Epilepsy

Prof Akram M Al-Mahdawi

CABM,MRCP,FRCP,FACP,FAAN

‘Sacred illness’• ‘Sacred illness’: 600 BC• Hippocrates 400 BC: It is thus with regard to the disease called

sacred: it appears to me to be in no way more divine nor more sacred than other diseases [...].The brain is the cause of this affliction [...].

Alexander the Great Julius Caesar Napoleon F. Dostoyevsky

Definition

Epilepsy: Chronic brain disorder of various etiologies characterized by recurrent unprovoked seizures.

Epileptic Sz: Discrete epileptic event due to transient, hyper-synchronous , abnormal neuronal behavior.

Epileptic Syndromes: Grouping of similar epileptic patterns according to sz type, EEG, age of onset, familial episodes, prognosis, other clinical signs.

Event that may mimic seizures

Physiological event Syncope TIA TGA Sleep disorder Dizziness/vertigo

Psychiatric-based events Panic/anxiety Conversion Dissociative Hyperventilation Acute psychosis malingering

Events features favoring epileptic seizures Aura Brief duration(1-2 min) Postical confusion Amnesia for the event Events arising from sleep Self injury Eye open at the onset of the event

Epileptic seizure versus syncopeSyncope Tonic-clonic seizure

Position Upright Any

Facial colour Paleness Cyanosis

Onset Gradual; introduced by dizziness, blurring of vision

Sudden; can start by ‘aura’ (simplex partial seizure)

Twitchings Rarely (‘convulsive syncope’) Always

Enuresis Rarely Often

Tongue bite No Often

Duration 10-20 seconds Few minutes

Postictal confusion No Yes

Perspiration Pronounced Not typical

Epilepsy: Etiology Vs. Age of Onset

0 10 20 30 40 50 60 70 80 90

Perinatal injury

Metabolic defect

cong. Malformation

Infection

Genetic Epilepsy

Pstnatal Trauma

Brain Tumor

Vascular dis.

Trigger factors for seizures

Sleep deprivation Alcohol (particularly withdrawal) Recreational drug misuse Physical and mental exhaustion Flickering lights, including TV and computer screens infections and metabolic disturbances Uncommonly: loud noises, music, reading, hot baths

Localization of Partial Seizure Focus

70%70% 10%10%

20%20%

Clinical features associated with localization

Temporal lobe-Déjà vu,epigastic aura,fear/fright,formed visual images.

Frontal lobe-muscle/motor activity,forced eye deviation,speech arrest.

Parietal lobe-parasthesias,sensory phenomenon Occipital-flashes,colors

Simple partial seizures No loss of consciousness Symptoms depend on area

of brain involved: Motor Sensory Autonomic Psychosensory

It can be the introductory phase of a complex partial or generalised tonic-clonic seizure (‘aura’)

Complex partial seizures Origin is most often in the temporal lobe A common seizure type in adulthood Can be introduced by a simplex partial psychosensory

seizure: olfactory hallucination déjà vu, jamais vu feeling of alienation

Loss of consciousness: stare, ‘going blank’ Automatisms:

oral automatisms fiddling with the hands

Temporal lobe epilepsy Most common epilepsy in adulthood;

can be heralded by a few seizures in childhood, but typical age of onset is 20-22 years

Seizure types: olfactory hallucination (simplex

partial) psychosensory seizures (simplex

partial) complex partial generalised tonic-clonic

Febrile convulsions in childhood Hippocampal sclerosis Often refractory to therapy

Benign centrotemporal epilepsy Age of onset: 3-15 years Seizure types: facial, oro-bucco-

pharyngeal motor and sensory simplex partial seizures; speech arrest

Nocturnal seizures Mild disease. Normal neurological and mental EEG- centrotemporal spike

waves Spontaneous remission by

puberty

West syndrome Age of onset: 3-5 months Seizure types: infantile spasms Causes: inborn metabolic, storage

diseases, perinatal hipoxic brain damage Cryptogenic in 40-50% Neurological symptoms, mental

retardation; bad prognosis; can transform into Lennox-Gastaut syndrome

EEG: hypsarrhythmia R:corticotropin,steroid,vigabatrin Prognosis: often poor but depend on

etiology

Lennox-Gastaut syndrome Age of onset:2-8 years 3-10 of childhood epilepsy Seizure types: atonic, axial tonic,

myoclonic, atypical absence, tonic-clonic

30%of WS syndrome will have LGS Causes: same as in West syndrome;

can develop from West syndrome Neurological symptoms, mental

retardation Unfavourable prognosis (refractory

seizure,mental handicap{80%}. Ketogenic diet,1st line AEDs

{valproate,lamotrigine,topiramate

Generalised tonic-clonic seizure(grand mal)

The most common seizure

Course: Cry, loss of consciousness, fall Tonic phase- generalised muscle

contraction, apnoe Clonic phase- rhythmic

contraction of muscles, tongue bite, foaming, enuresis

Terminal sleep and gradual regaining of consciousness (transient confusion)

10-25 yrs ,65 controlled with AEDs but relapse

Juvenile myoclonic seizure

Sudden, quick, arrhythmic muscle contraction, twitch of a limb; no loss of consciousness

EEG: generalised polyspike and wave activity

Occurs in genetic (idiopathic) epilepsies

90% remit with AEDs but relapse if AEDs withdrawn

R-Na valproate.Levetiracetam

Absence

Cognitive dysfunction with a sudden onset and end, lasting 5-10 seconds

Stare, expressionless face; arrest of ongoing activity; generally no motor phenomena

Occurs in genetic (idiopathic) epilepsies, mostly in children

CAE-4-8 yrs,frequent brief absence,3/sec spike and wave,R-ethosuximide,Na valproate.levetiracetam.40% develop GTCS,80 remit in adulthood

JAE.10-15 yrs, less frequent abcence,polyspike and wwave.R Na valproate,levetiracetam.80% develop GTCs,80% seizyre free in adulthood

Diagnostic steps History EEG

Negative EEG does not exclude epilepsy Positive EEG without clinical signs does not prove

epilepsy EEG after sleep withdrawal or during sleep Long-term EEG / video monitoring CT, MRI

EEG Abnormalities

•Background abnormalities

-Significant asymmetries and/or degree of slowing inappropriate for clinical state

•Transient abnormalities associated with seizures

-Spikes (< 70 m sec)

-Sharp waves (~70 – 200 msec)

-Spike-wave complexes

•May be focal, lateralized or generalized

Indications for brain imaging in epilepsy

Epilepsy starting after the age of 20 years Seizures having focal features clinically EEG showing a focal seizure source Control of seizures difficult or deteriorating

How to administer first aid for seizures

Move person away from danger (fire, water, machinery, furniture) After convulsions cease, turn into 'recovery' position (semi-prone) Ensure airway is clear, but do NOT insert anything in mouth (tongue-biting occurs at

seizure onset and cannot be prevented by observers) If convulsions continue for more than 5 minutes or recur without person regaining

consciousness, summon urgent medical attention Do not leave person alone until fully recovered (drowsiness and confusion can persist for

up to 1 hour

First Seizure

•Whether to treat first seizure is controversial

•Increased risk of relapse

1-Abnormal imaging 2-Abnormal EEG 3-Family history of epilepsy

•Currently, most patients are not treated for the first seizure unless there is an increased risk for relapse

Medical treatment of epilepsy When do we start antiepileptic medication

(AED)? Which AED to choose? When and how do we switch AEDs? When is polytherapy needed? When can AEDs be discontinued? Pregnancy Driver’s licence

Therapeutic principles Aim: maximal seizure control, minimal side

effects Monotherapy Usually gradual introduction of AED Assessment of AED effect (seizure frequency)

After AED has reached steady state Depends on the average time interval of seizures

before treatment

AEDsOld

Primidon Phenobarbital Phenytoin Clobazam Clonazepam Ethosuximid Valproate Carbamazepine

New Lamotrigine Oxcarbazepine Topiramate Gabapentin Vigabatrin Levatiracetam Zonisamide Tiagabin

Mechanism of action of AEDsInhibition of voltage gated Na, Ca channels

Na: phenytoin, carbamazepine, oxcarbazepine, lamotrigine, topiramate, felbamate, zonisamide

Ca: ethosuximid, valproate? lamotrigine, topiramate, zonisamide

Potentiaton of GABA mediated inhibition

phenobarbital, benzodiazepins, vigabatrin, tiagabine, topiramate, valproate, gabapentin, felbamate

Decrease of glutamate mediated excitation

felbamate, topiramate

Pharmacology of AEDs I.Hepatic metabolism valproate, carbamazepine,

oxcarbazepine, lamotrigine, topiramate, clobazam, clonazepam, phenobarbital, primidon, phenytoin, ethosuximid, felbamate, tiagabin

No metabolism gabapentin, vigabatrin

topiramate, levatiracetam

Hepatic enzyme induction carbamazepine, phenytoin, phenobarbital, primidon (oxcarbazepine)

Hepatic enzyme inhibition valproate

Drug interactionsEnzyme inductors

carbamazepine, phenytoinphenobarbital, primidon

Increase of metabolism / decrease of efficacy

valproate, lamotrigine, topiramate, carbamazepine

oral contraception

oral anticoagulation

Enzyme inhibitors

valproate

Decrease of metabolism / increase in efficacy - toxicity

lamotrigine, carbamazepine, phenytoin

Does not cause interaction

lamotrigine, gabapentin, topiramate, vigabatrin

Guidelines for anticonvulsant therapy

Start with one first-line drugStart at a low dose; gradually increase dose until effective control of seizures is achieved

or side-effects develop (drug levels may be helpful) Optimize compliance (use minimum number of doses per day) If first drug fails (seizures continue or side-effects develop), start second first-line drug

whilst gradually withdrawing first If second drug fails (seizures continue or side-effects develop), start second-line drug in

combination with preferred first-line drug at maximum tolerated dose (beware interactions)

If this combination fails (seizures continue or side-effects develop), replace second-line drug with alternative second-line drug

If this combination fails, check compliance and reconsider diagnosis (is there an occult structural or metabolic lesion or are seizures truly epileptic?)

If this combination fails, consider alternative, non-drug treatments (e.g. epilepsy surgery, vagal nerve stimulation)

Do not use more than two drugs in combination at any one time

Side effects of AEDs Allergy Central nervous system side effects

(dose dependent) drowsiness, headache dizziness, dysequilibrium cognitive dysfunction (memory)

Idiosynchratic reactions / chronic side effects bone marrow suppression hepatic failure rash weight gain, weight loss tremor polycystic ovary syndrome visual field defect

Summary of Serious and Non-serious Adverse Events of the Newer AEDs

AED Serious Adverse Events Nonserious Adverse Events

Gabapentin None Weight gain, peripheral edema, behavioral changes

Lamotrigine Rash, including Stevens Johnson and toxic epidermal necrolysis (increased risk for children, also more common with concomitant valproate use and reduced with slow titration); hypersensitivity reactions, including risk of hepatic and renal failure, DIC, and arthritis

Tics and insomnia

Levetiracetam None Irritability/behavior change

Oxcarbazepine Hyponatremia (more common in elderly), rash None

Topiramate Nephrolithiasis, open angle glaucoma, hypohidrosis (predominantly children)

Metabolic acidosis, weight loss, language dysfunction

Zonisamide Rash, renal calculi, hypohidrosis (predominantly children)

Irritability, photosensitivity, weight loss

Possible causes of AED inefficacy Inadequate dose → dose escalation Lack of compliance → measure blood AED levels False diagnosis: the patient doesn’t have epilepsy ‘Pseudoseizures’ → precise description of seizure, EEG

/ video monitoring Inadequate selection of AED True inefficacy of AED → AED switch

Other AED on monotherapy AED combination

Withdrawing anticonvulsant therapy

Withdrawal of medication may be considered after apatient has been seizure-free for more than 2 years. Childhood-onset epilepsy, particularly classical absenceseizures, carries the best prognosis for successful drug withdrawal. Other epilepsy syndromes, such as juvenile myoclonic epilepsy, have a marked tendency to recur after drug withdrawal.

Seizures that begin in adult life, particularly those with partial features, are also likely to recur, especially if there is an identified structural lesion.

Overall, the recurrence rate after drug withdrawal depends on the individual's epilepsy history.

Patients should be advised of the risks of recurrence, to allow them to decide whether or not they wish to withdraw.

If undertaken, withdrawal should be slowly, reducing dose gradually over weeks or months. Withdrawal may necessitate precautions around driving or occupation.

Discontinuation of AED Discontinuation of AED is not recommended:

Earlier unsuccessful AED withdrawal Earlier refractoriness to treatment Known brain lesion Juvenile myoclonic epilepsy

contraception

AEDs induce hepatic enzymes that metabolise synthetic hormones, increasing the risk of contraceptive failure. This is most marked with carbamazepine,

phenytoin and barbiturates, but clinically significanteffects can be seen with lamotrigine and topiramate.

If the AED cannot be changed, this can be overcome by giving higher-dose preparations of the oral contraceptive.

Sodium valproate and levetiracetam have no interactionwith hormonal contraception.

Risks of Congenital Abnormalities

Congenital malformations Most common: orofacial clefts, heart defects Less common: microcephaly, neural tube defects

Major malformations General population: 2% to 4% Newborns prenatally exposed to AEDs: 4% to 8% Multiple AEDs and higher doses may substantially increase malformation rate

Minor malformations

Epilepsy and breast feeding

Breast feeding is not contraindicated with women on AEDs.

Sleep deprivation can provoke seizures.

Epilepsy and driving

Driving is prohibited for one year after a seizure with loss of consciousness

Driving is permitted: 2-3 years of seizure free interval with patients on

AEDs 2-3 years of seizure free interval after withdrawal of

AEDs

AEDs and Bone Health

Status Epilepticus

1-10 mg IV Diazepam or 4 mg IV lorazepam bolus, can repeated onceStage of Established status(SZ continue after 30 Stage of Established status(SZ continue after 30

min)min)1-Phenobarbit infusion 10mg/kg at 100 mg/min2-phenytoin infusion 15mg/kg at 50mg/min or

Fosphenytoin 15mg/kg at 100mg/min.Can repeate another 5-10mg/kg of phyentoin

3-if SZ continue after 30-60min (refractory)

Propofol 2mg/kg----1-3 mg/kg/hr Thiopental 100-250mg given once 20

sec—-----3-5mg/kg/hr Midazolam 0.1-0.3 mg/kg—NOT exceeding 4mg/min

slowly IV infusion----0.05-0.4 mg/kg/hr SZ control—300mg/day phenytoin or 400-1200 mg/day

by nasogastric tube When seizure control for 12 hr ,then the anaesthetic drugs

withdrawn slowly over 12 hrs,if recure again 12 hrs