Description of the condition
Epilepsy is a highly prevalent neurological disorder affecting an estimated 70 million people worldwide (Ngugi 2010). There are 50 new cases per 100,000 people globally each year and up to 82 new cases per 100,000 people in developing countries (Ngugi 2011). One of the world's oldest recognised conditions, epilepsy affects all age groups and has various presentations and mechanisms. Epilepsy is characterised by repeated unprovoked seizures (episodes of continual discharges of brain activity) and can be considered a consequence of an underlying condition, such as a tumour, or of genetic alterations, malformations, infection, intoxication or another illness (Shorvon 2011). Although antiepileptic medications produce clinical improvement in most patients with epilepsy, a 2008 study conducted in France estimated that 22.5% of patients have 'drug-resistant' epilepsy (Picot 2008), leading to increased risks of premature death, injury, psychosocial dysfunction and a reduced quality of life (Kwan 2011). Patients whose epilepsy is resistant to medication may pursue alternative therapies including surgery, high-fat, low-carbohydrate diets and vagus nerve stimulation. Despite these interventions, there remains a need for non-invasive and more effective therapies.
Description of the intervention
Transcranial magnetic stimulation (TMS) was developed in 1985 in the UK to study and map different areas of brain activity (Kimiskidis 2010). In the study of epilepsy, TMS has been used to probe cortical excitability in various epilepsy syndromes, to assess the effects of antiepileptic drugs on the brain and to help identify areas of the brain more prone to seizure for surgical removal (Kimiskidis 2010). Once it became known that repeated pulses of TMS could either excite or suppress neural activity for a prolonged period of time, TMS was studied as a potential therapy for a number of neurological and psychiatric conditions, ranging from stroke to depression to amyotrophic lateral sclerosis (Ridding 2007). Recently, studies have looked at TMS as a potential treatment for epilepsy (Kimiskidis 2010). TMS is a procedure that uses magnetic fields to stimulate nerve cells in the brain to improve the symptoms of epilepsy. With TMS, a large electromagnetic coil is placed against the scalp. The electromagnet creates electrical currents that stimulate nerve cells in the region of the brain involved in epilepsy.
How the intervention might work
The prolonged inhibitory effects of TMS may theoretically reduce cortical hyperexcitability associated with various epilepsies. Although the exact mechanisms involved remain elusive, TMS can generate either excitatory or inhibitory responses in cortical tissue. A TMS device employs either one or two copper coils, positioned superficial to a site of interest in the brain, to non-invasively produce a brief (100 to 400 µs) magnetic pulse (generating a 1.5 to 2 T magnetic field) to an estimated depth of ˜2 cm. This magnetic pulse induces an electrical current in a patch of cortical tissue of few square centimetres (Reithler 2011) causing a depolarisation of nearby axons. Such local stimulation can even affect distant areas in ways that are poorly understood (Reithler 2011). It has been observed that repetitive pulses of TMS can cause long-lasting effects, persisting for more than one hour after a treatment (Huang 2005). Aside from physical positioning of the device, there is no known way to target particular cell types and various interactions between excitatory and inhibitory processes may occur. However, repetition at higher frequencies generally has an overall excitatory effect while, conversely, low-frequency repetitive pulses have an inhibitory effect on neurons and may suppress the activity related to seizures. Earlier animal studies showed that a single TMS pulse follows a particular time course, producing an initial facilitation or excitation followed by delayed and prolonged suppression (Moliadze 2003). Thus, low-frequency repetitive stimulation has been hypothesised to result in prolonged synaptic depression when each incoming pulse arrives during the late inhibitory phase produced by the previous pulse, however this has not been not proven (Reithler 2011). Other important parameters in the use of TMS include intensity and duration.
Why it is important to do this review
Repetitive transcranial magnetic stimulation (rTMS) is an emerging therapy for epilepsy, a highly prevalent neurological condition for which a significant proportion of patients do not achieve an adequate response to medications. Drug-resistant epilepsy is associated with reduced quality of life and such patients often face surgery or other invasive therapies, which carry significant risks. Even patients responsive to pharmacological therapy may struggle with the possible adverse effects of their medications. In contrast, rTMS is a painless, non-invasive approach that, if effective, could have significant advantages over both antiepileptic drugs and surgical management. This systematic review will clarify the available scientific evidence to help clinicians and patients assess the safety and effectiveness of this approach for the treatment of epilepsy.
To evaluate the safety and efficacy of repetitive transcranial magnetic stimulation for the treatment of epilepsy.
We will assess the following hypotheses in patients with epilepsy:
- TMS reduces the frequency of seizures.
- TMS reduces the epileptiform discharges on electroencephalography.
- Treatment with TMS is associated with certain adverse effects.
Criteria for considering studies for this review
Types of studies
Eligible studies included will be:
- randomised controlled trials (RCTs); and
- double, single or unblinded; and
- placebo/sham-controlled; or
- no treatment/active controlled (e.g. antiepileptic drug treatment).
Types of participants
Any patient of any age with any type of epilepsy syndrome, which includes unclassified types of epilepsy and post-surgical epilepsy patients.
Types of interventions
Repetitive transcranial magnetic stimulation of any frequency, either single or double-coiled, for any duration and at any intensity.
Types of outcome measures
Reduction in seizure frequency
- The proportion of people with a 50% or greater reduction in seizure frequency following the treatment period.
- The difference in pre- and post-treatment seizure rates.
Improvement in quality of life
- The difference in quality of life scores for patients surveyed before and after treatment.
Reduction in epileptiform discharges
Mean number of epileptiform discharges seen on electroencephalography (EEG) during the period between seizures.
The proportion of people experiencing any of the following adverse effects that are considered to be common and important adverse effects of transcranial magnetic stimulation:
- Behavioural changes
- Cognitive disturbances
The proportion of people experiencing the six most common adverse effects if different from the list above.
Changes in medication requirements
- The proportion of people who required fewer seizure medications after treatment.
- The proportion of people who required more seizure medications after treatment.
- The proportion of people who had no changes to their medication after treatment.
- The proportion of people withdrawn from the study for any reason.
- The proportion of people withdrawn from the study due to lack of efficacy or side effects.
Search methods for identification of studies
We will search the following databases:-
- Cochrane Epilepsy Group Specialised Register, using the following search term: transcranial magnetic stimulation;
- Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library), using the search strategy outlined in Appendix 1;
- MEDLINE (Ovid 1946-Present), using the search strategy outlined in Appendix 2;
- SCOPUS (1823-Present), using the search strategy outlined in Appendix 3;
- World Health Organization International Clinical Trials Registry Platform search portal (http://apps.who.int/trialsearch/), using the following search strategy: transcranial magnetic stimulation AND epilepsy NOT NCT*; and
- ClinicalTrials.gov (http://www.clinicaltrials.gov/), using the following search strategy: 'transcranial magnetic stimulation' AND epilepsy.
We will not impose any date or language restrictions.
Searching other resources
We will check the reference lists of retrieved reports for additional reports of relevant studies. We will contact the authors of any conference proceedings to identify any unpublished data and experts in the field to identify any further ongoing trials.
Data collection and analysis
Selection of studies
Two review authors (RC and DS) will independently assess articles for inclusion. Any disagreements will be resolved though mutual discussion; failing this advice from a third party (JP) will be sought. The same review authors will independently carry out data extraction and assess risk of bias in the included studies. Again, any disagreements will be discussed and in the event a consensus cannot be reached, a third party opinion will be sought.
Data extraction and management
We will extract the following information from each trial using a data extraction sheet:
- Method of randomisation and allocation concealment.
- Method of blinding.
- Number of people excluded from reported analyses.
- Duration of baseline period.
- Duration of treatment period.
Individual participant/demographic information
- Total number of participants allocated to each treatment group.
- Number of participants within each epilepsy type.
- Seizure frequency during baseline period.
- Type of background antiepileptic drugs taken.
- Total number of intervention groups and comparisons.
- Intervention details.
- Potential biases.
- Outcomes and time points reported.
- Definition of outcome.
- Unit of measurement.
Assessment of risk of bias in included studies
Two review authors (RC and DS) will independently make an assessment of the risk of bias for each trial using the Cochrane 'Risk of bias' tool as described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We will discuss any disagreements and reach a consensus. If an agreement cannot be made a third party opinion (JP) will be sought. We will rate included studies as adequate, inadequate or unclear on six domains of bias applicable to RCTs: method of randomisation, method of concealing allocation, method of blinding, incomplete outcome data, selective outcome reporting and other sources of bias. We will create a 'Summary of findings' table using the GRADE approach for assessing the quality of evidence.
Measures of treatment effect
We will present an overall effect estimate for seizure reduction as a risk ratio. We will present the secondary outcome of reduction in the number of epileptiform discharges seen on EEG during the period between seizures as a mean difference. We will present overall effect estimates for adverse effects and withdrawals as risk ratios.
Unit of analysis issues
Seizure reduction may be reported using different measures in trials. In this event, we will seek data from study authors in order to obtain data suitable to be combined in meta-analysis.
Dealing with missing data
We will seek any missing data from study authors. We intend to carry out intention-to-treat, best-case and worst-case analyses in order to account for any missing data. We will present all analyses in the main report.
Assessment of heterogeneity
We will assess clinical heterogeneity by comparing important participant and intervention factors among trials including: age, seizure type, duration of epilepsy, number and type of antiepileptic drugs taken at time of randomisation, study methods, loss to follow-up and missing data. We will examine statistical heterogeneity using a Chi
Assessment of reporting biases
We will assess the included studies for reporting biases using the Cochrane 'Risk of bias' tool. In the event outcome reporting bias is suspected we will investigate this using the ORBIT classification system (Kirkham 2010). We will request all protocols from study authors to enable a comparison between a list of a priori listed outcomes and what is reported in the matching papers. We will examine publication bias by identifying certain aspects of each study including sponsors of the research and research teams involved. We will examine funnel plots in the event that an appropriate number of studies can be combined.
We will employ a fixed-effect meta-analysis to synthesise data. Comparisons we expect to carry out include:
- intervention group versus control on seizure reduction;
- intervention group versus control on reduction in epileptiform discharges;
- intervention group versus control on adverse effects;
- intervention group versus control on treatment withdrawal.
We will stratify each comparison by type of control group (e.g. placebo, other active treatment, no treatment) to enable appropriate combination of study data.
Our preferred effect estimate will be a risk ratio. For all outcomes except adverse effects we will use 95% confidence intervals. For individual adverse effects we will use 99% confidence intervals to make allowance for multiple testing.
All analyses will include all participants in the treatment group to which they were allocated. For the efficacy outcome of seizure reduction we plan to undertake three analyses:
- Primary (intention-to-treat) analysis: participants not completing follow-up or with inadequate seizure data will be assumed non-responders. To test the effect of this assumption, we plan to undertake the following sensitivity analyses.
- Worst-case analysis: participants not completing follow-up or with inadequate seizure data will be assumed non-responders in the magnetic stimulation group, and responders in the control group.
- Best-case analysis: participants not completing follow-up or with inadequate seizure data will be assumed responders in the magnetic stimulation group and non-responders in the control group.
Subgroup analysis and investigation of heterogeneity
Subgroup analysis will be carried out for:
- adverse effects; and
- heterogeneity, if this is found.
We intend to carry out sensitivity analysis if deemed appropriate. For example, if peculiarities are found between studies with regards to quality, characteristics of participants, interventions and/or outcomes, we will conduct a sensitivity analysis to explore these differences.
Appendix 1. CENTRAL search strategy
#1MeSH descriptor: [Transcranial Magnetic Stimulation] explode all trees
#2"transcranial magnetic stimulation":ti,ab,kw (Word variations have been searched)
#3#1 or #2
#4(epilep* or seizure* or convuls*):ti,ab,kw (Word variations have been searched)
#5MeSH descriptor: [Epilepsy] explode all trees
#6MeSH descriptor: [Seizures] explode all trees
#7(#4 or #5 or #6) in Trials
#8#3 and #7
Appendix 2. MEDLINE search strategy
This strategy is based on the Cochrane Highly Sensitive Search Strategy for identifying randomised trials (Lefebvre 2011).
1. exp Transcranial Magnetic Stimulation/
2. transcranial magnetic stimulation.tw.
3. 1 or 2
4. exp Epilepsy/
5. exp Seizures/
6. (epilep$ or seizure$ or convuls$).tw.
7. 4 or 5 or 6
8. exp Pre-Eclampsia/ or exp Eclampsia/
9. 7 not 8
10. (randomized controlled trial or controlled clinical trial).pt. or (randomized or placebo or randomly).ab.
11. clinical trials as topic.sh.
13. 10 or 11 or 12
14. exp animals/ not humans.sh.
15. 13 not 14
16. 3 and 9 and 15
Appendix 3. SCOPUS search strategy
(TITLE-ABS-KEY("Transcranial Magnetic Stimulation")) and ((TITLE-ABS-KEY(epilep* OR "infantile spasm" OR seizure OR convuls* OR (syndrome W/2 (aicardi OR angelman OR doose OR dravet OR janz OR jeavons OR "landau kleffner" OR "lennox gastaut" OR ohtahara OR panayiotopoulos OR rasmussen OR rett OR "sturge weber" OR tassinari OR "unverricht lundborg" OR west)) OR "ring chromosome 20" OR "R20" OR "myoclonic encephalopathy" OR "pyridoxine dependency") AND NOT (TITLE(*eclampsia) OR INDEXTERMS(*eclampsia))) OR (TITLE-ABS-KEY(lafora* W/4 (disease OR epilep*)) AND NOT (TITLE(dog OR canine) OR INDEXTERMS(dog OR canine)))) and (TITLE((randomiz* OR randomis* OR controlled OR placebo OR blind* OR unblind* OR "parallel group" OR crossover OR "cross over" OR cluster OR "head to head") PRE/2 (trial OR method OR procedure OR study)) OR ABS((randomiz* OR randomis* OR controlled OR placebo OR blind* OR unblind* OR "parallel group" OR crossover OR "cross over" OR cluster OR "head to head") PRE/2 (trial OR method OR procedure OR study)))
Contributions of authors
RC, DS and JP have written the review protocol. All authors will be responsible for carrying out the review methods and writing up the review. RC will be responsible for updating the finished review.
Declarations of interest
Sources of support
- No sources of support supplied
- National Institute for Health Research, UK.This review presents independent research commissioned by the National Institute for Health Research (NIHR). The views expressed in this publication are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health.