Recent advances in treatment of Epilepsy

Dr Salil P Shinde,

Resident,

Department of Pharmacology & Therapeutics

• Seizure: transient alteration of behavior due to the disordered, synchronous and rhythmic firing of populations of brain neurons

• Seizures: Non epileptic ; evoked Epileptic; un provoked

• Epilepsy: Disorder of brain function characterized by periodic and unpredictable occurrence of seizures

Causes for Acute Seizures

• Trauma• Encephalitis• Drugs• Birth trauma• Withdrawal from

depressants• Tumor

• High fever• Hypoglycemia• Extreme acidosis• Extreme alkalosis

Hyponatremia• Hypocalcemia• Idiopathic

Epilepsy

• Second most common chronic neurological disorder

• Results from abnormal and sudden discharge of cerebral neurons

• Produces changes in a person's movement, behavior or consciousness

• Affects 1-2 % (40-50 million people) of the world‘s population

• 75-80 % of patients respond to standard therapy• In 20-25 % of patients seizures are uncontrollable

• Causes

– Heredity• Risk of getting epilepsy is 2.5

times greater with a family history of seizures

– Head trauma• The more severe the injury, the

greater the risk of developing epilepsy

– Brain tumour and stroke – Poisoning

• Lead • Alcohol

– Infections– Maternal injury

• Infection or systemic illness affecting the fetus' developing brain during pregnancy.

 

Classification of Seizure Types

Self-limited seizure types• Partial seizures

– Simple partial • Focal with minimal spread of abnormal discharge• Consciousness is maintained

– Complex partial• Local onset, then spreads• Usually starts with blank stare, followed by

automatisms (random motor activity).• Person appears unaware of surroundings.

– Partial seizures secondarily generalized• Begins focally• Varies in the duration and intensity of tonic and

aclonic phases• Lasts between 1-2minutes

• Generalized seizures

– Generalized tonic–clonic (grand mal)• Sudden cry, fall, rigidity, followed by muscle jerks,

shallow breathing or temporarily suspended breathing, bluish skin, possible loss of bladder control (usually lasts a couple of minutes).

– Absence (petit-mal) • Blank stare (lasts few seconds)

– Atonic• Sudden loss of postural tone (collapse and fall; 10

sec- 1 min)

– Clonic and Myoclonic• Sudden brief,

massive muscle jerk that may involve the whole body or parts of the body

– Infantile spasms• Quick, sudden

movements that start between 3 months and 2 years of age.

Continuous seizure types

Status Epilepticus

More than 30 minutes of continuous seizure activity OR

Two or more sequential seizures spanning this period without full recovery of normal alertness in between

• Medical emergency required to prevent hypoxic cerebral damage or metabolic complication

Focal status epilepticus

Precipitating stimuli for reflex seizures

o Visual stimuliFlickering light -colour to be specified when possiblePatternsOther visual stimuli

o Thinkingo Musico Eatingo Somatosensoryo Proprioceptiveo Readingo Hot watero Startle

Pathophysiology of Seizures

• The Interictal Spike (paroxysmal depolarization shift)

• Increased excitability

– Membrane depolarization, potassium buildup

– Increased excitatory (EAA, glutamate) input

– Decreased inhibitory (GABA) input

Evidence for the Pathophysiology of Seizures

Increased EAA• Increased Excitatory

Amino Acid Transmission• Increased sensitivity to

EAA• Progressive increase in

glutamate release during kindling

• Increased glutamate and aspartate at start of seizure

• Upregulation of NMDA receptors in kindled rats

Decreased GABA• Decreased binding of

GABA and benzodiazepines

• Decreased Cl- currents in response to GABA

• Decreased glutamate decarboxylase activity (synthesizes GABA)

• Interfere with GABA causes seizures

Cellular and Synaptic Mechanisms of Epileptic Seizures

(From Brody et al., 1997)

Scheme of Seizure Spread

small group of neurons. Contralateral discharge

evidence of anterior temporal lobe focal abnormalities. Bilateral.

Both hemispheres are involved from outset

Thalamocortial relays are believed to act on a hyperexcitable cortex

Antiepileptic Drugs

Therapy Has Improved Significantly !!

• “Give the sick person some blood from a pregnant donkey to drink; or steep linen in it, dry it, pour alcohol onto it and administer this”.

– Formey, Versuch einer medizinischen Topographie von Berlin 1796, p. 193

Strategies in Treatment

– Inhibition of excitatory neurotrasmission• Glutamate

– Enhancement of inhibitory neurotransmission• GABA

– Blockage of voltage-gated positive current• Na+• Ca2+

– Increase outward positive current• K+

• Many anti-seizure drugs act via multiple mechanisms

Actions on Na+ Channels

A. Resting State

B. Arrival of Action Potential causes depolarization and channel opens allowing sodium to flow in.

C. Refractory State, Inactivation

Phenytoin, Carbamazepine, Lamotrigine, TopiramateValproic acid

Na+

Na+

Na+

Sustain channel in this conformation

GABA-A ReceptorBinding Sites

Cl-

Benzodiazepines(diazepam, clonazepam) Barbiturates (phenobarbital)Valproic acid Gabapentin

TGB

VGBBZD

TPM

VGB

GBP

GABA-T

GABA-T

Modulators of GABA Transmission

TGB

Actions on Ca+2 Channels

Block calcium channels, decreasing neuronal impulse transmission

Ethosuximide, Valproic acid

Classification of AEDsClassical

• Phenytoin• Phenobarbital• Primidone• Carbamazepine• Ethosuximide• Valproate (valproic

acid)• Trimethadione (not

currently in use)

Newer• Lamotrigine• Felbamate• Topiramate• Gabapentin• Tiagabine• Vigabatrin• Oxycarbazepine• Levetiracetam• Fosphenytoin

In general, the newer AEDs have less CNS sedating effects than the classical AEDs

Characteristics of AEDs

• Most classical antiepileptic drugs exhibit similar pharmacokinetic properties.

• Good absorption (although most are sparingly soluble).

• Low plasma protein binding (except for phenytoin, BDZs, valproate, and tiagabine).

• Conversion to active metabolites (carbamazepine, primidone, fosphenytoin).

• Cleared by the liver but with low extraction ratios.• Distributed in total body water.• Plasma clearance is slow.• At high concentrations phenytoin exhibits zero

order kinetics.

PHENOBARBITAL

• Except for the bromides, it is the oldest antiepileptic drug.

• Although considered one of the safest drugs, it has sedative effects.

• Many consider them the drugs of choice for seizures only in infants.

• Acid-base balance important.• Useful for partial, generalized tonic-

clonic seizures, and febrile seizures• Prolongs opening of Cl- channels.• Blocks excitatory GLU (AMPA)

responses. Blocks Ca2+ currents (L,N).

• Inhibits high frequency, repetitive firing of neurons only at high concentrations.

Toxicity:• Sedation.• Cognitive

impairment.• Behavioral

changes.• Induction of liver

enzymes.• May worsen

absence and atonic seizures.

PHENYTOIN• Oldest nonsedative

antiepileptic drug.• Fosphenytoin, a more

soluble prodrug is used for parenteral use.

• “Fetal hydantoin syndrome”.• It alters Na+, Ca2+ and K+

conductances.• Inhibits high frequency

repetitive firing.• Alters membrane potentials.• Alters a.a. concentration.• Alters NTs (NE, ACh, GABA)

Toxicity:•Ataxia and nystagmus.•Cognitive impairment.•Hirsutism•Gingival hyperplasia.•Coarsening of facial features.•Dose-dependent zero order kinetics.•Exacerbates absence seizures.•At high concentrations it causes a type of decerebrate rigidity.

PRIMIDONE

• Metabolized to phenobarbital and phenylethylmalonamide (PEMA), both active metabolites.

• Effective against partial and generalized tonic-clonic seizures.

• Absorbed completely, low binding to plasma proteins.

• Should be started slowly to avoid sedation and GI problems.

• Its mechanism of action may be closer to phenytoin than the barbiturates.

Toxicity:•Same as phenobarbital•Sedation occurs early.•Gastrointestinal complaints.

ETHOSUXIMIDE

• Drug of choice for absence seizures.

• High efficacy and safety.• VD = TBW.• Not plasma protein or fat binding• Mechanism of action involves

reducing low-threshold Ca2+ channel current (T-type channel) in thalamus.

At high concentrations:• Inhibits Na+/K+ ATPase.• Depresses cerebral metabolic

rate.• Inhibits GABA aminotransferase.

• Phensuximide = less effective

• Methsuximide = more toxic

Toxicity:•Gastric distress, including, pain, nausea and vomiting•Lethargy and fatigue•Headache•Hiccups•Euphoria•Skin rashes•Lupus erythematosus (?)

CARBAMAZEPINE

• Tricyclic, antidepressant (bipolar)

• 3-D conformation similar to phenytoin.

• Mechanism of action, similar to phenytoin. Inhibits high frequency repetitive firing.

• Decreases synaptic activity presynaptically.

• Binds to adenosine receptors (?).• Inh. uptake and release of NE,

but not GABA.• Potentiates postsynaptic effects

of GABA.• Metabolite is active.

Toxicity:•Autoinduction of metabolism.•Nausea and visual disturbances.•Granulocyte supression.•Aplastic anemia.•Exacerbates absence seizures.

CLONAZEPAM

• A benzodiazepine.• Long acting drug with

efficacy for absence seizures.• One of the most potent

antiepileptic agents known.• Also effective in some cases

of myoclonic seizures.• Has been tried in infantile

spasms.• Doses should start small. • Increases the frequency of

Cl- channel opening.

Toxicity:• Sedation is prominent. • Ataxia.• Behavior disorders.

VALPROATE

• Fully ionized at body pH, thus active form is valproate ion.

• One of a series of carboxylic acids with antiepileptic activity. Its amides and esters are also active.

• Mechanism of action, similar to phenytoin.

levels of GABA in brain.• Facilitates Glutamic acid

decarboxylase (GAD).• Inhibits the GABA-transporter in

neurons and glia (GAT). [aspartate]Brain?

• May increase membrane potassium conductance.

Toxicity:•Elevated liver enzymes including own.•Nausea and vomiting.•Abdominal pain and heartburn.•Tremor, hair loss, •Weight gain.•Idiosyncratic hepatotoxicity.•Negative interactions with other antiepileptics.•Teratogen: spina bifida

What is the Role of the New AEDs??

• Different mechanism of action – treatment of refractory seizures

• Rational polytherapy

• Different (less ?) adverse effects

• Less drug interactions

• Potential advantages in the use of Women with epilepsy

FELBAMATE

• Effective against partial seizures but has severe side effects.

• Because of its severe side effects, it has been relegated to a third-line drug used only for refractory cases.

Toxicity:•Aplastic anemia•Severe hepatitis

GABAPENTIN

• Used as an adjunct in partial and generalized tonic-clonic seizures.

• Does not induce liver enzymes.• not bound to plasma proteins.• drug-drug interactions are

negligible.• Low potency.

Toxicity:•Somnolence.•Dizziness.•Ataxia.•Headache.•Tremor.

LAMOTRIGINE

• Add-on therapy with valproic acid .• Almost completely absorbed

• T1/2 = 24 hrs

• Low plasma protein binding• Effective in myoclonic and

generalized seizures in childhood and absence attacks.

• Involves blockade of repetitive firing involving Na channels, like phenytoin.

• Also effective in myoclonic and generalized seizures in childhood and absence attacks.

Toxicity:•Dizziness•Headache•Diplopia•Nausea•Somnolence•Life threatening rash “Stevens-Johnson”

TOPIRAMATE

• Rapidly absorbed, bioav. is > 80%, has no active metabolites, excreted in urine.T1/2 = 20-30 hrs

• Blocks repetitive firing of cultured neurons, thus its mechanism may involve blocking of voltage-dependent sodium channels

• Potentiates inhibitory effects of GABA (acting at a site different from BDZs and BARBs).

• Depresses excitatory action of kainate on AMPA receptors.

• Teratogenic in animal models.

Toxicity:• Somnolence• Fatigue• Dizziness• Cognitive

slowing• Paresthesias• Nervousness• Confusion• Weak carbonic

anhydrase inhibitor

• Urolithiasis

TIAGABINE

• Derivative of nipecotic acid.• 100% bioavailable, highly protein

bound.

• T1/2 = 5 -8 hrs

• Effective against partial seizures in pts at least 12 years old.

• Approved as adjunctive therapy.• GABA uptake inhibitor

aminibutyric acid transporter (GAT) by neurons and glial cells.

Toxicity:•Abdominal pain and nausea (must be taken w/food)•Dizziness•Nervousness•Tremor•Difficulty concentrating•Depression•Asthenia•Emotional liability•Psychosis•Skin rash

LEVETIRACETAM• SV2A, a synaptic vesicle protein, has

recently been identified as the likely target for levetiracetam.

• SV2A is an abundant protein component of synaptic vesicles that is structurally similar to 12-transmembrane domain transporters, although a transporter activity for SV2A has not yet been identified.

• It seems reasonable that the SV2A ligands could protect against seizures through effects on synaptic release mechanisms.

• Does not induce liver enzymes.• not bound to plasma proteins.• Useful as adjunct in refractory

epilepsy.

Toxicity:•Somnolence.•Dizziness.•Asthenia.

OXCARBAZEPINE

• Closely related to carbamazepine.• With improved toxicity profile.• Less potent than carbamazepine.• Active metabolite.• Use in partial and generalized

seizures as adjunct therapy.• May aggravate myoclonic and

absence seizures.• Mechanism of action, similar to

carbamazepine It alters Na+

conductance and inhibits high frequency repetitive firing.

Toxicity:•Hyponatremia•Less hypersensitivityand induction of hepaticenzymes than with carbamazepine

ZONISAMIDE • Marketed in Japan. Sulfonamide

derivative. Good bioavailability, low pb.

• T1/2 = 1 - 3 days

• Effective against partial and generalized tonic-clonic seizures.

• Approved by FDA as adjunctive therapy in adults.

• Mechanism of action involves voltage and use-dependent inactivation of sodium channels.

• Inhibition of Ca2+ T-channels.• Binds GABA receptors• Facilitates 5-HT and DA

neurotransmission

Toxicity:•Drowsiness•Cognitive impairment•Anorexia•Nausea•High incidence of renal stones (mild anhydrase inh.).•Metabolized by CYP3A4

VIGABATRIN (-vinyl-GABA)

• Absorption is rapid, bioavailability is ~ 60%, T 1/2 6-8 hrs, eliminated by the kidneys.

• Use for partial seizures and West’s syndrome.

• Contraindicated if preexisting mental illness is present.

• Irreversible inhibitor of GABA-aminotransferase (enzyme responsible for metabolism of GABA) => Increases inhibitory effects of GABA.

• S(+) enantiomer is active.

Toxicity:•Drowsiness•Dizziness•Weight gain•Agitation•Confusion•Psychosis

INTERACTIONS BETWEEN ANTISEIZURE DRUGS

With other antiepileptic Drugs:- Carbamazepine with

phenytoin Increased metabolism of carbamazepinephenobarbitalIncreased metabolism of epoxide.

- Phenytoin withprimidone Increased conversion to phenobarbital.

- Valproic acid withclonazepam May precipitate nonconvulsive status

epilepticusphenobarbitalDecrease metabolism, increase toxicity.phenytoin Displacement from binding, increase toxicity.

ANTISEIZURE DRUG INTERACTIONS

With other drugs:antibiotics phenytoin, phenobarb, carb.anticoagulants phenytoin and phenobarb

cimetidine displaces pheny, v.a. and BDZsisoniazid toxicity of phenytoinoral contraceptives antiepileptics metabolism.salicylates displaces phenytoin and v.a. theophyline carb and phenytoin may

effect.

The Cytochrome P-450 System

Inducers Inhibitors

phenobarbital valproate

primidone topiramate (CYP2C19)

phenytoin oxcarbazepine (CYP2C19)

carbamazepine felbamate (CYP2C19)

felbamate (CYP3A) (increase phenytoin, topiramate (CYP3A) phenobarbital)oxcarbazepine (CYP3A)

Gabapentin, Lamotrigine, Tiagabine, Levetiracetam, Zonisamide

Drugs in the pipeline

Levetiracetam Analogs

• Seleteracetam and brivaracetam - Both have 10-fold greater affinity for SV2A than does levetiracetam, brivaracetam may also have modest sodium-channel blocking activity.

• Overall, seletracetam seems to have a similar pharmacological profile to levetiracetam, but is more potent.

• In contrast, brivaracetam has a broader spectrum of activity

• However, it has a lower protective index than levetiracetam.

Valproate-Like Agents

• Analogs of valpromide that resist metabolic hydrolysis to their corresponding acids - valnoctamide (2-ethyl-3-methylpentanamide) and diisopropyl acetamide (PID)

• exhibit greater anticonvulsant potency than valproate and their corresponding acids.

• Valnoctamide has been marketed as an anxiolytic and sedative (as Axiquel and Nirvanil) in the U.S., Italy, the Netherlands and Switzerland.

• Whether it is useful in epilepsy remains to be determined.

Valproate-Like Agents

• valrocemide (valproyl glycinamide) - does not cause embryotoxicity in rats and rabbits.

• cyclic analogs possess two quaternary carbons in the β-position to the carbonyl and cannot be biotransformed into metabolites with a terminal double bond, which is presumed to be the souce of hepatotoxicity - MTMCD (N-methyl-tetramethylcyclopropanecarboxamide) and 2,2,3,3-tetramethylcyclopropanecarbonylurea (TMCU)

• Dried roots of valerina species – isovaleramide, very safe in phase I trials

Carbamates:

• Flurofelbamate and RWJ-333369

• Felbamate - formation of an aldehyde - that reacts with proteins. Substitution of a fluorine atom for a hydrogen prevents the formation of this reactive aldehyde.

• Fluorofelbamate may inhibit NMDA receptors and might also affect sodium channels.

• RWJ-333369 is currently in Phase II clinical development for the treatment of partial epilepsy and migraine headache.

Carbamazepine Analogs

• Licarbazepine and (S)-Licarbazepine Acetate

• Oxcarbazepine - metabolites (R)- and (S)-licarbazepine, which appear in plasma and urine in a 4:1 ratio. As metabolite ? Advantage.

• (S)-licarbazepine acetate (BIA 2-093) is also in Phase III clinical trials. BIA 2-093 only forms (S)-licarbazepine,. In addition, BIA 2-093, as is the case for other sodium channel blocking AEDs inhibits sodium channel-dependent release of neurotransmitters with similar potency to carbamazepine and oxcarbazepine.

• Although BIA 2-093 is chemically distinct from licarbazepine and could potentially have distinct pharmacodynamic properties related to its novel structure, there is little evidence that it is substantially different mechanistically.

Benzodiazepine-like Agents

• Benzodiazepine-like agents that act as partial agonists at the benzodiazepine recognition site - RWJ-51204 is of particular interest as it has highly potent anticonvulsant activity and a favorable protective index.

• None of the partial benzodiazepine agonists, however, has been proven to lack tolerance in clinical trials.

Stiripentol

• Increase γ-aminobutyric acid (GABA) levels in brain tissue

• involves at least two independent neurochemical mechanisms: inhibition of synaptosomal uptake of GABA and inhibition of GABA transaminase

• The drug is currently undergoing phase III clinical trials – good results in refractory partial epilepsy.

• Characterized by nonlinear pharmacokinetics and inhibition of liver microsomal enzymes.

New Scaffolds and Mechanisms

Functionalized Amino Acids• lacosamide (formerly

harkoseride), SPM 927.• Lacosamide may act as an

antagonist of NMDA receptors through an interaction with the strychnine insensitive glycine site.

• Phase II clinical studies have been promising and Phase III trials are in progress.

AMPA Receptor Antagonists• Glutamine – Agonist AMPA

• The first selective AMPA receptor antagonists to be identified were quinoxalinedione derivatives, such as NBQX

• However, they tend to produce motor impairment at doses similar to those that are protective against seizures.

• The early quinoxalinediones had poor solubility and so that they precipitated in the kidney, leading to crystaluria and nephrotoxicity.

• Newer agents include the water soluble quinoxalinedione-analog zonampanel; YM872, and ZK200775.

• Unfortunately, the results were not encouraging, largely because of sedative side effects and a negative impact on the level of consciousness.

Neuroactive Steroids

• Endogenous steroid hormones when reduced at the 5- and 3-positions of the steroid A-ring, form metabolites that lack classical hormonal activity but instead are high affinity, positive allosteric modulators of GABA-A receptors.

• Ganaxolone, the 3β-methyl analog of the endogenous steroid allopregnanolone has been most extensively evaluated, and early clinical trials have been completed.

• Open label clinical studies have provided indications of efficacy in infantile spasms and complex partial seizures.

• may be useful in catamenial epilepsy – useful in pregnancy.

Rufinamide

• Compound that bears some structural similarity with lamotrigine.

• Has been reported to prolong the inactivation of sodium channels and to limit the frequency of action potential firing in cultured and acutely isolated neurons

• Several late stage clinical trials of rufinamide have been completed in patients with partial seizures, primary generalized tonic-clonic seizures and the Lennox-Gastaut syndrome.

• Some of these studies reached statistically significant endpoints and applications with regulatory agencies to market the drug have been filed.

Retigabine

• Retigabine - the desazaanalog of flupirtine (a nonopiate analgesic approved in Europe for general nocioceptive pain).

• Retigabine has undergone clinical testing in several Phase II clinical trials, largely in patients with partial seizures with or without secondary generalization who were refractory to available therapies.

• The drug is a “potassium channel opener” - is specific for M-type potassium current.

• The critical action of the drug is to increase potassium current near resting potential, which reduces excitability and presumably is responsible, at least in part, for the anticonvulsant effect of retigabine. There are

• Retigabine acts on all neuronal KCNQ subunits, but not on KCNQ1 which is expressed in cardiac muscle

Anti – Epileptogens?

• Single and repeated administrations of LEV in adult SERs produce unusual long-lasting anti-seizure effects (>4 weeks), which are not considered to be merely due to LEV accumulation in the brain.

• Receptor tyrosine kinase - TrkB – the plasticity of epileptogenesis is eliminated in

TrkB(-/-) mice.– Its requirement for epileptogenesis in kindling

implicates TrkB and downstream signaling pathways as attractive molecular targets for drugs for preventing epilepsy.

New Treatment options

Vagus Nerve Stimulator (VNS)

• Is an FDA approved device

• Provides chronic intermittent electrical stimulation of the vagus nerve

• Exact mechanism is unknown

VNS candidates

• Patients with refractory epilepsy

– Partial or generalized– Lennox-Gastaut Syndrome– Poor surgical candidates

• Contraindicated in:

– Patients with left or bilateral vagotomy

Deep Brain Stimulation

• Pros

– Minimal invasive– Safe, Well tolerated

• Cons

– Malfunction– Unknown long term

benefits/complications

• Based on stimulating widespread inhibitory pathways

– Thalamus• Anterior Thalamic Nucleus• Centromedian Nucleus of the Thalamus

– Cerebellum

Melatonin

• Regulates sleep

• Anti-seizure properties

• Blocks effects of Glutamate, enhances Gaba actions

• Potentiates the effect of carbamazepine and phenobarbital

• Given orally 30 minutes to one hour before bedtime, dose ranges from 3-10 mg

NICE Guidelines 2004

Individuals with epilepsy and their families and/or carers should be given, and have access to sources

of, information about (where appropriate):

• epilepsy in general• diagnosis and treatment options• medication and side effects• seizure type(s), triggers and seizure control• management and self-care• risk management• first aid, safety and injury prevention at home and at

school or work• psychological issues• social security benefits and social services• insurance issues• education and healthcare at school• employment and independent living for adults

Individuals with epilepsy and their families and/or carers should be given, and have access to sources of,

information about (where appropriate):

• importance of disclosing epilepsy at work, if relevant (if further information or clarification is needed, voluntary organisations should be contacted).

• road safety and driving• prognosis• sudden death in epilepsy (SUDEP)• status epilepticus• life style, leisure and social issues (including

recreational drugs,• alcohol, sexual activity and sleep deprivation)• family planning and pregnancy• voluntary organisations, such as support groups and

charitable organisations, and how to contact them

Investigations• The EEG should not be used in isolation to make a

diagnosis of epilepsy.

• MRI should be the imaging investigation of choice in individuals with epilepsy

• In an acute situation, CT may be used to determine whether a seizure has been caused by an acute neurological lesion or illness.

DiagnosisQuestions used that, if positive, support a diagnosis of epilepticseizure:

• At times do you wake up with a cut tongue after your spells?

• At times do you have a sense of déjà vu or jamais vu before your spells?

• At times is emotional stress associated with losing consciousness?

• Has anyone noticed your head turning during a spell?

• Has anyone ever noted that you are unresponsive, have unusual posturing or have jerking limbs during your spells or have no memory of your spells afterwards?

• Has anyone noticed that you are confused after a spell?

Diagnosis

Questions used that, if positive, support a diagnosis of syncope:

• Have you ever had light-headed spells?

• At times do you sweat before your spells?

• Is prolonged sitting or standing associated with your spells?

Treatment recommendations• Only start one drug at a time and only make one change at a

time.

• Prior base-line biochemistry and full blood count

• Started in a dose no higher than recommended by the manufacturer.

• Start at a low dose and work up slowly.

• Dosing will be determined by adverse effects and continuation of seizures with the aim being to have seizure freedom and no adverse effects.

• The rate of changes and the end dose will be determined by the individual’s response to therapy. The balance of seizure control and adverse effects should be discussed with the individual.

Treatment recommendations• Formulation or brand.

• Individuals and carers should be given clear instructions to seek medical attention urgently for symptoms including rash, bruising, or drowsiness with vomiting especially in the first weeks of treatment.

• If an AED has failed because of adverse effects or continued seizures, start a second drug (which may be an alternative first-line or secondline drug), build up to an adequate or maximum tolerated dose and then taper the first drug slowly. If the combination is successful, some individuals may prefer to remain on the combination.

• If the second drug is unhelpful, taper off either drug depending on the side effects and how well the drug is tolerated, maintaining the alternative drug, before starting a third drug.

TreatmentSeizure type

First-line drugs

Second-line drugs

Other drugs Drugs to beavoided

Generalised tonic–clonic

CarbamazepineLamotrigineSodium valproateTopiramate

ClobazamLevetiracetamOxcarbazepine

AcetazolamideClonazepamPhenobarbitalPhenytoinPrimidone

TiagabineVigabatrin

Absence EthosuximideLamotrigineSodium valproate

ClobazamClonazepamTopiramate

CarbamazepineGabapentinOxcarbazepineTiagabineVigabatrin

Myoclonic Sodium valproate(Topiramate)

ClobazamClonazepamLamotrigineLevetiracetamPiracetamTopiramate

CarbamazepineGabapentinOxcarbazepineTiagabineVigabatrin

TreatmentSeizure type First-line

drugsSecond-line drugs

Other drugs Drugs to beavoided

Tonic LamotrigineSodium valproate

ClobazamClonazepamLevetiracetamTopiramate

AcetazolamidePhenobarbitalPhenytoinPrimidone

CarbamazepineOxcarbazepine

Atonic LamotrigineSodium valproate

ClobazamClonazepamLevetiracetamTopiramate

AcetazolamidePhenobarbitalPrimidone

CarbamazepineOxcarbazepinePhenytoina

Focal with/withoutsecondarygeneralisation

CarbamazepineLamotrigineOxcarbazepineSodium valproateTopiramate

ClobazamGabapentinLevetiracetamPhenytoinaTiagabine

AcetazolamideClonazepamPhenobarbitalaPrimidonea,

Pregnancy & seizures

• mother– injury– SUDEP– obstetric complications

• baby– hypoxia/ischemia

• foetal death• premature delivery• growth retardation• malformation

AEDs – pregnancy outcome

• exposure to AED in utero

– 2-3 x inc in background rate (1-2%)

• cardiac• cleft lip/palate • neural tube

– polytherapy increases risk– retrospective small

studies – ‘older’AEDs

Reducing risk in pregnancy – best practice

Pre-pregnancy assessment• diagnosis• AED monotherapy,

– lowest effective dose• folic acid

SIGN (2003) NICE (2004)

Reducing risk in pregnancy – best practice

care during pregnancy & delivery

• high risk • shared care between the obstetrician & specialist• high resolution ultrasound scan at 18-20 weeks • hospital delivery with appropriate facilities • no need for routine monitoring of AED levels• should be given 1mg of vit K parenterally at

delivery (enzyme-inducing AEDs)• breastfeeding should be encouraged

SIGN (2003) NICE (2004)

TDM of some important drugs

Conclusion• Many new AEDs, better tolerated and fewer drug

interactions than the older AEDs

• Most patients can find an AED that is effective and causes minimal or no side effects

• Herbal meds : untested– Studies finally in progress on this and other

alternative treatment modalities (Melatonin)

• More advances coming every year (ER preparations)…

Cool stuff for the (near) future• New Drugs

– Prevention of Epilepsy

• New Diets (ketogenic)

• Brain Stimulation

• Direct brain drug delivery

• Gamma Knife

• Stem Cells