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Immunomodulatory interventions for focal epilepsy syndromes

  1. Lauren Walker*,
  2. Munir Pirmohamed,
  3. Anthony G Marson

Editorial Group: Cochrane Epilepsy Group

Published Online: 27 JUN 2013

Assessed as up-to-date: 26 JUN 2013

DOI: 10.1002/14651858.CD009945.pub2


How to Cite

Walker L, Pirmohamed M, Marson AG. Immunomodulatory interventions for focal epilepsy syndromes. Cochrane Database of Systematic Reviews 2013, Issue 6. Art. No.: CD009945. DOI: 10.1002/14651858.CD009945.pub2.

Author Information

  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.

Publication History

  1. Publication Status: New
  2. Published Online: 27 JUN 2013

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Characteristics of included studies [ordered by study ID]
van Rijckevorsel 1994

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


ParticipantsInclusion 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


Interventions7-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


Outcomesi) 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)


NotesThe 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 risk3 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

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

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-

 
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.