Epilepsy and children By

Dr.Shahnawaz M.K Dal M.B.B.S, D.P.M

Consultant Neuropsychiatrist Sir Cowasjee Institute of Psychiatry Hyderabad

M.K Hospital Hyderabad shahnawazbest74@gmail.com

EPILEPSY

Epilepsy & its management

What is epilepsy ?

An epileptic seizure is a transient occurrence of signs

and or symptoms due to abnormal excessive or

synchronous neuronal activity in the brain.

Epilepsy is a disorder of the brain characterized by an

enduring predisposition to generate epileptic seizures and by the neurobiologic,

cognitive, psychological, and social consequences of this

condition.

Facts about epilepsy

At least two animals still have epilepsy for this reason:

Mexican Waltzing Mouse

Papio Papio baboon

History

The word ‘EPILEPSY’ derived from Greek words meaning “ To

seize upon ” or “Taking held of ”.

In 1870,British neurologist

HUGHLINGS JACKSON defined word EPILEPSY

“An excessive & disorderly discharge of

cerebral nervous tissue on muscles.”

This discharge may be in the form of loss of

consciousness, altered psychological

functions, disturbance of sensations,

convulsive movements or some combination

there of.

So the terminology ‘CONVULSION’ is not

proper as it only involves intense

paroxysm of involuntary muscle

contractions which is improper because this disorder may involve only alteration of the

sensorium or consciousness.

So the SEIZURE is the proper terminology for

that.

Burden of Epilepsy

Persistent stigma

Cognitive problems

Psychiatric disturbances

Long term effects of

AEDs

Low quality of life

Accidents

Sudden death

The goals of the treatment

Seizure freedom

Keep the patient safe

Keep the patient functional

Keep the patient autonomous

Seizure control and the adverse effects are pharmacodynamic measures of a drug effect on the body.

A seizure is a paroxysmal event due to excessive , hyper synchronous , abnormal discharge from the aggregate of the central nervous system.

Definitions

A sudden, brief disruption of the normal functioning of neurons in the brain

A neurological condition causing the tendency for repeated seizures of primary cerebral origin

Epilepsy is not contagious, it is not a mental illness or a cognitive disability.

“Paroxysmal excessive neuronal discharge from the cortical or sub-cortical areas”

CLASSIFICATION

Classification of epilepsy are based on various points….

- Idiopathic(primary) or symptomatic(secondary)

- Generalized or focal

- Isolated ,cyclic or repetitive

GASTAUT in 1970 has refined a definition of epilepsy with the help of ILAE(international league against epilepsy)

By this classification epilepsy has been broadly classified in two major groups based on EEG features & it is accepted world wide.

EPILEPSY:PREVELNCE • There are over 50 million sufferers in the world today, 85% of whom live in

developing countries.1

• At least 50% of cases begin at childhood or adolescence.1

• High prevalence 3.38/1000 was found in children from Government run educational institutions.2

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BARRIERS TO EDUCATION• Embarrassment about having seizures in front of peers can lead to children feeling uncomfortable in the school environment.

• Stigma – feelings of being different to peers – may lead to emotional problems, worry, stress and anxiety.

• Bullying and reluctance to attend school as a result can lead to school refusal.

• Frustration concerning the inability of school staff to understand epilepsy can impact on some young people.

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BARRIERS TO EDUCATION• Impact on self-esteem through negative school experiences can lead to loss of

confidence and self-doubt.

• Fear of seizures can impact on willingness to take part in activities.

• Stressful experiences at school can trigger seizures.

• Fear of Sudden Unexpected Death in Epilepsy (SUDEP) can have a negative impact

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Epilepsy and Related Conditions

• One of the most prominent cognitive changes that occurs in people • with epilepsy is a memory problem (Zemen et al. 2012)

• Epilepsy may be impacting on sleep if children are experiencing seizure activity at night and this may lead to tiredness during the day and impact on learning.

• Anti-epileptic drugs (AEDs) and side effects may be impacting on learning.

• Attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) will be impacting on some of the pediatric epilepsy population.

• Anxiety and depression will be impacting on some of the paediatric epilepsy population.

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Types of Epilepsy

Two major categories, namely

1.partial 2. generalised

seizures.

Partial seizures

Epilepsy - Pathogenesis

A. Result of complex genetic mutations and environmental factors can cause

• 1. Abnormal brain wiring AND/OR• 2. Chemical (neurotransmitter) imbalances AND/OR• 3. Abnormal connections made when attempting to repair an injury

B. Hypersensitive neurons may exhibit a sudden or violent depolarization

• 1. epileptogenic (able to cause epilepsy)• 2. Easily activated by hyperthermia, • hypoxia, hypoglycemia, hyponatremia,

sensory stimulation, certain sleep phases

Clinical Manifestations

Often manifests as strange

sensations, emotions & behaviors (including

convulsions)

Many may experience the same seizure events over

and over, while some have many different

types of seizures that cause different

symptoms each time.

Patients should be evaluated

thoroughly after an initial seizure

(complete history)

The type of seizure a person has depends on

a variety of things

The area of the brain affected

Underlying cause of

seizure• Partial or generalized• Time of day of the

event• Occurred during

wakefulness or sleep

Known triggers• flickering

light ,severe sleep deprivation

Tx

Medications used to treat patients with epilepsy are called anticonvulsants.

These drugs each have a different mechanism of action, but all serve to reduce the frequency of epileptic seizures. Monotherapy, treatment with a single agent, is the goal. Many seizures will stop without pharmacological intervention.

Status epilepticus & febrile convulsions.

Status epilepticus is a life-

threatening condition in which seizure activity is

uninterrupted.

Febrile convulsion is associated with temperatures101 in a child under age of 6 years .

PARTIAL SEIZURES

• Seizures that initially affect one specific area in one hemisphere of the brain

• May or may not cause an alteration of consciousness

• Symptoms can include muscle twitching, repetitive motions, and the appearance of “daydreaming”

• Partial seizures can become generalized seizures

DEFINING DIFFERENT SEIZURE TYPES

GENERALIZED SEIZURES

• Seizures that affect both hemispheres of the brain

• Result in a loss of consciousness• Symptoms can include blank stares,

falling to the floor, sudden muscle jerks, and repetitive stiffening and relaxing of muscles

Simple Partial Seizure

Rhythmic movements - isolated twitching of arms, face, legs

Sensory symptoms - tingling, weakness, sounds, smells, tastes , feeling of upset stomach, visual distortions

Psychic symptoms - déjà vu, hallucinations, feelings of fear or anxiety

Usually last less than one minute

May precede a generalized seizure

Difference between

SIMPLE PARTIAL SEIZURES

Complex Partial Seizure

Characterized by altered awareness

Confusion, inability to respond

Automatic, purposeless behaviors such as picking at clothes, chewing or mumbling.

Emotional outbursts

May be confused with:Drunkenness or drug use

Willful belligerence, aggressiveness

COMPLEX PARTIAL SEIZURES

Myoclonus A single abrupt shock like extensor movement of a limb.

Petit Mal Used to describe absence seizures as well as atypical absence.

Tonic Sustained contraction of one or more muscle groups, independent of position (i.e. can be flexed, extended, or opisthotonic).

Aura A generic term for a warning. A colloquial term for simplepartial seizure.

Convulsion Tonic, clonic or tonic-clonic seizure

Generalized Seizures INTERNATIONAL CLASSIFICATION OF EPILEPTIC SEIZURES (abridged version)

Absence seizures

Atypical absence

Myoclonic seizures,

Myoclonic jerks (simple or multiple)

Clonic seizures

Tonic seizures

Tonic-clonic seizures

Atonic seizures (astatic)

GENERALIZED TONIC- CLONIC SEIZURE

Grand mal epilepsy Petit mal epilepsy

Myoclonic seizure Atonic seizure

Status epilepticus Febrile convulsions

Between

Seizures:

• Normal

Appearance

During Seizure:

• Vacant stare • Eyes roll upward• Lack of response

ABSENCE SEIZURE

Includes all seizures that cannot be classified because of inadequate or incomplete data and some that defy classification in described categories. This includes some neonatal seizures, e.g., rhythmic eye movements, chewing, and swimming movements.

UNCLASSIFIED EPILEPTIC SEIZURES

TREATMENT PRIORITIES

No AEDs until diagnosis is confirmed

If uncertainty then period of observation will clarify the epilepsy syndrome

Two seizures

May be started after single seizure in certain circumstances

What Is the Difference Between Epilepsy & Seizures?

A seizure is a symptom of epilepsy

The Brain Is the Source of Epilepsy

Classifying Epilepsy and Seizures

Seizure types:

•Partial Generalized

• Simple Absence • Complex

Consciousnessis maintained

Consciousnessis lost or impaired

Altered awareness

Characterized bymuscle contractionswith or without lossof consciousness

Everything you do, you do with your brain!

Different parts have different functions, and different seizures!

Seizure Triggers

Missed medication (#1 reason)

Stress, anxietyHormonal changes, Menses

DehydrationLack of sleep, extreme fatigue

PhotosensitivityIllicit Drug, alcohol use

Certain Medications

Fever in Some Children

Treatment Goals in Epilepsy

Help person with epilepsy lead full and productive life

Tailor treatment to needs of individuals/special populations :• Women, Children, Elderly,

Hepatic or renal failure and other diseases

What if not treated?

Seizures can be potentially life threatening with brain failure, heart and lung failure, trauma, accidents

Sudden Unexpected Death in Epilepsy (SUDEP)

Even subtle seizures can cause small damage in brain

Long Term problems: fall in IQ, depression, suicide, Social Problems, Quality of Life

Considerations in Epilepsy Management

Age andGender

Seizure Frequency

Underlying Pathology

Comorbidities

Medication Side Effects

Syndrome vs.

Seizure Type

Factors That Affect the Choice of Drug

Seizure type/

Epilepsy syndrome

Side effects & safety

Patient age

Ease of Use

Lifestyle

Age, Sex, Childbearing potential

Other medications

New AEDs offer

Alternative as an add-on

Alternative in case of adverse

effects

Less AED-AED interactions

Less drug-drug interactions in

specific conditions

Better tolerability

Consistent use

Inadequate dosage or ineffective medication

Drug factors

Disease

Factors That Influence Response to Medication

History of Antiepileptic Drug Therapy

1857 - Bromides

1912 - Phenobarbitone

1937 - Phenytoin

1944 - Trimethadione

1954 - Primidone

1960 - Ethosuximide

History of AED therapy

1974 – Carbamazepine

1975 - Clonazepam

1978 - Valproate

1990 - Oxcarbazepine

1993 - Felbamate, Gabapentin

1995 – Lamotrigine, Levetiracetam

1997 - Topiramate, Tiagabine

Choice of AED

syndro

me

age

Life style

comorbidity

Associa

ted drugs

Adverse effectstolerability

Efficacy

A

EDph

arm

acok

in

etic

gender

interactions

cost

Correct diagnosis of the type of epilepsy influences treatment, prognosis and genetic counseling.

One best drug to fit the fit, fit the patient; Sequential monotherapy

Use the least expensive AED (all things being equal, like efficacy).

Prefer AEDs which can be taken od over bid / tid.

AEDs almost never need qid dosing

Start with one AED and push the dose to clinical toxicity or seizure control.

Withdraw AEDs that are not effective.

Never have a patient on more than three (3) AED's.

Principles of AED Selection…cont.

Principles of AED Selection… cont.

Don't use combination medications (e.g., phenytoin with phenobarbital).

No proof that multiple AEDs are synergistic in the treatment of epilepsy.

Polypharmacy is expensive, increases side effects and increases the complexity of adjusting AEDs in the refractory patient.

Antiepileptic drug (AED) - Limitations

A drug which decreases the frequency and /or severity of seizures in people with epilepsy.

Treats the symptom of seizures, not the underlying epileptic condition.

Improves quality of life by minimizing seizures.

Seizure freedom after failure with first AED (Brodie 2000)

Seizure ManagementPharmacologic Treatment

Partial seizures

• Oxcarbazepine• Carbamazepine• Phenytoin• Phenobarbital• Levetiracetam• Lamotrigine• Topiramate• Lacosamide• Zonisamide

Absence seizures

• Ethosuaximide• Valproic acid• Lamotrigine

Seizure ManagementPharmacologic Treatment

Tonic-Clonic Seizures

• Phenytoin• Valproic acid• Carbamazepine• Topiramate• Levetiracetam• Lamotrigine• Zonisamide

Myoclonic and Atonic Seizures

• Clonazepam• Lamotrigine• Levetiracetam• Infantile Spasms• ACTH• Topamax• Zonisamide• Valproic acid

Antiepileptic drugs – “newer

drugs” since 1990

•Felbamate•Gabapentin•Lamotrigine•Topiramate•Vigabatrin•Oxcarbazepine •Zonisamide•Leveteracetam•Pregabalin•Rufinamide•Lacosamide

Choosing the right treatment; balancing efficacy and tolerability

New AEDs offer

Alternative as an add-on

Alternative in case of adverse

effects

Less AED-AED interactions

Less drug-drug interactions in

specific conditions

Better tolerability

Broad Spectrum anti epileptic, used to treat refractory epilepsy

Levetiracetam:

TRADITIONAL ANTI-EPILEPTIC CONCERNS

• Memory impairment & Impaired attention is associated with traditional Anti-Epileptics.

• Liver failure resulting in death has occurred in patients receiving Divalproex Sodium.

• laboratory monitoring needed /LFTs Requires

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An Ideal Anti-epileptic Drug

• Broad spectrum of efficacy• Goal of Epilepsy Management - Seizure freedom• Sustained efficacy• Optimal therapy with no known clinically

significant drug interactions• Improved quality of life• Dosage convenience

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1. Levetiracetam is a new antiepileptic drug, structurally and mechanistically dissimilar to other marketed antiepileptic drugs.

2. Levetiracetam  is an anticonvulsant medication used to treat epilepsy. It is the S-enantiomer of etiracetam, structurally similar to the prototypical nootropic drug piracetam.

3. It is effective in reducing partial seizures in patients with epilepsy, both as adjunctive treatment and as monotherapy.

4. Having favorable pharmacokinetic characteristics (good bioavailability, linear pharmacokinetics, insignificant protein binding, lack of hepatic metabolism, and rapid achievement of steady-state concentrations) and a low potential for drug interaction.

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MECHANISM OF ACTION

• The exact mechanism by which Levetiracetam acts to treatepilepsy is unknown. However, the drug binds to a synaptic vesicle protein, , which is believed to impede nerve conduction across synapses.

• appear to be important for the availability of calcium-dependent neurotransmitter vesicles ready to release their content. The lack of results in decreased action potential-dependent neurotransmission, while action potential-independent neurotransmission remains normal.

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INDICATIONS

• Monotherapy in the treatment of partial onset seizures with or without secondary generalization in patients from 16 years of age with newly diagnosed epilepsy.

• Adjunctive therapy in the treatment of partial onset seizures with or without secondary generalization in adults and children from 4 years of age with epilepsy.

• Adjunctive therapy in the treatment of myoclonic seizures in adults and adolescents from 12 years of age.

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Dosage

EPICETAM-Features• Broad spectrum of potential efficacy

• No hepatic induction

• Well tolerated in most; good cognitive profile

• Excellent safety profile

• No laboratory monitoring needed

• Levetiracetam pharmacology• LEV is rapidly and almost completely absorbed after oral

intake, with peak plasma concentrations approximately one hour after oral administration. Food reduces the peak plasma concentration by 20% and delays it by 1.5 hours, but does not reduce LEV bioavailability (Patsalos 2000, 2003). There is a linear relationship between LEV dose and LEV serum level over a dose range of 500–5000 mg (Radtke 2001). LEV protein binding, at less than 10%, is not clinically relevant. LEV metabolism is not dependent on the liver cytochrome P450 enzyme system. LEV is predominantly excreted unchanged through the kidneys, with only about 27% metabolized.

Mechanism of action

• The exact mechanism by which levetiracetam acts to treat epilepsy is unknown. However, the drug binds to a synaptic vesicle glycoprotein, and inhibits presynaptic calcium channels reducing neurotransmitter release and acting as a neuromodulator. This is believed to impede impulse conduction across synapses

Lamotrigine

Oxcarbazepine

Topiramate

Levetiracetam

Licensed to Monotherapy

ILAE Treatment Guideline (Glauser T, et al.2006 ) NICE (National Institue for Clinical Excellence 2004) guidance on newer drugs for epilepsy in adults SIGN (Scottish Intercollegiate Guideline Network, 2005) SANAD (standard and new antiepileptic drug trial (Marson et al.2007) BESET (Belgian Study on Epilepsy treatment, Legros B, et al. 2007))

SIGN(Scottish Intercollegiate Guideline Network)

All AEDs are equivalent in

new onset epilepsy

First drugs to introduce in new onset epilepsy is

standart AEDs and LTG, OXC

Cosmetic side effects• Hirsutismus Alopecia • Gingiva hyperplasia Coarse face

Reproductive health• Hyperandrogenism Ovulatory disorders

• PCOS Sperm quality, number

Sexual dysfunction• 20-30% W, 50% M; Reduced libido• Anorgasmia

Bone health

Thyroid functions • total, free thyroxine↓

Peripheral neuropathies

Cerebellar atrophy

CBZ VPA PB ESM PHT

Somnolence *

GIS * * **

Liver *

Depression * * *

Blood * * * * *

Cognition * ** *

Osteoporosis (*) (*) * *

Side effects-I

Side effects-II

LTG OXC TPM LEV GBP PGB

Somnolence * ** * * *

GIS * * **Liver

Blood

Cognitive *Osteoporosis

Depression

Engel J, Pedley TA, Epilepsy, 2008

Idiosyncratic side effects

Vigabatrin

Felbamate

Lamotrigine

Topiramate

Topiramate

Oxcarbazepine

Visual field defects

Aplastic anemia

Rash Renal stones

Glaucoma

Hyponatremia

Weight and AEDs

Weight gain Weight loss No effect

VPA

GBP

PGB

VGB

TPM

ZNS

FBM

OXC

LTG

PHT

LEV*

Enzyme inducers vs non-inducer AEDs

Carbamazepine

Phenytoin

Phenobarbital

Primidone

Felbamate

Lamotrigine

Oxcarbazepine

Topiramate

Ethosuximide

Gabapentin

Levetiracetam

Pregabalin

Tiagabin

Valproat*

Vigabatrin

Zonisamide

Narrow-spectrum inducers Non-inducersInducers

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