Immunomodulatory interventions for focal epilepsy syndromes

  • Review
  • Intervention

Authors

  • Lauren Walker,

    Corresponding author
    1. Institute of Translational Medicine, University of Liverpool, Department of Molecular and Clinical Pharmacology, Liverpool, Merseyside, UK
    • Lauren Walker, Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Block A: Waterhouse Buildings, 1-5 Brownlow Street, Liverpool, Merseyside, L69 3GL, UK. lauren.walker@liv.ac.uk.

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  • Munir Pirmohamed,

    1. Institute of Translational Medicine, University of Liverpool, Department of Molecular and Clinical Pharmacology, Liverpool, Merseyside, UK
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  • Anthony G Marson

    1. Institute of Translational Medicine, University of Liverpool, Department of Molecular and Clinical Pharmacology, Liverpool, Merseyside, UK
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Abstract

Background

Epilepsy is a common neurological disorder made particularly disabling in the 30% of patients who do not achieve freedom from seizures despite multiple trials of antiepileptic drugs (AEDs). Experimental and clinical evidence supports a role for inflammatory pathway activation in the pathogenesis of epilepsy which, if effectively targeted by immunomodulatory interventions, highlights a potentially novel therapeutic strategy.

Objectives

To evaluate the efficacy and tolerability of immunomodulatory interventions as additional therapy in focal epilepsy syndromes in adults.

Search methods

We searched the Cochrane Epilepsy Group Specialised Register (2 August 2012), the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library 2012, Issue 7), MEDLINE (Ovid, 1946 to July week 3, 2012), the World Health Organization's International Clinical Trials Registry (2 August 2012), ClinicalTrials.gov (2 August 2012) and the Current Controlled Trials International Standard Randomised Controlled Trial Number Register (2 August 2012). There were no language restrictions. We reviewed the bibliographies of retrieved studies to search for additional reports of relevant studies.

Selection criteria

Randomised controlled trials of add-on immunomodulatory drug interventions for the treatment of focal epilepsy in adults (aged over 16 years).

Data collection and analysis

Three review authors independently assessed trial quality and extracted data. The primary outcomes were 50% or greater reduction in seizure frequency and seizure freedom; the secondary outcomes included serious and commonly occurring adverse effects, allergy, withdrawal and quality of life assessment.

Main results

We identified one study involving both children and adults (n=61) that assessed the effect of intravenous immunoglobulin (IVIG) as add-on therapy for the treatment of epilepsy. The authors found no significant difference between IVIG and placebo for the primary outcomes of seizure freedom or 50% or greater reduction in seizure frequency. The study reported a statistically significant effect for global blind assessment (rating scale involving multiple seizure-related parameters) in favour of IVIG. Secondary outcomes including adverse effects and allergies were not demonstrated.

Authors' conclusions

It is not possible to draw any conclusions about the role of immunomodulatory interventions in reducing seizure frequency or the safety of these agents in adults with epilepsy. Further randomised controlled trials are needed.

Résumé scientifique

Interventions à base de médicaments immunomodulateurs pour les syndromes d'épilepsie focale

Contexte

L'épilepsie est un trouble neurologique courant s'avérant particulièrement invalidant chez les 30 % de patients qui souffrent toujours de crises d'épilepsie malgré les multiples essais portant sur des médicaments antiépileptiques (MAE). Des preuves expérimentales et cliniques corroborent un rôle de l'activation de la voie de signalisation inflammatoire dans la pathogenèse de l'épilepsie qui, si elle est efficacement ciblée par les interventions à base de médicaments immunomodulateurs, met en évidence une stratégie thérapeutique potentiellement innovante.

Objectifs

Évaluer l'efficacité et la tolérance des interventions à base de médicaments immunomodulateurs en tant que thérapie complémentaire dans les syndromes d'épilepsie focale chez l'adulte.

Stratégie de recherche documentaire

Nous avons effectué une recherche dans le registre spécialisé du groupe Cochrane sur l'épilepsie (02.08.12), le registre Cochrane des essais contrôlés (CENTRAL, The Cochrane Library 2012, numéro 7), MEDLINE (Ovid, de 1946 à la 3ème semaine de juillet 2012), le Système d'enregistrement international des essais cliniques de l'OMS (ICTRP) (02.08.12), ClinicalTrials.gov (02.08.12) et le registre ISRCTN (International Standard Randomised Controlled Trial Number Register) (02.08.12). Il n'y avait aucune restriction concernant la langue. Nous avons analysé les références bibliographiques des études trouvées pour rechercher d'autres rapports d'études pertinentes.

Critères de sélection

Les essais contrôlés randomisés portant sur des interventions associées à base de médicaments immunomodulateurs pour le traitement de l'épilepsie focale chez l'adulte (âgés de plus de 16 ans).

Recueil et analyse des données

Trois auteurs de la revue ont indépendamment évalué la qualité méthodologique des essais et extrait des données. Les critères de jugement principaux étaient une réduction de 50 % ou plus de la fréquence des crises d'épilepsie et l'absence de crise ; les critères de jugement secondaires incluaient les effets indésirables graves et survenus le plus couramment, l'allergie, l'arrêt prématuré du traitement et l'évaluation de la qualité de vie.

Résultats principaux

Nous avons identifié une étude impliquant des enfants ainsi que des adultes (n = 61) ayant évalué l'effet de l'immunoglobuline intraveineuse (IgIV) comme traitement associé pour le traitement de l'épilepsie. Les auteurs n'ont trouvé aucune différence significative entre l'IgIV et le placebo pour les résultats principaux d'absence de crise d'épilepsie ou de réduction de 50 % ou plus de la fréquence des crises d'épilepsie. L'étude a rapporté un effet statistiquement significatif pour l'évaluation globale en aveugle (échelle d'évaluation comprenant de multiples paramètres liés aux crises d'épilepsie) en faveur de l'IgIV. Les résultats secondaires incluant les effets indésirables et les allergies n'ont pas été démontrés.

Conclusions des auteurs

Il n'est pas possible de tirer la moindre conclusion sur le rôle des interventions à base de médicaments immunomodulateurs dans la diminution de la fréquence des crises d'épilepsie ou dans l'innocuité de ces agents chez l'adulte souffrant d'épilepsie. D'autres essais contrôlés randomisés devront être réalisés.

Plain language summary

Immunomodulatory interventions (treatments that target the immune system) for focal epilepsy syndromes

Epilepsy is a common neurological condition affecting approximately 50 million people worldwide. We still do not fully understand the mechanisms by which the brain becomes epileptic. Recently, it has been suggested that the immune system and how it responds to injury may play an important role in this process. We identified a single randomised controlled trial of a treatment that targets the immune system. The results of the trial suggest that this treatment (called intravenous immunoglobulin therapy) may be effective in reducing seizure frequency in some patients with epilepsy (on the basis of a global blind assessment including various methods for assessing seizures and quality of life) but more trials are necessary before any definite conclusions and recommendations can be made.

Résumé simplifié

Interventions à base de médicaments immunomodulateurs (traitements ciblant le système immunitaire) pour les syndromes d'épilepsie focale

L'épilepsie est un trouble neurologique courant qui touche près de 50 millions de personnes à travers le monde. Les mécanismes par lesquels le cerveau devient épileptique restent encore mal compris. Récemment, il a été suggéré que le système immunitaire et la manière par laquelle il réagit à la lésion peuvent jouer un rôle important dans ce processus. Nous avons identifié un seul essai contrôlé randomisé portant sur un traitement qui cible le système immunitaire. Les résultats de l'essai suggèrent que ce traitement (appelé traitement à l'immunoglobuline intraveineuse) peut être efficace pour réduire la fréquence des crises d'épilepsie chez certains patients atteints d'épilepsie (sur la base de l'évaluation globale en aveugle incluant diverses méthodes d'évaluation des crises d'épilepsie et de la qualité de vie) mais d'autres essais sont nécessaires pour pouvoir tirer des conclusions définitives et émettre des recommandations.

Notes de traduction

Traduit par: French Cochrane Centre 7th August, 2013
Traduction financée par: Pour la France : Minist�re de la Sant�. Pour le Canada : Instituts de recherche en sant� du Canada, minist�re de la Sant� du Qu�bec, Fonds de recherche de Qu�bec-Sant� et Institut national d'excellence en sant� et en services sociaux.

Background

Description of the condition

Epilepsy is a chronic neurological condition characterised by recurrent seizures. Seizures result from excessive discharge within a population of hyperexcitable neurons. Focal epilepsy occurs as a consequence of neurological insult. Many such insults (including neuroinfection, neurotrauma and stroke) are known to be associated with a high risk of both blood-brain barrier (BBB) disruption and epilepsy.

Between 2% to 3% of the world's population will be diagnosed with epilepsy at some time in their lives (Hauser 1993). The majority of patients achieve complete seizure remission. Unfortunately, antiepileptic drugs (AEDs) fail to achieve seizure remission in approximately 30% of epilepsy sufferers (Kwan 2000). Despite the emergence of many new AEDs over the last 20 years, the prevalence of treatment-resistant epilepsy remains unchanged.

The mechanisms underlying this resistance remain unclear. Data from experimental epilepsy models and resected human brain tissue support the involvement of innate immune system activation and consequent inflammation in epilepsy (Minami 1991; Vezzani 2005a; Vezzani 2005b). Initial insights arose from studies of the pro-inflammatory cytokine interleukin (IL)-1β (IL-1β), its target, interleukin-1 receptor type 1 (IL-1R1), and its naturally occurring competitive antagonist, interleukin-1β receptor antagonist (IL-1RA) (Vezzani 2011). In rodents, both chemically and electrically induced seizures cause up-regulation of all three in the brain (Vezzani 2008) with sustained elevation of IL-1β long after the initial seizure event (De Simoni 2000), suggesting that sustained, localised inflammation may be important in epilepsy. A similar pattern of over-expression is observed in human epileptogenic brain tissue in association with a variety of pathologies including hippocampal sclerosis, focal cortical dysplasia and tuberous sclerosis (Boer 2008; Crespel 2002; Ravizza 2006b; Ravizza 2008). Also, in human studies seizures have been associated with significantly increased levels of the pro-inflammatory cytokine interleukin-6 in blood and cerebrospinal fluid (CSF) (Lehtimaki 2004; Peltola 1998). Furthermore, a highly pro-inflammatory cytokine profile (high IL-6, low IL-1RA, low IL-1RA/IL-1β ratio) has been identified in the plasma from patients with epilepsy (Hulkonnen 2004).

Lastly, in addition to over-expression arising as a consequence of seizures, targeting IL-1β can modulate susceptibility to seizure-inducing stimuli. IL-1RA has direct anticonvulsant activity following intracerebral administration and transgenic mice that over-express this protein in astrocytes have reduced seizure susceptibility (Auvin 2010; Vezzani 2000). Similarly, IL-1R1 knock-out mice exhibit reduced sensitivity to chemically induced seizures (Vezzani 2000).

The innate immune response exists to protect the central nervous system (CNS) from insult and, ordinarily, the process is halted by removal of the injurious stimuli. However, as a result of incompletely understood processes, this important biological switch-off mechanism may become compromised, resulting in persistent microglial activation and cytotoxicity. In this way, the inflammatory response may well contribute to the development of recurrent seizures and, furthermore, may be implicated in a person's response to AEDs. Targeting brain inflammation may represent a novel therapeutic strategy for epilepsy.

This review focuses on adult focal epilepsy, the pathophysiology of which is likely to differ significantly from paediatric epilepsy syndromes. A Cochrane review of immunomodulatory agents in paediatric epilepsy syndromes found no evidence for the efficacy or safety of corticosteroids (Gyatri 2007) and hence paediatric patients are considered in this review.

Description of the intervention

Possible immunomodulatory drug interventions would include glucocorticoids in all formations and immunosuppressant drugs (see Table 1 for breakdown)

Table 1. Immunomodulatory agents
ClassDrugs
Antimetabolitesurine synthesis inhibitors (azathioprine, mycophenolic acid), pyrimidine synthesis inhibitors (leflunomide, teriflunomide) and antifolate drugs (methotrexate)
Macrolides and other IL-2 Inhibitorstacrolimus, ciclosporin, pimecrolimus, abetimus, gusperimus
TNF/TNFα Inhibitorsthalidomide, lenalidomide, etanercept, pegsunercept
IL-1 Receptor AntagonistAnakinra
Intravenous Immunoglobulins 
mTOR signalling pathway interferencesirolimus, deforolimus, everolimus, temsirolimus, zotarolimus, biolimus A9
Monoclonal antibodiescomplement component 5 (ecluzimab), TNFs (infliximab, adalimumab, certolizumab pegol, afelimomab, golimumab), IL-5 (mepolizumab), immunoglobulin (Ig) E (omalizumab), interferon (faralimomab), IL-6 (elsilimomab), IL-12 and IL-13 (lebrikizumab and ustekinumab), CD3 (muromonab-CD3, otelixizumab, teplizumab, visilizumab), CD4 (clenoliximab, keliximab, zanolimumab), CD11a (efalizumab), CD18 (erlizumab), CD20 (rituximab, afutuzumab, ocrelizumab, pascolizumab), CD23 (lumiliximab), CD40 (teneliximab, toralizumab), CD62 L/L-selectin (aselizumab), CD80 (galiximab), CD147/basigin (gavilimomab), CD154 (ruplizumab), BLyS (belimumab), CTLA-4 (ipilimumab, tremelimumab), CAT (bertilimumab, lerdelimumab, metelimumab), integrin (natalizumab), IL-6 receptor (tocilizumab), lymphocyte function-associated antigen (LFA)-1 (odulimumab), IL-2 receptor/CD25 (basiliximab, daclizumab, inolimomab), T-lymphocyte (zolimomab aritox), miscellaneous (atorolimumab, cedelizumab, dorlixizumab, fontolizumab, gantenerumab, gomiliximab, maslimomab, morolimumab, pexelizumab, reslizumab, rovelizumab, siplizumab, talizumab, vapaliximab, vepalimomab
Polyclonal antibodiesanti-thymocyte globulin and anti-lymphocyte globulin.

How the intervention might work

Glucocorticoids suppress both cell-mediated and humoral immunity; they do so by inhibiting genes encoding various pro-inflammatory cytokines including IL-1, IL-2, IL-4, IL-6 and tumour necrosis factor (TNF). They also cause B cells to reduce expression of IL-2, which in turn limits B-cell expansion. They also suppress cyclo-oxygenase expression and limit lipocortin-1, which binds to leukocyte membranes limiting numerous inflammatory actions including epithelial adhesion, chemotaxis, phagocytosis and release of further cytokines and chemokines from monocytes and macrophages.

Immunosuppressive agents inhibit or prevent activity of the immune system by a number of different mechanisms. This can include antimetabolic activity, cytokine signalling/production interference and monoclonal/polyclonal antibodies directed towards identified antigens. (Detailed breakdown above.)

The direct mechanism underlying how immunomodulatory drugs might improve epileptic seizures is still incompletely understood. However, considering the emerging data regarding the role of inflammation in epileptogenesis, it is not unreasonable to assume that suppression of inflammation following an epileptogenic insult may reduce the resultant epileptic focus and reduce future seizures.

Why it is important to do this review

Pharmacoresistance and ongoing, debilitating seizures remain the greatest challenge in the management of epilepsy. Understanding the contribution that inflammation plays in the pathogenesis and, furthermore, the role that immunomodulatory drugs play in limiting this development, may allow us to target therapies at particularly susceptible patient groups (post-central nervous system (CNS) injury) to prevent development of pharmacoresistant seizures.

Objectives

To assess the efficacy and tolerability of immunomodulatory interventions as additional therapy in focal epilepsy syndromes in adults.

Methods

Criteria for considering studies for this review

Types of studies

Studies meeting the following criteria were included:

  1. randomised controlled studies with adequate methods of concealment of randomisation;

  2. single, double-blind or unblinded;

  3. parallel-group;

  4. with no minimum treatment period.

Types of participants

Adults (over 16 years) of either gender with focal epilepsy syndromes. This includes patients with a recent diagnosis as well as those with chronic epilepsy.

Types of interventions

The experimental interventions include glucocorticosteroids or immunosuppressants by oral, intravenous, intramuscular or subcutaneous route taken in addition to AEDs.

Glucocorticosteroids include hydrocortisone, prednisolone, methylprednisolone and dexamethasone.

Immunosuppressants include intravenous immunoglobulins, azathioprine, mycophenolic acid, leflunomide, teriflunomide, methotrexate, tacrolimus, ciclosporin, pimecrolimus, abetimus, gusperimus, thalidomide, lenalidomide, etanercept, pegsunercept, anakinra, sirolimus, deforolimus, everolimus, temsirolimus, zotarolimus, biolimus A9, ecluzimab, infliximab, adalimumab, certolizumab pegol, afelimomab, golimumab, mepolizumab, omalizumab, faralimomab, elsilimomab, lebrikizumab, ustekinumab, muromonab-CD3, otelixizumab, teplizumab, visilizumab, clenoliximab, keliximab, zanolimumab, efalizumab, erlizumab, rituximab, afutuzumab, ocrelizumab, pascolizumab, lumiliximab, teneliximab, toralizumab, aselizumab, galiximab, gavilimomab, ruplizumab, belimumab, ipilimumab, tremelimumab, bertilimumab, lerdelimumab, metelimumab, natalizumab, tocilizumab, basiliximab, daclizumab, inolimomab, zolimomab aritox, atorolimumab, cedelizumab, dorlixizumab, fontolizumab, gantenerumab, gomiliximab, maslimomab, morolimumab, pexelizumab, reslizumab, rovelizumab, siplizumab, talizumab, vapaliximab and vepalimomab.

Control interventions include placebo, no additional treatment or another immunomodulatory drug intervention analysed separately.

Types of outcome measures

Primary outcomes
  1. Seizure freedom: proportion of patients that achieve complete seizure cessation during the treatment period.

  2. 50% or greater reduction in seizure frequency compared to baseline seizure frequency.

Secondary outcomes

The proportion of patients experiencing any of the following side effects that are considered by the review authors to be common and important side effects of immunomodulatory drugs:

  1. All adverse effects secondary to glucocorticoids, including:

    1. diabetes mellitus;

    2. impaired glucose tolerance;

    3. infection;

    4. weight gain;

    5. osteoporosis;

    6. menstrual irregularity;

    7. euphoria/psychosis;

    8. glaucoma;

    9. cataracts.

  2. All adverse effects secondary to long-term immunomodulation including:

    1. infection;

    2. induction of malignancy.

  3. Cognitive side effects including confusion, delirium, drowsiness and sedation.

  4. Allergic reactions.

  5. Other serious side effects (as defined by the European Medicines Agency (EMEA 1995)):

    1. results in death;

    2. is life-threatening;

    3. requires inpatient hospitalisation or prolongation of existing hospitalisation;

    4. results in persistent or significant disability/incapacity;

    5. is a congenital anomaly/birth defect; or

    6. requires intervention to prevent permanent impairment or damage.

  6. Patients that experience any adverse effect.

  7. Withdrawal due to intolerable side effects or lack of efficacy.

  8. Quality of life using a validated score.

Search methods for identification of studies

Electronic searches

We searched the following databases, with no restrictions on language.

  1. The Cochrane Epilepsy Group Specialised Register (2 August 2012).

  2. The Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library 2012, Issue 7) using the search strategy set out in Appendix 1.

  3. MEDLINE (Ovid, 1946 to July week 3, 2012), using the search strategy set out in Appendix 2.

  4. The World Health Organization's International Clinical Trials Registry Platform Search Portal (http://apps.who.int/trialsearch/ searched on 2 August 2012) using 'epilepsy OR seizure' in the 'Condition' field and the interventions listed in the MEDLINE search strategy in the 'Intervention' field.

  5. ClinicalTrials.gov (http://clinicaltrials.gov/ct2/search searched on 2 August 2012) using 'epilepsy OR seizure' in the 'Condition' field and the interventions listed in the MEDLINE search strategy in the 'Intervention' field.

  6. Current Controlled Trials International Standard Randomised Controlled Trial Number Register (http://www.controlled-trials.com/isrctn/ searched on 2 August 2012) using 'epilepsy' or 'seizure' and the interventions listed in the MEDLINE search strategy, in the search box.

Searching other resources

We searched the bibliographies of any included studies for further references.

Data collection and analysis

Selection of studies

Two review authors (LW, AM) independently screened all the titles and abstracts of publications identified by the searches to assess their eligibility. Publications that did not meet the criteria were excluded at this stage. We then reviewed the full text of eligible citations for inclusion and reached consensus on the selection of trials and the final list of studies.

Data extraction and management

The review authors independently extracted the following characteristics of each included trial where available.

Participant factors
  • Age

  • Sex

  • Epilepsy classification/seizure type

  • Aetiology

  • Duration of epilepsy

  • Age at onset of first non-febrile convulsion

  • Seizure frequency prior to randomisation

  • Number and types of AEDs previously taken

  • Number and types of AEDs currently taking

  • Comparability of groups at baseline

  • Presence of neurological signs at baseline

  • Electroencephalography results at baseline

  • Neuroimaging results at baseline

Trial design factors
  • Criteria/classification system used to diagnose epilepsy

  • Inclusion and exclusion criteria

  • Method of randomisation

  • Method of allocation concealment

  • Method of blinding

  • Stratification factors

  • Number of participants allocated to each group

Intervention and controls
  • Intervention given to control group

  • Duration of immunosuppressant given

  • Interval between doses of immunosuppressants

  • Total number of corticosteroid infusions and total number of days per course

  • Duration of treatment period

Follow-up data
  • Duration of follow-up

  • Reasons for incomplete outcome data

  • Drop-out or loss to follow-up rates

  • Methods of analysis (intention-to-treat, per protocol, worst-case/best-case scenario analysis)

Assessment of risk of bias in included studies

All review authors assessed the risk of bias of each trial according to the approaches described in theCochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We assessed the risk of bias as Yes (indicating low risk of bias), No (indicating high risk of bias) and Unclear (indicating lack of information or uncertainty over the potential for bias). There was no disagreement in assessing the risk of bias between the review authors.

We evaluated the following characteristics:

  1. Was the allocation sequence adequately generated?

  2. Was there sufficient blinding of participants, personnel and outcome assessors?

  3. Were incomplete outcome data adequately addressed (yes/no)?

  4. Free of selective reporting?

  5. Free of other bias?

Measures of treatment effect

The review authors used statistical methods in accordance with theCochrane Handbook for Systematic Reviews of Interventions (Higgins 2011) to measure treatment effect. We used mean difference with 95% confidence interval (CI) for continuous data and risk ratio with 95% CI for dichotomous data.

Unit of analysis issues

No unit of analysis issues were identified.

Dealing with missing data

We analysed data according to intention-to-treat analysis in those instances of missing data due to drop-out or loss to follow-up.

Studies where data required to calculate outcomes of interest were missing would have been followed up by writing to the trial author, if necessary. The potential implications of missing data (e.g. no outcome obtained, lack of compliance, ineligibility) are addressed in the Discussion section.

Assessment of heterogeneity

Clinical and methodological heterogeneity of the included trial was to be evaluated by comparing the patient factors (age, gender, epilepsy classification, seizure types, seizure frequency, epilepsy duration), interventions (administration method, dosage and duration, co-interventions) and trial design issues (study duration, randomisation, allocation concealment and blinding methods) between studies.

As only one trial was identified meta-analysis was not possible and therefore statistical heterogeneity between trials could not be evaluated.

Assessment of reporting biases

We could not investigate potential publication biases using funnel plots and visual inspection for asymmetry as only one study was identified.

Data synthesis

As only one trial was identified we were unable to perform meta-analysis. The data from the trial have been summarised narratively.

Sensitivity analysis

We had planned to assess the robustness of the results of the meta-analysis by the following methods:

  • comparing fixed-effect and random-effects estimates (in the presence of residual unexplained heterogeneity);

  • comparing the results of different types of trials;

  • removing trials of low methodological quality;

  • exploring large effect sizes with a funnel plot.

However, because only one trial was identified we did not perform sensitivity analysis.

Results

Description of studies

Results of the search

From the formal search of the literature we identified 315 potentially relevant non-duplicated studies. After initial screening we were able to reject 309. After careful examination, four of the remaining studies were excluded leaving two trials suitable for inclusion. One of the trials was in Slovak ( Simko 1997) and we were unable to translate the study and hence it has been excluded currently; this may be included in a future review if we are successful in obtaining translation. We also found one ongoing clinical trial. Search results and included/excluded studies are summarised in Figure 1.

Figure 1.

Study flow diagram.

Included studies

One study fulfilled the inclusion criteria of the present review (double-blind trial of immunomodulatory intervention assessing the primary outcome of the review (50% reduction in seizure frequency from baseline)). However, the trial (van Rijckevorsel 1994) does not relate exclusively to focal epilepsy syndromes and includes both adults and children (without separate analysis).

The van Rijckevorsel 1994 study was a randomised, prospective, add-on, double-blind, placebo-controlled trial of intravenous immunoglobulins (IVIG) for the treatment of epilepsy, including focal epilepsy syndromes, in adults and children. The trial lasted for six months. Participants were randomly assigned to receive an active compound (at either 100, 250 or 400 mg/kg per infusion) or placebo in addition to their current AED therapy. The infusion schedule consisted of four infusions in the first week followed by further single infusions in the second, third and sixth week. The trial included an optional booster at the end of the six months if the investigators felt this was indicated. A total of 61 patients were randomised to receive either: i) placebo consisting of 2% human albumin solution (18 participants, seven females, mean age of group 18.5 years) or ii) active compound, sub-divided into iia) 100 mg/kg (14 participants, three females, mean age of group 26.2 years, two excluded), iib) 250 mg/kg (14 participants, four females, mean age of group 24.6 years, one excluded) or iic) 400 mg/kg (15 participants, five females, mean age of group 24.4 years). The patient's seizure history for the previous 12 months was taken retrospectively where available. The mean duration of epilepsy in years was 12.54 in the placebo group, 19.44 in the 100 mg/kg IVIG group, 15.33 in the 250 mg/kg IVIG group and 16.33 in the 400 mg/kg group IVIG group. In terms of seizure frequency, statistical analysis of changes was only performed where data were available for both the preceding 12 months (average) and at study conclusion. Seizure frequency is the total number of seizures, daily, irrespective of type, occurring in the preceding 12 months.

Excluded studies

The reasons for exclusion in the majority of studies were non-relevant age group (children) or non-focal epilepsy syndromes. Some excluded studies could not be assessed due to the presence of confounding conditions. Barbaro et al evaluated the use of steroids only in conjunction with radiosurgery in the presence of brain oedema (Barbaro 2009). In addition, Barile-Fabris et al evaluated the use of immunomodulatory agents in the treatment of neurological manifestations of an underlying autoimmune condition (Barile-Fabris 2005).

Risk of bias in included studies

Allocation

The study van Rijckevorsel 1994 does not specify the method of randomisation.

Blinding

The trial used a placebo which they specify was "otherwise the same as the verum." The investigators were aware of the dosage group but unaware of the substance infused. The external assessors (neurologists) were completely blinded to the therapy received, both dose and IVIG or placebo.

Incomplete outcome data

There is mention that one patient had to stop infusions due to possibly related adverse effects (vomiting) but it is not clear whether or not this individual was included in the final analysis. The analysis of all patients and of the partial epilepsy subgroup was performed with the exclusion of three patients (all within the IVIG group). The exclusions occurred for the following reasons: one patient dropped out for unknown reasons (100 mg/kg group), one patient had continuous partial motor seizures (250 mg/kg group) from the beginning and one patient had unaccountable seizures after baseline (100 mg/kg).

Effects of interventions

Seizure freedom

Two patients in the IVIG group achieved seizure freedom compared to zero patients in the placebo group.

50% or greater reduction in seizure frequency

Patients were labelled as responders if they achieved 50% or greater reduction in daily seizure frequency at six months. At six months, intention-to-treat analysis showed no statistically significant improvement in favour of intravenous immunoglobulin (IVIG) in the total refractory epilepsy group (risk ratio (RR) 1.76, 95% confidence interval (CI) 0.79 to 3.93) or the sub-classified group with refractory partial epilepsy (RR 3.08, 95% CI 0.84 to 11.34). Separate dose results for the different groups were not reported. No relationship was found between dose and efficacy (P = 0.31).

There was a non-significant positive trend in favour of IVIG treatment (52.5% response in the intervention group versus 27.78% response in the placebo group, P = 0.095). Subgroup analysis of patients with partial epilepsy showed a significant improvement in favour of IVIG treatment (N = 46, P = 0.041).

Adverse events

No serious adverse events occurred during the trial period. A single patient in the IVIG group had to cease infusions due to vomiting. Further data relating to adverse events associated with IVIG were not reported.

Allergic reactions

Data relating to allergic reactions were not reported.

Cognitive effects

Data relating to cognitive side effects were not reported.

Withdrawal

A single patient from the IVIG group dropped out of the study.

Quality of life assessment

Although QALY assessment not formally made in the study, patient and family perspectives were included as part of the global blind assessment.

Other outcome measures specific to this study:

Global blind evaluation

Intention-to-treat analysis showed a significant improvement in the IVIG-treated group with refractory epilepsy compared to placebo (RR 3.21, 95% CI 1.10 to 9.36, P = 0.0327).

Discussion

Only one trial met the inclusion criteria for this review and hence meta-analysis was not possible at this stage. The van Rijckevorsel 1994 study included only 61 patients and this small sample size may be insufficient to detect a significant effect following IVIG, if it exists. What is more, the duration of treatment was limited to six weeks which may be insufficient to produce long-term effects.

The search identified one ongoing clinical trial in this area (NCT01545518) and the authors are aware of at least one other trial ( French, J 2012) of immunomodulatory drug interventions in adults with focal epilepsy, therefore a future review is certainly warranted.

Summary of main results

No reliable conclusions can be drawn at present regarding the efficacy of immunomodulatory drug intervention as a treatment for epilepsy.

Authors' conclusions

Implications for practice

It is not possible to draw any conclusions about the role of immunomodulatory interventions in reducing seizure frequency or the safety of these agents in people with epilepsy.

Implications for research

There is a growing amount of animal research suggesting that it might be useful to evaluate the efficacy of immunomodulatory drug interventions for the treatment of epilepsy in humans. None of the existing clinical research is of sufficient quality or size to answer this question. Further studies, including large, well-conducted, randomised clinical trials with adequate follow-up beyond six months, are required before a definite conclusion can be reached concerning the efficacy, safety and tolerability of immunomodulatory interventions in patients with epilepsy. Studies should systematically evaluate and report adverse events.

Acknowledgements

None.

Data and analyses

Download statistical data

This review has no analyses.

Appendices

Appendix 1. CENTRAL search strategy

#1         MeSH descriptor Epilepsy explode all trees

#2         MeSH descriptor Seizures explode all trees

#3         (epilep*) or (seizure*) or (convuls*)

#4         (#1 OR #2 OR #3)

#5         MeSH descriptor Adrenal Cortex Hormones explode all trees

#6         MeSH descriptor Steroids explode all trees

#7         MeSH descriptor Prednisolone explode all trees

#8         MeSH descriptor Hydrocortisone explode all trees

#9         MeSH descriptor Methylprednisolone explode all trees

#10       MeSH descriptor Dexamethasone explode all trees

#11       MeSH descriptor Adrenocorticotropic Hormone explode all trees

#12       MeSH descriptor Immunosuppressive Agents explode all trees

#13       MeSH descriptor Adjuvants, Immunologic explode all trees

#14       MeSH descriptor Methotrexate explode all trees

#15       MeSH descriptor Azathioprine explode all trees

#16       (corticosteroid*)

#17       steroid*

#18       prednisolone

#19       hydrocortisone

#20       dexamethasone

#21       methylprednisolone

#22       ACTH

#23       (adrenocorticotrophic NEXT hormone) or (adrenocorticotropic NEXT hormone)

#24       immunosuppressant*

#25       immunomodulator*

#26       methotrexate

#27       azathioprine

#28       MeSH descriptor Immunoglobulins, explode all trees

#29       (immunoglobulin*)

#30       (#5 OR #6 OR #7 OR #8 OR #9 OR #10 OR #11 OR #12 OR #13 OR #14 OR #15 OR #16 OR #17 OR #18 OR #19 OR #20 OR #21 OR #22 OR #23 OR #24 OR #25 OR #26 OR #27 OR #28 OR #29)

#31       (#4 AND #30) 

Appendix 2. MEDLINE search strategy

This strategy is based on the Cochrane Highly Sensitive Search Strategy for identifying randomised trials published in Lefebvre 2011.

1. randomized controlled trial.pt.

2. controlled clinical trial.pt.

3. randomized.ab.

4. placebo.ab.

5. clinical trials as topic.sh.

6. randomly.ab.

7. trial.ti.

8. 1 or 2 or 3 or 4 or 5 or 6 or 7

9. exp animals/ not humans.sh.

10. 8 not 9

11. exp Epilepsy/

12. Seizures/

13. (epilep$ or seizure$ or convuls$).tw.

14. 11 or 12 or 13

15. exp Adrenal Cortex Hormones/

16. exp Steroids/

17. exp Prednisolone/

18. exp Hydrocortisone/

19. exp Methylprednisolone/

20. exp Dexamethasone/

21. exp Adrenocorticotropic Hormone/

22. exp Immunosuppressive Agents/

23. exp Adjuvants, Immunologic/

24. exp Methotrexate/

25. exp Azathioprine/

26. corticosteroid$.tw.

27. steroid$.tw.

28. prednisolone.tw.

29. hydrocortisone.tw.

30. dexamethasone.tw.

31. methylprednisolone.tw.

32. ACTH.tw.

33. (adrenocorticotrop?ic adj hormone).tw.

34. immunosuppressant$.tw.

35. immunomodulator$.tw.

36. methotrexate.tw.

37. azathioprine.tw.

38. immunoglobulin$.tw.

39. Immunoglobulins/

40. or/15-39

41. 10 and 14 and 40

Contributions of authors

AGM and MP were responsible for conceiving the review.

AGM and LW were responsible for designing and producing the protocol.

AGM, MP and LW have been involved in all stages of review preparation.

Declarations of interest

Anthony Marson has received honoraria from GlaxoSmithKline for a lecture given. Also, a consortium of pharmaceutical companies (GSK, EISAI, UCB Pharma) funded the National Audit of Seizure Management in Hospitals (NASH) through grants paid to University of Liverpool.

Lauren Walker has no known conflicts of interest.

Munir Pirmohamed received funding from the MRC for the Clinical Pharmacology Training Scheme, which supports Dr Lauren Walker.

Characteristics of studies

Characteristics of included studies [ordered by study ID]

van Rijckevorsel 1994

  1. a

    EEG: electroencephalogram
    IVIG: intravenous immunoglobulin

MethodsProspective, randomised, add-on, double-blind, placebo-controlled trial including a 6-week treatment period and follow-up to 6 months total study time
Participants

Inclusion criteria:

i) West syndrome, Lennox-Gastaut syndrome or early myoclonic encephalopathy, ii) refractory epilepsy of greater than 1 year duration with seizure frequency greater than once weekly

Exclusion criteria:

i) Any form of neoplasia, ii) progressive or expansive cerebral disorders (except Rasmussen syndrome), iii) features of severe renal insufficiency (serum creatinine > 3 mg/100 ml), iv) known intolerance of blood products, v) seropositivity to HIV 1 and 2 or vi) a known chromosomal abnormality

N = 61

Race: Caucasian

Male to female ratio: 42 to 19

Age range: 2 to 51

Types of seizures: all

Interventions

7-S native immunoglobulins prepared from standard polyvalent gamma globulins, fractionated from a pool of 1000 plasma donors screened for seronegativity towards hepatitis A, B and C viruses as well as HIV 1 and 2. Doses allocated at 100, 250 or 450 mg/kg per infusion. Infusion schedule: 1st week 4 infusions followed by once a week in the 2nd, 3rd and 6th weeks

Placebo consisting of 2% human albumin solution

Outcomes

i) 50% reduction in mean number of seizures per day between baseline (4 weeks prior to 1st infusion) and 6 months following first infusion. For the whole group, intention-to-treat analysis showed no statistically significant improvement in favour of IVIG in the total refractory epilepsy group (risk ratio (RR) 1.76, 95% confidence interval (CI) 0.79 to 3.93) or the sub-classified group with refractory partial epilepsy (RR 3.08, 95% CI 0.84 to 11.34). A non-significant trend in favour of IVIG (P = 0.095) was noted. In subgroup analysis of those with partial epilepsy only, 19 patients responded compared with 2 in the placebo group (P = 0.041)

ii) Global blind evaluation providing a rating (markedly, slightly or not improved) which includes reduction in seizure frequency in addition to seizure severity, evolution of EEGs, interictal status and the perception of the patient, family and nursing staff. Intention-to-treat analysis showed a significant improvement in the IVIG-treated group with refractory epilepsy compared to placebo (RR 3.21, 95% CI 1.10 to 9.36, P = 0.0327). There was a significant difference in terms of marked improvement in the intervention group (P = 0.015) with a significant correlation between lower serum IgG2 level pre-treatment and an improvement by the end of the study (P = 0.011).

No significant difference between the treatment and placebo group was observed by 3 months after the initiation of therapy. Only from the 4th month of therapy was a positive effect of IVIG noted

No relationship was found between dose and efficacy (P = 0.31). Separate dose results for the different groups were not reported

Adverse events: 1 patient from the IVIG had to stop infusions for possible related side effects (vomiting)

Notes

The study includes both adults and children without separate analysis

The study was not restricted to focal epilepsy

The study included both patients diagnosed with epilepsy syndromes immediately from diagnosis (West, Lennox Gastaut Syndrome and early myoclonic epilepsy) and chronic drug refractory epilepsy. The aetiology of the 2 epilepsy groups is likely to be distinctly different

All 3 patients that were excluded were from the active treatment (IVIG) group

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskPatients were randomly assigned to treatment or placebo, however no further information is given
Allocation concealment (selection bias)Unclear riskNo information given
Blinding of participants and personnel (performance bias)
All outcomes
Low riskThe investigators were aware of the dosage group but unaware of the substance infused (IVIG or placebo)
Blinding of outcome assessment (detection bias)
All outcomes
Low riskThe trial was double-blind with investigators blinded to which treatment was received (IVIG or placebo) and the external outcome assessors (neurologists) were also blinded
Incomplete outcome data (attrition bias)
All outcomes
Low risk

3 patients in the treatment arm were excluded from the statistical evaluation of seizure frequency

1 patient in the 100 mg/kg group dropped out (reasons unknown)

1 patient had continuous partial motor seizures (250 mg/kg group)

1 patient had unaccountable seizures after baseline (100 mg/kg)

The excluded patients contributed to the best and worst-case scenario analyses

Selective reporting (reporting bias)Unclear riskInformation unavailable.
Other biasUnclear riskN/A

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
  1. a

    MRI: magnetic resonance imaging
    SLE: systemic lupus erythematosus

Barbaro 2009Study predominantly evaluating radiosurgery; some patients were given oral steroids where there was MRI evidence of oedema causing brain shift
Barile-Fabris 2005Not specific to focal epilepsy and patients already had underlying immunological condition (SLE)
Klein 1970Review of studies including only children
Laxer 2000Study of the neurosteroid ganaxolone; ganaxolone does not have any known immunomodulatory functions and is therefore excluded
Simko 1997Article in Slovak, unable to obtain translation.

Characteristics of ongoing studies [ordered by study ID]

French, J 2012

Trial name or titleVX-765, a Novel, Investigational Anti- inflammatory Agent Which Inhibits IL-1β Production: Proof-of-Concept Trial for Refractory Partial Onset Seizures
MethodsProof-of-Concept Trial
Participantsn=60 (48 refractory focal epilepsy/12 placebo)
InterventionsVX-765
OutcomesSafety
Starting date 
Contact information 
Notes 

NCT01545518

  1. a

    IVIG: intravenous immunoglobulin

Trial name or titleIVIG treatment for refractory immune-related adult epilepsy
MethodsDouble-blind, cross-over study of IVIG treatment
ParticipantsMales and females aged 18 to 50 with uncontrolled epilepsy
InterventionsIVIG
Outcomes50% or greater decrease in seizure frequency 2 months following treatment with IVIG
Starting dateNovember 2011
Contact information-
Notes-

Ancillary