þ þ e þ þ þ þ ¼ þ þ ¼ ¼ þ ¼ þ ¼
þ þ þ þ ¼ þ þ ¼ þ ¼ þ þ e þ þ ¼ ¼ þ þ þ þ
Table 3 e Seizures ¼ number of clinical seizures since TPM introduction. Clinical outcome is a global evaluation based on cognitive and behavioural evolution reported by family and carers since TPM introduction. Patient
TPM dose (mg/kg/d)
Other AED
5,5 4 8,3 6 8 7,5 2,3 e 5 3,9 8,6 4,8 7,3 5,5 5,8 5,5 5,5 4 5,3 4,5 4
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21
3.4.
EEG
Seizures
Clinical outcome
SI (%)
Localisation
Grade
e e CLB þ LTG LTG e LTG e
0 0 85 60 95 85 10
NA NA diff ant pred L generalized generalized diff ant LF
0 0 4 4 5 4 1
0 0 1 1 2 0 0
¼ þ ¼ þ e þ þ
e e ESM e e e VPA þ ESM VPA þ ESM ESM VPA e e CLB
0 45 70 10 15 30 60 60 35 70 90 45 45
NA R CT diff pred L R CT þ L T R FC diff ant diff pred R bilat CT pred L diffuse PT bilat diffuse CT bilat R CPT þ L CT
0 1 3 1 1 2 2 2 2 2 4 2 2
0 0 0
þ þ þ þ e þ ¼ ¼ ¼ þ e þ þ
Tolerance
The primary adverse event observed was loss of appetite, reported in four children (Patients 2, 4, 11 and 14). Patient 2 also manifested weight loss. Irritability was reported for Patient 3, fatigue for Patient 18, metabolic acidosis for Patient 20, and worse EEG results and cognitive status in Patient 8. TPM was discontinued in this last patient. Otherwise, the possibility of TPM-related cognitive side-effects cannot be excluded, yet
these are difficult to distinguish from the natural history of the disease.
4.
Discussion
To the best of our knowledge, this is the first study to specifically evaluate administering TPM in CSWS encephalopathy treatment in a large series of children. Overall, our results
Please cite this article in press as: Vrielynck P, et al., Topiramate in childhood epileptic encephalopathy with continuous spike-waves during sleep: A retrospective study of 21 cases, European Journal of Paediatric Neurology (2016), http://dx.doi.org/10.1016/ j.ejpn.2016.08.015
e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y x x x ( 2 0 1 6 ) 1 e6
were positive, considering the severity of this syndrome. In the short-term, sleep EEG improved in over 80% of cases. The majority of those exhibiting a decrease in EEG abnormalities also manifested clinical improvement. This positive effect is in agreement with some previous reports, whereas in two recent CSWS series TPM was not found to be effective.11,13,15,16 One possible explanation for these contradictory results is the higher proportion of cryptogenic cases in our series. Indeed, cases with a structural lesion or an abnormal development before CSWS are associated with a worse outcome.17 This may also explain why our responder rate is relatively high, compared with results of a recent meta-analysis showing improvement (i.e., cognition or EEG) in 49% of patients with standard AEDs, 68% with benzodiazepines and 81% with steroids. However, results are difficult to compare with that of other trials, owing to differences in inclusion criteria and methods of evaluation. In particular, the definition of drug responders varies from one study to another. Considering the rate of EEG normalization, our short-term result of 19% is less favourable than that achieved previously with diazepam (60%: 9/15 patients in the De Negri et al. study) and hydrocortisone (48%: 21/44 patients in Buzatu et al.), although it is generally similar to results with other standard AEDs typically used in CSWS cases, including STM (28%: 15/53 patients in Fejerman et al.) and LEV (7%: 2/20 patients in Atkins et al.; 0/12 in Aeby et al.; 5/71 in Chen et al.).14,18e22 In our series, relapse occurred in the long-term in 44% of the initial responders. High relapse rates have also been reported with corticosteroids (42%: 14/34 responders in Buzatu et al.; 5/11 in Kramer et al.) and LEV (30%: 4/7 responders in Aeby et al.; 3/11 in Atkins et al.; 8/32 in Chen et al.).14,15,19,21,22 Surprisingly, no relapse was reported in the series of 40 children responders to STM.20 The long-term effect of a short course of benzodiazepines appears, as with diazepam, to also be associated with a high rate of relapse.15 Chronic use of clobazam may carry a lower risk of relapse (1/9 responders in Kramer et al.).20 In our study, we found that good control of seizures associated with CSWS was possible with TPM, with a majority of patients becoming seizure-free (71% at 3 months, considering only the subgroup with frequent seizures). These results are globally comparable to studies evaluating STM (58%: 31/53 in Fejerman et al.), hydrocortisone (80%: 33/41 in Buzatu et al.) and LEV (53%: 6/9 in Atkins et al.; 25/50 in Chen et al.).19e22 We observed one case of EEG aggravation under TPM, which was associated with clinical deterioration. Electroclinical aggravation is a well-known phenomenon in CSWS with some AEDs, especially CBZ and OXC.9 Suspicion of CSWS induced by TPM, after 11 months of treatment, was already reported in one patient.23 Cases of deterioration are also rarely reported with the standard AEDs commonly used in CSW. When using LEV, one case of deterioration was reported in a series of 17 children, yet there were no reports in three other series.14,15,21,22 The cognitive side-effects of TPM could explain some children's lack of clinical improvement, despite EEG improvement. Adverse cognitive effects are, in fact, the main drawbacks to TPM treatment. A significant number of children and adults may have difficulties finding their words, along with attention
5
and memory impairment when receiving TPM.25 These effects have also been reported in children with mental retardation.26 Polytherapy, high dosages, and rapid titration increase the risk of adverse cognitive effects.24,26,27 In an RCT conducted in a population of children with benign epilepsy with centrotemporal spikes (BECTS), low-dose TPM monotherapy (maximum: 4 mg/kg/d) with slow titration caused only slight aggravation of some neuropsychological variables compared to CBZ.28 In our series, the majority of children responders to TPM received relatively low doses (between 2 and 5 mg/kg/d) and over half were on monotherapy after one year, which probably helped minimize any adverse cognitive effects. From a methodological point of view, our study introduces an original grading scale that we developed to better quantify EEG abnormalities, taking into account two parameters: frequency (i.e., SI) and spatial extent of IEDs. The scales used in previous studies depended solely on SI or spatial distribution of IEDs.14,29,30 Encephalopathy with CSWS is currently considered to fall at the most severe end of the spectrum of age-related conditions in which IEDs are believed to display a deleterious impact on cognition.8 There is an EEG-clinical continuum between BECTS, atypical benign partial epilepsy, Landau Kleffner syndrome, and CSWS encephalopathy. On this spectrum, the degree of spatial extent of IEDs has been shown to influence cognitive status. To illustrate, in comparison with typical BECTS without significant cognitive impairment, the EEG results of an idiopathic focal epilepsy patient with educational problems more frequently reveal bilateral and generalized IEDs, in addition to higher activation of IEDs during sleep.31,32 On the CSWS spectrum, therefore, SI is not the only EEG parameter associated with cognitive impairment. For example, in a recent large series, no significant clinical difference was observed between children with an SI > 85 and <85%.33 We therefore believe that our grading scale, which is easy to use in clinical practice, reflects more adequately than SI the severity of the different EEG patterns of the CSWS spectrum. Nevertheless, the clinical validity of this scale still needs to be established by further studies assessing EEG-clinical correlations. Finally, we can retain three methodological points that limit the interpretation of these results. First, the retrospective nature of the study causes a certain degree of selection bias. Secondly, in the absence of a control group, the possibility of spontaneous improvement cannot be excluded. Thirdly, electroeclinical correlations are limited by the absence of systematic standardized clinical and neuropsychological assessment. In conclusion, TPM may decrease EEG abnormalities in epileptic encephalopathy with CSWS, which leads to clinical improvement in the majority of patients. However, relapse may occur in the long-term in nearly half of the cases. In addition, TPM has been shown to be particularly useful in reducing seizure frequency in refractory cases. Our results are globally comparable to those of other studies investigating the effects of the standard AEDs commonly used for this syndrome, such as LEV and STM. Taking into account its unfavourable cognitive adverse event profile in comparison to both of these other AEDs, TPM should probably not constitute a first choice for CSWS treatment. It remains, however, potentially useful in refractory cases, especially those with high seizure frequency.
Please cite this article in press as: Vrielynck P, et al., Topiramate in childhood epileptic encephalopathy with continuous spike-waves during sleep: A retrospective study of 21 cases, European Journal of Paediatric Neurology (2016), http://dx.doi.org/10.1016/ j.ejpn.2016.08.015
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Conflict of interest The authors have no conflict of interest to disclose.
Appendix A. Supplementary data Supplementary data related to this article can be found at http://dx.doi.org/10.1016/j.ejpn.2016.08.015.
references
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15. Kramer U, Sagi L, Goldberg-Stern H, Zelnik N, Nissenkorn A, Ben-Zeev B. Clinical spectrum and medical treatment of children with electrical status epilepticus in sleep (ESES). Epilepsia 2008;50(6):1517e24. 16. Degerliyurt A, Yalnizoglu D, Bakar EE, Topc¸u M, Turanli G. Electrical status epilepticus during sleep: a study of 22 patients. Brain Dev 2015;37(2):250e64. 17. van den Munckhof B, de Vries EE, Braun KP, et al. Treatment of electrical status epilepticus in sleep: a pooled analysis of 575 cases. Epilepsia 2015;56(11):1738e46. 18. De Negri M, Baglietto MG, Battaglia FM, Gaggero R, Pessagno A, Recanati L. Treatment of electrical status epilepticus by short diazepam (DZP) cycles after DZP rectal bolus test. Brain Dev 1995;17(5):330e3. 19. Buzatu M, Bulteau C, Altuzarra C, Dulac O, Van Bogaert P. Corticosteroids as treatment of epileptic syndromes with continuous spike-waves during slow-wave sleep. Epilepsia 2009;50(Suppl. 7):68e72. simo R, Ferraro SM, 20. Fejerman N, Caraballo R, Cerso Galicchio S, Amartino H. Sulthiame add-on therapy in children with focal epilepsies associated with encephalopathy related to electrical status epilepticus during slow sleep (ESES). Epilepsia 2012;53(7):1156e61. 21. Atkins M, Nikanorova M. A prospective study of levetiracetam efficacy in epileptic syndromes with continuous spikeswaves during slow sleep. Seizure 2011;20(8):635e9. 22. Chen J, Cai F, Jiang L, Hu Y, Feng C. Levetiracetam efficacy in children with epilepsy with electrical status epilepticus in sleep. Epilepsy Behav 2015;44:73e7. 23. Montenegro MA, Guerreiro MM. Electrical status epilepticus of sleep in association with topiramate. Epilepsia 2002;43(11):1436e40. 24. Arroyo S, Dodson WE, Privitera MD, et al. Randomized dosecontrolled study of topiramate as first-line therapy in epilepsy. Acta Neurol Scand 2005;112(4):214e22. 25. Coppola G, Verrotti A, Resicato G, et al. Topiramate in children and adolescents with epilepsy and mental retardation: a prospective study on behavior and cognitive effects. Epilepsy Behav 2008;12(2):253e6. 26. Loring DW, Williamson DJ, Meador KJ, Wiegand F, Hulihan J. Topiramate dose effects on cognition: a randomized doubleblind study. Neurology 2011;76(2):131e7. 27. Pandina GJ, Ness S, Polverejan E, et al. Cognitive effects of topiramate in migraine patients aged 12 through 17 years. Pediatr Neurol 2010;42(3):187e95. 28. Kang HC, Eun BL, Wu Lee C, et al. The effects on cognitive function and behavioral problems of topiramate compared to carbamazepine as monotherapy for children with benign rolandic epilepsy. Epilepsia 2007;48(9):1716e23. 29. Beaumanoir A. Eeg data. In: Beaumanoir A, Bureau T, Deonna T, Mira L, Tassinari CA, editors. Continuous spikes and waves during slow sleep. Oxford: John Libbey & Company Ltd; 1995. p. 217e23. 30. Mikati MA, Saab R, Fayad MN, Choueiri RN. Efficacy of intravenous immunoglobulin in Landau-Kleffner syndrome. Pediatr Neurol 2002;26(4):298e300. 31. Massa R, de Saint-Martin A, Carcangiu R, et al. EEG criteria predictive of complicated evolution in idiopathic rolandic epilepsy. Neurology 2001;57(6):1071e9. 32. Nicolai J, van der Linden I, Arends JB, et al. EEG characteristics related to educational impairments in children with benign childhood epilepsy with centrotemporal spikes. Epilepsia 2007;48(11):2093e100. 33. Caraballo RH, Veggiotti P, Kaltenmeier MC, et al. Encephalopathy with status epilepticus during sleep or continuous spikes and waves during slow sleep syndrome: a multicenter, longterm follow-up study of 117 patients. Epilepsy Res 2013;105(1e2):164e73.
Please cite this article in press as: Vrielynck P, et al., Topiramate in childhood epileptic encephalopathy with continuous spike-waves during sleep: A retrospective study of 21 cases, European Journal of Paediatric Neurology (2016), http://dx.doi.org/10.1016/ j.ejpn.2016.08.015
Official Journal of the European Paediatric Neurology Society
Original article
Topiramate in childhood epileptic encephalopathy with continuous spike-waves during sleep: A retrospective study of 21 cases P. Vrielynck*, P. Marique, S. Ghariani, F. Lienard, V. de Borchgrave, K. van Rijckevorsel, C. Bonnier William Lennox Neurological Hospital, Reference Center for Refractory Epilepsy, Universite Catholique de Louvain, Ottignies, Belgium
article info
abstract
Article history:
Objective: Encephalopathy with continuous spike-wave during sleep (CSWS) is a particu-
Received 9 January 2016
larly difficult-to-treat childhood epileptic syndrome. This study sought to present the EEG
Received in revised form
improvement and clinical efficacy of topiramate (TPM), a broad spectrum antiepileptic drug
28 August 2016
(AED), in a series of 21 children with CSWS encephalopathy.
Accepted 29 August 2016
Methods: We retrospectively reviewed the EEG results and clinical data of children with CSWS followed-up in our institution and treated with TPM. Sleep EEGs were performed 0e3
Keywords:
months prior to TPM introduction and then at 3 and 12 months. The exclusion criteria were
CSWS
(1) introduction of another AED and (2) withdrawal of a potentially aggravating AED during
ESES
the first 3 months of treatment. In addition to spike index (SI), the severity of EEG abnor-
Topiramate
malities was rated using an original scale that also considered the spatial extent of
Epilepsy
interictal epileptiform discharges.
Childhood
Results: 21 patients were included (18 males, 4-14y, three symptomatic cases). At 3 months, sleep EEG was improved in 14 and normalized in four (TPM doses: 2e5.5 mg/kg/day). Among these 18 patients, 16 manifested cognitive or behavioural improvement. In a subgroup of seven patients with frequent seizures, five became seizure-free and one had over 75% decrease in seizure frequency. At the one-year follow-up, 20 children were still on TPM and 10 exhibited persistent EEG improvement without any other AED being introduced, most of them with clinical benefits. Conclusion: TPM can decrease EEG abnormalities in epileptic encephalopathy with CSWS, achieving clinical improvement in the majority of patients. However, relapse may occur in the long-term in nearly half of cases. Otherwise, TPM has proven particularly useful in reducing seizure frequency in refractory cases. © 2016 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.
e de Clerlande 6, BE-1340 Ottignies, Belgium. * Corresponding author. Centre Hospitalier Neurologique William Lennox, Alle E-mail address: [email protected] (P. Vrielynck). http://dx.doi.org/10.1016/j.ejpn.2016.08.015 1090-3798/© 2016 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved. Please cite this article in press as: Vrielynck P, et al., Topiramate in childhood epileptic encephalopathy with continuous spike-waves during sleep: A retrospective study of 21 cases, European Journal of Paediatric Neurology (2016), http://dx.doi.org/10.1016/ j.ejpn.2016.08.015
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Encephalopathy with continuous spike waves during sleep (CSWS) is an epileptic syndrome affecting children, characterized by cognitive or behavioural degradation associated with a particular age-dependant electroencephalography (EEG) pattern, with or without clinical seizures. There is currently no consensus on the definition of this EEG pattern.1 Classically, diagnosis requires observation of diffuse epileptiform discharges with a spike index (SI) superior to 85% during sleep.2 Yet this definition is probably too restrictive, potentially reflecting only the “tip of the iceberg”.3 Several authors have, in fact, widened their definition to include an SI inferior to 85%, and no SI cut-off has so far been specified in the International League Against Epilepsy (ILAE) definition of 1989.4,5 The causes of encephalopathy with CSWS include early structural lesions in about 40% of cases and genetic factors, most frequently GRIN2A mutation, though the aetiology remains undetermined for a significant proportion of patients.6,7 Decreases in interictal epileptiform discharges (IED) have been linked to clinical improvement.8 In the absence of any randomized controlled trial (RCT) data, there are currently no evidence-based therapeutic guidelines available. The treatments usually considered are: (1) standard antiepileptic drugs (AEDs) like valproate (VPA), levetiracetam (LEV), sulthiame (STM); (2) benzodiazepines; (3) corticosteroids.9 Nevertheless, many children are drugresistant. There is also no methodological consensus on EEG abnormality quantification and treatment efficacy evaluation. Topiramate (TPM) is a “broad spectrum” AED with multiple mechanisms of action, including carbonic anhydrase inhibition, sodium channel blockage, GABAergic activity, and decrease in glutamate-mediated excitation via the AMPA/ kainate receptor.10 TPM has been proven effective in RCTs as add-on therapy in the following epileptic syndromes of childhood: symptomatic focal epilepsy, idiopathic generalized epilepsy with tonic-clonic seizures, and Lennox-Gastaut syndrome.10 Open studies have also suggested TPM efficacy in West syndrome and Dravet syndrome.11,12 Until now, the efficacy of TPM has never been specifically studied in CSWS encephalopathy. Positive results have been suggested in some large case series of refractory childhood epilepsies.11,13 This retrospective study sought to evaluate, over the long and short term, EEG findings and clinical response to TPM in a series of 21 children with CSWS encephalopathy.
imaging (MRI), and IQ scores. The exclusion criteria were: (1) introduction of another AED and (2) withdrawal of a potentially aggravating AED, such as carbamazepine (CBZ) or oxcarbazepine (OXC), during the first 3 months of TPM treatment. The dosages and titration of the TPM varied depending on the clinician's choice. SI was defined as the percentage of 1-second periods of EEG containing at least one spike-wave, as described by Aeby et al.14 Overnight EEG was monitored during the first hour of sleep by three neurologists (VdB, FL, and PV). In addition to SI, the severity of EEG abnormalities was rated a posteriori using an original gradation scale, also taking into account the spatial extent of the IEDs, as described in Fig. 1. This scale was based on a score resulting from two numbers between 0 and 4 multiplied together, the first being the SI, the second reflecting the spatial distribution of IEDs. The scale included six grades, from 0 (no EEG abnormality) to 5 (continuous generalized IEDs during more than 80% of sleep). Some examples of sleep EEG recordings with their corresponding grade are shown in Supplementary Materials. EEG improvement was defined as a decrease by at least one grade. All children were hospitalized in our institution during topiramate treatment. They benefitted from multidisciplinary care with speech therapy, occupational therapy, education and for some of them neuropsychological and psychomotor therapy. IQ was performed 1e11 months before TPM introduction (mean 2,7 months). IQ scales used were WISC-III, Hiskey Nebraska or KABC. Clinical evaluation was based on neuropsychological, psychological, and speech therapist qualitative reports and/or quantitative assessments, as well as remarks from the family and clinicians taken from the medical files. The clinical data was reviewed independently by a neuropsychologist (PM) and paediatric neurologist (CB), neither of whom were directly involved in the children's treatment, both blinded to the EEG results. At 3 months, the cognitive and behavioural aspects were considered separately. At 1 year, only the clinical global tendency was considered. Clinical outcome was defined as improvement, no significant change, or aggravation. Evolution was considered positive if majority of therapists described improvement, stable if only a slight progress was noted or quantified evaluation showed no change, and negative if therapists described no improvement or regression, or quantified evaluation showed degradation. The number of seizures was taken from family and nursing reports.
2.
3.
Results
3.1.
Patients (Table 1)
1.
Introduction
Methods
We retrospectively reviewed EEG and clinical data from children with epileptic encephalopathy associated with CSWS followed-up in our institution and treated with TPM. The following inclusion criteria applied: (1) cognitive or behavioural degradation in relation with abundant epileptic activity on sleep EEG; (2) bilateral IED significantly increased during sleep, with an SI of at least 50%; (3) sleep EEG performed 0e3 months before TPM initiation, and then at 3 and 12 months; (4) availability of clinical history, brain magnetic resonance
From 1999 onwards, 32 children had been treated with TPM in our institution for CSWS and cognitive or behavioural disturbance. We did not include 11 as they did not fulfil inclusion criteria, primarily due to lack of EEG data. Data from 21 patients was analysed, which included 18 boys aged 4y4m to 14y with global IQs of between 44 and 121. MRI was normal in all but three children. GRIN2A mutation was found in one case.
Please cite this article in press as: Vrielynck P, et al., Topiramate in childhood epileptic encephalopathy with continuous spike-waves during sleep: A retrospective study of 21 cases, European Journal of Paediatric Neurology (2016), http://dx.doi.org/10.1016/ j.ejpn.2016.08.015
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Fig. 1 e Spatial extension score depends on cerebral regions involved by IED. Focal ¼ a limited part of one hemisphere; hemispheric ¼ a major part of one hemisphere; diffuse ¼ major parts of both hemispheres; generalized ¼ all cerebral regions. Frequency of IED score is based on SI.
Table 1 e VPA ¼ valproate, CBZ ¼ carbamazepine, LTG ¼ lamotrigine, LEV ¼ levetiracetam, CLB ¼ clobazam, CLN ¼ clonazepam, HCT ¼ hydrocortisone, cort ¼ corticosteroids. Patient number Sex 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21
m m m m m f m m m m m m m f m m m f m m m
Age
Age at onset
IQ
MRI
Past AED
Seizures in the last year
9y7m 9y3m 8y4m 6y9m 4y4m 11y10m 14y0m 7y6m 8y8m 9y3m 8y3m 5y7m 6y9m 7y10m 5y10m 11y5m 4y10m 4y2m 10y3m 5y10m 6y6m
7y 8y 6y1/2 5y 3y 11y 13y 7y 6y 4y1/2 5y1/2 4y 5y 6y1/2 4y1/2 10y1/2 3y1/2 3y 7y 4y 3y
61 54 52 48 NA 57 53 72 56 83 63 41 94 94 57 121 71 75 41 44 46
normal normal normal normal thalamic haemorrhage normal periventricular leucomalacia normal normal normal normal nodular heterotopia normal normal normal normal normal normal normal normal normal (GRIN2A mutation)
VPA,LTG VPA,LTG VPA,LTG,CLB,CLN,cort VPA,LTG,CBZ CBZ,HCT,VPA CBZ,VPA,LTG,CLB VPA,CLB VPA VPA VPA,LTG,CBZ CBZ,VPA VPA,LTG VPA VPA VPA VPA e VPA VPA,CBZ VPA LEV,CLB
0 0 >monthly 1 1 >10 0 1 0 3 >monthly weekly 0 7 3 monthly 0 monthly 4 0 0
All except one were refractory to standard AEDs like VPA or benzodiazepine. Two were unsuccessfully treated with corticosteroids. On TPM initiation, all children received one or two AEDs, except for Patient 2. Seizures were reported in 13 children in the year before TPM initiation. A subgroup of seven children had had more than six seizures in the previous year (Patients 3, 6, 11, 12, 14, 16, and 18).
3.2.
Short-term results (Table 2)
At 3 months, at least one concomitant AED had been discontinued in seven patients, five of which continuing to receive TPM as monotherapy. Sleep EEG grade improved in 18/21 children (86%) with a mean TPM dose of 3.5 mg/kg/day (range: 2e5.5). Sleep EEG normalized in four (19%). Of these 18 patients exhibiting EEG improvement, 16 also demonstrated cognitive or behavioural improvement. The sleep EEG remained unchanged in two children and worsened in one. In these three, no clinical improvement was noted. Clinical variables (age at onset, duration of CSWS, IQ, and gender) did not influence the outcome. All the better responders, i.e. those exhibiting EEG normalization, had normal MRIs.
Seizure outcome was very good in the subgroup of seven patients with frequent seizures: five became seizure free and one benefitted from an over 75% decrease in seizure frequency.
3.3.
Long-term results (Table 3)
At the 1 year follow-up, 20 children were still receiving TPM. A new AED was added in six patients due to worse EEG results. Among the 18 children who initially showed EEG improvement, this persisted without any other AED being introduced in 10 (Patients 1, 2, 7, 9, 10, 12, 14, 18, 20 and 21). In these patients, the mean TPM dose was 4.4 mg/kg/d (range: 2.3e5.5); nine exhibited cognitive or behavioural improvement in comparison with their initial status and one was considered clinically stable. Thus, EEG grade remained improved over the long term in 10/21 children (48%), the majority of whom exhibited clear clinical benefit. Of the 13 children who had had seizures, seven continued to receive TPM with no other AED until 1 year later, at which point three were seizure-free, two exhibited a reduction in seizure frequency >75%, one was stable and one suffered from increased seizure frequency.
Please cite this article in press as: Vrielynck P, et al., Topiramate in childhood epileptic encephalopathy with continuous spike-waves during sleep: A retrospective study of 21 cases, European Journal of Paediatric Neurology (2016), http://dx.doi.org/10.1016/ j.ejpn.2016.08.015
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Table 2 e Diff ¼ diffuse, F ¼ frontal, C ¼ central, T ¼ temporal, P ¼ parietal, ant ¼ anterior, post ¼ posterior, pred ¼ predominance. Clinical outcome: « þ » ¼ improvement, « ¼ » ¼ no change, « - » ¼ worsening. EEG before TPM SI (%)
Localisation
Grade
80 80 90 50 95 90 80 80 80 75 70 80 80 75 75 80 60 80 80 90 65
generalized generalized generalized generalized generalized generalized diff ant pred L diff pred R generalized diff pred R CT generalized bilat T pred L bilat CT pred R generalized generalized bilat CT pred L R CT þ L PT bilat PT pred R diff ant pred L diff pred CT diff post
5 5 5 4 5 5 4 4 5 3 4 3 3 4 4 3 2 3 4 4 3
TPM dose (mg/kg/d)
AED after 3 months TPM
5.5 3.3 4 4 5 3.1 2 2.5 5 3.4 2.8 5 3.8 4 4.3 2.7 2 2 2.8 3 3
VPA þ LTG 0 ESM þ CLB LTG VPA LTG 0 VPA þ CLB 0 LTG VPA VPA VPA 0 VPA VPA 0 VPA VPA VPA CLB
EEG after 3 months TPM
Clinical outcome
SI (%)
Localisation
Grade
Cognition
Behavior
0 0 80 40 80 70 20 75 0 65 60 45 0 60 70 80 15 65 55 45 55
NA NA LT diff pred R generalized diffuse, ant L FC generalized NA bilat CT pred R CP pred L L CT þ R CP NA diff ant diff post pred R bilat CTP pred R bilat C L TP þ R T diff ant pred L bilat CT RT
0 0 2 2 5 3 1 5 0 2 2 2 0 3 3 3 1 2 3 2 1
¼ þ þ þ e þ þ e þ þ þ þ ¼ þ þ ¼ ¼ þ ¼ þ ¼
þ þ þ þ ¼ þ þ ¼ þ ¼ þ þ e þ þ ¼ ¼ þ þ þ þ
Table 3 e Seizures ¼ number of clinical seizures since TPM introduction. Clinical outcome is a global evaluation based on cognitive and behavioural evolution reported by family and carers since TPM introduction. Patient
TPM dose (mg/kg/d)
Other AED
5,5 4 8,3 6 8 7,5 2,3 e 5 3,9 8,6 4,8 7,3 5,5 5,8 5,5 5,5 4 5,3 4,5 4
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21
3.4.
EEG
Seizures
Clinical outcome
SI (%)
Localisation
Grade
e e CLB þ LTG LTG e LTG e
0 0 85 60 95 85 10
NA NA diff ant pred L generalized generalized diff ant LF
0 0 4 4 5 4 1
0 0 1 1 2 0 0
¼ þ ¼ þ e þ þ
e e ESM e e e VPA þ ESM VPA þ ESM ESM VPA e e CLB
0 45 70 10 15 30 60 60 35 70 90 45 45
NA R CT diff pred L R CT þ L T R FC diff ant diff pred R bilat CT pred L diffuse PT bilat diffuse CT bilat R CPT þ L CT
0 1 3 1 1 2 2 2 2 2 4 2 2
0 0 0
þ þ þ þ e þ ¼ ¼ ¼ þ e þ þ
Tolerance
The primary adverse event observed was loss of appetite, reported in four children (Patients 2, 4, 11 and 14). Patient 2 also manifested weight loss. Irritability was reported for Patient 3, fatigue for Patient 18, metabolic acidosis for Patient 20, and worse EEG results and cognitive status in Patient 8. TPM was discontinued in this last patient. Otherwise, the possibility of TPM-related cognitive side-effects cannot be excluded, yet
these are difficult to distinguish from the natural history of the disease.
4.
Discussion
To the best of our knowledge, this is the first study to specifically evaluate administering TPM in CSWS encephalopathy treatment in a large series of children. Overall, our results
Please cite this article in press as: Vrielynck P, et al., Topiramate in childhood epileptic encephalopathy with continuous spike-waves during sleep: A retrospective study of 21 cases, European Journal of Paediatric Neurology (2016), http://dx.doi.org/10.1016/ j.ejpn.2016.08.015
e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y x x x ( 2 0 1 6 ) 1 e6
were positive, considering the severity of this syndrome. In the short-term, sleep EEG improved in over 80% of cases. The majority of those exhibiting a decrease in EEG abnormalities also manifested clinical improvement. This positive effect is in agreement with some previous reports, whereas in two recent CSWS series TPM was not found to be effective.11,13,15,16 One possible explanation for these contradictory results is the higher proportion of cryptogenic cases in our series. Indeed, cases with a structural lesion or an abnormal development before CSWS are associated with a worse outcome.17 This may also explain why our responder rate is relatively high, compared with results of a recent meta-analysis showing improvement (i.e., cognition or EEG) in 49% of patients with standard AEDs, 68% with benzodiazepines and 81% with steroids. However, results are difficult to compare with that of other trials, owing to differences in inclusion criteria and methods of evaluation. In particular, the definition of drug responders varies from one study to another. Considering the rate of EEG normalization, our short-term result of 19% is less favourable than that achieved previously with diazepam (60%: 9/15 patients in the De Negri et al. study) and hydrocortisone (48%: 21/44 patients in Buzatu et al.), although it is generally similar to results with other standard AEDs typically used in CSWS cases, including STM (28%: 15/53 patients in Fejerman et al.) and LEV (7%: 2/20 patients in Atkins et al.; 0/12 in Aeby et al.; 5/71 in Chen et al.).14,18e22 In our series, relapse occurred in the long-term in 44% of the initial responders. High relapse rates have also been reported with corticosteroids (42%: 14/34 responders in Buzatu et al.; 5/11 in Kramer et al.) and LEV (30%: 4/7 responders in Aeby et al.; 3/11 in Atkins et al.; 8/32 in Chen et al.).14,15,19,21,22 Surprisingly, no relapse was reported in the series of 40 children responders to STM.20 The long-term effect of a short course of benzodiazepines appears, as with diazepam, to also be associated with a high rate of relapse.15 Chronic use of clobazam may carry a lower risk of relapse (1/9 responders in Kramer et al.).20 In our study, we found that good control of seizures associated with CSWS was possible with TPM, with a majority of patients becoming seizure-free (71% at 3 months, considering only the subgroup with frequent seizures). These results are globally comparable to studies evaluating STM (58%: 31/53 in Fejerman et al.), hydrocortisone (80%: 33/41 in Buzatu et al.) and LEV (53%: 6/9 in Atkins et al.; 25/50 in Chen et al.).19e22 We observed one case of EEG aggravation under TPM, which was associated with clinical deterioration. Electroclinical aggravation is a well-known phenomenon in CSWS with some AEDs, especially CBZ and OXC.9 Suspicion of CSWS induced by TPM, after 11 months of treatment, was already reported in one patient.23 Cases of deterioration are also rarely reported with the standard AEDs commonly used in CSW. When using LEV, one case of deterioration was reported in a series of 17 children, yet there were no reports in three other series.14,15,21,22 The cognitive side-effects of TPM could explain some children's lack of clinical improvement, despite EEG improvement. Adverse cognitive effects are, in fact, the main drawbacks to TPM treatment. A significant number of children and adults may have difficulties finding their words, along with attention
5
and memory impairment when receiving TPM.25 These effects have also been reported in children with mental retardation.26 Polytherapy, high dosages, and rapid titration increase the risk of adverse cognitive effects.24,26,27 In an RCT conducted in a population of children with benign epilepsy with centrotemporal spikes (BECTS), low-dose TPM monotherapy (maximum: 4 mg/kg/d) with slow titration caused only slight aggravation of some neuropsychological variables compared to CBZ.28 In our series, the majority of children responders to TPM received relatively low doses (between 2 and 5 mg/kg/d) and over half were on monotherapy after one year, which probably helped minimize any adverse cognitive effects. From a methodological point of view, our study introduces an original grading scale that we developed to better quantify EEG abnormalities, taking into account two parameters: frequency (i.e., SI) and spatial extent of IEDs. The scales used in previous studies depended solely on SI or spatial distribution of IEDs.14,29,30 Encephalopathy with CSWS is currently considered to fall at the most severe end of the spectrum of age-related conditions in which IEDs are believed to display a deleterious impact on cognition.8 There is an EEG-clinical continuum between BECTS, atypical benign partial epilepsy, Landau Kleffner syndrome, and CSWS encephalopathy. On this spectrum, the degree of spatial extent of IEDs has been shown to influence cognitive status. To illustrate, in comparison with typical BECTS without significant cognitive impairment, the EEG results of an idiopathic focal epilepsy patient with educational problems more frequently reveal bilateral and generalized IEDs, in addition to higher activation of IEDs during sleep.31,32 On the CSWS spectrum, therefore, SI is not the only EEG parameter associated with cognitive impairment. For example, in a recent large series, no significant clinical difference was observed between children with an SI > 85 and <85%.33 We therefore believe that our grading scale, which is easy to use in clinical practice, reflects more adequately than SI the severity of the different EEG patterns of the CSWS spectrum. Nevertheless, the clinical validity of this scale still needs to be established by further studies assessing EEG-clinical correlations. Finally, we can retain three methodological points that limit the interpretation of these results. First, the retrospective nature of the study causes a certain degree of selection bias. Secondly, in the absence of a control group, the possibility of spontaneous improvement cannot be excluded. Thirdly, electroeclinical correlations are limited by the absence of systematic standardized clinical and neuropsychological assessment. In conclusion, TPM may decrease EEG abnormalities in epileptic encephalopathy with CSWS, which leads to clinical improvement in the majority of patients. However, relapse may occur in the long-term in nearly half of the cases. In addition, TPM has been shown to be particularly useful in reducing seizure frequency in refractory cases. Our results are globally comparable to those of other studies investigating the effects of the standard AEDs commonly used for this syndrome, such as LEV and STM. Taking into account its unfavourable cognitive adverse event profile in comparison to both of these other AEDs, TPM should probably not constitute a first choice for CSWS treatment. It remains, however, potentially useful in refractory cases, especially those with high seizure frequency.
Please cite this article in press as: Vrielynck P, et al., Topiramate in childhood epileptic encephalopathy with continuous spike-waves during sleep: A retrospective study of 21 cases, European Journal of Paediatric Neurology (2016), http://dx.doi.org/10.1016/ j.ejpn.2016.08.015
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e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y x x x ( 2 0 1 6 ) 1 e6
Conflict of interest The authors have no conflict of interest to disclose.
Appendix A. Supplementary data Supplementary data related to this article can be found at http://dx.doi.org/10.1016/j.ejpn.2016.08.015.
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Please cite this article in press as: Vrielynck P, et al., Topiramate in childhood epileptic encephalopathy with continuous spike-waves during sleep: A retrospective study of 21 cases, European Journal of Paediatric Neurology (2016), http://dx.doi.org/10.1016/ j.ejpn.2016.08.015