Effects of antiepileptic drugs on interictal epileptiform discharges in focal epilepsies: an update on current evidence.

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Review

Effects of antiepileptic drugs on interictal epileptiform discharges in focal epilepsies: an update on current evidence Expert Rev. Neurother. 15(8), 947–959 (2015)

Melania Guida, Alfonso Iudice, Enrica Bonanni and Filippo Sean Giorgi* Department of Clinical and Experimental Medicine, Neurology Unit, University of Pisa-Pisa University Hospital, Pisa, Italy *Author for correspondence: Tel.: +39 0 5099 2000 Fax: +39 0 5055 4808 [email protected] or [email protected]

Interictal epileptiform discharges (IEDs), occurring in the electroencephalograms (EEG) of patients with focal epilepsy, are crucial for diagnosis, while their relationship with seizure severity and recurrence is controversial. The effects of antiepileptic drugs (AEDs) on IEDs are even more debated. In general, it is currently believed by experts in the field that most of the classical AEDs do not significantly affect IEDs occurrence in these patients, and that monitoring their EEG effects during treatment is useless. In this review, we update the existing literature on the effects of classical and newer AEDs on focal IEDs, emphasizing the scarcity of data concerning the latter. We also discuss potential limits of available clinical and experimental data and future perspectives. KEYWORDS: antiepileptic drugs . electroencephalogram . focal epilepsy . hippocampal slices . interictal epileptiform discharges

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temporal lobe epilepsy

Electroencephalography (EEG) is a fundamental tool in the diagnosis of epilepsy. Even though EEG can occasionally detect the onset and spreading of seizures, in the majority of patients, the main role of EEG is the identification of interictal epileptiform discharges (IEDs). When IEDs are present in an EEG, their features and distribution play an important role for better characterizing the epilepsy syndrome and the site of seizure onset in the single patient. Scalp EEG IEDs are generally considered as a manifestation of the hyperexcitability of neuronal cells causing the seizure onset and are the rough manifestation of complex cellular phenomena (for a review see [1], and below). In idiopathic generalized epilepsy (IGE), there is a strong association between IEDs and seizures [2], while in partial epilepsy, this relationship is more controversial ([3] and below). Repeated standard scalp EEG recordings are often performed in the single patient to monitor therapy with antiepileptic drugs (AEDs) by many neurologists managing epilepsy. This is informahealthcare.com

10.1586/14737175.2015.1065180

probably often based on the concept that potentially AEDs can suppress IEDs and that the presence of IEDs in EEG is associated with seizure recurrence. This assumption is essentially correct for IGE, in which it has been clearly shown since the very early studies on EEG and epilepsy, and repeatedly confirmed thereafter, that the diffuse IEDs discharges in the single patients disappear in parallel with the cessation of seizures [2]. This is likely to be due to the fact that IEDs sequences occurring in childhood absence epilepsy, as well as in juvenile myoclonic epilepsy, can be considered already as ‘initial’ ictal discharges, which become clinically evident when lasting long enough [4]. Also concerning focal epilepsy syndromes, many neurologists still assume that the persistence of focal IEDs is associated with a higher seizure recurrence likelihood, and that, on the contrary, IEDs disappearance indicates a low risk for occurrence of new seizures. Thus, according to this assumption, showing in the single patient that an AED reduces EEG IEDs

2015 Informa UK Ltd

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Review

Guida, Iudice, Bonanni & Giorgi

recurrence (in terms of, e.g., IEDs/min) would represent an early index of a significant beneficial effect of the drug on seizure recurrence; hypothetically, it might also lead the prescribing physician to further increase the dosage of the putative effective AED to induce a complete disappearance of IEDs. By the same token, a lack of efficacy of an AED on IEDs would allow early to predict its lack of efficacy on seizures. The hypothesis of a potential correlation of IEDs with seizure recurrence explains why in the past 40 years there have been a lot of studies in which the effects of AEDs on IEDs have been assessed. Unfortunately, as it will be described below, such a direct link between IEDs and seizure recurrence in focal epilepsy has not been confirmed as a general rule. In this review, after briefly mentioning the physiopathological basis of IEDs and their modulation by AEDs, we summarize the main findings on the effects of each single AED on focal IEDs. A final commentary on the meaning of these studies and potential future directions are provided at the end of the article. Interictal epileptiform discharges

IEDs recorded in scalp EEG reflect simultaneous activation of cortical neurons from relatively large cortical areas. The mechanisms underlying IEDs generation are still largely unknown. However, several experimental data in the past years provided some important information on their origin (for extensive reviews, see [1,5]). Actually, experimental data on IEDs have been obtained by a variety of approaches, significantly differing from one another, and these differences might affect by themselves the discrepancies among different studies, even though some common features among them have also been shown. IEDs have been ‘reproduced’ in vitro, in brain tissue collected form rodents, or in surgical specimens obtained from focal epilepsy patients. Concerning in vitro studies, in entorhinal cortexhippocampal slices extracellular population spikes occur after bath application of different compounds, especially g-aminobutyric (GABA)ergic antagonists, glutamatergic agonists or 4-amynopiridine (4AP) (a blocker of potassium currents). While the mechanisms of IEDs induction in the two former ones appear rather intuitive (i.e., simplistically, a block of inhibition or an enhancement of excitation), IEDs reproduced by the latter approach rely on more complex mechanisms, and are abolished by glutamatergic AMPA receptor antagonists or GABA receptor antagonists [1,6]. The latter observation suggests a role for a ‘GABA-mediated’ hypersynchronism in mediating such IEDs. This has been confirmed not only in the entorhinal cortex of in vitro isolate guinea pig brain [1], but, more interestingly, also during in vitro recordings of IEDs from hippocampal specimens of temporal lobe epilepsy (TLE) patients, which are abolished by both glutamatergic and GABAergic receptor antagonists [7,8]. Thus, both excitatory and inhibitory mechanisms can trigger and sustain IEDs onset. 948

Finally, a crucial role for both extracellular potassium levels and astrocytes activation and subsequent glutamate release has been claimed in the spreading [9] and in the onset of IEDS [10] respectively. Even from this brief summary on IEDs pathophysiology, it is evident how many different factors might contribute to modulate focal IEDs onset and spreading. Data obtained from experimental models are insufficient, as yet, to clarify in detail the mechanisms underlying IEDs onset, mainly because of the intrinsic methodological limits of these models themselves: indeed, each one of them probably reproduces partially the mechanisms of some IEDs substrates. Furthermore, it is worth mentioning that there are different types of IEDs (e.g., rushes preceding spikes – observed in some types of focal cortical dyplasia – or ripples observed before IEDs – described in several TLE patients, and which seem to be strictly dependent of healthy gap–junction transmission) [1], which are likely to be due to different molecular mechanism, and thus potentially to respond differently to different AEDs. Similarly, the site(s) of IEDs as well is likely to influence the effect of the different drugs, given the sharp differences in terms of excitability and ionic channel/receptor distribution existing between the different types of cortical and hippocampal neuronal subtypes. In any case, the above-mentioned experimental models are not sufficient by themselves to allow predicting, and adequately testing, the effect of different AEDs on interictal spikes, mainly because: a) different AEDs have multiple effects on different ionic channels and receptors, and affect simultaneously the whole brain. The effects of a given mechanism on the epileptic focus might be counteracted by the effect of the same drug on a different site, which can modulate the excitability of the epileptic focus; b) some antiepileptic drugs might have also different, still unknown, mechanisms of actions, which potentially might affect significantly, but of course in an unpredictable way, the epileptic focus. The effects of antiepileptic drugs on interictal epileptiform discharges in focal epilepsy

In the following paragraphs, we briefly summarize the existing studies in which the effects on IEDs of single AEDs (when administered alone or in combination) have been tested. A summary of the main findings of published studies is reported in TABLE 1, and a schematic summary is listed in TABLE 2. Carbamazepine

To our knowledge, there are no studies assessing the effect of acute administration of carbamazepine (CBZ) on EEG, although evidence on chronic administration is available. In the early studies addressing the effect of AEDs on EEG, CBZ failed in suppressing IEDs and no correlation between IEDs amount and seizure control was found [11–13]. In some patients participating in these studies, CBZ was even reported to increase IEDs amount [11,12]: this led Jeavons in 1972 to suggest that ‘it is in the best interest of patients never to carry out Expert Rev. Neurother. 15(8), (2015)

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CBZ

CBZ

CBZ

PHT

PB

VPA

VPA

LEV

LEV

LEV

Pryse-Phillips and Jeavons. (1970)

Rodin et al. (1974)

Marciani et al. (1993)

Milligan et al. (1983)

Kellaway et al. (1978)

Gram et al (1977)

Adams et al. (1978)

Stodieck et al (2001)

Aeby et al. (2005)

Kossoff et al. (2007)

Chronic

Chronic

Acute

Chronic

Chronic

Chronic

Acute

Chronic

Chronic

Chronic

Type of administration

6/children

12/ children

10/adults

10/adults

35/adults

12/ children

6/adults

15/ children and adults

37/adults

22/not specified

Patients (number/ age)

Other AEDs withdrawal

Yes (1–2 AEDs)

Yes (1–2 AEDs)

Yes

Yes

Not specified

BECTS

CSWS

Focal epilepsy

Focal and generalized epilepsy


Focal epilepsy

Focal epilepsy

Focal epilepsy

No

Yes

Focal epilepsy


Epilepsy syndrome or seizure type

Yes (2 drugs)

yes

Concomitant AEDs

[21]

PHT reduces IEDs

10 min EEG before and each 3 h for 7 times after drug administration

LEV decreases IEDs in 3 patients and improves EEG in 7 patients Prospective

Retrospective

30 min EEG before and after 6 m of therapy

LEV decreases IEDs

[37]

LEV decreases IEDs 20 min EEG, one EEG each 3 h for six times after acute administration of drug or placebo awake and sleep EEG before and after 2 m of LEV therapy

[32]

VPA decreases IEDs

EEG before and after 12 w of therapy

Prospective

Double-blind, placebocontrolled, crossover study

[31]

No effect of VPA on IEDs

EEG before and after therapy


[35]

[30]

PB decreases IEDs

24–36 h EEG before and after therapy

[26]

[19]

Prospective

Single-blind, placebocontrolled, crossover

Prospective

[16]

No effect of CBZ on IEDs


12 h EEG before and after 3 w of therapy

[12]

Ref.

4 h EEG before and after 2 m of therapy


EEG before and after 1 m of therapy and after CBZ discontinuation

Double blind, placebocontrolled Double blind, placebocontrolled, crossover

Conclusion

EEG assessment

Study design

ADHD: Attention-deficit/hyperactivity disorder; AEDs: Antiepileptic drugs; BECTS: Benign epilepsy with centrotemporal spikes; CBZ: Carbamazepine; CSWS: Continuous spike and wave during sleep; EEG: Electroencephalogram; GBP: Gabapentin; h: Hours; IEDs: Interictal epileptiform discharges; LCM: Lacosamide; LEV: Levetiracetam; LTG: Lamotrigine; m: Months; min: Minutes; OXC: Oxcarbazepine; PB: Phenobarbital; PHT: Phenytoin; TPM: Topiramate; VGB: Vigabatrin; VPA: Valproic acid; vs: Versus; w: Weeks.

Drug

Author (year)

Table 1. Overview of the main findings of published studies addressing the effect of AEDs on IEDs in focal epilepsy.


Effects of antiepileptic drugs on interictal epileptiform discharges in focal epilepsies

Review

949

950

Chronic

Chronic

Chronic

LEV

LEV

LEV

LEV

LTG

LTG

LTG

LTG

OXC

OXC

TPM

Von Stu¨lpnagel et al. (2010)

Larsson et al. (2010)

Atkins and Nikanorova M. (2011)

Bakke et al. (2011)

Binnie et al. (1986)


Akman et al. (2003)

Pressler et al. (2005)

Tzitiridou et al. (2005)

Franzoni et al. (2009)

Placidi et al. (2004)


36/ children

70/ children

61/ children



16/adults

19/ children

20/ children

17/ children

32/ children



Yes or no

Focal epilepsy Focal epilepsy

Yes (1–5 AEDs) or no

BECTS

No

No



Yes (1–4 AEDs)

Yes


Focal or generalized epilepsy and ADHD

CSWS

Focal epilepsy

Focal epilepsy


Yes

Yes (1–2 AEDs)

Yes

Other AEDs withdrawal

Yes

Concomitant AEDs

Prospective

Prospective

Prospective

Long term video-EEG before and after 4 m of therapy

EEG before and after 3 m, 12 m, 24 m and 36 m of therapy

EEG before and after 3 m, 6 m and 18 m of therapy

[46]

[44]

OXC decreases IEDs TPM decreases IEDs

[45]

OXC decreases IEDs

[43]

LTG decreases IEDs

24 h ambulatory EEG before and after therapy Double-blind, placebocontrolled, crossover study

[42]

Retrospective

[39]

LTG decreases IEDs

24-h video-EEG before and after 4 m of therapy

Prospective

LTG decreases IEDs

Routine EEG before and during therapy, one EEG each 3 m for 24 m

EEG before and after drug administration

Prospective

[34]

LEV decreases IEDs

[41]

24-h ambulatory EEG before and after 4 m of therapy

Retrospective

[38]

[33]

[36]

Ref.

LEV decreases IEDs

LEV decreases IEDs

LEV decreases IEDs

Conclusion

LTG decreases IEDs

24 h EEG before LEV and each 6 m during therapy

2 h EEG before and after 2–31 m of LEV therapy

20 min EEG before and after 3 m of therapy

EEG assessment

Prospective

Prospective

Retrospective

Study design


Chronic

Chronic

Chronic

Chronic

Chronic

Chronic

Acute

Chronic


Drug

Author (year)

Table 1. Overview of the main findings of published studies addressing the effect of AEDs on IEDs in focal epilepsy (cont.).


Review Guida, Iudice, Bonanni & Giorgi

Expert Rev. Neurother. 15(8), (2015)

45/adults

213/ children

Chronic

Chronic

Chronic

Chronic

GBP


LCM

LCM

VGB

VGB

CBZ vs PHT

CBZ vs PB vs VPA

CBZ vs VGB

PHT vs sulthiame

LTG vs diazepam

Li et al. (2013)

Giorgi et al. (2013)

Ben-Menachem and Treiman. (1989)


Wilkus et al. (1978)

Libenson and Caravale B. (2001)

Gobbi et al. (1999)

Wilkus and Green. (1974)

Jawad et al. (1986)

6/adults

54/adults

80/ children

14/adults

13/adults

10/adults

17/adults

18/adults

Yes

Yes

No

No

No

No

Yes (1–2 drugs)

Yes (1–4 AEDs)

Yes (median 2 AEDs)

Yes (1–4 AEDs)

Yes (1–4 AEDs)

Concomitant AEDs

Not specified

Focal epilepsy

Focal epilepsy



Focal epilepsy

Focal epilepsy

Focal epilepsy

Focal epilepsy

Focal epilepsy

Focal epilepsy



Double-blind, crossover

[23]

[40]

Diazepam >LTG > placebo Routine EEG before and after drug acute administration, one EEG each 30 min for 4 h

EEG before and after 12 m of therapy

PHT > sulthiame; no statistically significant results

[18]

EEG during baseline (tp with PHT) and during treatment period (tp with PHT or sulthiame)

VPA > CBZ > PB in focal IEDs; no statistically significant results

[17]

[52]

[53]

[50]

[20]

Routine EEG before and after AEDs therapy

Retrospective

No effect of CBZ and PHT in focal epilepsy

No effect of VGB on IEDs

VGB decrease IEDs

No effect of LCM on IEDs

[49]

[48]

No effect of GBP on IEDs No effect of LCM on IEDs

[47]

Ref.

No effect of GBP on IEDs

Conclusion

VGB > CBZ; statistically significant results

EEG before and after 4 m of therapy

Double-blind, crossover

prospective

24 h video-EEG before and after 3 m therapy

EEG before and after 3 and 12 m of therapy

1,5 h video-EEG before and after 6 m of therapy

4 day video-EEG (2 day baseline, 2 day treatment)

Video-polysomnography before and after 4 m of therapy

24 h video-EEG before and after 3 m of therapy

EEG assessment

Prospective

Single-blind, placebo lead-in

Prospective

Prospective

Prospective

Prospective

Study design


Acute

Chronic

Chronic

Chronic

Acute

Chronic

25/adults

Placidi et al. (2000)

Chronic

GBP


Mattia et al. (2000)


Drug

Author (year)

Table 1. Overview of the main findings of published studies addressing the effect of AEDs on IEDs in focal epilepsy (cont.).



Review

951

Review


Adults

Children

Adults

Children

CBZ

na

na

=

=

PHT

#

na

=

na

PB

na

na

na

#

VPA

na

na

#/=

#/=

More recently, Marciani et al. tested CBZ in 15 patients (including adults and pediatric ones) with focal epilepsy [19]. After 2 months of therapy, IEDs frequency was unchanged or only slightly decreased in the majority of subjects experiencing a reduction in seizure frequency, while it was even increased in two patients who continued to have attacks, and thus the authors concluded that IEDs were influenced by the seizure frequency rather than by CBZ treatment [19]. Finally, in a more recent study by Gobbi et al. [20], CBZ did not affect the percentage of EEG with IEDs in de novo focal epilepsy children even at 1 year after starting treatment.

LEV

#

na

na

#

Phenytoin

LTG

#

na

#

#

OXC

na

na

na

#

TPM

na

na

#

#

GBP

na

na

=

na

LCM

#/=

na

#/=

na

VGB

na

na

#/=

#

ZNS

na

na

na

na

RTG

na

na

na

na

ESL

na

na

na

na

PRP

na

na

na

na

PGB

na

na

Na

na

Table 2. Schematic summary of AEDs effect on IEDs in focal epilepsy.


Drug

Acute administration

Chronic administration

CBZ: Carbamazepine; ESL: Eslicarbazepine; GBP: Gabapentin; LCM: Lacosamide; LEV: Levetiracetam; LTG: Lamotrigine; OXC: Oxcarbazepine; PB: Phenobarbital; PHT: Phenytoin; PGB: Pregabalin; PRP: Perampanel; VPA: Valproic acid; RTG: Retigabine; TPM: Topiramate; VGB: Vigabatrin; ZNS: Zonisamide.

In a single-blind, placebo-controlled trial in six patients with drug-resistant focal epilepsy, acute intravenous administration of 500–1000 mg of PHT produced a significant decrease in IEDs frequency [21], which was evident from up to 90 min after the infusion [21]. Conversely, chronic administration of PHT did not appear to influence IEDs frequency in several studies. In fact, in a double-blind, crossover study versus CBZ in 45 adult epileptic patients, PHT did not affect IEDs occurrence in focal epilepsy [17]. Similarly, in a double-blind, crossover study versus sulthiame in 54 patients with focal epilepsy, the number of IEDs was slightly inferior in the group taking PHT, but the difference was not statistically significant. The reports addressing the relationship between PHT blood levels and IEDs frequency have given controversial results, since while some authors have described a positive correlation between higher PHT levels and IEDs rate improvement [22,23], others did not confirm such a link [17,24]. Phenobarbital

EEG investigations during therapy with carbamazepine’ [14]. Actually, reconsidering these reports according to current knowledge, IEDs worsening was limited to patients with IGE, a phenomenon repeatedly confirmed thereafter [15]. Earlier observations were confirmed in two subsequent double-blind, crossover trials. In the first one, CBZ was compared with placebo in patients with focal epilepsy taking phenobarbital (PB) and phenytoin (PHT): after 3 weeks of therapy with CBZ, no significant change in IEDs rate in the whole group of patients was detected [16]. On considering each patient, the authors detected an increase in IEDs amount in 15 patients during treatment with CBZ; however, they ascribed the worsening to fluctuation in blood PHT levels [16]. In the second trial, CBZ was compared with PHT in a group of 45 patients with either focal or generalized epilepsy: no differences were found between the two drugs in IEDs amount in focal epilepsy, while CBZ caused an increase of IEDs in generalized epilepsy [17]. Accordingly, in a retrospective study in epileptic children, CBZ was compared with PB and valproic acid (VPA): a normalization of EEG was reported in 31.7% of patients with focal epilepsy treated with CBZ, but the differences between the three drugs were not statistically significant [18]. 952

To our knowledge, there are no studies evaluating the effect of acute administration of PB on IEDs, and only two studies assessing the effects of its chronic administration on EEG. In an old study most of patients were likely to have generalized seizures only, and thus it was not included in the present analysis [25]. The relationship between the ability of PB in suppressing IEDs and the extent of seizure control was shown in 12 children with focal epilepsy in a study by Kellaway et al. [26]. More recently, PB was compared with CBZ and VPA in a retrospective study in epileptic children: even though a complete disappearance of IEDs was reported in 23.3% of focal epilepsy patients taking PB alone, this effect was lower, even though not statistically significant, than the effects of VPA or CBZ (see below) [18]. Valproic acid

The efficacy of VPA in suppressing IEDs in IGE is well known [27–29], while its effect on IEDs in focal epilepsy is much more controversial. To our knowledge, only chronic administration of VPA has been tested thus far in patients with focal epilepsy. In a double-blind, placebo-controlled, crossover trial in 35 adult patients with focal and generalized epilepsy, Expert Rev. Neurother. 15(8), (2015)



VPA did not change significantly IEDs rate even though it improved seizure control in 60% of patients [30]. In another study in 10 adults with focal and generalized epilepsy, VPA was added to pre-existing AED therapy: IEDs activity improved not only in all patients with generalized epilepsy but also in three out of six patients with focal epilepsy, and EEG changes were reported to decrease in parallel with seizure frequency [31]. Finally, in a recent retrospective study in epileptic children, the authors reported a full clearing of IEDs in EEG of 42.1% of patients with focal seizures taking VPA, 31.7% of those taking CBZ and 23.3% of those taking PB, but the difference between the three drugs was not statistically significant [18]. Levetiracetam

The acute efficacy of levetiracetam (LEV) on IEDs has been assessed only in one study, which was performed in 10 patients with focal epilepsy, in a double-blind, placebo-controlled, crossover design [32]. The authors described a significant decrease of IEDs number in 8 out of 10 patients after acute administration of LEV [32] and did not find any correlation between IEDs control and LEV blood levels. To our knowledge, there are no published studies specifically designed to assess the effect of chronic administration of LEV on IEDs in focal epilepsy. Nonetheless, there are some studies assessing the antiepileptic efficacy of LEV in which the authors also reported, as a secondary outcome, the chronic effects on IEDs (TABLE 1). In particular, under LEV treatment, a significant IEDs decrease was reported in 10 out of 17 children with focal epilepsy [33] and in 16 out of 17 children with epilepsy and ADHD [34]. A similar outcome has been obtained also in children with epilepsy and epileptiform activity during sleep, such as benign epilepsy with centro-temporal spikes (BECTS) [35,36], Landau–Kleffner syndrome [36] and epileptiform activity during sleep classified as continuous spike and wave during sleep [36–38]. Lamotrigine

The first demonstration of the acute efficacy of lamotrigine (LTG) in suppressing IEDs dates back to 1986, when Binnie et al. [39] observed a reduction in IEDs during continuous EEG monitoring after a single dose of LTG in 16 patients with focal and generalized epilepsy. This result was later confirmed in a study by Jawad et al. [40]. These authors performed a doubleblind, placebo-controlled, crossover study of LTG versus diazepam or placebo and found that LTG was more effective than placebo, but less effective than diazepam, in suppressing IEDs in six patients with epilepsy after acute oral administration. The effect of LTG became evident 1 h after its administration, while diazepam effect was faster [40]. Interestingly, they did not find any correlation between acute LTG plasma levels and IEDs incidence, even though the effect of LTG appeared to be stronger at concentration of 1–3 mg/ml [40]. The epilepsy syndrome of the patients included in this study was not detailed, but they were likely to be mostly focal ones. informahealthcare.com

Review

Other studies subsequently assessed the effect of chronic administration of LTG in both focal and symptomatic generalized epilepsy. Marciani et al. [41] found that LTG reduced significantly IEDs incidence when compared with baseline EEG. Unfortunately, they did not perform any subanalysis taking into account the different epilepsy syndromes, but claimed that, independent of etiological features, LTG succeeded in reducing the IEDs spreading in focal epilepsy, thus allowing a better definition of the epileptic focus [41]. The effects of LTG on IEDs incidence were confirmed in a more recent study, also in this case, performed in patients with either focal or symptomatic generalized epilepsy [42]: after 2 years of follow-up, the number of IEDs decreased in 38%, increased in 11% and remained unchanged in 51% of subjects. When comparing patients with different seizure types, they found that the improvement was greater in subjects with complex partial seizures than in those with generalized seizures or multiple seizure types (61 vs 41 vs 18%). The small sample of patients per each syndrome did not allow discriminating for a specific syndrome-related effect of LTG on IEDs [42]. Finally, a suppressive effect of chronic LTG administration on IEDs in patients with focal seizures was observed also in a double-blind, placebo-controlled, crossover study in children with either focal or generalized epilepsies by Pressler et al. [43]: in their subanalysis, these authors observed a decrease of IEDs frequency and duration in 44% of patients with focal epilepsy. Also in this study, no significant differences between epilepsy syndromes have been identified [43]. Oxcarbazepine

To our knowledge, also concerning oxcarbazepine (OXC), there are no published studies designed ad hoc to assess its effects on IEDs. Nevertheless, a normalization of EEG after OXC therapy has been reported, as a collateral finding, in a few efficacy studies performed in pediatric populations. In particular, a complete IEDs disappearance was reported in approximately 25% of children with focal epilepsy [44] and 74% of children with BECTS [45] after chronic OXC treatment. It should be noted, however, that in BECTS a disappearance of IEDs can occur spontaneously during development, as acknowledged also by Tzitiridou et al. themselves in their article [45]. Topiramate

In the only study assessing the effect of topiramate (TPM) on IEDs, the authors reported a significant decrease in the mean number of spikes/10 min after 4 months of TPM treatment in 26 patients with focal epilepsy [46]. In these patients, TPM did not modify the spatial distribution or IEDs spreading. The acute effects of this drug on IEDs have not been specifically addressed thus far. Again, even in patients treated with TPM, no correlation between IEDs and seizure frequency was found among subjects with a relevant reduction of IEDs [46]. 953

Review



Gabapentin

Concerning gabapentin (GBP), two studies, performed specifically with the aim of addressing its effect on EEG, have shown that chronic administration of GBP did not modify IEDs rate in patients with focal epilepsy. In the first one, the authors recorded a 24-h video-EEG in 25 adults with drug-resistant focal epilepsy before and after 3 months of treatment with GBP. They did not find a statistical difference in the number of spikes/10 min, in the EEG recordings performed before and after GBP, even though they described a decrease in tendency to IEDs spreading after GBP [47]. These results were confirmed in another study in 18 patients with focal epilepsy, in which the authors did not find any significant changes in spikes incidence in EEG videopolysomnography recorded before and after 4 months of GBP treatment [48]. In both studies, no correlation between seizure frequency and IEDs rate has been identified [47,48]. No data on the effect of acute administration of GBP on IEDs are available. Lacosamide

The evidence on the effect of lacosamide (LCM) on IEDs is scarce. In some studies, a tendency toward the reduction of IEDs incidence after acute [49] and chronic administration [50] in small samples of patients with focal epilepsy has been reported, even though the results were not statistically significant and the patient samples were too small to allow clear conclusions. Vigabatrin

To our knowledge, the acute effect of vigabatrin (VGB) administration on EEG has not been assessed. Concerning chronic administration, double-blind trial designed to assess clinical efficacy of VGB in drug-resistant focal epilepsy failed in demonstrating an effect of VGB on IEDs (for a review of them, see [51]). The same results were obtained in a prospective, open-label study by Marciani et al. [52] in 14 subjects with focal epilepsy. In the latter study, VGB determined a decrease in IEDs/10 min in five patients, but the difference in mean number of IEDs in the whole sample before and after therapy was not statistically different. A decrease in IEDs occurrence in approximately 40% of subjects after 3 months and 12 months of therapy with VGB has been reported by Ben-Menachem and Treiman [53] in a study in 13 patients with drug-resistant focal epilepsy. Also for VGB (as described for other AEDs-see above), IEDs incidence modification did not seem to correlate with seizure frequency change [52,53]. Finally, in a study comparing the effects of VGB and CBZ in children with focal epilepsy, Gobbi et al. [20] described a statistically significant decrease of IEDs after 12 months of treatment with VGB, which was much higher than that induced by CBZ. Other antiepileptic drugs

To our knowledge, there are no available published data concerning the effects of pregabalin, retigabine, perampanel, 954

zonisamide and eslicarbazepine on IEDs in patients with focal epilepsy. Some experimental data on the effects of AEDs on IEDs

Experimentally, the effects of AEDs on IEDs have been assessed mainly in vitro. Even though a detailed description of these data is beyond the aims of this review, some of these studies are worth mentioning. Among them, the 4AP model has been the most extensively used with this respect: Fueta and Avoli [54] showed that PHT, PB, VPA, TPM, at concentrations sufficient to block ictal discharge, did not affect significantly hippocampal IEDs-like discharges, and similar data were obtained again with CBZ by Watts and Jefferys [55] and with PHT, PB and VPA by Bru¨ckner and Heinemann [56]. Avoli’s group, almost 20 years after their above quoted study, further explored the effects of CBZ, VPA and TPM on entorhinal cortex IEDs-like discharge, and did not observe, again, any significant effect on IEDs but only on more prolonged ictal-like discharges [57]. These observations are generally in line with what was observed in patients, except for TPM, which has been shown to reduce IEDs in both pediatric and adult focal seizures (see above). By assessing also the concomitant action of GABAA receptor antagonist on the type of IEDs and on the effects of AEDs, these authors suggested that GABAA receptormediated inhibition had to be fully operational for AEDs exerting their effects, and that in their in vitro model this mechanism was likely to be crucial for determining long seizure-like discharges, but not for the short IED-like discharges [57]. The true relationship of these two types of in vitro discharges (i.e., prolonged vs. short ones), with ictal discharges and IEDs respectively in TLE patients remain, as reported by these authors themselves, speculative. Interestingly, another in vitro model, hippocampal slices exposed to low calcium concentrations showed a powerful effect of both CBZ and PHT on IEDs [58]; in this model, VPA was much less effective than the other ones. In any case, the activity described in this study might have been arbitrarily interpreted as interictal, while it could have been, actually, an ictal event. Thus, these latter findings are not directly comparable with those obtained with the 4AP model [54–56], and once again show how difficult is to get a clear idea on the true correspondence between discharges obtained experimentally and human EEG IEDs. For the abovementioned reasons, it is very difficult to attempt any interpretation on the significant of the opposite findings obtained by the same AEDs in two different IED in vitro models. Finally, it is worth mentioning that in the low-magnesium in vitro model, VGB has been shown to block interictal-like hippocampal discharges [59]. Effects of AEDs withdrawal on IEDs

Another way to indirectly assess the relationship between AEDs and focal IEDs might be to evaluate the EEG effects of AEDs withdrawal. There are some studies, dating back already to the 1980s, obtained in patients undergoing AEDs (mostly classical sodium channel-blocking ones) reduction for Expert Rev. Neurother. 15(8), (2015)



presurgical evaluation: in these patients, an increase in IEDs was rarely observed, despite a seizure rebound (see, for instance, [60,61]). More recent data, obtained with intracranial recordings in patients with focal epilepsies (mostly TLE, but also with parietal or frontal epileptic foci), and thus allowing a more detailed quantification of IEDs, provided even more conflicting results [62]. In particular, even though within 24 h after a seizure, IEDs were generally increased in frequency (confirming well-known previous data [63]), this was not the case during the hours preceding a seizure, and, remarkably, AEDs dose reduction even led to a reduction in IEDs [62]. Thus, these types of study showed an even weaker correlation between AEDs and IEDs and IEDs and seizures, when compared with the abovementioned ones evaluating the effect of an AED introduction. Expert commentary

In the routine clinical practice, frequent EEG recordings still continue to be prescribed to patients with focal epilepsy, not only by general practitioners but also by neurologists, often on demand by the patients, and not only in those patients with pharmacoresistant seizures but also in patients in whom a full seizure control has been already achieved. This is in striking contrast with the general lack of knowledge on the effects of AEDs on IEDs, and, even more, with the lack of data on the relationship between focal IEDs recurrence and seizure proneness. In this review, we briefly reported an update on the most salient data concerning the effects of different AEDs on IEDs in focal epilepsy patients. Most of studies on this issue were not designed ad hoc to address this aspect, but the EEG data were reported as secondary measures. As reported in TABLE 2, there are striking differences among the effects of different AEDs, when comparing the acute effects with the chronic effects on IEDs, as well as the effects in children with those in adults. Actually, the acute effects on IEDs have been evaluated only for a few AEDs, namely PHT, LEV, LTG and LCM, and only in adult patients. Interestingly, all of them induced IEDs reduction; in the case of LCM, such a reduction was not statistically significant, but the low number of patients assessed was likely to be involved in this result. Chronic effects of AEDs are likely to be more relevant, since the efficacy of AEDs are established only assessing its effects on seizures on a timeframe of at least some months. Concerning chronic effects, LTG and TPM have been shown to reduce IEDs both in adults and in children. In children, a similar effect was observed also for PB, LEV, OXC and VGB. In adults, not only relatively newer AEDs, such as GBP and VGB, but also classical AEDs, such as PHT and CBZ, have not shown a clear-cut effect on IEDs chronically; VPA gave conflicting results among different studies. It should be noted that even though some of them are already widely used, no data at all on the effects of newer AEDs (pregabalin, zonisamide, retigabine, eslicarbazepine and perampanel) or only very scarce data for a few of them (LCM, LEV and OXC) are available. informahealthcare.com

Review

As said, the main issue to be addressed, however, to fully set the scene for clarifying the role of EEG monitoring during AED treatment is to clarify what is the real role of IEDs in the prediction of seizure control in focal epilepsy, that is whether a reduction or disappearance of IEDs in a patient with focal seizures is an early index of seizures reduction or disappearance, respectively. From the analysis of the literature on this issue, thus far, this does not seem to be the case. In fact there is not clear evidence on any correlation of focal IEDs with the frequency of seizures. This aspect, given its potential crucial implications, has been the subject of analysis different reviews by authoritative researchers in the past decades [3]. In particular, even though it is widely accepted the concept that within hours/few days after seizures there is an increase in IEDs frequency [62,63], the role and correlation of focal IEDs with subsequent seizure frequency have been a matter of long debate. This has been particularly addressed in patients with TLE, due to its high prevalence among pharmacoresistant epilepsy patients. In these patients, IEDs frequency does not correlate with subsequent seizure occurrence [3,60,64]. Experimental models have even led to the hypothesis that, in TLE, IEDs might bear an antiepileptogenic effect, that is, the more IEDs there are, the less likely it is the occurrence of new seizures [65]. However, the latter hypothesis has also been challenged by experimental data showing an opposite effects, that is, a precipitating role of IEDs toward subsequent seizures [66,67]. Also some of the data reported in this review indirectly support the lack of correlation between focal IEDs amount and seizure recurrence. In fact, for the classical AEDs, such as CBZ, PHT and VPA, several studies did not show significant IEDs modification, despite their strong antiepileptic effect. Furthermore, also indirect data obtained during AEDs withdrawal confirm these conclusions. There are several pathophysiological hypotheses explaining such discordance between IEDs and seizure recurrence that go beyond the aims of this review. It is worth mentioning, however, that one of the reasons for the lack of correspondence between a reduction of IEDs and seizure recurrence might be related to the fact that IEDs and seizures might not originate from the same focus in the same subject. This has been shown in in vitro models of TLE, where IEDs and seizures originated from different sites in the limbic system, reciprocally connected with each other [65,66,68,69]. Potentially, another effect of AEDs on IEDs in focal epilepsy patients, and justifying performing serial EEGs during AED treatments, might be that of reducing the spatial distribution of IEDs, helping to better pinpointing the epileptic focus [41,46]: this, for instance, might lead to an improvement in the epileptic focus identification, which would help in identifying potential candidates for epilepsy surgery. However, the extent of IEDs distribution during AEDs administration has not been investigated in detail, with only few inconclusive exceptions [41,46]. Thus this potential effect is only speculative. The above-reported evidence for a potential lack of correlation between IEDs occurrence and seizure proneness would 955


Review


seem sufficient to halt, by themselves, further investigations on the role of AEDs on focal IEDs. And this is likely to be at least one of the reasons why for the newest AEDs we do not have data on their effects on IEDs of the newer AEDs. However, we would like to point out that: a) thus far, most of the experimental studies on the correlation between IEDs and seizures have been performed on TLE: in humans, this syndrome is responsible for many cases, but in most of patients with focal seizures, these originate from extratemporal foci; b) detailed experimental data on specific etiopathogenic mechanisms of IEDs and seizures in rather common causes of focal epilepsy in humans still lack: this is the case, for instance, of postischemic/ hemorrhagic focal epilepsy; and most of the studies available in patients have been performed in pediatric populations, and the mechanisms underlying seizures in these patients are often strikingly different from those of acquired symptomatic seizures occurring in adults. Last but not the least, as above reported, most of the data on the effects of AEDs on IEDs concern older drugs, while data addressing the effects of the newer ones is scarce. Since these latter ones often act on molecular targets (e.g., potassium channels currents, carbonic anhydrase, slow inactivation of voltage-gated sodium channels, glutamatergic receptors, etc.) strikingly different from the ones known to be targeted by the classical AEDs, they might potentially affect in a completely different manner either IEDs or ictal discharges, or both. In other words, in our opinion, it cannot be fully foreseen at present whether monitoring the effects of these drugs on IEDs might be useful or not in focal epilepsy patients for predicting the likelihood of seizure recurrence according to their effects toward IEDs. Five-year view

As briefly mentioned in the introduction, and elegantly detailed by De Curtis et al. [1], not all IEDs are equal, but there are specific subtypes of IEDs that are likely to be so due to specific molecular mechanisms (e.g., spikes preceded by rushes or ripples – see second paragraph). Even classical IEDs (e.g., spikes, spikes and slow-waves, sharp waves, etc.) might theoretically be associated with etiologies sharing some similarities in terms of cell types included in the epileptic focus (e.g., astrocytes vs neurons and different neuronal subtypes) and of molecular main features: these phenomena play a fundamental role in the mechanisms underlying IEDs and, thus, also in the efficacy of different AEDs bearing different mechanisms of action. Finally, the site(s) of focal IEDs as well is likely to influence the effect of the different drugs, given the sharp differences in terms of excitability and ionic channel/receptor distribution existing between the different types of cortical and hippocampal neuronal subtypes. In brief, there are probably many different types of patients with different types of IEDs linked to many different mechanisms. These aspects might explain, at least, in part, why thus far very conflicting results have been obtained concerning both the effects of single AEDs on IEDs and the correlation of such an 956

effect with subsequent seizure recurrence. Indeed, the fact that in these studies data from patients bearing very inhomogeneous etiologies as well as different sites and types of IEDs might have contributed to provide such inconclusive results. Thus, trying to address, the specific role of IEDs in predicting seizures occurrence, and whether it is possible, in the single patient, to predict the role of different AEDs in reducing seizure by monitoring their effects on IEDs, would need more complex study approaches. In our opinion, these questions can be addressed adequately only by large-scale studies on hundreds of patients in which there are: reliable interictal EEG analysis (with a full description of sites and types of IEDs); etiological characterization for each patient; and availability of EEGs and seizure recurrence data, collected before and after chronic AEDs treatment. Post-hoc multivariate analysis taking into account the role of each one of these variables (especially the EEG and etiological features) might eventually clarify whether specific IEDs subtypes, occurring at specific cortical sites and in specific etiological subtypes, might show a decrease/disappearance after specific AED treatment, and whether this might be associated with seizure disappearance. However, we are skeptical that the international epileptologists’ community will decide, in the next few years, to devote a large joint effort to perform such studies, since these are not likely considered as ‘trendy’ as other ones in the epilepsy field currently are. Alternatively, a more feasible approach would be using EEG as a secondary measure in pre- and post-marketing efficacy randomized controlled trials on AEDs. These trials usually already provide sufficiently accurate data on the number and types of seizures and etiological features of patients enrolled, and are currently being set up on a regular basis by the international community of epileptologists to assess AEDs efficacy either as add-on or as monotherapy. Adding a baseline and post-treatment routine EEG to these current protocols would provide precious data for post hoc analysis on the effects of AEDs toward specific IEDs and on their correlation with efficacy outcomes in patients with specific etiologies and site of seizure onset. With this approach, it is likely that most of data available in the coming years would concern mainly newer AEDs, which are the ones for which most controlled trials will be developed. A reasonable timeframe for having already some interesting data with this respect would be just a few years from now. In parallel, it is likely that in the coming years new, more sophisticated experimental models will be developed with the aims of reproducing more closely the different etiopathogenetic phenomena underlying the different causes of focal human epilepsy, and IEDs pathogenesis, as recently stated also by authoritative representatives of ad hoc created ILAE/AES commissions [70,71]. These models hopefully will provide a chance to better detail experimentally the role of AEDs on IEDs. Finally, the advances in our knowledge of the main mechanisms underlying the different etiological subtypes of acquired/ congenital focal epilepsies, in parallel with the development of AEDs with specific molecular effects, might reveal unexpected effects of AEDs on IEDs in specific epilepsy subtypes, and with potential prognostic role. Expert Rev. Neurother. 15(8), (2015)


Financial & competing interests disclosure

A Iudice has received research grants and consulting fees from Janssen, UCB, Eisai, Novartis, Biogen, Merck-Serono, Teva, Cyberonics and AIFA. The authors have no other relevant

Review

affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Key issues .

Interictal epileptiform discharges (IEDs) occurring in the electroencephalograms (EEG) of patients with focal epilepsy are neurophysiological hallmarks playing a fundamental role in diagnosis.

.

The first studies on the effects of antiepileptic drugs (AEDs) on IEDs date back to more than 40 years ago and were performed with the


aim of assessing the potential use of IEDs as markers of seizure control. Many neurologists still continue to regularly prescribe, with this aim, routine EEGs to their patients with focal epilepsy. .

Concerning studies on the chronic effects of AEDs on focal IEDs, lamotrigine and topiramate have been shown to reduce IEDs, both in adults and children. Valproic acid might show a similar trend, but with conflicting results among studies. In children, a similar effect was observed also for levetiracetam, oxcarbazepine and vigabatrin. In adults, not only relatively newer AEDs such as gabapentin and vigabatrin but also classical AEDs such as phenytoin and carbamazepine have not shown a clear-cut effect on IEDs chronically.

.

For most of those AEDs for which both the acute and the chronic effects on EEG of IEDs have been assessed, the chronic effects are in line with the acute ones.

.

There are a number of IEDs experimental models in vitro, but they seem insufficient as yet to clarify in detail the mechanisms underlying IEDs onset, mainly because probably each one of them reproduces only partially the mechanisms of some of the IEDs substrates. Furthermore, thus far, experimental data have been obtained mainly in models of temporal lobe epilepsy, while there are not enough data on models of other common causes of focal epilepsy (e.g., postischemic/hemorrhagic).

.

In any case, from our updated review of existing literature in patients, we confirm the opinion of many expert epileptologists concerning the role of EEG in patients with focal epilepsy treated with classical and relatively new AEDs. In these patients, repeating EEG and analyzing whether IEDs occurrence changes during AED treatment does not add any significant information in terms of seizure control, that is, a reduction/disappearance of IEDs does not seem to correlate with a reduction/disappearance of seizures.

.

We emphasize that, for the newer AEDs, there are no (or are only very limited) recent data in patients concerning their effects on focal IEDs.

.

Only developing more detailed experimental models and setting-up large, multicenter, controlled studies in focal epilepsy patients, designed ad hoc to address simultaneously the effect of different AEDs on both EEG and seizures, might provide evidence for the prognostic utility of EEG IEDs monitoring in different subcategories of patients under specific AED treatment.

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Direct Causal Networks for the Study of Transcranial Magnetic Stimulation Effects on Focal Epileptiform Discharges.

Impaired social cognition in patients with interictal epileptiform discharges in the frontal lobe.

Interictal epileptiform discharges induce hippocampal-cortical coupling in temporal lobe epilepsy.

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Interictal Epileptiform Discharges Might Be More Likely During Particular Phases of Brain Activity.

Hemodynamic Response to Interictal Epileptiform Discharges Addressed by Personalized EEG-fNIRS Recordings.

Lateralized effects of subclinical epileptiform EEG discharges on scholastic performance in children.

Epileptiform discharges during slow wave sleep on polysomnogram.

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Interictal epileptiform activity and autism.

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Negative effects of chronic hemicerebellectomy of epileptiform after-discharges elicited by focal cortical stimulation in baboons (Papio papio).

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Focal Epileptogenic Lesions in Adult Patients with Epilepsy and Generalized Epileptiform Discharges.

Vigabatrin-induced generalized epileptiform discharges in a patient with focal epilepsy.

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Spatial relationship between fast and slow components of ictal activities and interictal epileptiform discharges in epileptic spasms.

Effect of partial drug withdrawal on the lateralization of interictal epileptiform discharges and its relationship to surgical outcome in patients with hippocampal sclerosis.