Praxis induction. Definition, relation to epilepsy syndromes, nosological and prognostic significance. A focused review

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Review

Praxis

induction.

Deﬁnition,

relation

to

epilepsy

syndromes,

nosological

and

prognostic

signiﬁcance.

A

focused

review

Elza

Ma´rcia

Yacubian

a,

*,

Peter

Wolf

b

a_Department_of_Neurology_and_{Neurosurgery,}_Universidade_Federal_de_Sa˜o_Paulo,_Sa˜o_Paulo,_Brazil b_Department_of_Neurology,_Danish_Epilepsy_Centre,_Dianalund,_Denmark

1. Backgroundanddefinition

Overthe lastyears,increasingawarenesshas developedthat reflexepilepticmechanismsprovideuniquepossibilitiestostudy seizuregeneration(ictogenesis)innaturalhumanepilepsies.Praxis induction(PI)isoneofthereflexepileptictraitswhichhavebeenin focus. It is defined as the precipitation of epileptic seizures or epileptiform EEG discharges (ED) by complex, cognition-guided tasksofteninvolvingvisuomotorcoordinationanddecision-making.

2. Historyanddelineation

ThetermwasﬁrstusedbyDanieleetal.1_but_there_is_an_earlier

literaturepresentingspeciﬁcaspectsofPIsuchasplayingchess,card orothergames,2–5_{calculations,}6,7_writing,8,9_drawing10_and_decision

making.11_Inoue_et_al.12_reviewed _the_literature_and_proposed_to

considerPIasacommondenominator.Theyobservedthatthevast majorityofpatientssufferedfromidiopathicgeneralizedepilepsy (IGE),particularlyjuvenilemyoclonicepilepsy(JME).12

In 1980, Okuma et al.13 devised an EEG activation method which they termed neuropsychological EEG activation (NPA) protocol involving speaking, reading, writing, calculation, con-structiveactsasdrawingﬁguresandblockdesigntests(Table1). ThisNPAprotocolwascarried outwhenparoxysmaldischarges hadbeeninducedinasimpler formofa 5minNPA comprising readingsilentlyandaloud,speaking,mentalandwritten calcula-tion, writing and spatial construction during routine EEG examinations.13_NPA_was_used_by_Matsuoka_et_al.14_and _also_in

agroupofpatientswith‘‘graphogenicepilepsy’’15_as_well_as_in_a

largeunselectedpatientgroup.16

Thinking-induced seizures17 _according _to _some _authors _are

another variant of PI whereasothers consider them a separate entity.18 Since spatial thinking is central in thinking-induced seizures,anydifferenceisprobablygradual.However,Zifkin18_in

this discussion pointed out that seizures induced by thinking without any motor component often provoke absences and generalizedtonic–clonicseizures(GTCS)butnomyoclonicseizures. Thesecasestypicallyinvolvethe solutionofcomplex arithmetic taskswhichcouldbeexplainedbyanetworkincludingbilateral parietalcorticalareas19_but_not_more,_unlike_in_PI._Guaranha_et_al.20

conﬁrmedthatmereplanningofprecipitatingactionswasatrigger byitself,thedifferencebeingonlyquantitative.Inductionbywriting

ARTICLE INFO

Articlehistory:

Received26November2013

Receivedinrevisedform11January2014 Accepted15January2014

Keywords: Praxisinduction

Juvenilemyoclonicepilepsy Idiopathicgeneralizedepilepsies Reﬂextraits

Systemepilepsies

ABSTRACT

Purpose:Thereisincreasingawarenessthatreﬂexepilepticmechanismsprovideuniqueinsightinto

ictogenesisinhumanepilepsies.Severalofthedescribedtriggershaveincommonthattheyimply

complexvisuomotorcoordinationanddecision-making;theyaretodayregardedasvariationsofone

principle,i.e.praxisinduction(PI).ThisfocusedreviewconsidersPIfromtheaspectsofhistoryand

delineation, clinical and electroencephalographic presentation, syndromatic relations, prevalence,

mechanismsofictogenesisandnosologicalimplications,treatmentandprognosis.

Methods:WereviewedaseriesofpublishedarticlesandcasereportsonPIinordertoclarifyclinicaland

electroencephalographicﬁndings,treatmentandoutcome.

Results:Findingsofbothinductionandinhibitionbythesamestimuli suggestwideningthereﬂex

epilepsyconceptintoabroaderoneofepilepsieswithexogenousmodiﬁcationofictogenesis.PIisclosely

relatedtojuvenilemyoclonicepilepsy(JME)wherehyperexcitabilityandhyperconnectivityoftheentire

networkofvisuomotorcoordinationseemtoprovidethepreconditionforelicitingreﬂexmyocloniinthe

musculatureactiveintheprecipitatingtask.

Conclusion:TheconclusionsonictogenesisderivedfromPIsupporttheconceptofJMEasasystem

disorderofthebrain.

ß2014BritishEpilepsyAssociation.PublishedbyElsevierLtd.Allrightsreserved.

* Correspondingauthor.Tel.:+551155764136. E-mailaddress:[email protected](E.M.Yacubian).

ContentslistsavailableatScienceDirect

Seizure

j o urn a lhom e pa g e :ww w . e l se v i e r. c om / l oca t e / y se i z

http://dx.doi.org/10.1016/j.seizure.2014.01.011

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hasbeenreportedbothwithPI12_,_with_primary_reading_epilepsy

(PRE)21_and_separately.9_Because_of_the_linguistic_involvement_its

placecanbedebated.Likewise,seizuresinducedbyvideogamesare most often related to photosensitivity22 _but _may _also _involve

visuomotorcoordination.The signiﬁcanceofthese overlaps will becomeapparentbelow.

3. Description

Onset usuallyis in thesecond decadeoflife. Praxis-induced seizurestypicallystartwithadelayofsomeminutesofactivity, occasionallymore,assingleorrepetitivearrhythmicmyocloniin musclesinvolvedintheprecipitatingactivity.Atypicalexampleis presentedin Video 1. Ifthe patientcontinues hisactivity they usuallyevolveintoaGTCS,sometimesratherrapidly.

Supplementarymaterialrelatedtothisarticlecanbefound,in the online version, at http://dx.doi.org/10.1016/j.sei-zure.2014.01.011.

Spontaneous seizures occur rarely in 76% of patients.5

Occasionally, PI can commence later in life.23,24 _Some _familial

cases have been described, e.g. two sisters with seizures exclusivelyinduced by writing,9 _and _the_genetic _aspects _seem

nottodifferfromotherpatientswithIGE.25

4. Prevalenceandsyndromaticrelations

Matsuoka etal.14_performed_NPA_in₂₅ _JME_patients. _Mental

activitiesinvolvingthehands(writing,calculationanddrawing) precipitatedseizuresin19patients(76%).NPAwasmoreeffective in inducing ED (21 patients=84%) than established activation methodssuchasdrowsiness(17patients=68%),hyperventilation (10patients=40%)andphoticstimulation(9patients=36%).14

All25casesreportedbyGoossensetal.5_had_IGE_with_clinical

patternssuggestive of either juvenile absenceepilepsy or JME. Theseauthorsassociatedtheoccurrenceofseizurestoactivationof theparietallobe.

Senanayake26_reported_increase_of_ED_and_seizures_with_NPA_in

148JMEpatients. In twelve, >50% and in seven,all myoclonic

seizureswere precipitated by tasks involving problem solving,

calculationandspatialprocessing.HeagreedwithGoossensetal.5

that these patients presented regional hyperexcitability of the dominantparietalcortex.26

Becauseof theirclinicaland EEGsimilarities,Inoueet al.12

compared the clinical features of 32 PI patients with 132 unselectedJMEpatients.TheyconcludedthatallPIpatientswith aspecificdiagnosishadIGE(JME21,juvenileabsenceepilepsy3, unspecifiedIGE4);4/32hadundeterminedepilepsy.Oftheir132 unselected JME patients, 19 (14%) had predominantly, and another24(18%) incidentalreflex seizures.However, patients with predominant PI differed from the others by a male predominance of 3.7/1 (in agreement with Goossens et al.5_;

ratio3:1)andalowerincidenceofthephotoconvulsiveresponse, suggestingadispositionaldifferencewithinJME.12InaBrazilian seriesyoungermalepatientswere morepronetoPIinduction thanolderones(25%uptoage30versus6%above)whichwas attributed to more frequent activities demanding ﬁne ﬁnger movementssuchasgameplayingandcomputermanipulationby theyoungergeneration.27

AccordingtoJanzand Durner,28_mental_tasks_involving_hand

movements,leadingtopsychictensionanddemanding decision-makingcouldprovokebothmyoclonicjerksandmajorseizuresin JME.

Inoue and Kubota29 _reported _PI _in ₂₇ _of ₂₁₃ _JME _patients

(12.2%). They conﬁrmed the following differences: slight male predominance(2.3:1);moreabsenceseizures;no photosensitivi-ty; higher amplitude of sensory evoked potentials (suggesting increasedcortical excitability)and slightlyless favorable treat-mentprognosis.29

Matsuokaetal.16inamulticenterstudytested480unselected epilepsy patients with an enhanced NPA protocol for praxis-inducedepileptiform activityand seizures.They foundPI in38 patients (7.9%), 36 of whomhad IGEincluding JME. The most signiﬁcant ﬁndings were with writing (n=26, 68%), spatial construction (n=24, 63.2%) and written calculation (n=21, 58.3%).Of 45 JMEpatientsED weretriggeredin 22 (48.9%),by farthehighestrateofallsyndromes.16

Wolf and Mayer30 _reported _on ₆₂ _JME _patients _who _had

answeredaquestionnaireaddressingspecificprecipitationfactors. PIwas describedby 19 (31%) comprising writing(7), decision-making(4),computertasksandvideogames(6),calculations(6), thinking(8)andplayingthepiano(1).Theseauthors,forthefirst time,emphasizedanothertypeofreflexmyocloniinJMEpatients: theperioralreflexmyoclonia(PORM)whichwerereportedin22of theresponses(35%).29_In_a_follow-up_study_{investigating}₂₅_JME

patientswithvideo-EEGandusingamodiﬁcationofMatsuoka’s NPA,31_PORM_were_found_in_nine_patients_(36%),_and_PI_in_six_(24%;

4manipulatingwithRubikcube,2writingand1,calculating). Karachristianouet al.32_studied ₃₀_JME_patients _with_a _NPA

protocolandfoundEEGactivationin23(76.6%)includingmanual taskssuchasdoodlingﬁguresin18(60%)orwrittencalculationsin 13 (43.3%), but also in non-manual activities like mental calculations in15 (50%) and mentalspatial manipulationin 15 patients(50%).

Among75 Brazilian JMEpatients answeringa questionnaire induction of seizures by hand activities and complex ﬁnger manipulationswasknownto15(20%)27_whereas_they_considered

stress(62casesor83%)andsleepdeprivation(58or77%)byfarthe mainseizureprecipitants.

Inavideo-EEGNPAstudy,Guaranhaetal.20_described_praxis

induceddischargesand/ormyoclonicseizuresin22of76patients (29%;puzzlesin19;writtencalculationin9;writingin6;drawing in6).

ItcanthereforebeconcludedthatPIisstronglyassociatedwith JMEbutalsooccursinothertypesofIGEwhereasitisveryrarein other epilepsies. The prevalence ﬁgures in JME, however, vary Table1

DetailedneuropsychologicalEEGactivationprotocol.13

(1)Writing

1.Spontaneouswriting 2.Dictation

3.Copying

4.Spontaneouswritingblindfolded 5.Dictationblindfolded

6.Dictationbyfood

EachwasexaminedforJapaneseletters (Hiragana,Katakana,Kanji),

RomanlettersandEnglishletters

(5)Constructionalpraxis 1.Spontaneousdrawing 2.Sketchingmaps 3.Copyingﬁgures 4.Matchstickpattern

reproduction

5.Blockdesigntest(WAIS) 6.Makingplasticmodels (6)Othertests

1.Fingertapping 2.Finemovementofthe

ﬁnger(tremolo) 3.Usingascrew-driver 4.Bourdoncancelationtest 5.Undoingpuzzlerings 6.Hand,eyeandeartests

(HHead) 7.Fingergnosiatests 8.Dressing 9.Colorclassiﬁcation 10.Humming 11.Singing (2)Speaking

1.Spontaneousspeaking 2.Readingaloud 3.Repeating

EachwasexaminedinJapanese andEnglish

(3)Otherverbalactivation 1.Readingsilently 2.Visualizingletters

3.Makingsentencesinthemind (4)Calculation

1.Calculationwithhands 2.Mentalcalculation 3.Calculationusinganabacus

4.Calculationusinganelectriccalculator Eachwasexaminedforsubtraction,

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between8%and60%,probablyduetodifferencesinsamplingand investigation protocols. But even in the studies using similar protocolsthereisvariationfrom24and29%inGermanyandBrazil, andalmost50%inJapan.Atpresentthesedifferentratesremain unexplained.Sincecorticalexcitabilityvariesduringtheday33_and

oneofthestrongesttriggerinJMEisstress27_we_may_infer_they

mustberelatedtodifferencesinNPAprotocolssuchasexecution oftasksonawakeningaftersleepdeprivationorafullnightofsleep and speciﬁc characteristics of the tasks as the use of stressful material,theirduration,complexity,etc.

5. Precipitationandinhibition

Matsuokaetal.16werepuzzledbytheﬁndingthatNPAinmany casesseemedtoinhibitratherthanenhanceEDwhenthesewere present in the unprovoked EEG; in a few patients even both, activationandinhibitionweredescribed.Thiswasconﬁrmedby Mayeratal.31_and_by_Guaranha_et_al.20_who_paid_special_attention

tothisproteanresponse.Thequestionbecametheobjectofan internationalmulticenter investigationof 60 JMEpatients with methodsthattookintoconsiderationthespontaneousﬂuctuations ofED.34_In_this_study_inhibition_by_NPA_was_less_frequent_than_in

theearlierreportsbutwasstillseenin29%ofthepatientswhereas provocationoccurredin18%.However,provocationappearedtobe task-speciﬁc whereas inhibition could be explained by a non-speciﬁc effectof cognitiveactivation or arousal as such.34 _The

questionremainsopeniftheconceptofreﬂexepilepsiesneedsto be replaced by a broader view of epilepsies with exogenous modiﬁcationofictogenesis.

6. Mechanismsofictogenesisandnosologicalimplications

Themostinterestingscientificaspectofreflexepilepsiesisthe possibility they provideto study natural ictogenesis in human epilepsysinceinthem,aspecific,oftenevenquantitativelydefined stimulus evokes a specific epileptic response. Advanced study methodsofbrainfunctioncanprovideinsightsofunprecedented precision into these relations. Thus, Moeller et al.35 _have

demonstratedthatthespike-wavedischargesofthe photoparox-ysmalresponseresultfromacascadeoftranscorticaleventsnot involvingthethalamus.

PIisofparticularinterestbecauseofitsassociationwithJME. Glenn et al.23 hypothesized local excitation associated with proprioceptive input as a mechanism of seizure generation, analogoustophotosensitivityandreading- orlanguage-induced epilepsy.Thehyperexcitationwould thenpropagatetoadjacent motorcortexthroughatranscorticalpathwaygenerating myoclo-nus.36_This_requires_a_stimulus_strong_enough_to_activate_a_critical

massofcortextoproduceepilepticactivity.37

Zylicz et al.38 _discussed _the _role _of _speciﬁc _functional

anatomicalsystemsactingasawhole.Patientswithreflexseizures would have sensitive areaswithin suchsystems. Specificareas involvedinsensoryorcognitivestimulationwouldoverlapwith hyperexcitableareassoarestrictedstimuluscouldinfluencean entiresystem.

Butreﬂexmyocloniusuallyarequiterestricted.Thus,whereas cognitivefunctionalanatomicalsubsystemsbecomeoverexcited asawholetheepilepticresponseisgeneratedlocallywithinthe system, e.g. proprioception of hand movements involved in a complexictogenicactivityprecipitates,inatruepathologicalreﬂex mechanism,myocloniintheactivehand.

Ahighlyimportantcontributiontotheunderstandingof the ictogenesisinJMEhighlightingthemechanismsofPIwasmadeby Vollmaretal.39_who_exposed₃₀_patients_with_JME_to_a_demanding

frontal lobe test of visuo-motor coordination and working memory.Theyperformedaswellas26healthycontrolsbuttheir

fMRI showed, with increasing cognitive demand, increasing coactivation of the primary motor cortex and supplementary motor area, and increasedfunctional connectivity between the motorsystemandfrontoparietalcognitivenetworks.Furthermore, theconcomitantphysiological deactivationof thedefault mode network during the task was impaired. They concluded that, together, these ﬁndings provide an explanation how cognitive effortcancausemyoclonicjerksinJME.39

Theseﬁndingsaddanewdimensiontoearlierconsiderations abouttheroleoffunctionalanatomicalsystemsinIGEwhichwere baseduponphotosensitivityandpatternsensitivityasreviewedby Binnie40_._They_provided_an_important_contribution_to_the_theory_of

systemepilepsies41,42_because_they_demonstrated_that_the_central

mechanismsofseizuregenerationintheseepilepsies‘‘hijack’’,by hyperexcitation,pre-existing functionalanatomicsubsystemsof thecentralnervoussystem(CNS).Thesystemepilepsiesconcept thereforeprovidesabetterunderstandingoftheseconditionsthan themisleadingterm‘‘generalized’’epilepsies.42

7. EEG

Normal background and generalized spike and wave or polyspikeandwavecomplexeswerefoundintherestingEEGor during hyperventilation.25 _In _ﬁve _subjects _with _{‘‘graphogenic}

epilepsy’’ anda clinicaldiagnosisofIGEaNPA protocolproved remarkablyprovocative,inducingeitherbriefburstsofgeneralized spike-and-wave complexes 3–5Hz or bilateral spike-and-wave complexes predominating in the central regions, frequently asymmetricalandoftenaccompaniedbymyoclonicseizures.15

Insomepatientstheparoxysmsveriﬁedduringtheexecutionof motortasksareisolated,fastspikes, followedbyslowwavesor shortvolleysoflowamplitude,poorlyformed,veryfastandbrief spike and wave complexes morphologically similar to those recordedwhilereadingandinreadingepilepsy(Fig.1).Sometimes theyaresobriefthatitisdifﬁculttodistinguishthemfromthe accompanyingmyogenicartifacts.21,27,31

8. Significancefortreatmentandprognosis

Goossensetal.5_described_PI_as_an_easily_controllable_condition

with satisfactory response to treatment, with three of the 25 patientsseizurefreeonlybyavoidingprecipitatingfactors.When antiepilepticdrugs(AEDs)wererequired,valproicacid(VPA)and benzodiazepinessuchasclonazepamandclobazamwereeffective. Mostcasereportsindicatedgoodseizurecontrolespeciallywith VPA.Itisdifﬁculttoassesstheultimateremissionratesincemost patientscontinuedtotakeantiepilepticmedicationandtherateof spontaneousremissionisfundamentallyunknown.7,9,23,24

Matsuoka,43_however,_reported_negative_impact_of_sensibility_to

NPA on prognosis of JME. Among 32 JME patients, nine with seizuresfrom20to39yearsdespitetreatmentwithVPAwithor withoutotherAEDs,besides morefocal dischargeson EEG,had much stronger response to NPA from the onset. The author suggestedthatNPAwouldbeapredictorofprognosisinJMEand thattheseverityofdiseaseprocessitselfratherthanpsychosocial factorsmightbecrucialtodetermineitslongtermcourse.43

Inoueetal.12_reported_that_{seizure-freedom}_for_more_than_three

yearsdroppedfrom49/71(69%)inpatientswithnoneoronly non-speciﬁctriggersto5/16(31.2%)forpredominantlypraxissensitive patients. Two patients were particularly medically refractory. Almost all patients in thePI group couldrecognize impending seizuresandtriedtoavoidprecipitatingstimuliintheirdailylives. VPA,clonazepamandzonisamidewerethemosteffectivedrugs.12

Similarly, Inoue andKubota29 _analyzing_a _series _of₁₃₄_JME

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non-speciﬁctriggersto18/32(56%)inphotosensitiveand12/25 (48%)for praxissensitive patients. Thisseemedtosuggest that reﬂex epileptictraits couldrepresentan aggravatingfeature in JME.

IntwoJMEpatientsdescribedbyMatsuokaetal.44_PI_under_a

continuousidenticaldrugregimenpersisteduptotheﬁfthdecade of life despite decrease of spontaneous myoclonic seizures, suggestingthattheseizurepropensityofJMEimprovesovertime butpersistslong.

Likewise,inthreeofagroupoffourpatientswithreﬂexseizures inducedby complex stimuli, language and praxis, triggered by combined speciﬁc activitiessuch as visuo-spatial tasks, praxis, decision-makingandemotionalcomponents,itwasobservedthat PORMandPIpersistedforonetotwodecadesafterepilepsyonset although treatment with VPA and other AEDs was considered reasonableeffectiveinIGEandJME.27

Again, Guaranha et al.,45 _following _JME_patients _treated _for

5.721.91yearswithVPA,lamotrigine,topiramate,phenobarbital andbenzodiazepines,foundthattherateofseizurefreedomdropped from15/27(55.6%)inpatientswithnoneornon-speciﬁctriggersto5/ 22(22.7%)forpatientswithPIasdocumentedinvideo-EEG.

9. Conclusions

PIisareﬂexepileptictraitcloselyrelatedtoIGE,inparticular JMEwhereinvideo-supportedstudiesitwasfoundin24–49%of patients.Functionalimaging studiesindicateas anunderlying ictogenic mechanism hyperexcitability of the functional ana-tomical CNS network physiologically subserving visuomotor

coordination.Onthisbackground,local myocloniin theactive musculature manifest as the reﬂex epileptic response. The ﬁndingswithPIsupporttheviewofJMEasasystemepilepsy.PI may identify a subset of JME with less favorable treatment responseandprognosis.

Conflictofinterest

Noneoftheauthorshasanyconﬂictofinteresttodisclose.

Acknowledgments

Dr.YushiInoueofShizuokakindlyhelpedtoaccesssomeofthe Japanese literature. This work was supported by FAPESP from Brazil.This studybelongs tothe EpExMocooperation, anopen internationalresearchinitiativeforthestudyofepilepsieswith externalmodulation(EpExMo)ofictogenesis.Participatingcenters in this study were: Universidade Federal de Sa˜o Paulo-Escola PaulistadeMedicina,Sa˜oPaulo,Brazil(E.M.Yacubian)andDanish EpilepsyCentre,Dianalund,Denmark(P.Wolf).

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