EpilepsyOnce sacred disease

Milan Brzdil 1st Department of NeurologyMedical Faculty and St. Anne Hospital

Nesejet the danger coming from god*

DefinitionA chronic neurologic disorder manifesting by repeated epileptic seizures (attacks or fits) which result from paroxysmal uncontrolled discharges of neurons within the central nervous system (grey matter disease).

The clinical manifestations range from a major motor convulsion to a brief period of lack of awareness. The stereotyped and uncontrollable nature of the attacks is characteristic of epilepsy.

PathogenesisThe 19th century neurologist Hughlings Jackson suggested a sudden excessive disorderly discharge of cerebral neurons as the causation of epileptic seizures.

Recent studies in animal models of focal epilepsy suggest a central role for the excitatory neurotransmiter glutamate (increased in epi) and inhibitory gamma amino butyric acid (GABA) (decreased)

Epidemiology and courseEpilepsy usually presents in childhood or adolescence but may occur for the first time at any age.

NewbornsEarly school ageAdolescentsSeniors

Epidemiology and course5% of the population suffer a single sz at some time0.5-1% of the population have recurrent sz = EPILEPSY

70% = well controlled with drugs (prolonged remissions)30% epilepsy at least partially resistant to drug treatments = INTRACTABLE (FARMACORESISTANT) EPILEPSY.

Epilepsy versus epileptic syndromesEpilepsy is not a nosological entity not one disease! Not unique aetiology...

Might be a symptom of numerous disorders symptomatic epilepsy (TBI, tumours, inflammation, stroke, neurodegeneration, ...)

Sometimes the cause remains unclear despite careful history taking,examination and investigation!

Epilepsy - ClassificationThe modern classification of the epilepsies is based upon the nature of the seizures rather than the presence or absence of an underlying cause.

Seizures which begin focally from a single location within one hemisphere are thus distinguished from those of a generalised nature which probably commence in a deeper structures (brainstem? thalami) and project to both hemispheres simultaneously.

CausesHeriditoryIdiopathicInfectionHead injuryNeoplasmDegenerative diseases

pathophysiologyElectrical changes: electrodes placed in epileptic foci show excitattory synaptic potentials and spike dischargesImbalance between excitatory and inhibitory impulses at cellular or synaptic levelExtracellular concentration of ca+ drops significantlyExtracellular K+ rises after a brief delay when compared to the drop in Ca+

Extracellular Na+ falls significantly with a small rise in extracellular Cl-Synaptic level:- for the excitatory neurotransmiter glutamate (increased in epi) and inhibitory gamma amino butyric acid (GABA) (decreased)

SpreadSynchronous discharge of many neurones locally which spreads with the changes such as high K+ and low Mg+.Factors that decrease GABA mediated inhibition also facilitate spread

Epilepsy - ClassificationFocal seizures account for 80% of adult epilepsies

Simple partial seizuresComplex partial seizuresPartial seizures secondarilly generalised

Generalised seizures

Unclassified seizures

What are seizures?Definition of seizure: paroxysmal episodes of brain dysfunction manifested by stereotyped alteration in behaviorClinical manifestation depends on region of brain seizingCauses: primary CNS dysfunction, metabolic disorderEpilepsy: recurrent and unprovoked seizuresCellular definition: excessive or oversynchronized discharges of cortical neurons GABA receptor mediates inhibition responsible for normal termination of a seizure NMDA (Glutamate) receptor activation required for propagation of seizure activity

SeizureNMDA RcptrActivationReduced GABARcptr function

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EpidemiologyApproximately 1% population (3 million epilepsy cases in US).Second most common neurological diseaseComparable prevalence in men vs. women

Begley CE et al. Epilepsia 2000;41:342-351MMWR Weekly. November 11, 1994/43(44);810-811,817-818Sander JW. Cur Opin neurol 2003;16:165-170

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Seizure termsIctal= seizurePost-ictal= confusion following seizureAura= abnormal sensation preceding locAutomatisms= nonsensical involuntary movements Tonic= tonic contraction producing extension and archingClonic= alternating muscle contraction-relaxation

Complex= consciousness impairedSimple= consciousness unimpairedPartial= focal region involvedGeneralized= whole brainConvulsions= shakingGrand mal and petite mal=street terms for convulsive and non-convulsive seizure respectively

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EtiologyCNSHead traumaSeizure in 1 week of injury not predictive of epilepsyStrokeVascular malformationsMass (tumor/abscess)Meningitis/encephalitisCongenital malformations/ cortical dysplasiasIdiopathic

SystemicHypo/hyperglycemiaHypo/hypernatremiaHypocalcemiaUremiaHepatic encephalopathyHypoxiaHyperthermiaDrug overdose or withdrawalEtOH withdrawal sz occurs within 48h

Classification of seizure types

Partial (focal)Simple partial MotorSomatosensoryAutonomicPsychologicalComplex partialSimple partial with impaired consciousnessPartial seizures with secondary generalization

GeneralizedAbsenceTonic Clonic Tonic-clonicAtonic Myoclonic

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ClassificationPartial seizures (focal onset)Simple partial (without impaired consciousness) Motor symptoms (focal motor seizure)Involves motor stripManifested by abnormal movement of an extremityJacksonian march- spread to involve contiguous regionsTodds paralysis- post ictal transient hemibody weaknessSomatosensory symptomsInvolves sensory strip, temporal(hearing and smell) or occipital(visual) lobe Autonomic symptomsInvolves temporal lobe (tachycardia, pallor, flushing, sweating) Psychic symptomsInvolve frontal or temporal lobe (limbic system): dj vu, jamais vu, affective disturbances, cognitive deficits, hallucinations

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Homunculus

Neurology and Neurosurgery Illustrated. Lindsay, Kenneth, Bone Ian, 3rd edition. Churchill Livingstone, 1999.London

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ClassificationPartial seizuresComplex partial (impaired consciousness)Typically frontal or temporal lobe onsetOften stereotyped for the individual patientAverage duration 1-3 minutesSimple partial onset can be followed by impaired consciousnessMany times will progress to a generalized seizureFrequently seen in adult onset epilepsy Automatisms: coordinated involuntary movements, typically orobuccolingual or nonpurposeful hand movements

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Classification of SeizuresGeneralized (diffuse onset)Absence5-10s LOC w/o loss of postural toneMild head turn, blinking commonImmediate return of awarenessTypically resolves by 20yTonic arrest of ventilation can cause cyanosisClonic without tonic phaseTonic clonicMyoclonic brief, shock-like contractions, may be localized or generalizedAtonic - drop attacks

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ClassificationPseudoseizuresNon-epileptic seizuresMay be manifestation of conversion disorder, factitious disorder or malingeringFeatures that may distinguish from epileptic seizuresPre-attack preparation, absence of post-ictal confusionDisorganized movements, pelvic thrusting, thrashingBilateral convulsions without loss of consciousnessViolent or goal-directed behavior, obscene language, Video EEG may help to diagnose

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Seizure Phenotypesthink of anatomy!!

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CortexFrontal EyeFieldBrocass Speech Area

Primary Auditory CortexSylvian FissureWernickes Speech

Primary VisualCortexVisual Assoc.CortexCentral Sulcus

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Frontal LobeFrontal eye field (Brodmans 8)Lesion: deviation of eyes to ipsilateral sideSz: overstimulation->eyes to contralateral sidePrefrontal cortex (Brodmans 9-12,46,47)Lesion: deficits in concentration, judgment and behaviorSz: agitation, odd behaviorBrocas speech area (Brodmans 44,45)Lesion/sz: expressive nonfluent aphasiaPrimary motor cortex (Brodmans 4)Lesion: contralateral hemiparesis, late manifestation spasticitySz: contralateral twitching, posturing or convulsions

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Temporal LobeHippocampal cortex Bilateral lesions: memory dysfunctionSz: chronic seizures lead to deficits in short term memoryWernickes speech area (Brodmans 22)Lesion/sz: loss of receptive speech, fluent aphasiaAnterior temporal lobe Bilateral lesions: Kluver-Bucy syndrome- visual agnosia, hyperorality, hyperphagia, hypersexuality, docilitySz: staring/freezing, oral automatismsPrimary auditory cortex (Brodmans 41, 42)Bilateral lesion: cortical deafnessSz: auditory hallucinationsOlfactory bulb (Brodmans 34)Lesion: anosmiaSz: olfactory and gustatory hallucinations

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Parietal and Occipital LobesPrimary sensory cortex (Brodmans 3,1,2)Lesion: contralateral hemihypestheisa and astereognosisSz: contralateral sensory symptoms ie tingling, heatOccipital lobe (Brodmans 17)Lesion: contralateral hemianopsia with macular sparingSz: flashing or colored lights in contralateral visual field

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Focal (partial) seizuresSimple partial seizures

Motor, sensory, vegetative or psychic symptomato- logy Typically consciousness is preserved

Focal (partial) seizuresSimple partial seizures

Motor, sensory, vegetative or psychic symptomatology Typically consciousness is preserved

Focal (partial) seizuresSimple partial seizures

Motor, sensory, vegetative or psychic symptomatology Typically consciousness is preserved

Focal (partial) seizuresComplex partial seizures (= psychomotor seizures)

Initial subjective feeling (aura), loss of consciousness, abnormal behavior (perioral and hand automatisms) Usually originates in TL

Focal (partial) seizuresPartial seizures evolving to tonic/clonic convulsions secondary generalised tonic/clonic seizures (sGTCS)

Generalized seizures(convulsive or non-convulsive)AbsencesMyoclonic seizuresClonic seizuresTonic seizuresAtonic seizures

Generalized seizuresAbsencesMyoclonic seizuresClonic seizuresTonic seizuresAtonic seizures

Seizure Management

DiagnosisClinical historyPhysical examination: focal deficits, Todds paralysisDiagnostic work-up: pulse ox, glucose, electrolytes, calcium, CBC, renal function, hepatic function, tox screen/EtOH levelHead imaging: CT/MRILP if fever or meningeal signs presentEEG confirmation if possible: ictal event or inter-ictal spikes, polyspike discharges, spike-wave complexes

Epilepsy InvestigationThe concern of the clinician is that epilepsy may be symptomatic of a treatable cerebral lesion. Routine investigation: Haematology, biochemistry (electrolytes, urea and calcium), chest X-ray, electroencephalogram (EEG).

Neuroimaging (CT/MRI) should be performed in all persons aged 25 or more presenting with first seizure and in those pts. with focal epilepsy irrespective of age.Specialised neurophysiological investigations: Sleep deprived EEG, video-EEG monitoring.Advanced investigations (in pts. with intractable focal epilepsy where surgery is considered): Neuropsychology, Semiinvasive or invasive EEG recordings, MR Spectroscopy, Positron emission tomography (PET) and ictal Single photon emission computed tomography (SPECT)

Epilepsy Differential DiagnosisThe following should be considered in the diff. dg. of epilepsy:Syncope attacks (when pt. is standing; results from global reduction of cerebral blood flow; prodromal pallor, nausea, sweating; jerks!)Cardiac arrythmias (e.g. Adams-Stokes attacks). Prolonged arrest of cardiac rate will progressively lead to loss of consciousness jerks!Migraine (the slow evolution of focal hemisensory or hemimotor symptomas in complicated migraine contrasts with more rapid spread of such manifestation in SPS. Basilar migraine may lead to loss of consciousness!Hypoglycemia seizures or intermittent behavioral disturbances may occur.Narcolepsy inappropriate sudden sleep episodesPanic attacks PSEUDOSEIZURES psychosomatic and personality disorders

Seizure treatmentAcute Management90% of seizures stop without treatment in under 5 minutesCan give lorazepam or diazepam for seizures >5minMonitor ABCDs, avoid injury and aspirationTreat underlying medical conditionsLong Term ManagementDecide if therapy needed Sz due to secondary causes (metabolic d/o, EtOH withdrawal, immediately following head trauma/stroke) may not need longterm txSingle generalized tonic-clonic seizure recurs in about 50%Anti-epileptic medicationsTry single therapyAdd second medication if: sz not controlled with single drug and maximal levels/side effects are achievedTreat the seizures, not drug levels

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Anti-epileptic medicationsOlder AgentsPhenytoinCarbamazepine PhenobarbitalPrimidoneValproic acidEthosuxamide

Newer AgentsLamotrigineLevetiracetamTopiramateOxcarbazepineLacosamideZonisamide

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Other treatment optionsKetogenic diet in childrenSurgeryRemoval of epileptic focusMostly for patients with temporal lobe seizuresPossibility of a 70% chance of cure!!VNS (Vagal nerve stimulator)Current given to vagus nerve with theory of decreasing seizures over time

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Treatment of the seizing patientEnsure airway protection/ position to prevent aspirationDo not place anything in the mouth except when to suctionDO NOT try to force suction/airway through clenched teethWhen the patient stops convulsing, place patient in lateral decubitus. Begin supplemental oxygenAssess safety of patientEnsure lights in room are onRemove any object within reach of patient that could cause injury Loosen clothingSide rails should be up if patient is in bedDo not try to hold the patient downObtain vitals including pulse ox, obtain stat accucheckIf glucose is < 70 mg/dl (or if accucheck unobtainable) administer amp D50.Note: Ideally,100mg thiamine IVPB should be given prior to, or soon after, glucoseOrder diagnostic labs: cbc, cmp, mg, phos, tox screens, etoh level, AED levelsMost seizures cease w/o medical intervention in 1-3 minutes

Status epilepticusLorazepam 0.1 mg/kg IV push at rate of 2 mg/min (can be given IM)Phenytoin 20 mg/kg IV no faster than 50 mg/minFosphenytoin 20 mg/kg IV up to 150 mg/min (can be given IM)Additional 5-10 mg/kg of either can be givenConsider phenobarbital 20 mg/kg or VPA 10-15 mg/kg IVIf seizure continues: intubation requiredGeneral anesthesia titrate to burst suppression (continuous EEG monitoring required)Pentobarbital (5 mg/kg load, 0.5-3 mg/kg/hr maint.)Propofol (1-2 mg/kg load over 5 min, 2-10 mg/kg/hr maint.)Midazolam (0.2 mg/kg slow IV bolus, 0.05-0.5 mg/kg/hr maint.)

Epilepsy - TreatmentThe majority of pts respond to drug therapy (anticonvulsants). In intractable cases surgery may be necessary. The treatment target is seizure-freedom and improvement in quality of life!

The commonest drugs used in clinical practice are: Carbamazepine, Sodium valproate, Lamotrigine (first line drugs) Levetiracetam, Topiramate, Pregabaline (second line drugs) Zonisamide, Eslicarbazepine, Retigabine (new AEDs)

Basic rules for drug treatment: Drug treatment should be simple, preferably using one anticonvulsant (monotherapy). Start low, increase slow. Add-on therapy is necessary in some patients

Epilepsy Treatment (cont.)If pt is seizure-free for three years, withdrawal of pharmacotherapy should be considered. Withdrawal should be carried out only if pt is satisfied that a further attack would not ruin employment etc. (e.g. driving licence). It should be performed very carefully and slowly! 20% of pts will suffer a further sz within 2 yrs.

The risk of teratogenicity is well known (~5%), especially with valproates, but withdrawing drug therapy in pregnancy is more risky than continuation. Epileptic females must be aware of this problem and thorough family planning should be recommended. Over 90% of pregnant women with epilepsy will deliver a normal child.

Epilepsy Surgical TreatmentA proportion of the pts with intractable epilepsy will benefit from surgery.Epilepsy surgery procedures: Curative (removal of epileptic focus) and palliative (seizure-related risk decrease and improvement of the QOL)Curative (resective) procedures: Anteromesial temporal resection, selective amygdalohippocampectomy, extensive lesionectomy, cortical resection, hemispherectomy.Palliative procedures: Corpus callosotomy and Vagal nerve stimulation (VNS).

Status Epilepticus

Status epilepticusDefinitionContinuous seizure lasting greater than 30 minutesTwo or more sequential seizures without recovery of full consciousness lasting >30 minutesTypesGeneralized convulsive (GCSE)Nonconvulsive status epilepticus (absence, CPS)Simple partial status epilepticus

Status EpilepticusA condition when consciousness does not return between seizures for more than 30 min. This state may be life-threatening with the development of pyrexia, deepening coma and circullatory collapse. Death occurs in 5-10%.Status epilepticus may occur with frontal lobe lesions (incl. strokes), following head injury, on reducing drug therapy, with alcohol withdrawal, drug intoxication, metabolic disturbances or pregnancy. Treatment: AEDs intravenously ASAP, event. general anesthesia with propofol or thipentone should be commenced immediately.

Nesejet the danger coming from god**

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