Therapeutic approach to epileptic encephalopathies

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1 EPILEPTIC ENCEPHALOPATHIES Therapeutic approach to epileptic encephalopathies *Federico Vigevano, Alexis Arzimanoglou, Perrine Plouin, and *Nicola Specchio *Department of Neuroscience, Bambino Gesu Children s Hospital, IRCCS, Rome, Italy; Epilepsy, Sleep and Pediatric Neurophysiology Department, University Hospitals of Lyon (HCL) and Lyon s Neuroscience Research Centre (CRNL), INSERM U1028, CNRS 5292, UCB Lyon 1, Lyon, France; and Clinical Neurophysiology, Hospital Necker Enfants Malades, et INSERM U663, Paris, France SUMMARY Epileptic encephalopathies (EEs) are electroclinical entities with a peculiar course of disease; seizures and electroencephalographic (EEG) epileptiform abnormalities, ictal and interictal, contribute to progressive disturbance of cerebral functions. Frequently EEs are drug resistant, and consequences may be catastrophic. The main goal of treatment is to stop the peculiar course of epilepsy, operating on three parameters: seizure control, reduction of EEG abnormalities, and developmental outcome. For a correct therapeutic approach it is mandatory to have an as accurate as possible syndromic and etiologic diagnosis. Given the poor efficacy of conventional antiepileptic drugs (AEDs), the use of specific drugs for EEs, such as adrenocorticotropic hormone (ACTH) and corticosteroids or stiripentol is suggested. In some cases the choice of treatment is strictly related to the etiology: vigabatrin in tuberous sclerosis, ketogenic diet in glucose transporter type 1 (GLUT-1) deficiency, and pyridoxine in pyridoxine deficiency. Some AEDs combinations, such as sodium valproate with lamotrigine, have also provided interesting results, for example, in Lennox- Gastaut syndrome, although controlled studies are lacking. Finally, early surgery can be an option in children with focal structural abnormalities responsible for EEs preferably before irreversible damage on developmental outcome. Multispecialist support is recommended in EE. Management should be global from the onset, integrating not only seizure control but also all issues related to comorbidities, particularly neuropsychological and psychiatric. KEY WORDS: Epileptic encephalopathy, Treatment, Cognitive disability, Adrenocorticotropic hormone, Steroids, Stiripentol,, Surgical treatment. According to the International League Against Epilepsy (ILAE) Commission Report definition, epileptic encephalopathies (EEs) are conditions in which the epileptiform abnormalities are believed to contribute to progressive disturbance in cerebral function (Engel, 2001). This means that not only epileptic seizures, but also severe epileptiform electroencephalography (EEG) abnormalities contribute to progressive decline of cerebral functions. In this definition are highlighted three main features that characterize EEs: epileptic seizures, EEG abnormalities, and developmental delay. This new concept embodies the notion that the epileptic activity itself may contribute to severe cognitive and Address correspondence to Federico Vigevano, Department of Neuroscience, Bambino Gesù Children s Hospital- IRCCS, P.zza S. Onofrio 4, Rome, Italy. federico.vigevano@opbg.net Wiley Periodicals, Inc International League Against Epilepsy behavioral impairments above and beyond what might be expected from the underlying pathology alone, and that these can worsen over time (Berg et al., 2010). This perspective is useful to understand what EEs really are (this was detailed in another article of this supplement), and how they should be clearly differentiated from brain diseases that are responsible for early onset severe epilepsy. In addition, this concept has essential consequences regarding the therapeutic approach. Treatment of EEs might stop or at least reduce cognitive and behavioral impairment, but has not had any effect on the underlying pathology. On the other hand, treatments focused on the underlying pathology, such as in metabolic diseases or in conditions that are suitable for the surgical treatment, might be effective not only for the condition responsible for the epilepsy but also for the secondary EE. EEs should be considered as conditions that might appear during the evolution of different epilepsies, often 45

2 46 F. Vigevano et al. in symptomatic cases, and less frequently in cases without clear-cut brain lesions. EEs are conditions with typical onset in childhood, very often resistant to treatment, with persistence of seizures and deleterious effect on the developing brain. Therefore the main goal of the therapeutic approach to EEs is to restore the neurologic status preceding the EEs, or at least to reduce the consequences of this peculiar course of epilepsy. Evaluation of Efficacy of Treatment in EEs To evaluate the effectiveness of the treatment in EEs the following should be considered. First, it is essential to follow three main parameters: seizures control, decrease or resolution of EEG abnormalities, and developmental outcome. As is possible for all epilepsies, also in EEs there may be a spontaneous remission. In infantile spasms a spontaneous remission may arrive in 10 25% of cases (Hrachovy et al., 1991). In some EEs, seizures may be very brief or manifest with subtle symptoms that are difficult to evaluate only with observation by parents. As an example, to prove the cessation of epileptic spasms, video-eeg monitoring is essential. Finally, in contrast with all other epilepsies, the response to treatment in EEs is all or none : a 50% decrease in seizure frequency in infantile spasms or in atonic seizures, affecting quality of life, is irrelevant. Although the effects of treatment on seizure frequency and on EEG abnormalities might be quantifiable, the effect on developmental delay is not so easily assessed. In some EEs it is difficult to evaluate how much of the developmental delay is determined by epileptic activity and how much is related to an early onset of the epilepsy, or to the preexisting cognitive impairment caused by brain disease. On the other hand, in cases, such as in West syndrome in which the spasms develop in normal infants, or in continuous spikes and waves during sleep (CSWS) that become evident in patients with idiopathic focal epilepsies, regression strictly related to EEs is clearly evident; therefore, effects of treatment on cognitive development will be manifest and quantifiable. Finally, it is notable that despite a large number of publications on this topic, evidence regarding the efficacy of different treatments is limited, and therefore, therapeutic options and recommendations are based more on case series, expert consensus, or personal experience. This is much more evident in newborns, for whom there are no recommendations regarding treatment: Experiences are based on treatment of EEs in infants and children, and the use of antiepileptic drugs (AEDs) is based mainly on personal experiences and case reports. Treatment of EEs with Specific Drugs Hormonal treatment and vigabatrin As in all epilepsies, also in EEs the most appropriate treatment is based on the accurate diagnosis of the epilepsy syndromes. Following what has been suggested in a recent publication by McTague and Cross (2013), it is possible to summarize treatment of EEs using the recommendations of the expert consensus of the National Institute for Clinical Excellence (NICE) ( Table 1 shows treatments suggested for different epileptic syndromes with EEs. Efficacy of conventional AEDs is poor in EEs; in Table 1 medications are listed that we might consider specific for EEs, as they are used exclusively used in some syndromes; these medications include adrenocorticotropic hormone (ACTH) and corticosteroids, or stiripentol. ACTH has been used for the treatment of infantile spasms (IS) worldwide since the work of Sorel and Dusaucy-Bauloye (1958). Even if corticosteroids and vigabatrin (VGB) demonstrated efficacy in the treatment of IS, ACTH still should be considered as a first-line option for this condition (MacKay et al., 2004). After ACTH treatment about 60% of patients with spasms become seizure free; this is a higher percentage than in cases treated with corticosteroids and VGB. Relapse rate after treatment with ACTH is about 30% (Hrachovy et al., 1983). Although has been gain experience for >50 years, there is no consensus on which agent should be used preferentially and, particularly in the case of ACTH, on the optimal dosing schedule. The only finding through a Cochrane review aimed to determine the efficacy of corticosteroids in terms of seizure control, improvements in cognition, and quality of life is one crossover trial with a small number of patients (Gayatri et al., 2007). In 2004, MacKay et al. performed an exhaustive meta-analysis of the literature on the medical treatment of IS. Their work confirmed that, despite the widespread use of ACTH and steroids, there are few prospective studies and only five randomized trials showing the efficacy of this drug. Moreover, treatment protocols differ significantly as concerns the dosage, ranging between 0.2 IU/kg and 150 IU/m 2, the duration of highest dose, ranging from 7 to 40 days, and the duration of treatment, ranging from 3 to 12 weeks. Recently Pelloch et al. published the consensus of the U.S. Infantile Spasms Working Group (ISWG) (Pellock et al., 2010) confirming that ACTH should be considered as a first-line treatment for IS, and a low dose treatment with short duration (approximately 2 weeks followed by taper), was suggested.

3 Treatment of Epileptic Encephalopathies 47 Table 1. AED option by epilepsy syndrome EIEE MPSI Infantile spams/west syndrome not due to tuberous sclerosis Infantile spams/west syndrome due to tuberous sclerosis Dravet syndrome CSWS First-line AED Levetiracetam Levetiracetam Clonazepam ACTH Sodium Valproate Topiramate Adjunctive AEDs Zonisamide Phenobarbitone Stiripentol Bromides ACTH, prednisolone Stiripentol Sodium valproate Ethosuximide Sulthiame LGS Sodium valproate Lamotrigine Levetiracetam LKS Valproate Sulthiame Multiple subpial transection MAE Sodium valproate Lamotrigine Clonazepam Rufinamide Felbamate Ethosuximide AEDs that may be considered on referral to tertiary care Felbamate Rufinamide Topiramate Vagal nerve stimulation AEDs that may worsen the EE Gabapentin Lamotrigine Oxcarbazepine Phenytoin Pregabalin Tiagabine Phenobarbital Phenytoin Gabapentin Oxcarbazepine Pregabalin Tiagabine n.r. Phenytoin Adapted and modified from National Institute for Clinical Excellence (NICE) guidelines CG137 (National Institute for Clinical Excellence, 2012) and from McTague A and Cross JH (2013). EIEE, early infantile epileptic encephalopathy; MPSI, migrating partial seizures of infancy; CSWS, continuous spikes and waves during sleep; LGS, Lennox-Gastaut syndrome; LKS, Landau-Kleffner syndrome; MAE, myoclonic astatic epilepsy. Oral corticosteroids seem to be less effective than ACTH: the more used drug is prednisolone, even if hydrocortisone is preferred in France. After broad use in several types of epilepsies, and following the discovery of a peripheral visual field defect as a specific adverse effect, VGB is now exclusively used in the treatment of IS. Some studies confirmed the efficacy of VGB in around 50% of nonselected cases; this percentage increases to 100% in cases with IS that are symptomatic of tuberous sclerosis (Chiron et al., 1997). The United Kingdom Infantile Spasms Study (UKISS) (Lux et al., 2005; Darke et al., 2010) compared the use of ACTH or oral prednisolone with VGB in a prospective study and found that after 2 weeks of treatment, spasm cessation was achieved in 40 (73%) of 55 patients randomized to hormonal treatment, compared to only 28 (54%) of 52 patients randomized to VGB, even though long-term seizure outcome did not differ between the two treatments. Hormonal treatment was also associated with a better developmental outcome. In a randomized study by Vigevano and Cilio (1997), evidence for a superior efficacy of ACTH over VGB in IS not due to tuberous sclerosis, at least in the short-term, has also been provided. VGB could be considered as an alternative option to hormonal treatment, even if the duration of treatment should be the shortest the possible, considering the risk of visual field defect. The hormonal treatment is considered as a first-line treatment also in CSWS, and in Landau-Kleffner syndrome (LKS) (Veggiotti et al., 2012). Both entities are

4 48 F. Vigevano et al. characterized by an extreme activation of EEG abnormalities that are continuous during sleep. The increase of EEG epileptiform abnormalities is associated with a severe cognitive and behavioral impairment. Van Bogaert et al. (2006) in a multicenter study clearly demonstrated that the efficacy of conventional AED, mainly valproate (VPA), ethosuximide (ETS), and sulthiame, is often incomplete and transitory. (CBZ), phenobarbital (PB), and phenytoin (PHT) are ineffective and may even increase EEG epileptiform abnormalities and the clinical conditions. The hormonal treatment with prednisolone or hydrocortisone, short and prolonged ACTH, or corticosteroid therapy, or intravenous methylprednisolone pulses followed by oral prednisolone, result in an improvement of language, cognition, and behavior in almost all patients, and is usually accompanied by an improvement on the EEG. Some patients might relapse during steroid withdrawal, requiring second hormonal treatment. The risk of relapse seems to be related to a brief duration of treatment. The relapse is not the rule, and in several patients a unique treatment may arrest the disease. The positive response to hormonal treatment is highly significantly associated with reversal of cognitive impairment in long-term evaluation (Buzatu et al., 2009). The hormonal treatment is also used in early infantile epileptic encephalopathy (EIEE) and in Lennox-Gastaut syndrome (LGS) without significant success. Stiripentol Stiripentol is a drug that is used exclusively for the treatment of Dravet syndrome (DS) (Chiron & Dulac, 2011). The efficacy of DS in combination with clobazam and VPA has been demonstrated in a randomized placebocontrolled trial (Chiron et al., 2000). Stiripentol acts both through cytochrome P450 (CYP) inhibition and increasing the action and the plasmatic levels of clobazam and VPA, sometimes requiring a reduction of dosage. Likely stiripentol also has a direct anticonvulsant activity owing to enhancement of inhibitory c-aminobutyric acid (GABA)ergic neurotransmission (Quilichini et al., 2006; Grosenbaugh & Mott, 2013). Stiripentol seems to be active in the reduction of the number of prolonged seizures that are the hallmark of DS. In addition, stiripentol has been used recently to treat other conditions. Few anecdotical case have been reported showing its efficacy, though data should be confirmed. The ketogenic diet (KD) is an alternative treatment used in association with conventional AEDs to treat drug-resistant epilepsies in children, and frequently to treat EEs (Freeman et al., 2006). It has been found to be particularly effective in myoclonic astatic epilepsy (MAE) with positive results in >50% of patients, almost 30% of them becoming seizure free (Caraballo et al., 2006). Caraballo (2011) also reported very good results with KD in DS, with 10 of 16 patients having a 75 99% decrease in seizure frequency and the remaining having a 50 74% decrease in seizures. Similar results to that reported with other conventional AEDs have been documented in the treatment of LGS (Lemmon et al., 2012). Following McTague and Cross (2013), KD seems to be particularly effective in EEs with generalized seizures, especially in cases with a prominent myoclonic component. It is noteworthy that KD is a first-line treatment for patients with GLUT-1 defects and with pyruvate dehydrogenase deficiency, as it provides an alternative cerebral energy source. Pyridoxine It should be noted that EEs with a suppression-burst pattern might be evident in neonates with pyridoxine or pyridox(am)ine phosphate oxidase (PNPO) deficiency; therefore, in cases without a clear etiology, a treatment with intravenous pyridoxine and/or oral pyridoxal-5-phosphate should be tried. Treatment of EEs with Conventional AEDs Conventional AEDs are usually used in treatment of EEs with discouraging results. As already noted, EEs represent a peculiar course of epilepsy that is seen in patients with epilepsy who are already treated with conventional AEDs. Therefore, the development of EEs might be seen in patients who are already treated with AEDs. Valproate and lamotrigine (LTG) are considered as a first-line treatment in LGS and MAE (Arzimanoglou et al., 2009; Doege et al., 2013; Lemmon & Kossoff, 2013). It is our experience that excellent results are possible with clonazepam in MAE, with a 60% seizure-free outcome (Trivisano et al., 2011). Since its availability in 1993, felbamate (FBM) showed efficacy in several types of drug-resistant epilepsies, particularly in LGS. Following the publication of reports regarding aplastic anemia and hepatic failure, the use of FBM has been drastically reduced, but several tertiary centers still use it. Its efficacy in LGS and MAE has been recently confirmed by Zupanc et al. (2010): 22% of patients with LGS became seizure free; 68% had a >50% reduction in seizure frequency. In the MAE group, complete seizure control was achieved in six of eight patients.

5 Treatment of Epileptic Encephalopathies 49 Rufinamide (RFN) in a randomized controlled trial in patients with LGS led to a significant reduction of seizures, mainly drop attacks, with reduction of the risk of related injuries (Glauser et al., 2008). Finally in EIEE and migrating partial seizures of infancy (MPSI) potassium bromide has been used with some positive results. This drug has been also used in DS, with a transitory seizure control in 30% of patients (Lotte et al., 2012). As already reported, CBZ, PB, and DPH may increase EEG epileptiform abnormalities and clinical features of CSWS. Also in DS and MAE, VGB and the so-called sodium channel blocker drugs, such as CBZ and PHT, are not indicated because of the possible aggravation of the clinical condition, mainly increasing frequency of myoclonic seizures. Surgical Treatment Drug-resistant focal epilepsies might evolve into an EE. Early onset focal epilepsies may progress toward West syndrome and later toward an LGS. During childhood, patients with symptomatic focal epilepsies might present with CSWS. Symptomatic cases of focal or hemispheric lesions might improve in response to surgical treatment, such as lobectomy, hemispherotomy, or hemispherectomy, with better results the earlier the surgery is performed. The best results are reached in cases with type 2 focal cortical dysplasia. Some patients with LKS have been treated with multiple subpial transections and have showed some improvement, but not normalization of language functions (Irwin et al., 2001). However a surgical approach to treat this condition seems to be too aggressive, given that in LKS a spontaneous improvement is usually seen in puberty. Patients with LGS and drop attacks might improve with callosotomy. However, in the most recent protocols the use of vagus nerve stimulation (VNS), before callosotomy, is preferred (Lancman et al., 2013). Conclusion EEs are the most severe types of epilepsies because, other than multiple seizures, they cause a progressive disturbance of cerebral functions in the developing brain. Drug resistance is frequent and the persistance of seizures and EEG epileptiform abnormalities might have catastrophic consequences. A correct therapeutic approach is fundamental, starting from an accurate syndromic and etiologic diagnosis. Keeping in mind that the main goals of treatment are seizure control, the decrease or resolution of EEG abnormalities, and the achievement of normal developmental milestones, a strict monitoring of those parameters should be done. In addition to EEG or video-eeg, at regular time intervals a neuropsychological and psychiatric assessment should be performed. Even if the prognosis for EEs is severe, we should acknowledge that there are some conditions with catastrophic evolution in which our intervention may significantly alter the course of the disease; this might happen in patients with IS and hypsarrhythmia if treated with hormonal treatment, in patients with EE due to focal cortical dysplasia or hemimegalencephaly if surgical treated, and in patients with pyridoxine or PNPO deficiency if treated with intravenous pyridoxine and/or oral pyridoxal- 5-phosphate. In early onset EEs with suppression-burst and in LGS, the possibilities to significantly modify the disease evolution are poor, and our intervention should be more focused on improving quality of life. Finally some EEs may manifest a transient drug resistance and spontaneously improve with puberty, as it happens in CSWS and MAE. Disclosure None of the authors has any conflict of interest to disclose. 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