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Ростовский Государственный Медицинский Университет

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Box6.6GazePreferenceDuringandAfteraSeizure

Gazepreferencemustalsobeconsidered.Patientstypicallylook“towardtheirstroke”and “awayfromtheirseizure”(seepage62).IfwethinkCarlton’sseizurebeganinhisleft hemisphere,heshouldbelookingtotherightifheisactivelyseizing.Butwedon’tthinkheis activelyseizing;instead,wesuspectthatheispostictal.JustasaToddparalysiscauses weaknessdueto“burnedout”neurons,gazepreferenceoftenreversessidespostictallydue to“burnedout”frontaleyefields.Theeyefieldswereinitiallypushingtheeyestolookaway fromtheseizurefocusbutarenowexhausted,andthustheeyesdriftbackintheopposite direction—inCarlton’scase,totheleft—whichisthesamedirectionyouwouldexpectifhe’d hadalefthemisphericstroke.

(A)Ablation(duetostrokeorthepostictalstateafteraseizure)ofthefrontaleyefields,and(B) stimulation(fromaseizure)ofthefrontaleyefields.

Sohowdowedistinguishthepostictalstatefromstroke?Thereisnoeasyanswer.Wemusttakethe wholeclinicalpictureintoaccount:whatwefindonexamination,whatweseeonimagingand—often mostimportant—whatweareabletoobtainfromacarefulhistory.If,forinstance,wecontactCarlton’s spousewhotellsusthathehasaknownseizuredisorderandranoutofhismedicationsseveraldaysago, welikelyhaveouranswer.Perfusionimagingstudiescanalsohelptodetermineifthereisdecreased bloodflowtothebrainsuggestiveofstroke(seeChapter2).Butsometimeswejustcan’tbecertain,and inthosecases,wetreatthepatientasifheorshehashadastrokeevenifwesuspectseizure.The potentialdownsideofmissingtheopportunitytotreatastrokeisoftenfarworsethanthatfromgiving thrombolytictherapytoapostictalpatient.

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SeizureEtiology

Seizurescanbeduetolotsofthings,butwecansimplifyittofour:

1. Anepileptogeniclesion

2. Toxic-metabolicderangements

3. Medicationsandothersubstances

4. Anepilepsysyndrome

EpileptogenicLesions

Epileptogeniclesionsarelesionsinthebrainthatactasseizurefoci.Theycanbepresentfrombirthor acquiredlaterinlife.Somecommonexamplesinclude:

 Mesial temporal sclerosis (MTS). This is a pathologic diagnosis (although often detectable on MRI)definedbyneuronallossandgliosis(theproliferationofglialcellsatasiteofdamage)within thehippocampus.Itisthemost commonunderlyingcauseoftemporallobe epilepsy.Its etiologyis unclear, although a history of childhood febrile seizures seems to increase the risk. A possible associationwithhumanherpesvirus6hasalsobeensuggested.BecauseMTSiscommoninpatients with seizures, we order “seizure protocol” MRIs (which specify thin cuts through the temporal lobes)inpatientswhopresentwithfirst-timeseizures. Corticaldysplasiaandneuronalmigrationdisorders.Thisrathercomplicatedterminologyrefers toa situationwhen neurons fail todevelop correctlyor to reachtheparts of the braintheywere meanttoendupin;thesecellsoftenhaveahighpropensitytocauseseizures. Prenatalorperinatalcerebralinjury Poststrokeorpost-traumaticencephalomalacia Braintumors Brainabscesses Vascularanomalies(suchasarteriovenousorcavernousmalformations)

Acuteintracerebralhemorrhageandischemicstrokecanalsopresentwithseizure.

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MesialtemporalsclerosisonMRI,characterizedbyvolumelossandincreasedsignalofthehippocampus (arrow).Itcanbebilateralbutisoftenasymmetric.(ReprintedfromYamadaT,MengE.PracticalGuidefor ClinicalNeurophysiologicTesting.WoltersKluwer;2011.)

Toxic-MetabolicDerangements

Thiscategoryisacatchallforseizurescausedbymetabolicandothersystemicprocesses.Common examplesinclude:

Hypoglycemia Hyperglycemia Hyponatremia Hypocalcemia Hypomagnesemia Uremia

Seizuresduetoanyofthesemetabolicderangementswouldbeconsideredprovokedseizures.There arenodefinitiveguidelinesregardingtheuseofantiepilepticmedicationsinthesesituations.Mostoften, ifthetoxic-metabolicderangementissevere,youshouldstartmedicationandcontinueitthroughhospital discharge.Ifthetoxic-metabolicderangementiscorrectedandthepatientremainsclinicallystablefor severalweeks,youcanconsidertaperingthemedicationasanoutpatient.

MedicationsandOtherSubstances

Manymedicationsandillicitdrugsdecreasetheseizurethresholdinpatientswhoarealreadyproneto

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seize.Theseagentstypicallydonotinandofthemselvescauseseizuresbutincertainsituations—inthe settingofoverdose,forinstance,orwithsevereliverorrenalimpairment—theycancauseseizuresin patientswhodonothaveanyotherreasontoseize.Commonexamplesincludepainmedications(suchas tramadol),severalantibiotics(thecarbapenems,cephalosporins,andfluoroquinolonesarehighestrisk) andpsychiatricmedications(mostoftenbupropionathighdoses).Alcoholandbenzodiazepine withdrawalareothercommoncausesofseizures.

Manymedicationsandothersubstancescancauseseizures.

Box6.7SeizureTriggers

Incontrasttotheabovecategories,whichalonecanpredisposetoseizures,seizuretriggers arethingsthatprovokeseizuresinpatientswhoarealreadypredisposed.Inotherwords, whatcausesapatientwithaknownepileptogeniclesiontoseizetoday?Weoftendon’t know,butthereareahostofthingsweaskaboutwhentryingtofindanexplanation.These mostcommonlyinclude:

Infection(systemicorneurologic) Severestressoranxiety Lackofsleep Missedantiepilepticmedications Useofseizure-thresholdloweringmedications Menstrual periods (when seizures consistently occur at specific times during the menstrualcycle,itiscalledcatamenialepilepsy)

Ifapatientwithapreviouslywell-controlledseizuredisorderpresentstoyourofficewitha breakthroughseizure,itiscrucialtoaskabouteachoftheseitemsasitwillhelpdetermine yourmanagement.If,forexample,yourpatienthadabreakthroughseizureinthesettingof pullinganall-nighterwhilestudyingforamidterm,youmaynotneedtochangethatpatient’s medications;aconversationregardingtheimportanceofconsistentsleepmightsuffice. However,ifnoneofthesetriggersarepresent,thepatientlikelyneedsmedication adjustment.

https://t.me/med1917

EpilepsySyndromes

Epilepsysyndromesaredisordersdefinedbyspecificfeaturesthatusuallyoccurconjointly.These featurescanincludeparticularseizuretypesandEEGpatterns,ageatseizureonset,andthecharacteristic presenceorabsenceofotherassociatedfeaturessuchasdevelopmentaldelayandmotorregression. Therearehundredsofepilepsysyndromes;hereareafewyoushouldbefamiliarwith.Allbutthelast havetheironsetveryearlyinlife.

WestSyndrome

Etiology:Approximately70%ofpatientshaveunderlyingbrainlesions(suchaslesionsassociated with tuberous sclerosis or neurofibromatosis; see Chapter 17). Thirty percent are considered cryptogenic(i.e.,ofuncertainetiology). Ageatonset:Typically<1yearold. Clinicalfeatures:

Infantilespasms(symmetric, briefmusclecontractionsusuallyinvolving thetrunk,neck,and/orextremities, followedbyseveral secondsoftonicstiffening;oftenoccurinclusters,ofteninthemorning) Arrestofpsychomotordevelopment

EEG:

 Hypsarrhythmia (an electrographic pattern characterized by high-voltage, irregular and diffuse slow waves and multifocal spikesseenpredominantlyinterictally,i.e.,betweenseizures;disappearsduringREMsleep)

Treatment:

Hormonaltherapy(corticotropin/ACTH) Vigabatrin(agamma-aminobutyricacid [GABA]analogthatincreasesGABAactivity;cancauseperipheralvisualfielddefects andthusrequiresregularophthalmologicmonitoring)

Prognosis: Poor, with significantly increased morbidity and mortality; associated with the developmentofLennox-Gastautsyndrome(seepage172).

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Hypsarrhythmiaonelectroencephalogram(EEG),characterizedbyahigh-amplitude,chaoticinterictal backgroundwithmultifocalspikes.(ReprintedfromGreenfieldLJ,CarneyPR,GeyerJD.ReadingEEGs:A PracticalApproach.2nded.WoltersKluwer;2020.)

ChildhoodAbsenceEpilepsy

Etiology:Presumedtobegenetic(butnocleargenedefectyetidentified) Ageatonset:Childhood(usually5to10yearsold) Clinicalfeatures:

Absenceseizures(canbehundredsperday,oftenprovokedbyhyperventilation) Generalizedtonic-clonicseizures(canoccur,butrarelybeforepuberty)

EEG:3Hzspike-and-wavedischarges(seenduringseizures,withabruptonsetandoffset);usually normalbetweenseizures Treatment:Ethosuximide(firstlineinmostchildren),valproate,lamotrigine Prognosis:Mostchildrengrowoutofthis.YoucanusuallyweanAEDsifthepatientisseizure-free for1to2years.

DravetSyndrome

Etiology:Genetic (70%to80% ofcasesare duetomutations inthevoltage-gatedsodiumchannel knownasSCN1A;mostmutationsaredenovo) Ageatonset:Around6months Clinicalfeatures:

Drug-resistantepilepsywithmultipleseizuretypes(oftengeneralizedandfocal,oftenprovokedbyfeverandbrightlights) Cognitiveandmotordelay(developmentisusuallynormalpriortofirstseizure)

EEG: Evolves over time; typically normal up to 1 year of age, with progressive slowing, poor organization,andnonspecificandvariableepileptiformabnormalities

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Treatment: First lineis typicallyvalproate, oftenwith adjunctive clobazam.Other optionsinclude levetiracetamandtopiramate.Avoidsodiumchannelblockingagents(suchaslamotrigine).Because seizuresareoftendrug-resistant,ketogenicdietandvariousepilepsysurgeriesshouldbeconsidered asothertherapeuticoptions. Prognosis:Poor,withsignificantlyincreasedmorbidityandmortality.Thesepatientshaveahighrisk ofsuddenunexpecteddeathinepilepsy(SUDEP;seepage176).

Lennox-GastautSyndrome

Etiology: Approximately60% have underlyingsecondary etiologies (includingtuberous sclerosis, tumors, cortical malformations, and genetic syndromes). Forty percent of cases are considered cryptogenic. Ageatonset:Childhood(usually3to5yearsold) Clinicalfeatures:

Drug-resistant epilepsywith multiple seizure types (most often tonic and atypical absence, but myoclonic andfocal impaired awarenessseizuresareseenaswell) Intellectualdisability(developmentisusuallynormalpriortofirstseizure)

EEG:Slow1–2Hzspike-and-wavepattern(interictally) Treatment: Broad-spectrum, or generalized, agents (often required in combination; see AED discussion beginning on page 173). Narrow-spectrum agents are often added, given the high prevalence of mixed (generalized and focal) seizure types. As with Dravet Syndrome, nonpharmacologicmeasuresareoftenindicatedaswell. Prognosis:Poor,withsignificantlyincreasedmorbidityandmortality.

JuvenileMyoclonicEpilepsy

Etiology:Presumedtobegenetic(suspectedpolygenicormultifactorialmechanismsinmostcases) Ageatonset:Adolescence(usuallyseeninotherwisehealthyteenagers) Clinicalfeatures:

Triadofseizuretypes(frommosttoleastcommon:myoclonic,generalizedtonic-clonic,andabsence).Seizuresoftenoccurinthe morning,andcanbetriggeredbysleepdeprivationandalcoholuse.

EEG:4–6Hzpolyspike-and-wavepattern(interictally) Treatment: valproate is first line (but often avoided in teenage girls given teratogenicity); levetiracetam,lamotrigine,andtopiramatearealsooftenused Prognosis:Mostpatientsachieveexcellentseizurecontrolwithasingleagentbutoftenrequirelifelongtreatment.

Anti-EpilepticDrugs(AEDs)

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Therearealotofthem!

LearningtheAEDscanfeelalittlelikewadingthroughalphabetsoup.Thereare,happilyforourpatients, alotofthem,buttheirvaryingmechanismsofaction,pharmacologicpropertiesandsideeffectprofiles canbeoverwhelmingtomaster.Butthereisnoneedtodespair.Therearejustfourmainprinciplesyou needtoknow:

1. AlthoughsomeAEDsmaywork better thanothersforspecificseizuretypesorepilepsysyndromes,thereislittleevidencetoindicate any significant differences in general efficacy among them. Medication decisions are typically made based on age and sex of the patient,sideeffectprofileandrelevantdrug–druginteractions.

2. All of these medications work by suppressing neuronal activity. They do this by blocking sodium or calcium channels, inhibiting glutamatergic(excitatory)orincreasingGABAergic(inhibitory)neurotransmission,or—mostoften—somecombinationoftheabove.

3. We can divide these medications into broad-spectrum agents (those that work for both generalized and focal-onset seizures) and narrow-spectrum, or partial agents (which work for focal-onset seizures only). Because it can be difficult to distinguish between generalizedandfocal-onset seizures when patients are firstdiagnosedwith epilepsy,we oftenstart with broad-spectrum agents, and afterward(oncewehavemoredata,typicallyintheformofanEEGandMRI)narrowthetreatmenttopartialagents,ifindicated.

4. Approximately50%ofpatientswillachievecompleteornear-completeseizurecontrolwithasingleAED.Anadditional15%orsowill do sowithasecond AED.Thepercentwhowill significantlyimprovewitha thirdAED,however,dropsto3%–4%. Thisiswhythe definitionofdrug-resistantepilepsyisfailuretorespondtotwoormoreAEDs.

ListedbelowaresomeofthemostcommonlyusedAEDs.Thesetablesarebynomeanscomprehensive

butareaconcisesummaryofsomeofthemostimportantandrelevantinformationforeachdrug.

BROADSPECTRUMAGENTS

AED MechanismofAction Adverse Effects

Valproate GABAagonist

Sodiumandcalciumchannelantagonist

Common:weightgain,tremor,hairloss,gastrointestinal(GI)upset Rarebutserious:hepatotoxicity(canbefatalinchildren<2yearsold),

pancreatitis,thrombocytopenia,hyperammonemia, teratogenic(causesneuraltubedefects)

Levetiracetam BindstosynapticvesicleproteinSV2A

(decreasescalciuminfluxintothepresynaptic terminal)

Common:sedation,mooddisturbance(irritability,aggression,depression)

Topiramate Sodiumchannelantagonist

Carbonicanhydraseinhibitor

Common:paresthesias,weightloss,mentalslowingandword-finding difficultyRarebutserious:nephrolithiasis,acuteglaucoma,metabolic acidosis,hypohidrosis/heatstroke

Zonisamide Sodiumandcalciumchannelantagonist

Carbonicanhydraseinhibitor

Similartotopiramate

Lamotrigine Sodiumchannelantagonist

Inhibitsglutamaterelease

Common:dizziness,sedation,headache Rarebutserious:Stevens-Johnsonsyndrome

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Clobazam Abenzodiazepine:bindspostsynapticreceptors

onGABAaneuronsandincreasesthefrequency ofreceptoropening

Common:sedation,hyposalivation/drymouth,constipation Rarebutserious:respiratorydepression,Stevens-Johnsonsyndrome

COMMONNARROWSPECTRUMAGENTS

AED MechanismofAction Adverse Effects

Phenytoin Sodiumchannel

blocker

Whe ngivenIV:cardiacarrhythmias,hypotension,purpleglovesyndrome(infusionsitephlebitis) Long-term:lossofbonedensity,cerebellaratrophy,gingivalhyperplasia,coarsefacialfeatures,

generalizedlymphadenopathy Acuteoverdose:ataxia,diplopia,vertigo

Carbamazepine Sodiumchannel

blocker

Common:dizziness,fatigue,nausea Rarebutserious:hyponatremia(mostofteninpatients>65yearsold),aplasticanemia,

agranulocytosis,hepatitis,Stevens-Johnsonsyndrome

Oxcarbazepine Sodiumchannel

blocker

Similartocarbamazepine(typicallybettertolerated,buthasahigherriskofhyponatremia)

Eslicarbazepine Sodiumchannel

blocker

Similartocarbamazepine(butlowerriskofhyponatremia)

Lacosamide Sodiumchannel

blocker

Common:dizziness,nausea Rarebutserious:PRprolongation,bradyarrhythmias,hypotension,syncopalepisodes

Gabapentin Modulatescalcium

channelactivity

Common:sedation,dizziness Lesscommon:tremor/abnormalmovements,peripheraledema,weightgain

Pregabalin Modulatescalcium

channelactivity

Common:sedation,weightgain,peripheraledema Lesscommon:tremor/abnormalmovements

Box6.8Drug-ResistantEpilepsy

Patientsarediagnosedwithdrug-resistantepilepsyiftheyhavefailedtwoormore appropriatelychosenantiepilepticmedications.Approximatelyone-thirdofepilepsypatients aredrug-resistant.Althoughitisoftenreasonabletocontinuetotrydifferentcombinationsof AEDs,thereareothernonpharmacologicinterventionsthatshouldbeseriouslyconsideredas well.

Epilepsysurgery.Whenfeasible,epilepsysurgerycanbethepatient’sbestchanceat betterseizurecontroland,forsome,seizurefreedom.Therearetwooptions:

Resectivesurgery.Theideahereistoresecttheseizurefocus.Candidacyrequiresanidentifiableseizurefocus inanonessential(orso-called“noneloquent”)andsafely-resectableareaofthebrain. Neuromodulationdevices.Theseincludetheresponsiveneurostimulationdevice(RNS),whichis implanted in theskullandcanrespondalmostinstantaneouslytoabnormalelectricalactivity(similartoaheart pacemaker), ideally stopping seizures before they even begin; and the vagal nerve stimulation device (VNS), which is implantedunderneaththeskininthechestwithawirewoundaroundthevagusnerve.Themechanismofaction oftheVNSisunknown.

 Dietary modification. Theclassic ketogenic diet is a high-fat, low-carbohydrate(in an approximately4:1 ratio) diet that can be effective for some patients (for reasonsthat remainlargelyunclear)regardlessof their ageorseizuretype. Butit canbedifficultto adhere to, given the significant side effects associated with such a drastic nutritional change, including GI upset, dyslipidemia, and hypoglycemia. The modified Atkins diet andlow–glycemicindextreatmentarenewerandslightlylessstringentalternatives.

Box6.9SuddenUnexpectedDeathinEpilepsy(SUDEP)

SUDEPissaidtooccurwhenapersonwithepilepsydiessuddenlywithoutanyobvious

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cause.Itcanbewitnessedorunwitnessed(themajorityofcasesareunwitnessed),andwith orwithoutanyevidenceofseizure.Seizure-inducedrespiratorychangesandcardiac arrhythmiashavebeenproposedaspotentialmechanisms,buttheetiologyremains unknown.ThemostsignificantriskfactorsforSUDEParethepresenceandfrequencyof generalizedtonic-clonicseizures,butyoungerage(SUDEPismostoftenreportedinchildren andyoungadults)andspecificgeneticvariantsalsoincreaserisk.SUDEPis,unfortunately, notuncommon;itisthoughttoberesponsibleforapproximately10%to15%ofalldeathsin patientswithepilepsy.Optimizingantiepileptictreatmentasbestaspossible,instructing patients(orpatient’sparents,ifthepatientisaninfant)totrytosleepinaproneposition, andinformingpatientsandpatients’familiesaboutthisrisk,are—fornow—thebestwecan do.OngoingstudieswillhopefullycontinuetoshedlightontothemechanismsofSUDEPand leadtobetterpreventionstrategies.

StatusEpilepticus

Statusepilepticuscanbe(butisnotalways)atrueneurologicemergencythatrequiresimmediate evaluationandmanagement.Itcanbescarytoseebutisofteneasytodiagnoseandrelatively straightforwardtotreat.Therearetwomaintypesofstatus:convulsiveandnonconvulsive.

1.  Convulsive status epilepticus was historically defined as a single, convulsive seizure lasting at least 30 minutes, or a series of convulsiveseizureslasting atleastatotal of30minuteswithoutinterictal(or“betweenseizure”)returntobaseline.However,because ofthenow-recognizedurgencytotreatgeneralizedconvulsivestatus,thesedefinitionshavebeenupdatedandnowinclude:

a.

5ormoreminutesofcontinuousseizureactivityOR

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