ARTICLE IN PRESS+ModelEPIRES-4745; No. of Pages 11

Epilepsy Research (2012) xxx, xxx—xxx

jou rn al h om epa ge: www.elsev ier .com/ locate /ep i lepsyres

REVIEW

Resting motor threshold in idiopathic generalizedepilepsies: A systematic review with meta-analysis

Francesco Brigoa,b,∗, Monica Storti c, Maria Donata Benedetti a,Fabio Rossini a, Raffaele Nardoneb,d, Frediano Tezzonb, Antonio Fiaschia,Luigi Giuseppe Bongiovannia, Paolo Manganotti a

a Department of Neurological, Neuropsychological, Morphological and Movement Sciences, Section of Clinical Neurology,University of Verona, Italyb Division of Neurology, Hospital ‘‘Franz Tappeiner’’, Merano, Italyc Department of Medicine, University of Verona, Italyd Department of Neurology, Christian Doppler Clinic, Paracelsus Medical University, Salzburg, Austria

Received 30 January 2012; received in revised form 13 March 2012; accepted 28 March 2012

KEYWORDSIdiopathicgeneralized epilepsy;Juvenile myoclonicepilepsy;Resting motorthreshold;Systematicreview/metaanalysis;Transcranial magneticstimulation

Summary Resting motor threshold (rMT) assessed by means of Transcranial Magnetic Stimula-tion (TMS) is thought to reflect trans-synaptic excitability of cortico-spinal neurons. TMS studiesreporting rMT in idiopathic generalized epilepsies (IGEs) yielded discrepant results, so that itis difficult to draw a definitive conclusion on cortico-spinal excitability in IGEs by simple sum-mation of previous results regarding this measure. Our purpose was to carry out a systematicreview and a meta-analysis of studies evaluating rMT values obtained during single-pulse TMS inpatients with IGEs. Controlled studies measuring rMT by single-pulse TMS in drug-naive patientsolder than 12 years affected by IGEs were systematically reviewed. rMT values were assessedcalculating mean difference and odds ratio with 95% confidence intervals (CI). Fourteen tri-als (265 epileptic patients and 424 controls) were included. Patients with juvenile myoclonicepilepsy (JME) have a statistically significant lower rMT compared with controls (mean differ-ence: −6.78; 95% CI −10.55 to −3.00); when considering all subtypes of IGEs and IGEs otherthan JME no statistically significant differences were found. Overall considered, the results areindicative of a cortico-spinal hyper-excitability in JME, providing not enough evidence for motor

hyper-excitability in other subtypes of IGE. The considerable variability across studies probablyreflects the presence of relevant clinical and methodological heterogeneity, and higher tempo-

easu

ral variability among rMT m

Please cite this article in press as: Brigo, F., et al., Restingsystematic review with meta-analysis. Epilepsy Res. (2012), ht

these patients.© 2012 Elsevier B.V. All rights re

∗ Corresponding author at: Department of Neurological, NeuropsycholoNeurology, University of Verona, Italy, Piazzale L.A. Scuro 10, 37134 Vero

E-mail address: dr.francescobrigo@gmail.com (F. Brigo).

0920-1211/$ — see front matter © 2012 Elsevier B.V. All rights reserved.http://dx.doi.org/10.1016/j.eplepsyres.2012.03.020

rements over time, related to unstable cortical excitability in

motor threshold in idiopathic generalized epilepsies: Atp://dx.doi.org/10.1016/j.eplepsyres.2012.03.020

served.

gical, Morphological and Movement Sciences, Section of Clinicalna, Italy. Tel.: +39 045 8124174; fax: +39 045 8124873.

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ontents

Introduction............................................................................................................... 00Methods................................................................................................................... 00

Objective............................................................................................................. 00Study selection ....................................................................................................... 00Data sources and search strategy ..................................................................................... 00Data extraction....................................................................................................... 00Statistical analysis.................................................................................................... 00

Results .................................................................................................................... 00Description of studies (Table 1)....................................................................................... 00Risk of bias ........................................................................................................... 00

Quantitative synthesis..................................................................................................... 00rMT values in all types of IGEs (Fig. 2) ................................................................................ 00rMT values in juvenile myoclonic epilepsy (JME) (Fig. 3).............................................................. 00rMT values in IGEs other than JME (Fig. 4) ............................................................................ 00Publication bias ...................................................................................................... 00

Discussion ................................................................................................................. 00Exploration of heterogeneity ......................................................................................... 00Strengths and limitations of the review............................................................................... 00

Conflict of interest statement ............................................................................................. 00Disclosure ................................................................................................................. 00Acknowledgements........................................................................................................ 00Appendix A. Supplementary data........................................................................................ 00Appendix A. Supplementary data........................................................................................ 00References ................................................................................................................ 00

ntroduction

pilepsy is a chronic disorder characterized by heteroge-eous and dynamic pathophysiological processes leadingo an altered balance between excitatory and inhibitorynfluences at cortical level, which may be counteracted byntiepileptic drugs (Tassinari et al., 2003). Idiopathic gen-ralized epilepsies (IGEs) encompass many distinct epilepticyndromes, and are supposed to be the expression of aidespread hyperexcitability involving subcortical and cor-

ical structures in both hemispheres, and especially inhalamo-cortical circuitry. However, each seizure type whichharacterizes IGEs (typical absences, myoclonic jerks andeneralized tonic—clonic seizures, alone or in varying com-inations and severity) involves a distinct hyperexcitableircuitry that in most instances does not comprise the wholerain (Capovilla et al., 2009). As a result of maturation, cir-uits involved may even differ with age. The concept of‘systems,’’ referring to structures and pathways involvedy the ictal event, has been therefore recently introducedWolf, 2006; Avanzini, 2009), based on the assumption thathe neuronal circuits involved in absence seizures, toniceizures, tonic—clonic seizures, and myoclonic seizures areot the same (Capovilla et al., 2009). A paradigmatic exam-le of ‘‘system epilepsy’’ is juvenile myoclonic epilepsyJME), in which an impairment of GABAa-mediated inhibi-

to study pathophysiological mechanisms underlying epilepsyin general, and IGE in particular.

TMS of the motor cortex in epilepsy can assess corti-cal excitability by determining different parameters. Motorthreshold (MT) represents the most easily recorded param-eter. It is defined as the minimum stimulus strengthwhich produces a small motor evoked potential (usually50—100 �V) in the target muscle (conventionally of thehand), in at least 50% of trials (Rossini et al., 1994).MT can be determined at rest (rMT) or during slight iso-metric muscle activation and reflects neuronal membraneexcitability rather than cortical excitability alone (Chen,2000). MT reflects the excitability and the local densityof a central core of excitatory interneurons and corti-cospinal neurons in the muscle representation at the primarymotor cortex level, as well as the excitability of the tar-get spinal motoneurons (Ziemann et al., 1996; Hallett,2000).

rMT represents therefore the physiological and method-ological basis for more complex TMS assessment of corticalexcitability such as the evaluation of intra-cortical inhibition(ICI) or facilitation (ICF) patterns obtained by paired-pulseparadigm (Kujirai et al., 1993). Therefore, in addition tostudies on ICI, ICF and cortical silent period, the determina-tion of rMT in patients with IGEs is essential for an overallassessment of motor excitability in this subgroup of epilepsy.

Please cite this article in press as: Brigo, F., et al., Restingsystematic review with meta-analysis. Epilepsy Res. (2012), ht

ion may lead to motor hyperexcitability (Manganotti et al.,000), without evidence of abnormal processing of cuta-eous afferents (Manganotti et al., 2004).

Trancranial magnetic stimulation (TMS) has been used tooninvasively and directly assess the cortical physiology andxcitability in vivo, thus representing a fascinating method

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urthermore, the rMT represents an important safety con-train for therapeutic brain stimulation in epilepsy (Cantello

motor threshold in idiopathic generalized epilepsies: Atp://dx.doi.org/10.1016/j.eplepsyres.2012.03.020

t al., 2007) and in other neurological disorders (Edwardst al., 2008). In the literature there are however importantiscrepancies among different studies reporting rMT in IGEs,ith some studies reporting increased, and others decreased

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Resting motor threshold in idiopathic generalized epilepsies

interictal values. These discrepancies make it very difficultto draw a definitive conclusion on cortico-spinal excitabil-ity in IGEs by simple summation of previous results. Wetherefore decided to carry out a systematic review and ameta-analysis of studies evaluating rMT values obtained dur-ing single-pulse TMS in drug-naive patients older than 12years affected by IGE.

Some reviews previously assessed the topic of motorcortex hyperexcitability in epilepsy (Ziemann et al., 1998;Macdonell et al., 2002; Tassinari et al., 2003; Chen et al.,2008), but always in a narrative and subjective way, withoutusing systematic and explicit methods to identify, select andcritically appraise studies, to extract data, and to analysethem with statistical methods. To our knowledge the presentreview represents therefore the first attempt to system-atically appraise the available literature on cortico-spinalexcitability in IGEs.

Methods

This review was guided by a written pre-specified proto-col describing research questions, review methods, plan fordata extraction and synthesis.

Objective

Our aim was to critically and systematically evaluate the lit-erature to evaluate rMT obtained during single-pulse TMS indrug-naive patients older than 12 years with IGE, comparedto healthy controls.

Study selection

Inclusion criteria were established a priori. Each controlledstudies reporting data on rMT obtained by single-pulse TMSin drug-naive patients (≥12 years) of either gender with IGE(defined according to International League Against Epilepsycriteria (ILAE, 1989)) and in healthy controls, regardless ofstimulator characteristics (such as coils’ shape, size andmaximum magnetic field strength), were included. rMT wasdefined as the lowest intensity (expressed as a percentage ofmaximal stimulator output) able to produce an electromyo-graphic response in a resting superficial muscle of the handof at least 50 �V peak-to-peak amplitude in at least 50% oftrials (Rossini et al., 1994). Studies indicating patients asaffected by IGE without further specifications on the diag-nostic criteria used were assumed to have adopted the ILAEcriteria (Fig. 1).

Uncontrolled studies, studies conducted in subjectsyounger than 12 years, and studies performing TMS withpaired magnetic stimuli or consecutive TMS were excluded.Also TMS studies using definitions of rMT different fromthat reported above were excluded. To include data in themeta-analysis, the studies must provide mean and standarddeviation (SD) values, or enough data to calculate them; if

Please cite this article in press as: Brigo, F., et al., Restingsystematic review with meta-analysis. Epilepsy Res. (2012), ht

not, principal investigators of provisionally included trialswere contacted and additional information requested. Weexcluded studies from which we did not manage to havedata on rMT mean and SDs.

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ata sources and search strategy

he MEDLINE (accessed by Pubmed; 1966—August 2011)nd EMBASE (1980—August 2011) electronic databases wereearched using the medical subject headings (MeSH):‘Epilepsy, Generalized’’, and following free terms, com-ined in multiple search strategies with Boolean operatorsn order to find relevant articles: ‘‘idiopathic generalizedpilepsy’’, ‘‘generalized epilepsy’’, ‘‘motor threshold’’see appendix).

Two independent reviewers working in pairs (FB and MS)creened the titles and abstracts of the initially identifiedtudies to determine if they satisfied the selection crite-ia. Any disagreement was resolved through consensus. Fullext articles were retrieved for the selected titles, andeference lists of the retrieved articles were searched fordditional publications. We also contacted the authors ofhe retrieved papers for any additional or unpublished stud-es, handsearched conference proceedings and contactedxperts in the field for information about any unpublishedr ongoing study. No language restrictions were applied.

ata extraction

e designed a data collection form before the implemen-ation of the search strategy. Two independent reviewerssed this form to extract the relevant information from theelected studies (FB and MS).

The following data were extracted: number and sex ofarticipants, age, seizure free interval, subtypes of epilepticyndrome/seizures, stimulator characteristics, site of EMGecording. Mean and SD values of rMT were extracted oralculated for inclusion in the meta-analysis (see appendix).n case of missing or incomplete data, principal investigatorsf included trials were contacted and additional informationequested. If requested information was not provided, meannd SD values were obtained from graphs or tables in theapers (if available).

Data were independently extracted and cross-checkedy two review authors (FB, MS), who also independentlyssessed the methodological quality of each study and riskf bias, focusing on blinding and other potential sources ofias.

tatistical analysis

or each included study the differences in demographicharacteristics (age, sex) among patients and healthy con-rols were evaluated using chi-square (categorical data) andndependent t tests (continuous data).

We planned to summarize the results in a meta-nalysis. rMT values (continuous data) were analyzed byalculating the mean difference for each trial, with thencertainty in each study being expressed using 95% con-dence intervals (CI). A weighted effect across studies waslso calculated. In studies performing TMS over both hemi-pheres, only data from left (or dominant) hemisphere were

motor threshold in idiopathic generalized epilepsies: Atp://dx.doi.org/10.1016/j.eplepsyres.2012.03.020

ncluded.In case of sufficient data, we planned to undertake

ubgroup analyses by assessing the effect of the type ofpileptic syndrome, age, time to the diagnosis, number

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4 F. Brigo et al.

Records iden�fied throughdatabase se arching

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Records excluded(n = 38 )

Full-text ar�cles assesse dfor eligibil ity(n = 39)

Full-text ar�cles exclud ed,with reasons(n = 16 )

Stud ies includ ed inqualita�ve synthesis

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Stud ies includ ed in quan�ta�ve synth esi s(meta-analysis)

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pa�ents; 4 studies in clud ed in subgroup anal ysis onpa�ents with IGE s other than JME)

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Figure 1 Flowchart of

nd type of seizures (myoclonic only versus myoclonic andeneralized tonic—clonic seizures, absences, etc.), and pre-enting results on the same Forest plot to give an overallmpression.

Homogeneity among study results was evaluated using standard chi squared test, combined with the I2 statis-ics, and the hypothesis of homogeneity was rejected ifhe P value was less than 0.10. The I2 (which quantifieshe percentage of variation attributable to heterogeneity)as reported as a measure of consistency across the stud-

es. The interpretation of I2 for heterogeneity was mades follows: 0—25%: represents low heterogeneity; 25—50%:oderate heterogeneity; 50—75%: substantial heterogene-

ty; 75—100%: high heterogeneity [Higgins et al., 2003modified)]. rMT values were combined to obtain a sum-ary estimate of value (and the corresponding CI) using a

andom-effects model. Random-effects model is consideredore conservative than a fixed-effect model, since it takes

nto account the variability between studies, thus leading to

Please cite this article in press as: Brigo, F., et al., Restingsystematic review with meta-analysis. Epilepsy Res. (2012), ht

ider CIs.To evaluate rMT values in all subtypes of IGEs (Table 1),

e combined data of subgroups (e.g. JME patients andther subtypes of IGE patients) into a single group, using a

bavo

selection and inclusion.

tatistical formula (appendix) to combine numbers into aingle sample size, mean and SD for each interventionroup (i.e., combining across JME and other subtypes of IGEatients); the adopted formula produces the SD of rMT val-es as if the combined group had never been divided intowo (Higgins and Green, 2011).

In order to overcome a unit-of-analysis error for stud-es that contributed multiple, correlated, comparisons wencluded pair-wise comparison separately, but with a sharedntervention groups divided out approximately evenly amonghe comparisons (Higgins and Green, 2011). This methodas undertaken in order to avoid to enter several com-arisons into the meta-analysis when one or more groupsere common (e.g. controls). Otherwise we would haveounted twice the participants in the ‘‘shared’’ interventionroup(s), creating a unit-of-analysis error with overestima-ion of the significance of an intervention with artificiallyxtreme P values, overly narrow CIs and greater weight tohe results of such studies. By dividing up only the total num-

motor threshold in idiopathic generalized epilepsies: Atp://dx.doi.org/10.1016/j.eplepsyres.2012.03.020

er of participants, with the means and SDs left unchanged,pproximate investigations of heterogeneity across inter-ention arms was still possible, although this method maynly partially overcome the unit-of-analysis error (because

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Table 1 Included studies (only data from subjects included in the meta-analysis comparisons are reported).

Study Diagnosis (no.of subjects,female/male)

Age(mean ± SD)

Subtypes ofepilepsy/seizures

Seizure freeinterval

Equipment,stimulator,Co/MF/CD

Migraine/menstrualphase

Site of EMG recording

Reutens andBerkovic(1992)

Ep (11,nr)C (71,nr)

Ep 26 ± 7C 28 ± 8NS

7 Absences,5 myoclonicseizures, 10GTCS

Not reported Magstim 200C/2.0/90

nr Abductor digitiminimi of thedominant hand

Reutenset al. (1993)

Ep (20,13/7)C (89,62/27)NS

Ep 20 ± nrC28 ± nr

6 JME, 8CAE-JAE, 6not clearlydefined/17GTCS alone,10myoclonicseizures, 12absence

Not reported Magstim 200C/2.0/90

nr Abductor digitiminimi of thedominant hand

Michelucciet al. (1997)

Ep (19, nr)C (50, nr)

Ep nrC nr

Notexplicitlyreported

Not reported Cadwellnr/nr/nr

nr Contralateral tenarmuscles (bilateralTMS)

Brodtmannet al. (1999)

Ep (7,2/5)C (16,9/7)NS

Ep 25 ± nrC 29 ± nr

3 JME, 1JAE, 3 GTCSalone

All patients hadexperienced aseizure within 2weeks of TMS.

Magstim 200C/-/140

nr Abductor pollicisbrevis of thedominant hand

Manganottiet al. (2000)

Ep (3,2/1)C (12,7/5)NS

Ep24.3 ± 0.6C (24-39)

3 JME Not reported Magstim 200E/-/70

nr Right thenareminence muscles

Macdonellet al. (2001)

Ep (21,nr)C (19,nr)

Ep 17.4 ± nrC 25.7 ± nr

9 JME, 1JAE, 11unspecified(CGTS only)

All patients hadexperienced aseizure within 2weeks of TMS.

Magstim 200C/-/140

nr Abductor digitiminimi of thedominant hand

Groppaet al. (2008)

Ep (17,12/5)C (13,10/3)NS

Ep14.9 ± 2.6C 36.8 ± 7S, P < 0.01

3 GTCSalone, 14JAE

At least 6months ofseizurefreedom beforeTMS

Magstim 200E/-/-

nr Right abductorpollicis brevis

Badawyet al. (2006)

Ep (15,8/7)C (13,6/7)NS

Ep 32.3 ± nrC 39.2 ± nr

5 JME, 10unspecified

All patients hadexperienced aseizurebetween 2 and4 weeks beforeTMS

Magstim 200C/-/140

nr Right abductorpollicis brevis

Please cite

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in press

as: Brigo,

F., et

al., Resting

motor

threshold in

idiopathic generalized

epilepsies: A

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review w

ith m

eta-analysis. Epilepsy

Res. (2012),

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Table 1 (Continued)

Study Diagnosis (no.of subjects,female/male)

Age(mean ± SD)

Subtypes ofepilepsy/seizures

Seizure freeinterval

Equipment,stimulator,Co/MF/CD

Migraine/menstrualphase

Site of EMG recording

Cantelloet al. (2006)

Ep (8, 3/5)C (18,8/10)NS

Ep19.4 ± 7.5C 25.3 ± 8.7NS

2 JME, 4absenceepilepsy, 2GTCS onawakening

At least 3weeks ofseizurefreedom beforeTMS

Magstim 200C/-/90

nr Contralateral firstdorsal interosseus(bilateral TMS)

Badawyet al. (2007)

Ep (35,18/17)C (29,12/17)NS

Ep 25 ± nrC33 ± nr

11 JME, 2JAE, 22unspecified

All patients hadexperienced aseizurebetween 2 and4, weeksbefore TMS

Magstim 200C/-/140

nr Contralateralabductor pollicisbrevis (bilateral TMS)

Badawyet al.(2009a,b)

Ep (20, 12/8)C (10,6/4)NS

Ep 31 ± nrC 29 ± nr

10 JME, 1JAE, 9,GTCS alone

At least 2weeks ofseizurefreedom beforeTMS

Magstim 200C/-/140

nr Abductor pollicisbrevis of thedominant hand

Klimpeet al. (2009)

Ep (15,10/5)C (20,12/8)NS

Ep30 ± 16.34C27.45 ± 8.32NS

9 JME, 6GTCS alone

At least 24 h ofseizurefreedom beforeTMS

Magstim 200E/2.2/90

nr First dorsalinterosseus of thedominant hand

Badawyet al.(2010a)

Ep (19,10/9)C (32,20/12)NS

Ep16.5 ± 6.5C 31 ± nr

19 JME At least 2weeks oftonic—clonicseizurefreedom beforeTMS

Magstim 200C/-/140

nr Abductor pollicisbrevis of thedominant hand

Badawyet al.(2010b)

Ep (55,nr)C (32,20/12)

Ep 28 ± 23C 31 ± nr

Notexplicitlyreported

Not reported Magstim 200C/-/140

TMS performedduring the samephase of themenstrual cycle

Abductor pollicisbrevis of thedominant hand

-: not reported; C: controls; CD: outer coil diameter (mm); Ci: circular; CNS: central nervous system; Co: Shape of coil; E: figure-of-eight; EMG: electromyography; Ep: epileptic patients;GTCS: generalized tonic—clonic seizures; JAE: juvenile absence epilepsy; JME: juvenile myoclonic epilepsy; MF: peak magnetic flux (Tesla); NS: difference not statistically significant; S:difference statistically significant; SD: standard deviation; TMS: transcranial magnetic stimulation.

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Resting motor threshold in idiopathic generalized epilepsies

the resulting comparisons remain correlated) (Higgins andGreen, 2011).

Statistical analyses were undertaken with the ReviewManager software developed by the Cochrane Collaboration(5.1).

Results

Description of studies (Table 1)

The search strategy described above yielded 243 results (25MEDLINE, 216 EMBASE, 2 conference abstracts found throughhandsearching). Of the 243 references, 166 duplicates(identified using reference manager and manual checks)were excluded. After the initial screening of the title andabstract, a further 38 citations were excluded, leaving 39articles for retrieval. Full text assessment of these arti-cles resulted in 23 eligible studies that were provisionallyincluded in our review. Of these 23 studies provisionally con-sidered for inclusion, 9 were later excluded: one (Delvauxet al., 2001) performed TMS in untreated patients havingexperienced only a first ‘‘grand mal’’ seizure, thus lackingthe minimum criteria for a diagnosis of epilepsy (definedaccording to ILAE, 1997); one study (Kazis et al., 2006)adopted a rMT definition different from that adopted inthe present review; one study was conducted on epilep-tic patients under antiepileptic treatment (Aguglia et al.,2000); one study performed consecutive TMS (Badawy et al.,2009a); from five studies it was impossible to obtain meanand SD values of rMT even after contacting principal inves-tigators (Michelucci et al., 1990; Tataroglu et al., 2004; Jooet al., 2008; Hwang et al., 2010; Badawy et al., 2011).

One study using TMS early in the morning and late in theafternoon to investigate the effect of diurnal variability oncortical excitability was included, since in pooled analysisdata regarding such a variable would be balanced (Badawyet al., 2009b). The same was made with another study eval-uating cortical excitability after sleep deprivation (Badawyet al., 2006). These studies performing multiple comparisons(morning/late afternoon; sleep deprivation/no sleep depri-vation) with one or more groups in common were assessed asdescribed above (statistical analysis and appendix) to avoidunit-of-analysis errors.

Patients of one study (Reutens et al., 1993) were classi-fied as affected by JME (6 patients) or other IGEs (8 patientswith absence seizures only) on the basis of clinical data pro-vided in the research paper; the other 6 patients were notincluded in meta-analysis B and C (rMT in JME patients/ rMTin IGEs other than JME) because it was not clear whetheralso these subjects may have a definite diagnosis of JME.

Thus 14 trials, including 265 epileptic patients and 424control subjects, contributed to this review: the earliest waspublished in 1992 and the most recent in 2010.

Risk of bias

Several studies had at least one author in common (Reutens,

Please cite this article in press as: Brigo, F., et al., Restingsystematic review with meta-analysis. Epilepsy Res. (2012), ht

Badawy) and were published within a few years apart, sothat the probability of overlapping cases and/or controlscould not be ruled out, also because, when contacted,Authors did not clarify such an aspect. Thus, it was

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mpossible to determine whether some included papers rep-esent duplicate publications (risk of multiple publicationias). The inclusion of duplicated data may therefore haveead to overestimation of results from these studies.

Only in one study the neurophysiologist performing TMSas blinded to the different groups of participants (Groppat al., 2008). However, unlike occipital TMS with evaluationf phosphene threshold, measuring rMT is an objective pro-edure, so that its results are not likely to be influenced byack of blinding.

uantitative synthesis

MT values in all types of IGEs (Fig. 2)

here were 14 studies with 689 participants (265 epilepsyatients, 424 controls). Statistically significant heterogene-ty among trials was detected. There was no statisticallyignificant difference in rMT between IGE and control group,lthough a trend towards lower values in IGE patients wasound (mean difference: −2.34; 95% CI −4.89 to 0.21).

MT values in juvenile myoclonic epilepsy (JME)Fig. 3)

ive studies with 201 participants (40 epilepsy patients, 161ontrols) reported rMT values of JME patients to allowing aubgroup analysis relative of this subset of IGEs. Statisticallyignificant heterogeneity among trials was detected. Thereas a statistically significant difference in rMT between JMEnd control group, with lower values in JME patients (meanifference: −6.78; 95% CI −10.55 to −3.00).

MT values in IGEs other than JME (Fig. 4)

our studies with 171 participants (41 epilepsy patients, 130ontrols) reported rMT values of patients with IGEs otherhan JME to allowing a subgroup analysis. No statisticallyignificant heterogeneity among trials was detected. Thereas no statistically significant difference in rMT betweenpilepsy patients and controls (mean difference: 2.54; 95%I −1.00 to 6.08).

ublication bias

unnel plot qualitative analysis showed no evidence of sig-ificant publication bias (Egger et al., 1997).

iscussion

n this systematic review we used systematic and explicitethods to identify, select and critically appraise studies,

nd to extract data, analysing them with a meta-analysis. meta-analysis is the statistical combination of resultsrom two or more separate studies, allowing an increase in

motor threshold in idiopathic generalized epilepsies: Atp://dx.doi.org/10.1016/j.eplepsyres.2012.03.020

tatistical power, and an improvement in precision, some-imes permitting to answer questions not posed by individualtudies and to settle controversies arising from conflictinglaims.

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Figure 2 rMT values in IGE (all subtypes). Badawy et al., 2006*a: rMT in IGE patients in rested state; Badawy et al., 2006*b: rMTin IGE patients in sleep-deprived state; Badawy et al., 2009a: rMT in IGE patients performed early in the morning within an hour ofwaking (values obtained with the formula reported in appendix); Badawy et al., 2009b: rMT in IGE patients performed early in theafternoon (values obtained with the formula reported in appendix).

Figure 3 rMT values in JME. Badawy et al., 2009a: rMT in JME patients performed early in the morning within an hour of waking;B the

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adawy et al., 2009b: rMT in JME patients performed early inantello et al. were approximated to 0.01 (original value: 0).

In the present meta-analysis we found that patients withME have a lower rMT compared with healthy controls; whenonsidering all subtypes of IGEs and IGEs other than JME, theifference is not statistically significant. The non-significantrend towards lower rMT values in IGEs is possibly relatedo the inclusion of JME patients. Overall considered (andlso taking into account the sample size of each compari-on and the global effect size), these results are indicativef a cortico-spinal hyper-excitability in JME, providing notnough evidence for motor hyper-excitability in other sub-ypes of IGE.

Please cite this article in press as: Brigo, F., et al., Restingsystematic review with meta-analysis. Epilepsy Res. (2012), ht

rMT is believed to reflect membrane excitability of cor-icospinal neurons and interneurons projecting onto theseeurons in the motor cortex, as well as the excitability of

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igure 4 rMT values in IGEs other than JME. Badawy et al., 2009aour of waking; Badawy et al., 2009b: rMT in IGE patients performe

afternoon. SD values of the two JME patients in the study of

otor neurons in the spinal cord. In addition to the mem-rane excitability itself, rMT relates to the activity of neuralnputs into pyramidal cells that affect their membranexcitability (i.e., tonic inhibitory and excitatory drives ontohe cortical output neurons), and provides insights into thefficacy of a chain of synapses from presynaptic corticaleurons to muscles (Kobayashi and Pascual-Leone, 2003).

Cortical excitability is better assessed by the paired-ulse paradigm (Kujirai et al., 1993) evaluating intra-ortical inhibition or facilitation patterns, or measuringhe silent-period, a parameter which refers to the dura-

motor threshold in idiopathic generalized epilepsies: Atp://dx.doi.org/10.1016/j.eplepsyres.2012.03.020

ion of interruption of voluntary motor activity after a TMSulse, and is thought to reflect cortical and spinal mecha-isms (Fuhr et al., 1991). Moreover, these two methods are

: rMT in IGE patients performed early in the morning within and early in the afternoon.

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ARTICLEEPIRES-4745; No. of Pages 11

Resting motor threshold in idiopathic generalized epilepsies

performed with different procedures, so that a direct com-parison of pooled results from studies using these techniqueswould be extremely difficult because of an excessive amountof methodological heterogeneity. A methodological hetero-geneity is intrinsic to paired-pulse TMS procedure since theamount of intra-cortical inhibitory and facilitatory eventscan vary depending on the size of test MEPs, so that it iscritical to maintain the patients relaxed and adjust the sizeof test MEPs across trials and subjects.

In IGE, myoclonic jerks are thought to depend on theinvolvement of thalamocortical structures, that recruit mus-cles via fast-conducting corticospinal pathways (Tassinariet al., 1998). In JME, generalized myoclonus is the main clin-ical feature, whereas in other IGE subtypes myoclonic jerksare an accessory finding. Interestingly, our meta-analysissuggests that the excitability of corticospinal pathways isgreater when considering JME alone than when consider-ing all subtypes of IGE. Lower rMT values in patients withJME compared with healthy controls are therefore indica-tive of an imbalance of excitatory and inhibitory influencesin the primary motor cortex, eventually resulting in hyper-excitability. This result is consistent with other findingsobtained by different neurophysiological methods of assess-ing motor excitability (ICI, ICF, and cortical silent period),that, overall, suggest that a GABAa-mediated inhibitionmay lead to motor hyperexcitability (Manganotti et al.,2000), without abnormal processing of cutaneous afferents(Manganotti et al., 2004). Such a rather selective involve-ment of distinct hyperexcitable circuitry might thereforejustify the concept of ‘‘system epilepsy’’ with regards toJME.

Although the results of meta-analytic comparison C (rMTvalues in IGEs other than JME) were not statistically signifi-cant and based on only 41 patients, the trend towards higherrMT values in IGE might represent an interictal protectivemechanism against the spread or recurrence of seizures, andis consistent with the findings of previous reports (Delvauxet al., 2001; Badawy et al., 2009a).

Exploration of heterogeneity

In the meta-analysis a considerable statistical heterogeneitybetween comparisons A (rMT values in all types of IGEs) and B(rMT values in JME), indicative of inconsistency in the resultsof included studies, was found. The term ‘‘statistical het-erogeneity’’ describes the degree of variation in the effectestimates from a set of studies, and indicates the presenceof variability among studies beyond the amount expecteddue chance alone.

The heterogeneity found in the meta-analysis is relatedto the presence of some outlying studies with results con-flicting with the rest of the studies. However, the limitednumber of included studies prevents us from performing asensitivity analysis to better investigate heterogeneity.

Such a statistical heterogeneity may be howeverexplained both by differences in clinical characteristics ofstudy participants (clinical heterogeneity) and by different

Please cite this article in press as: Brigo, F., et al., Restingsystematic review with meta-analysis. Epilepsy Res. (2012), ht

stimulation procedures (methodological heterogeneity).The main aspect to be considered is the homogene-

ity of included patients. IGEs should not be consideredas a homogeneous entity, but rather as a spectrum of

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pileptic syndromes, each of them with potentially differentathophysiological mechanisms. TMS studies should there-ore adopt strict inclusion criteria (e.g. grouping patientsy epileptic syndrome, etiology, severity, treatment, andeizure-free interval) in order to increase data consistencyTassinari et al., 2003).

Due to lack of data it was not possible to evaluate thetatistical differences in demographic features (age, sex) forll included studies. A statistically significant difference inge of epilepsy patients and controls was found in only onetudy (Groppa et al., 2008). However, because of the limitedtatistical power of this study (5.9%) it is unlikely that thislinical heterogeneity has affected the overall result of theomparison between rMT in IGEs and healthy controls.

Other clinical factors which might influence corticalxcitability are the ovarian cycle (Smith et al., 1999; Smitht al., 2002; Hattemer et al., 2006; Badawy et al., 2010c)nd the presence of migraine (Aurora et al., 1998, 1999,003). All included studies but one (Badawy et al., 2010b)id not explicitly assess these two variables, whose effectn cortical excitability is still matter of debate (Young et al.,001; Boros et al., 2009). Another relevant aspect to beaken into account, especially when evaluating JME, is theffect of sleep deprivation on rMT, as some studies haveuggested an increase in overall higher cortical excitabil-ty after sleep deprivation in this IGE subtype (Manganottit al., 2006; Del Felice et al., 2011). The inconsistencymong meta-analysis results might be explained also by anntrinsic high variability of results in MT values among IGEatients. Such a high variability might be due to higher tem-oral variability among MT measurements over time, relatedo unstable excitability levels in these patients (Delvauxt al., 2001; Badawy et al., 2009a).

Regarding methodological heterogeneity, potentially rel-vant aspects to be considered are the coils’ shape, sizend maximum magnetic field strength, and the directionf the current through the stimulating coil (mono- or bi-hasic); these stimulator characteristics are sometimes notxplicitly reported in the studies, although they may deeplynfluence the results. For example, compared with a figure-f-eight coil, a circular coil stimulates a larger cortical areaCohen et al., 1990; Hallett, 2000), and may generate, ateast theoretically, a stronger electric current.

trengths and limitations of the review

revious narrative reviews have evaluated the motor hyper-xcitability in IGE (Ziemann et al., 1998; Macdonell et al.,002; Tassinari et al., 2003; Chen et al., 2008), but ourystematic review is the first attempt to pool togetherhe different existing studies that evaluated rMT in IGE.oreover, results of this review contributed to settle theontroversies arising from discrepant data among studieseporting rMT in JME patients, providing further data toupport the presence of a cortical hyperexcitability in thispileptic syndrome.

Due to lack of enough data, the only subgroup analy-

motor threshold in idiopathic generalized epilepsies: Atp://dx.doi.org/10.1016/j.eplepsyres.2012.03.020

es which we managed to undertake were on JME patientsersus IGEs other than JME. Despite our intentions, we couldherefore not assess the effect of age, time to the diagnosis,umber and type of seizures presenting results on the same

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ARTICLEPIRES-4745; No. of Pages 11

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orest plot to give an overall impression. Considering theimited data available, which prevented us from performingubgroup analyses on each subgroup of IGE, and the con-iderable statistical heterogeneity found in meta-analyticomparisons, any definite conclusions should be cautious,nd further studies should be done to confirm or refute theesults of our analyses, especially with regards to IGEs otherhan JME.

In conclusion, the results of this systematic review arendicative of a cortico-spinal hyper-excitability in JME, pro-iding not enough evidence for motor hyper-excitability inther subtypes of IGE.

rMT showed considerable variability between studies.linical and methodological heterogeneity may accountor these discrepancies. A high temporal variability amongMT measurements over time, related to unstable corticalxcitability levels in these patients, should also be consid-red. Further studies adopting a unique, shared protocolith stricter inclusion criteria to study more homogeneousopulations are required to confirm our results.

onflict of interest statement

one of the authors has any conflict of interest to disclose.

isclosure

e confirm that we have read the Journal’s position on issuesnvolved in ethical publication and affirm that this report isonsistent with those guidelines.

cknowledgements

e are in debt with Dr. S. Groppa and Prof. R. Cantello, whoindly provided us additional information, thus allowing uso include also their studies in the meta-analysis. We alsohank Dr. G. Rubboli, Dr. A. Brodtmann and Dr. R. Badawyho kindly gave us information on their studies. We thankrancesco Passarella for graphical support.

ppendix A. Supplementary data

upplementary data associated with this article can beound, in the online version, at http://dx.doi.org/10.1016/.eplepsyres.2012.03.020.

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