8 epilpsy

EPILPSY“8”

Presented By:Dr. Raed Ahmed MBChB , FIBMSNeurologist

1

First Seizure

• Whether to treat first seizure is controversial

• 16-62% will recur within 5 years

• 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

4

Guidelines for anticonvulsant therapy• More than one non-provoked, well-documented seizure• Aim: maximal seizure control, minimal side effects• Monotherapy : start with one first-line drug • Start at a low dose; gradually increase dose until

effective control of seizures is achieved or side-effects develop

• Optimise compliance (use minimum number of doses/d) • • If first drug fails (seizures continue or side-effects

develop), start second first-line drug, followed if possible by gradual withdrawal of first

5

Therapeutic principles

• If second drug fails start second-line drug in combination with preferred first-line drug at maximum tolerated dose • If this combination fails replace second-line drug with alternative second-line drug• If this combination fails, check compliance and reconsider diagnosis (Are events seizures? Occult lesion? • Consider alternative, non-drug treatments (e.g. epilepsy surgery, vagal nerve stimulation)

AEDsOld

Primidon Phenobarbital Phenytoin Clobazam Clonazepam Ethosuximid Valproate Carbamazepine

New Lamotrigine Oxcarbazepine Topiramate Gabapentin Vigabatrin Levatiracetam Zonisamide Tiagabin

Mechanism of action of AEDs

Inhibition of voltage gated Na, Ca channels

Na: phenytoin, carbamazepine, oxcarbazepine, lamotrigine, valproate, topiramate, felbamate, zonisamideCa: 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 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, felbamate

9

Selection of AEDs

Idiopathic generalised epilepsies valproate, topiramate, lamotrigine, levatiracetam

Localisation related epilepsies (eg. temporale lobe epilepsy)

carbamazepine, oxcarbazepine, valproate, lamotrigine, topiramate, gabapentin, levatiracetam

Symptomatic generalised epilepsies West-syndrome Lennox-Gastaut syndrome

vigabatrinfelbamate, lamotrigine, valproate

Side effects of AEDs Allergy Central nervous system side effects (dose

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

Idiosynchratic reactions / chronic SE s bone marrow suppression (CMZ) hepatic failure(Valproate) rash(CMZ) weight gain (valproate) weight loss (topiramate) tremor(valproate) polycystic ovary syndrome(valproate) visual field defect (vigabatrin)

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 hypersensitivity reactions, including risk of hepatic and renal failure, DIC

Tics and insomnia

Levetiracetam None Irritability/behavior change

Oxcarbazepine Hyponatremia (more common in elderly), rash None

Tiagabine Stupor or spike wave stupor Weakness

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 Poor or 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 ? Refractory patients

Drug interactionsEnzyme inductorscarbamazepine, phenytoinphenobarbital, primidon

Increase of metabolism / decrease of efficacyvalproate, lamotrigine, topiramate, carbamazepineoral contraceptionoral anticoagulation

Enzyme inhibitorsvalproate

Decrease of metabolism / increase in efficacy - toxicitylamotrigine, carbamazepine, phenytoin

Does not cause interactionlamotrigine, gabapentin, topiramate, vigabatrin, tiagabin

Seizure-free for more than 2 years A decision of both the doctor and patient AED should be very slowly tapered, lasting

weeks- months Childhood-onset epilepsy **classical absence seizures JME : marked tendency to recur after drug withdrawal Seizures that begin in adult life, particularly those with

partial features, are also likely to recur

16

Contraception

• Some AEDs induce hepatic enzymes that metabolise synthetic hormones, increasing the risk of contraceptive failure.

• Most marked with carbamazepine, phenytoin and barbiturates, but clinically significant effects 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 interaction with hormonal contraception.

17

Epilepsy in pregnancy

• Great concern about teratogenesis associated with AEDs.

• Background risk of severe fetal malformation in the population is 2–3%.

• Teratogenesis with sodium valproate, which, at high dose, increases the risk to around 6–7%.

• Carbamazepine and lamotrigine have the lowest incidence of major fetal malformations. Levetiracetam may be safe.

• Learning difficulties in children: IQ may be lower when children are exposed to valproate in utero

18

• Seizures may become more frequent during pregnancy (carbamazepine levels may fall in the third trimester, Lamotrigine and levetiracetam levels may fall early in pregnancy)

• Menstrual irregularities and reduced fertility are more common in women with epilepsy, and are also increased by sodium valproate.

• Patients with epilepsy are at greater risk of osteoporosis, (higher female risk).

• Haemorrhagic disease of the newborn: anticonvulsants increase risk. oral vitamin K 20 mg daily to the mother during the last month of pregnancy and give IM vitamin K 1 mg to the infant at birth.

Epilepsy and pregnancy: what to do?

Before conception: Attained the best possible seizure control with the lowest

possible (effective) AED dose, preferably in monotherapy Pre-conception treatment with folic acid (5 mg daily)

During pregnancy: During first trimester supplement folic acid Change medication only if seizure control worsens Screening of fetal malformations (ultrasound on week 16 and 20,

AFP) In case of enzyme inductor AEDs, give vitamin K

Breast feeding is not contraindicated with women on AEDs BUT

Sleep deprivation can provoke seizures

AEDs and Bone Health

Epilepsy and drivingSingle seizure Cease driving until at least 6 mths have passed

without recurrence

Epilepsy Cease driving immediately Licence restored when patient is free from all types

of seizure for 1 yr or seizures have occurred exclusively during sleep for a period of at least 3 yrs

Withdrawal of anticonvulsants Cease driving during withdrawal period and for 6

mths thereafter

Prognosis Overall, generalised seizures are more readily controlled than

focal seizures.

Presence of a structural lesion reduces the chances of freedom from seizures.

Epilepsy: outcome after 20 years 50% are seizure-free, without drugs, for the previous 5 yrs

20% are seizure-free for the previous 5 yrs but continue to take medication

30% continue to have seizures in spite of anti-epileptic therapy

About Epilepsy Drug resistant epilepsy: is defined as failure of

adequate trials of two tolerated, appropriately chosen and used antiepileptic drug schedules to achieve sustained seizure freedom.

Intractable epilepsy: additionally connotes serious impairment of quality of life by either recurrent seizures or AED adverse effects, or both.

It has been estimated that approximately 15% of persons with epilepsy are medically intractable.

Status Epilepticus Status epilepticus is a medical emergency in which

seizures occur continuously or repeatedly without intervening resumption of consciousness for 30 minutes.

However, even 5 minutes of generalized tonic-clonic seizures cause hypoxia, lactic acidosis, muscle breakdown, and neuronal damage.

Diagnosis is usually clinical and can be made on the basis of the description of prolonged rigidity and/or clonic movements with loss of awareness.

As seizure activity becomes prolonged, movements may become more subtle.

Cyanosis, pyrexia, acidosis and sweating may occur, and complications include aspiration, hypotension, cardiac arrhythmias and renal or hepatic failure.

Causes of SE In patients with pre-existing epilepsy, the most

likely cause is a fall in anti-epileptic drug levels.

In de novo SE , it is essential to exclude precipitants such as infection (meningitis, encephalitis), neoplasia and metabolic derangement (hypoglycaemia,hyponatraemia, hypocalcaemia).

MANAGEMENT OF STATUS EPILEPTICUS

General: Immediate care (ABC) Secure intravenous access. Draw blood for glucose, urea and electrolytes (including Ca

and Mg), liver function and sample for future analysis (e.g. drug misuse)

Give diazepam 10 mg intravenously (or rectally)-repeat once only after 15 mins; or lorazepam 4 mg intravenously

Transfer to intensive care area, monitoring neurological condition, blood pressure, respiration and blood gases

Correct any metabolic trigger, e.g. hypoglycaemia

If seizures continue after 30 mins

• IV infusion (with cardiac monitoring) with one of: Phenytoin: 15 mg/kg at 50 mg/min Fosphenytoin: 15 mg/kg at 100 mg/min Phenobarbital: 10 mg/kg at 100 mg/min

• Cardiac monitor and pulse oximetry

Monitor neurological condition, blood pressure, respiration;

check blood gases 

If seizures still continue after 30–60 mins

• Transfer to intensive care

Start treatment for refractory status with intubation,ventilation and general

anaesthesia using propofol or thiopental

EEG monitor 

Once status controlled

• Commence longer-term anticonvulsant medication with one of: Sodium valproate 10 mg/kg IV over 3–5 mins, then 800–

2000 mg/day Phenytoin: give loading dose (if not already used as above) of

15 mg/kg, infuse at < 50 mg/min, then 300 mg/day Carbamazepine 400 mg by nasogastric tube, then 400–1200

mg/day

• Investigate cause