The Treatment of Epilepsy

The Treatment of Epilepsy

Contents

List of Contributors

Preface to the Fourth Edition

Preface to the First Edition

Historical Introduction: The Drug Treatment of Epilepsy from 1857 to 2015

SECTION I Introduction

CHAPTER 1 Definition (Terminology) and Classification in Epilepsy: A Historical Survey and Current Formulation, with Special Reference to the ILAE

Definition

Epilepsy and epileptic seizures

Classification

ILAE classifications of epileptic seizures and epilepsies

The future of classification schemes of epilepsy

Classification by aetiology

Classification by semiology and anatomical site

Definition

Acute symptomatic seizures

Epilepsy in remission

Provoked epilepsy and reflex epilepsy

Definition and classification – status epilepticus

Afterthought

Acknowledgement

References

CHAPTER 2 Differential Diagnosis of Epilepsy

Introduction

General approach to the diagnosis of episodic disturbances

Syncope

Non-epileptic seizures

Panic disorder

Migraine

Sleep disorders

Vertigo

Movement disorders

Cerebral ischaemia

Endocrine and metabolic abnormalities

Transient global amnesia

References

CHAPTER 3 Mechanisms of Epileptogenesis

Membrane ion channels

Voltage-gated channels

Membrane ion channels as targets for antibodies in acquired autoimmune disorders

Channel and receptor trafficking and plasticity

Network and system involvement in epileptogenesis

Local circuits

Networks

Systems

Epileptogenesis as a process

Plastic changes in channels and receptors

New targets for antiepileptic and antiepileptogenic strategies

New strategies targeting AMPA and GABA receptors

Conclusions

References

CHAPTER 4 Antiepileptic Drug Discovery

Characteristics of the ideal model system

The current era of AED discovery

Anticonvulsant Screening Program

Early identification of antiepileptic activity

MES, scPTZ and 6-Hz tests

Differentiation of anticonvulsant activity

Pharmacological profile and potential clinical utility

Pharmacoresistant seizure models

Therapeutic index and toxicity assessment

Aetiologically relevant model systems

Beyond the seizure

Antiepileptogenesis and disease modification (see also Chapter 8)

Conclusions

Acknowledgement

References

CHAPTER 5 Antiepileptic Drug Development

Introduction

Overview on clinical studies and trials for drug development

Lessons learned after two decades of AED trials

Opportunities for developing better antiseizure AEDs

Development of epilepsy drugs beyond suppressing seizures

Conclusions

Acknowledgements

References

CHAPTER 6 Mechanisms of Antiepileptic Drug Action

Main targets

Sodium channels

Calcium channels

GABA and GABA receptors

Other targets

Glutamate and glutamate receptors

Potassium channels

Cyclic nucleotide-gated channels

Synaptic vesicle protein SV2A

Monoamines

Intracellular signalling pathways

References

CHAPTER 7 Mechanisms of Drug Resistance and Tolerance

Introduction

The concept of drug resistance in epilepsy

Disease-related mechanisms of drug resistance in epilepsy

Epilepsy syndrome associated with drug resistance

Severity and progression of epilepsy

Structural brain alterations and/or network changes

Alterations in drug targets

Multidrug transporter hypothesis

Drug-related mechanisms of drug resistance in epilepsy

Development of tolerance

Pharmacogenetic mechanisms of drug resistance in epilepsy

Proof-of-concept of drug resistance hypotheses

Conclusions

References

CHAPTER 8 Epilepsy Biomarkers

Introduction

Need for biomarkers

Mechanisms of epilepsy

Potential biomarkers

Electrophysiological biomarkers

Neuroimaging biomarkers

Molecular and cellular biomarkers

Behavioural biomarkers

Research to identify biomarkers

Acknowledgements

References

SECTION II Principles of Medical Management

CHAPTER 9 General Principles of Medical Management

Aims of treatment

Complete seizure control

Reduction of seizure severity

Avoidance of adverse effects

Suppression of subclinical epileptic activity

Reduction of seizure-related mortality and morbidity

Addressing comorbidities

Avoidance of adverse drug interactions

Avoidance of obstruction to patient’s life

Prevention of epileptogenesis

When should treatment be started?

Individuals with a history of a single seizure

Individuals with a history of two or more unprovoked seizures

Individuals with seizures precipitated by specific triggers

Other situations

Initiation of treatment and dose optimization

Choice of the most appropriate drug

Dose escalation

Initial target maintenance dosage

Frequency of administration

Choosing among different formulations (including generics)

Adjusting dosage in individuals not responding to the initial target dosage

Dose optimization in special situations

Assessing clinical response

What next when the initial treatment fails? – monotherapy and combination therapy

Alternative monotherapy

Combination therapy

Are some drug combinations more useful than others (‘rational polytherapy’)?

How long should treatment be continued?

References

CHAPTER 10 Pharmacokinetic Optimization of Therapy

Introduction

Basic pharmacokinetic principles

Why do individuals respond differently to the same drug concentration?

The concept of reference range

The concept of individual therapeutic concentrations and interpretation of serum concentrations in the clinical setting

Main indications for measuring serum antiepileptic drug concentrations

Practical aspects in the application of TDM

When should blood samples be taken?

Monitoring unbound drug concentrations

Measurement of saliva concentrations

Other biological matrices

Development and progress of analytical methods

Application of TDM to individual antiepileptic drugs

First generation antiepileptic drugs

Second generation antiepileptic drugs

Tailored therapy and future developments for TDM

Conclusions

References

CHAPTER 11 Management of Chronic Active Epilepsy in Adults

Prognosis and outcome of treatment of chronic active epilepsy

Heterogenity of epilepsy

Extent of response to therapy in chronic active epilepsy

The term ‘drug-resistant epilepsy’

Clinical factors influencing prognosis in chronic epilepsy

Prediction of pharmacoresistance by pharmacogenomics

Provision of care

The epilepsy centre (CSAG model)

Treatment approach for chronic active epilepsy in adult patients

Assessment

Treatment

Epilepsy surgery

Limits on therapy

Counselling and information provision

Acknowledgement

References

CHAPTER 12 Management of Epilepsy in Remission

Introduction

Risk of relapse upon AED withdrawal

Medical Research Council Antiepileptic Drug Withdrawal Study

Akershus double-blind antiepileptic drug withdrawal study

Non-randomized controlled or uncontrolled studies

Early versus late withdrawal in children

Rapid versus slow withdrawal

Factors associated with seizure relapse after AED withdrawal

Syndromic classification

Seizure type

Age at onset

EEG findings

Severity of epilepsy and duration of seizure freedom

Influence of individual drugs

Models for prediction of relapse

Antiepileptic drug withdrawal after epilepsy surgery

Consequences of relapse

Seizure control after relapse

Risks associated with continuing AEDs (or benefits of withdrawal)

Patient attitudes

Clinical therapeutics

References

CHAPTER 13 Management of Epilepsy in Neonates and Infants

Introduction

Currently available drug therapies for neonates

Benzodiazepines

Bumetanide

Levetiracetam

Lidocaine

Phenobarbital

Phenytoin

Topiramate

Currently available drug therapies for infants

Hormonal treatments

Benzodiazepines

Carbamazepine

Levetiracetam

Lamotrigine

Oxcarbamazepine

Phenobarbital

Phenytoin

Rufinamide

Stiripentol

Topiramate

Valproic acid

Vigabatrin

Zonisamide

Polypharmacy

Ketogenic diet

Epilepsy surgery

Intravenous immunoglobulin

Treatment of acute neonatal seizures and neonatal status epilepticus

General guidelines

Treatment of neonatal status epilepticus

Treatment of focal seizures

Provoked seizures

Treatment of specific syndromes in the neonatal period

Benign familial neonatal seizures

Benign non-familial neonatal seizures

Early myoclonic encephalopathy

Early infantile encephalopathy with epilepsy or Ohtahara syndrome

KCNQ2 encephalopathy

Vitamin responsive seizures

Glucose transporter-1 deficiency

Glycine encephalopathy (neonatal non-ketotic hyperglycinaemia)

Treatment of specific syndromes in the infantile period

Malignant migrating partial seizures in infancy

West syndrome

Myoclonic epilepsy of infancy

Benign infantile epilepsy and benign familial infantile epilepsy

Dravet syndrome (severe myoclonic epilepsy in infancy)

Tuberous sclerosis complex

Sturge–Weber syndrome

Febrile seizures

Prognosis and complications of neonatal and infantile seizures

Acknowledgements

References

CHAPTER 14 Management of Childhood Epilepsy Syndromes

Introduction

Treatment of childhood epilepsy: the evidence base

Treatment of febrile seizures

Treatment of idiopathic generalized epilepsies

Treatment of idiopathic focal epilepsy syndromes of childhood

Treatment of epileptic encephalopathies

Lennox–Gastaut syndrome

Doose syndrome

Landau–Kleffner syndrome and the syndrome of continuous spikes and waves in slow sleep

Myoclonic absence epilepsy

References

CHAPTER 15 Management of Epilepsy in People with Intellectual Disabilities

The importance of the topic

Comprehensive epilepsy service

Multidisciplinary approach

Medical aspects

Psychological and cognitive aspects

Social and educational aspects

Antiepileptic drug treatment

Adherence

Older drugs

Newer drugs

Central nervous system side-effects

Paradoxical effects

Can the development of the disorder be influenced by treatment?

Influence of aetiology and disease mechanisms on epilepsy treatment

Non-pharmacological treatment

Epilepsy surgery

Vagus nerve stimulation

Ketogenic diet

Acute seizure treatment with benzodiazepines

Concomitant psychopharmacological treatment

Prognosis of epilepsy in intellectually disabled patients

Overall prognosis

Prognosis after withdrawal of AEDs

References

CHAPTER 16 Management of Epilepsy in the Elderly

Introduction

Epidemiology

Diagnosis

Clinical presentation of epilepsy in the elderly

Investigations

Electroencephalography

Neuroimaging

Risk of recurrence

Treatment of epilepsy in the elderly

Pharmacokinetic changes

Absorption

Protein binding

Hepatic clearance

Renal clearance

Pharmacodynamic changes

Antiepileptic drug choice

Older antiepileptic drugs

Newer antiepileptic drugs

Comorbid conditions and medication interactions

Epilepsy surgery

Aspects of the impact of epilepsy inold age

References

CHAPTER 17 Emergency Treatment of Seizures and Status Epilepticus

Status epilepticus

Epidemiology and causes

Status epilepticus and neuronal damage

Drug pharmacokinetics and pharmacodynamics

Acute drug pharmacokinetics

Peripheral and cerebral distribution of drugs during epileptic seizures

Development of resistance to AED action

Treatment of acute seizures and acute repetitive seizures

General (non-pharmaceutical) measures

Emergency drug therapy in acute repetitive seizures and prolonged seizures

Drugs used in the emergency therapy of acute repetitive seizures and prolonged seizures

Treatment of tonic–clonic status epilepticus

Diagnosis

Medical management and complications

Drug treatment of tonic–clonic status epilepticus

Protocol for the drug treatment of tonic–clonic status epilepticus (Table 17.4)

Treatment in the premonitory stage of tonic–clonic status epilepticus

Treatment in early status epilepticus

Treatment in established status epilepticus

Treatment in refractory and super-refractory status epilepticus

Treatment of common forms of non-convulsive status epilepticus

Diagnosis

Medical management

Summary of drug therapies most commonly used in status epilepticus

Diazepam

Fosphenytoin

Levetiracetam

Lorazepam

Midazolam

Phenobarbital

Phenytoin

Propofol

Thiopental/pentobarbital

Valproate

Acknowledgement

References

CHAPTER 18 Management of Medical Comorbidity Associated with Epilepsy

Introduction

Bone health in epilepsy

Overview of bone physiology and biochemistry

Fracture and osteoporosis risk in people with epilepsy

Screening for bone health in people with epilepsy

Prevention and treatment of bone loss in people with epilepsy

Organ dysfunction

Overview of AED pharmacokinetics and dosing in hepatic disorders

AED pharmacokinetics and dosing in renal disorders

Hepatic and renal impairment due to epilepsy and its treatment

Epilepsy and thyroid disease

Multiorgan dysfunction

Organ transplantation

Cancer and epilepsy

Infections and epilepsy

Human immunodeficiency virus infection and seizures

Cysticercosis and epilepsy

Connective tissue disorders

Pulmonary disease

Cardiac disease

Cardiac arrythmias

Ischaemic cardiovascular disease

References

CHAPTER 19 Psychiatric Features of Epilepsy and their Management

Anxiety and affective disorders

Prevalence of anxiety and affective disorders in epilepsy

‘Bidirectional relationship’ between epilepsy and depression

Diagnostic criteria

Atypical affective disorders in epilepsy

Interictal dysphoric disorder

Preictal, ictal and postictal depressive symptoms

Generalized anxiety disorder

Panic disorder

Obsessive–compulsive disorder

Suicide

FDA guidance on suicide risk associated with AEDs

Treatment of depression in epilepsy

Pharmacokinetic interactions between antidepressants and AEDs

Pharmacodynamic interactions

Cognitive behavioural therapy

Electroconvulsive therapy, transcranial magnetic stimulation and vagal nerve stimulation

Deep brain stimulation for treatment-resistant depression

Psychoses of epilepsy

Ictal delirium

Ictal psychosis (complex partial status epilepticus)

Postictal psychosis

Interictal psychosis

Definition

Prevalence

Duration and other clinical factors

Relationship to epilepsy subtype

‘Bidirectional relationship’ between epilepsy and schizophrenia

Psychopathology in interictal psychosis: comparison with schizophrenia

Therapy of psychosis in epilepsy

Postoperative psychiatric disorders

Forced normalization

Personality disorders in epilepsy

Epileptic personality

DSM-IV (Axis II) personality disorders

Mental and behavioural disorders secondary to AED use

References

CHAPTER 20 Prevention and Management of Side-effects of Antiepileptic Drugs

Types of adverse effects

Type A

Type B

Type C

Prevention and management of adverse effects

Analysis of risk factors

Strategies for prevention or minimization of adverse effects

Early identification

Treatment

References

CHAPTER 21 Ketogenic Diets

Introduction

Mechanisms of action

Seizure outcomes

Ketogenic diets and adults

Alternative ketogenic diets

Indications for the ketogenic diet

Calculation of the ketogenic diet

Initiation of the ketogenic diet

Handling increased seizures

Discontinuation of the ketogenic diet

Side-effects

Conclusions

Acknowledgements

References

CHAPTER 22 Complementary and Alternative Treatments for Epilepsy

Introduction

Importance of indirect benefits

The placebo effect

Stress and anxiety

Ancient medical traditions

Ayurvedic medicine

Traditional Chinese medicine

Herbal remedies

Bishop’s wort

Blue cohosh

Kava

Mistletoe

Itchweed

Mugwort

Ground holly

Skullcap

Cannabis

Homeopathy

Behavioural approaches

Comprehensive neurobehavioural approach

Neurofeedback

Aromatherapy

Music therapy

Meditation and hypnosis

Hypnosis

Conclusions

References

CHAPTER 23 Reproductive Aspects of Epilepsy Treatment

Fertility

Reproductive dysfunction

Birth control

Pregnancy in women with epilepsy

Effects of maternal seizures on the fetus

Maternal risks with uncontrolled seizures

Seizure control during pregnancy and delivery

Pharmacokinetics of antiepileptic drugs during pregnancy

Obstetric complications during pregnancy and delivery

Sensitive periods

Folate supplementation

Vitamin K supplementation and neonatal haemorrhage

Preconception counselling

Management during pregnancy

Labour and delivery

Puerperium

Implications for the treatment of women of child-bearing age

References

CHAPTER 24 Genetic Counselling in Epilepsy

Introduction

The pedigree as a diagnostic tool

Risk assessment

Genetic testing

Diagnostic tests

Carrier identification tests

Predictive tests

Susceptibility tests

Pharmacogenetics tests

Mode of inheritance of genetic disorders

Chromosomal inheritance

Mendelian inheritance

X-linked inheritance

Mitochondrial inheritance

Complex inheritance

Genetic counselling in epilepsy: approaching a heterogeneous disorder

Mendelian epilepsies

Complex epilepsies

Epileptic encephalopthies

Copy number variations and epilepsy

Genetic syndromes including epilepsy as an important clinical feature

Progressive myoclonus epilepsies

Conclusions

References

CHAPTER 25 Drug Interactions

Introduction

Mechanisms of drug interactions

Pharmacokinetic interactions

Absorption

Distribution

Metabolism

Clinically relevant pharmacokinetic druginteractions of AEDs

Pharmacodynamic interactions

Conclusions

References

CHAPTER 26 Medical Treatment of Epilepsy in Resource-Poor Countries

Introduction

Diagnosing epilepsy in LAMICS

Clinical history

Electroencephalogram

Neuroimaging

Blood investigations

Antiepileptic drug monitoring

Summary – the role of investigation

Treating epilepsy in LAMICs

Drug treatment of epilepsy

Stigmata of epilepsy in LAMICs

Non-pharmacological care of epilepsy

Epilepsy service organization in LAMICS

References

SECTION III Antiepileptic Drugs

CHAPTER 27 Introduction to the Choice of Antiepileptic Drugs

Spectrum of efficacy in relation to seizure types and epilepsy syndromes

Magnitude of efficacy in specific seizure types

Focal seizures

Generalized seizures

Adverse effect profile

Drug interaction potential

Impact on comorbidities

Other medication-related factors

Mechanisms of action

Availability of appropriate formulations

Dose escalation requirements

Monitoring requirements

Cost of treatment

Ease of use

Old or new drugs?

Approved versus off-label use

Importance of patient-related factors

Seizure types and epilepsy syndrome

Aetiology of epilepsy

Electroencephalographic features

Genotypes

Age and gender

Comorbidities and co-medications

Other patient-related factors

Conclusions

References

CHAPTER 28 Acetazolamide

Introduction

Chemistry

Mechanism of action and activity in animal models

Pharmacokinetics

Absorption

Distribution

Elimination

Drug interactions

Serum level monitoring

Efficacy

General overview of results of clinical trials

Absence seizures

Myoclonic seizures

Generalized tonic–clonic seizures

Focal seizures

Tolerance

Adverse effects

Idiosyncratic reactions

Common non-idiosyncratic adverse effects

Other adverse effects

Place in current therapy

Usefulness and limitations

Dosing recommendations

Precautions and contraindications

References

CHAPTER 29 Adrenocorticotropic Hormone and Corticosteroids

Introduction

Chemistry

Mechanisms of action

Pharmacokinetics

ACTH

Corticosteroids

Drug interactions

Serum level monitoring

Efficacy

Infantile spasms

Other epilepsy syndromes

Adverse effects

Current place in therapy

References

CHAPTER 30 Benzodiazepines Used in the Treatment of Epilepsy

Introduction

Chemistry

Mechanisms of action

Pharmacokinetics

Absorption

Distribution

Elimination

Drug interactions

Serum level monitoring

Efficacy

Clobazam

Clonazepam

Clorazepate

Diazepam

Lorazepam

Midazolam

Nitrazepam

Adverse effects

Clobazam

Clonazepam

Clorazepate

Diazepam

Lorazepam

Midazolam

Nitrazepam

Place of benzodiazepines in current therapy

Chronic epilepsy treatment

Emergency treatment

References

CHAPTER 31 Brivaracetam

Introduction

Chemistry

Pharmacology

Activity in experimental models of seizures and epilepsy

Evidence of activity in non-epilepsy indications

Mechanisms of action

Toxicology data

Studies conducted with the parent drug

Studies conducted with the inactive hydroxy acid metabolite

Pharmacokinetics

Absorption

Distribution

Elimination

Pharmacokinetics in special populations

Drug interactions

Effect of other drugs on brivaracetam pharmacokinetics

Effect of brivaracetam on the pharmacokinetics of other antiepileptic drugs

Effect of brivaracetam on the pharmacokinetics of other drugs

Serum level monitoring

Efficacy

Proof-of-concept study in photosensitive epilepsy

Randomized, placebo-controlled, adjunctive-therapy studies in uncontrolled focal epilepsy

Randomized flexible-dose adjunctive-therapy study in patients with focal or primarily generalized seizures

Other studies in patients with epilepsy

Studies in other indications

Adverse events

Place in current therapy

Acknowledgements

References

CHAPTER 32 Carbamazepine

Introduction

Chemistry

Pharmacology

Pharmacokinetics

Absorption

Distribution

Elimination

Relationship between serum concentration and dosage

Pharmacokinetics in special groups

Drug interactions

Interactions between carbamazepine and other AEDs

Interactions between carbamazepine and other drugs

Serum level monitoring

Efficacy

Focal seizures

Primary generalized tonic–clonic seizures

Epilepsy syndromes

Combination therapy

Efficacy in non-epilepsy conditions

Adverse effects

CNS effects

Cutaneous hypersensitivity reactions (including cutaneous reactions associated with systemic symptoms)

Haematological adverse effects

Hepatotoxicity

Endocrinological effects

Antidiuretic hormone and hyponatraemia

Thyroid hormones

Bone metabolism

Cardiac adverse effects

Teratogenic effects and postnatal development

Other adverse effects

Adverse effects and quality of life studies

Overdose

Place in current therapy

Mode of use

Dose and titration rates

Laboratory monitoring

References

CHAPTER 33 Eslicarbazepine Acetate

Introduction

Chemistry

Activity profile in animal models and mechanisms of action

Mechanisms of action and activity in experimental models [6]

Toxicology

Pharmacokinetics

Pharmacokinetics in healthy subjects and patients with epilepsy

Pharmacokinetics in special populations

Drug interactions

Effect of other drugs on ESL pharmacokinetics

Effect of ESL on other drugs pharmacokinetics

Serum drug level monitoring and pharmacokinetic–pharmacodynamic relationships

Efficacy

Randomized placebo-controlled trials

Open-label extensions studies

Adverse effects

Adverse events in adults with epilepsy

Adverse events in children with epilepsy

Other safety parameters

Place in current therapy

Acknowledgments

References

CHAPTER 34 Ethosuximide

Introduction

Chemistry

Pharmacology

Activity in experimental models of seizures and epilepsy

Activity in experimental models relevant to other indications

Mechanisms of action

Pharmacokinetics

Absorption

Distribution

Elimination

Pharmacokinetics in special populations

Drug interactions

Effects of other drugs on ethosuximide pharmacokinetics

Effect of ethosuximide on the pharmacokinetics of other drugs

Pharmacodynamic drug interactions

Serum level monitoring

Efficacy

Initial studies in patients with absence seizures

Double-blind comparison with valproic acid and lamotrigine in childhood absence epilepsy

Efficacy in specific syndromes other than childhood absence epilepsy

Adverse effects

Gastrointestinal effects

Neurological, behavioural and psychiatric effects

Other adverse effects, including idiosyncratic reactions

Manifestations of overdose

Place in current therapy

Indications

Dose and titration rates

Laboratory monitoring

References

CHAPTER 35 Felbamate

Introduction

Chemistry

Pharmacology

Activity in experimental models of seizures and epilepsy

Mechanisms of action

Pharmacokinetics

Absorption

Distribution

Elimination

Pharmacokinetics in special populations

Drug interactions

Serum level monitoring

Efficacy

Adverse effects

Place in current therapy

Update on risk–benefit ratio and indications

Dosing recommendations

Laboratory and clinical monitoring

Acknowledgement

References

CHAPTER 36 Gabapentin

Introduction

Chemistry

Pharmacology

Activity in experimental models

Mechanisms of action

Pharmacokinetics

Absorption

Distribution

Elimination

Pharmacokinetics in special groups

Drug interactions

Serum level monitoring

Efficacy

Adjunctive therapy in epilepsy

Monotherapy in epilepsy

Gabapentin in non-epilepsy indications

Adverse effects

General overview of the most common adverse effects

Serious, rare and long-term effects

Abuse and overdose

Use in pregnancy

Place in current therapy

Main indications

Administration and dosage

Acknowledgement

References

CHAPTER 37 Lacosamide

Introduction

Chemistry

Pharmacology

Activity profile in experimental models of seizures and epilepsy

Activity in models relevant to non-epilepsy indications

Mechanisms of action

Pharmacokinetics

Key pharmacokinetic features

Pharmacokinetics in special populations

Drug interactions

Effect of other drugs on the pharmacokinetics of lacosamide

Effects of lacosamide on the pharmacokinetics of other drugs

Pharmacodynamic drug interactions

Serum level monitoring

Efficacy

Placebo-controlled double-blind trials in focal seizures

Conversion to monotherapy double-blind trial in focal seizures

Open-label trials in patients with (mostly) focal seizures

Preliminary experience in the treatment of status epilepticus

Adverse effects

Most common adverse events reported in controlled trials

Special safety issues

Intravenous formulation

Place in current therapy

References

CHAPTER 38 Lamotrigine

Introduction

Chemistry

Pharmacology

Activity in animal models of seizures and epilepsy

Activity in other experimental models

Mechanism of action

Pharmacokinetics

Absorption

Distribution

Elimination

Factors (other than age and co-medication) that affect lamotrigine pharmacokinetics

Drug interactions

Effects of co-administered drugs on lamotrigine pharmacokinetics

Effects of lamotrigine on the pharmacokinetics of co-administered drugs

Pharmacodynamic interactions

Serum level monitoring

Efficacy

Adjunctive therapy studies in focal epilepsy

Conversion to monotherapy studies in refractory epilepsies

Monotherapy studies in newly diagnosed, predominantly focal, epilepsy

Adjunctive therapy studies in generalized epilepsies

Monotherapy studies in newly diagnosed generalized epilepsies

Other studies

Quality of life assessments

Risk of seizure aggravation

Use in non-epilepsy indications

Adverse effects

Overview of the most common adverse effects

Cognitive and psychomotor effects

Neurological and behavioural effects

Neuroendocrine effects

Child development

Idiosyncratic effects

Sudden unexpected death in epilepsy

Teratogenicity

Lamotrigine overdose

Place in current therapy

References

CHAPTER 39 Levetiracetam

Introduction

Chemistry

Pharmacology

Activity in experimental models of seizures and epilepsy

Mechanisms of action

Pharmacokinetics

Absorption

Distribution

Elimination

Pharmacokinetics in special populations

Drug interactions

Effect of other drugs on levetiracetam pharmacokinetics

Effect of levetiracetam on the pharmacokinetics of other drugs

Serum level monitoring

Efficacy

Adjunctive therapy trials in adults with refractory focal seizures

Adjunctive therapy trials in children with refractory focal seizures

Monotherapy trials in adults with focal seizures

Adjunctive therapy trials in adults and children with refractory generalized epilepsies

Monotherapy trials in patients with childhood and juvenile absence epilepsy

Studies in patients with myoclonus

Studies in patients with neonatal seizures

Studies in adults and children with status epilepticus

Studies in the palliative care setting

Studies in patients with traumatic brain injury

Studies on patient’s functioning and health-related quality of life in adults with epilepsy

Studies in non-epilepsy indications

Adverse effects

Safety and tolerability profile from clinical trials in adults

Safety and tolerability profile from clinical studies in children

Review of the comparative tolerability profile in adults and children

Behavioural adverse effects

Seizure aggravation

Tolerance

Cardiac effects

Idiosyncratic reactions

Tolerability and safety of the intravenous formulation

Teratogenicity

Overdosage

Place in current therapy

Acknowledgement

References

CHAPTER 40 Oxcarbazepine

Introduction

Chemistry

Pharmacology and mechanism of action

Pharmacokinetic properties

Absorption

Distribution

Biotransformation and elimination

Pharmacokinetics in special groups

Drug interactions

Serum level monitoring

Efficacy

Double-blind trials in comparison with carbamazepine

Double-blind trials in comparison with other AEDs

Randomized open-label trials in comparison with otherAEDs in new-onset seizures

Short-term double-blind monotherapy trials in comparison with placebo or low-dose active control

Double-blind adjunctive-therapy trials in comparison with placebo or low-dose active control

Uncontrolled studies

Use in non-epilepsy indications

Adverse effects

Worsening of seizures and/or EEG features

Other central nervous system adverse effects

Gastrointestinal effects

Rash and serious idiosyncratic reactions

Hyponatraemia

Other systemic effects and special populations

Teratogenicity

Adverse effects, seizures and quality of life

Mode of use

Dose initiation

Conversion from carbamazepine

Maintenance treatment

Monitoring serum sodium

Withdrawal

Current place in therapy

References

CHAPTER 41 Perampanel

Introduction

Chemistry

Pharmacology

Pharmacokinetics

Drug interactions

Effects of other drugs on the pharmacokinetics of perampanel

Effect of perampanel on the pharmacokinetics of other drugs

Serum level monitoring

Efficacy

Randomized placebo-controlled adjunctive therapy studies in focal epilepsy

Extension open label studies and additional observational studies

Randomized placebo-controlled adjunctive therapy study in primary generalized tonic-clonic seizures

Adverse effects

Overview of the tolerability and safety profile

Psychiatric adverse events

Place in current therapy

References

CHAPTER 42 Phenobarbital, Primidone and Other Barbiturates

Introduction

Phenobarbital

Chemistry

Activity in animal models and mechanisms of action

Pharmacokinetics

Drug interactions

Serum level monitoring

Efficacy

Adverse effects

Place in current therapy

Primidone

Chemistry

Activity in animal models and mechanisms of action

Pharmacokinetics

Drug interactions

Serum level monitoring

Efficacy

Adverse effects

Overdose

Place in current therapy

Other barbiturates

Barbexaclone

Metharbital

Methylphenobarbital (or mephobarbital)

References

CHAPTER 43 Phenytoin

Introduction

Chemistry

Pharmacology

Anticonvulsant activity in experimental models

Mechanisms of action

Pharmacokinetics

Absorption

Distribution

Elimination

Drug interactions

Interactions affecting phenytoin absorption

Interactions affecting phenytoin distribution

Interactions altering phenytoin metabolism

Phenytoin affecting other substances

Serum level monitoring

Efficacy

Adverse effects

Effects on the nervous system

Effects on the skin

Effects on the gums

Effects on bone

Effects on lymphoid tissue

Effects on folates

Cardiovascular effects

Other effects

Teratogenicity

Place in current therapy

References

CHAPTER 44 Piracetam

Introduction

Chemistry and mechanism of action

Pharmacokinetics

Absorption

Distribution

Metabolism and excretion

Drug interactions

Serum level monitoring

Efficacy

Adverse effects

Place in current therapy

References

CHAPTER 45 Pregabalin

Introduction

Chemistry

Pharmacology

Pharmacokinetics

Absorption

Distribution and elimination

Pharmacokinetics in special groups

Drug interactions

Serum level monitoring

Efficacy

Double-blind adjunctive-therapy trials versus placebo in focal epilepsy

Double-blind adjunctive-therapy trials in focal epilepsy in comparison with other antiepileptic drugs

Open-label uncontrolled studies of adjunctive use in focal epilepsy

Preliminary uncontrolled studies of adjunctive use in pediatric epilepsies

Conversion to monotherapy in patients with refractory focal epilepsy

Double-blind randomized comparison with lamotrigine in newly diagnosed focal epilepsy

Controlled studies on epilepsy comorbidities

Adverse effects

Adverse events in double-blind adjunctive-therapy trials

Adverse events reported in long-term studies and in routine clinical use

Potential for abuse

Teratogenicity

Place in current therapy

References

CHAPTER 46 Retigabine

Introduction

Chemistry

Pharmacology

Activity in experimental models of seizures and epilepsy

Activity in experimental models relevant for non-epilepsy indications

Mechanisms of action

Toxicology data

Pharmacokinetics

Absorption

Distribution

Metabolism and elimination

Pharmacokinetics in special populations

Drug interactions

Effect of other drugs on retigabine pharmacokinetics

Effect of retigabine on pharmacokinetics of other drugs

Serum level monitoring

Clinical efficacy

Phase 2 studies

Phase 3 studies

Long-term open label extension trials

Studies in patients with other disorders

Adverse effects

Current place in therapy

References

CHAPTER 47 Rufinamide

Introduction

Chemistry

Pharmacology

Activity in experimental models of seizures and epilepsy

Mechanism of action

Pharmacokinetics

Absorption and bioavailability

Distribution

Elimination and metabolism

Pharmacokinetics in special populations

Drug interactions

Effect of other drugs on rufinamide pharmacokinetics

Effect of rufinamide on the pharmacokinetics of other drugs

Serum level monitoring

Efficacy

Monotherapy studies in patients with focal seizures

Adjunctive therapy studies in patients with focalseizures

Adjunctive therapy studies in patients with generaliz edepilepsies

Open-label studies in various epileptic syndromes

General overview of efficacy data in epilepsy

Studies in other indications

Adverse effects

Overall safety profile

Effect on cognitive functions

Current place in therapy

Acknowledgement

References

CHAPTER 48 Stiripentol

Introduction

Chemistry

Pharmacology

Pharmacokinetics

Drug interactions

Serum level monitoring

Efficacy

Adverse effects

Current place in therapy

References

CHAPTER 49 Tiagabine

Introduction

Chemistry

Pharmacology

Activity in animal models of seizures and epilepsy

Mechanism of action

Pharmacokinetics

Key pharmacokinetic features

Pharmacokinetics in special populations

Drug interactions

Serum level monitoring

Efficacy

Randomized trials in adults with focal epilepsy

Other studies in (predominantly) adult patients with focal epilepsy

Studies in children

Efficacy as monotherapy

Adverse effects

Most common CNS adverse effects

Other CNS adverse effects

Visual field investigations

Idiosyncratic reactions

Teratogenicity

Place in current therapy

References

CHAPTER 50 Topiramate

Introduction

Chemistry

Pharmacology

Pharmacokinetics

Overall pharmacokinetic features

Pharmacokinetics in special populations

Drug interactions

Serum level monitoring

Efficacy

Monotherapy

Adjunctive therapy

Studies in other paediatric epilepsy syndromes

Special epilepsy populations

Elderly populations

Non-epilepsy indications

Adverse effects

Central nervous system adverse effects

Metabolic acidosis, bone effects and renal calculi

Weight loss

Ophthalmological adverse effects

Hepatic adverse effects

Adverse effects in children

Adverse effects during pregnancy/puerperium

Place in current therapy

References

CHAPTER 51 Valproate

Introduction

Chemistry

Pharmacology

Activity in animal models of seizures and epilepsy

Mechanisms of action

Pharmacokinetics

Rate and extent of absorption

Distribution

Elimination

Pharmacokinetics in special groups

Drug interactions

Effect of other drugs on valproic acid pharmacokinetics

Effect of valproic acid on the pharmacokinetics of other drugs

Pharmacodynamic drug interactions

Serum level monitoring

Efficacy

Absence seizures

Generalized tonic–clonic seizures

Myoclonic seizures

Infantile spasms and Lennox–Gastaut syndrome

Focal seizures

Status epilepticus

Other seizure disorders

Non-epilepsy indications

Adverse effects

Teratogenic effects (including effects on postnatal cognitive development after prenatal exposure)

Neurological adverse effects

Gastrointestinal adverse effects, including weight gain

Hepatic and pancreatic toxicity

Haematological adverse effects

Metabolic, endocrine and reproductive disorders

Miscellaneous adverse effects

Place in current therapy

Acknowledgement

References

CHAPTER 52 Vigabatrin

Introduction

Chemistry

Pharmacology and toxicology

Activity in experimental models of seizures and epilepsy

Animal toxicology data

Mechanism of action

Pharmacokinetics

Adults

Infants and children

Disease states

Drug interactions

Serum level monitoring

Efficacy

Infantile spasms (West syndrome)

Focal seizures

Generalized epilepsies

Adverse effects

Visual field constriction

MRI abnormalities

Place in current therapy

References

CHAPTER 53 Zonisamide

Introduction

Chemistry

Pharmacology

Activity in animal models

Mechanisms of action

Pharmacokinetics

Pharmacokinetics in special groups

Drug interactions

Serum level monitoring

Efficacy

Randomized controlled trials

Other studies

Adverse effects

Common adverse effects

Less common but potentially serious adverse effects

Teratogenicity

Place in current therapy

Acknowledgement

References

CHAPTER 54 Other Less Commonly Used Antiepileptic Drugs

Introduction

Bromide

Chemistry

Mechanisms of action and activity in experimental models of seizures and epilepsy

Clinical pharmacokinetics

Drug interactions

Clinical efficacy

Adverse effects

Place in current therapy

Lidocaine

Chemistry

Mechanism of action

Clinical pharmacokinetics

Drug interactions

Clinical efficacy

Adverse effects

Place in current therapy

Methsuximide

Chemistry

Mechanism of action

Clinical pharmacokinetics

Drug interactions

Clinical efficacy

Adverse effects

Place in current therapy

Paraldehyde

Chemistry

Mechanism of action

Clinical pharmacokinetics

Drug interactions

Clinical efficacy

Adverse effects

Place in current therapy

Sulthiame

Chemistry

Mechanism of action

Clinical pharmacokinetics

Drug interactions

Clinical efficacy

Adverse effects

Place in current therapy

Acknowledgement

References

CHAPTER 55 Drugs in Clinical Development

Introduction

Allopregnanolone (SAGE-547 Injection)

Chemistry

Activity in animal models and mechanism of action

Pharmacokinetics

Drug interactions

Efficacy

Adverse effects

Cannabinoids

Chemistry

Activity in animal models and mechanism of action

Pharmacokinetics

Drug interactions

Efficacy

Adverse effects

2-Deoxy-d-glucose

Activity in animal models and mechanism of action

Pharmacokinetics and drug interactions

Efficacy and adverse effects

Everolimus

Chemistry

Activity in animal models and mechanism of action

Pharmacokinetics

Drug interactions

Efficacy

Adverse effects

Ganaxolone

Activity in animal models and mechanism of action

Pharmacokinetics

Drug interactions

Efficacy

Adverse effects

Huperzine A (INS-001)

Activity in animal models and mechanism of action

Pharmacokinetics

Drug interactions

Efficacy and adverse effects

NAX 810-2

Activity in animal models and mechanism of action

Preclinical pharmacokinetics and drug interactions

Pitolisant

Activity in animal models and mechanism of action

Pharmacokinetics and drug interactions

Efficacy

Adverse effects

PRX-00023 (naluzotan)

Activity in animal models and mechanism of action

Pharmacokinetics

Drug interactions

Efficacy and adverse effects

Selurampanel

Activity in animal models

Pharmacokinetics and drug interactions

Efficacy and adverse effects

Tonabersat

Activity in animal models and mechanism of action

Pharmacokinetics

Drug interactions

Efficacy and adverse effects

YKP3089

Activity in animal models and mechanism of action

Pharmacokinetics

Efficacy

Adverse effects

Precision therapeutics and the promise of genomics

Conclusions

References

SECTION IV Presurgical assessment and epilepsy surgery

CHAPTER 56 Overview of surgical treatment for epilepsy

Introduction

Historical perspective

Epileptic disorders

The progressive nature of epilepsy

The concept of surgically remediable epilepsies

Types of surgical treatment for epilepsy

Standardized resections

Tailored resections

Disconnection surgery

Stereotactic ablative surgery and stimulation

Presurgical evaluation

Definition of terms

Candidate selection

Strategy for presurgical evaluation

Outcome

Outcome with respect to seizures

Quality of life, cognitive and social outcomes

Surgical complications

Acknowledgements

References

CHAPTER 57 Scalp EEG in the epilepsy surgery evaluation

Introduction

Technical considerations

Electrode locations

Types of scalp EEG recording

Interictal EEG

Unilateral focal temporal interictal epileptiform discharges

Bilateral independent interictal epileptiform discharges

Extratemporal interictal epileptiform discharges

Interictal non-epileptiform changes

Interictal epileptiform discharges that may preclude resective epilepsy surgery

Ictal scalp EEG

Ictal patterns

Postictal EEG changes

Inter-rater reliability of ictal EEG

Limitations of scalp ictal EEG

False lateralization: mesial temporal lobe epilepsy

False lateralization: lesional epilepsy

Late-appearing scalp ictal EEG

Bilateral independent temporal ictal EEG

Scalp ictal EEG in non-lesional MRI

Ictal behaviour: the role of video

Psychogenic non-epileptic seizures

Seizure activation during video-EEG monitoring

Antiepileptic drug withdrawal

Sleep deprivation

Hyperventilation

Photic stimulation

Potential complications

Conclusion

References

CHAPTER 58 Invasive EEG in presurgical evaluation of epilepsy

Introduction

Indications for intracranial EEG monitoring

Non-lesional extratemporal epilepsies

Neocortical temporal lobe epilepsy

Lesional epilepsy

Dual pathology

Mesial temporal lobe epilepsy

Special situations in MTLE often requiring invasive monitoring

Invasive monitoring and responsive neurostimulation

Identifying networks on intracranial EEG

Technical aspects in intracranial EEG

Specific intracranial electrode techniques

Technical aspects

Advantages

Disadvantages

Interpretation of invasive EEG recordings

Recording sessions

General comments

Background

Filter settings

Non-epileptiform findings

Interictal EEG

Ictal EEG

Functional cortical mapping and advanced electrophysiological techniques

General comments

Electrical cortical stimulation

Electrocorticography-based gamma mapping

Corticocortical evoked potentials

Electrocorticography (ECoG)

High-frequency oscillations

Ictal onset baseline shifts and infraslow activity (ISA)

References

CHAPTER 59 MEG in epilepsy surgery evaluation

Introduction

Method

Applications of magnetic source imaging in epileptic patients

Evoked activity

Spontaneous epileptic activity

MEG in presurgical evaluation

Acknowledgement

References

CHAPTER 60 MRI in presurgical evaluation

Introduction

When to use MR imaging and where to perform it

General MRI protocol

Common epileptogenic lesions

Class A: easy candidates

Class B: moderately difficult cases

Class C: very difficult surgical cases

Class D: palliative surgery candidates

Class E: non-surgical candidates

Specific MRI protocols

Diffusion-based imaging and tractography

Functional MRI

MR spectroscopy

Postprocessing

References

CHAPTER 61 PET and SPECT in presurgical evaluation of epilepsy

PET and SPECT in presurgical evaluation of patients with refractory partial epilepsy

PET

Methodology

FDG-PET and ictal onset zone in refractory focal epilepsy

FDG-PET hypometabolism in areas remote from the ictal onset zone

Clinical correlations of resolution of FDG hypometabolism in areas remote from the ictal onset zone after seizure remission

AMT-PET in refractory focal epilepsy

SPECT

Methodology

Ictal SPECT in presurgical evaluation

Multimodality imaging

References

CHAPTER 62 Special neurophysiological techniques

Introduction

Source imaging of interictal spikes: methodology and validation

Equivalent current dipole modelling of interictal spikes

Imaging of the spiking volume

Distributed sources models

Volumetric imaging of epileptic spikes

Accuracy of spiking volume localization

Limitation of spiking volume imaging

Validation studies of interictal spikes source imaging

Intracranial recordings

Source imaging of interictal spikes and MRI lesions

Source imaging of interictal spikes and metabolic abnormalities

Clinical relevance of spikes source imaging in presurgical evaluation of epilepsy

Does source imaging help to lateralize the focus in TLE with bilateral interictal spikes?

Is spike source imaging helpful to predict epilepsy surgery outcome?

Diagnostic yield of magnetic source imaging of spikes in MRI-negative patients

Is spike source imaging helpful to guide intracranial recordings?

The modelling of ictal discharges

Functional connectivity studies

Overview of the methods aimed at characterizing epileptic networks

What have we learned from studying epileptogenic networks?

Outstanding questions

Conclusions

References

CHAPTER 63 Neuropsychological testing in presurgical evaluation

Introduction

Determination of site of dysfunction

Potential pitfalls in presurgical evaluation

Temporal neocortex

Medial temporal lobe function: memory assessment

Traditional memory tests

Matched verbal and non-verbal learning and memory tests

Other verbal learning and memory tests

Non-verbal learning and memory tests

Accelerated long-term forgetting

Evaluation of frontal lobe function

Complex problem solving: Wisconsin Card Sorting Test

Generation of novel responses: word and design fluency

Susceptibility to interference (cognitive inhibition)

Planning: the Tower of London test

Motor tasks: strength, dexterity and coordination

Parietal lobes

Occipital lobes

Computer-assisted batteries

Summary

Intracarotid anaesthetic procedures

Description of the procedure

Interpretation of intracarotid anaesthetic procedure results: language dominance

Interpretation of intracarotid anaesthetic procedure results: memory

Controversial issues in the IAP

Non-invasive lateralization procedures

Conclusion

Acknowledgments

References

CHAPTER 64 Presurgical psychiatric evaluation

Introduction

The case for a presurgical psychiatric evaluation in every surgical candidate

High prevalence of psychiatric comorbidities in surgical candidates: can it get in the way of the presurgical evaluation?

Postsurgical psychiatric complications

Epilepsy surgery has a positive impact on presurgical psychiatric disorders

Anxiety and depressive disorders

Obsessive compulsive disorders

Psychotic disorders

Impact of presurgical psychiatric history on postsurgical psychosocial outcome

Gainful employment

Family dynamics

Impact of presurgical psychiatric illness on postsurgical seizure outcome

Psychiatric aspects of paediatric epilepsy surgery

Presurgical psychiatric protocols

The obstacles to perform presurgical psychiatric evaluation

Can epileptologists and neuropsychologists rely on a patient’s self-report of past or concurrent psychiatric history?

Suggested protocols

Presurgical evaluations in research

Disclosure of postsurgical psychiatric complications

Conclusions and future directions

References

CHAPTER 65 Mesial temporal lobe surgery and other lobar resections

Introduction

Current practices of medial temporal lobe surgery

Extratemporal resections and temporal lobe resections outside the medial temporal lobe

Frontal lobe surgery

Occipital lobe surgery

Parietal lobe surgery

Insular epilepsy

Multilobar resections

Lobar epilepsy surgery evaluation

Positron emission tomography

Single photon emission computed tomography

Other magnetic resonance imaging methods: magnetic resonance spectroscopy, diffusion tensor imaging, high field MRI

Magnetoencephalography or magnetic source imaging

Functional magnetic resonance imaging

Neurocognitive evaluation

‘Wada test’ in select cases

Transcranial magnetic stimulation

Intracranial studies

Epilepsy surgery outcomes

Epilepsy surgery complications

New therapies and future directions

Conclusion

Acknowledgement

References

CHAPTER 66 Resective surgery of neoplasms

Introduction

Focal or localization-related epilepsy

Mechanism of epileptogenesis associated with structural mass lesions

Pathology: neoplastic lesions

Brain tumour as a cause of chronic epilepsy

Gangliogliomas

Dysembryoplastic neuroepithelial tumours

Presurgical evaluation

Duration of epilepsy

Clinical seizure characteristics

History and examination

Age at onset of seizures

Routine electroencephalogram recording

Long-term video-electroencephalogram monitoring

Neuroimaging

Neuropsychological assessment

Intracranial electroencephalogram monitoring

Diffusion weighted imaging and diffusion tensor imaging

Magnetic resonance spectroscopy

Functional magnetic resonance imaging

Single photon emission computed tomography

Positron emission tomography

Invasive cortical mapping

Electrocorticography

Treatment

Indications for surgery

Patients with medically intractable epilepsy

Surgical methods

Outcome

Seizure outcome

Pathology

Completeness of lesion resection

Completeness of epileptic focus resection

Functional outcome

Psychological outcome

References

CHAPTER 67 Resective surgery of vascular and infective lesions for epilepsy

Introduction

Vascular lesions

Arteriovenous malformations

Cavernous haemangioma (cavernoma)

Intracranial aneurysms

Venous malformations

Capillary telangectasias

Infective lesions

Pyogenic cerebral abscess

Neurocysticercosis

Cerebral tuberculoma

Hydatid disease

References

CHAPTER 68 Surgery of developmental anomalies causing epilepsy

Introduction

Epidemiology

Selection of surgical candidates

Presurgical evaluation: to determine the extent of the epileptogenic zone

History, physical examination and seizure semiology

Role of imaging

Role of electrophysiology

Surgical outcome

Surgical outcome in grey matter heterotopia

Surgical outcome in lissencephaly

Surgical outcome in hemimegalencephaly

Surgical outcome in polymicrogyria and schizencephaly

Surgical outcome in porencephaly

Surgical outcome in focal cortical dysplasia

Conclusion

References

CHAPTER 69 Hemispheric operations for epilepsy

Introduction

Indications

Diagnostic evaluations

Special considerations in Rasmussen encephalitis

Evolution of the surgical techniques

Functional hemispherectomy

Vertical parasagittal hemispherotomy

Seizure outcome

Postoperative seizures

Early and late complications

Conclusion

References

CHAPTER 70 Corpus callosum operations

Introduction

Indications

Surgical technique

Conclusion

References

CHAPTER 71 Hypothalamic hamartoma

Introduction

Clinical features

Gelastic seizures

Intrinsic epileptogenesis

Other seizure types

Secondary epileptogenesis

Cognition and behaviour

Aetiology

Pallister–Hall syndrome

Somatic mutation of GLI3

Treatment

Antiepilepsy drugs

Vagus nerve stimulation

Ketogenic diet

Corpus callosotomy

Deep brain stimulation

Surgical treatment

Hypothalamic hamartoma classification and surgical anatomy

Pterional approach to hypothalamic hamartoma lesions

Transcallosal resection

Endoscopic resection and disconnection

Interstitial radiosurgery

Stereotactic radiosurgery (gamma knife radiosurgery)

Stereotactic thermoablation

Staged procedures for giant hypothalamic hamartoma

Reoperation after subtotal surgical treatment

References

CHAPTER 72 Multiple subpial transection

Introduction

Planning for multiple subpial transection

Cortical surgical anatomy

Operative procedure

Transections

Outcome

Indications for multiple subpial transection

Mesial temporal lobe epilepsy

Landau–Kleffner syndrome

Multifocal epilepsy

Super-refractory status epilepticus

Surgical morbidity

Acute postoperative morbidity

Chronic morbidity

Conclusions

Acknowledgment

References

CHAPTER 73 Awake surgery for epilepsy

Introduction

Preoperative and intraoperative functional assessments

Anaesthesia for awake craniotomy

Indications for awake tailored resection for medically refractory epilepsy versus anatomically guided resections

Technical aspects of temporal lobe resection tailored to intraoperative recording and stimulation

Preoperative preparation

Anaesthetic technique

Premedication and positioning

Local anaesthesia

Craniotomy

Intraoperative electrocorticography

Electrode placement and ECoG#1

Stimulation parameters

Motor and sensory mapping

Language mapping

Lateral cortical resection, ECoG#2 and hippocampal removal

References

CHAPTER 74 Epilepsy surgery in children

Introduction

Therapy-resistant epilepsy and the rationale for early seizure control

Which children are surgical candidates?

Risks of uncontrolled epilepsy

Why is it critical to control seizures as soon as possible in infants and children even if that means resective surgery?

Symptomatic substrates in surgically treated children

Pre-evaluation in paediatric epilepsy surgery

Surgical interventions for epilepsy in children

Anaesthesia and perioperative considerations

Outcomes in paediatric epilepsy surgery: seizure remission and cognitive/psychosocial results

Conclusion

Acknowledgement

References

CHAPTER 75 Complications of epilepsy surgery

Introduction

Complications of invasive procedures for presurgical assessment

Carotid amytal test

Invasive procedures for placing electrodes

Minor invasive techniques

Major invasive techniques

Summary

Therapeutic procedures

Introduction

Intracranial resective surgery

Reoperation

Functional surgery

Risk management

Conclusion

References

CHAPTER 76 Anaesthesia for epilepsy surgery

Overview

Preanaesthetic evaluation for epilepsy surgery

Anaesthesia and antiepileptic therapy

Anticonvulsant and proconvulsant effects of anaesthetics

Anaesthesia and intraoperative electrocorticography

Anaesthesia for diagnostic procedures prior to epilepsy surgery

General anaesthesia for epilepsy surgery

Anaesthesia for epilepsy surgery with awake intraoperative functional brain mapping

Anaesthesia for vagal nerve stimulator placement

Anaesthesia for epilepsy surgery in infants and children

Anaesthesia for stereotactic MRI-guided laser ablation of epileptogenic foci

Conclusion

References

CHAPTER 77 Vagus and trigeminal nerve stimulation

Introduction

Practical aspects of vagus nerve stimulation

Actions of vagus nerve stimulation and efficacy in animal models of epilepsy

Anatomy

Mechanism(s) of action of vagus nerve stimulation

Animal studies of vagus nerve stimulation

Efficacy studies of vagus nerve stimulation

The E03 and E05 studies

Long-term efficacy

Other efficacy studies

Safety and tolerability of vagus nerve stimulation

The E03 and E05 studies

Long-term safety and tolerability

Clinical use of vagus nerve stimulation for epilepsy

Emerging technologies for vagus nerve stimulation

Trigeminal nerve stimulation for epilepsy

Conclusion

References

CHAPTER 78 Brain stimulation for epilepsy

Introduction

Concept and requirements for programmed or chronic stimulation

Concept of responsive neurostimulation

Previous studies of chronic or programmed central neurostimulation

Stimulation of the cerebellum

Chronic stimulation of the thalamus

Chronic stimulation of the subthalamic region

Chronic stimulation of the hippocampus

Clinical studies of responsive neurostimulation

Unresolved questions

Conclusion

References

CHAPTER 79 Non-resective approaches for medically intractable epilepsy

Introduction

Preclinical evidence

Mesial temporal lobe epilepsy

Hypothalamic hamartoma-associated gelastic epilepsy

Arteriovenous malformations

Cavernous malformations

Long-term radiosurgical complications

Antiepileptic mechanisms of radiosurgery

Laser ablation

Focused ultrasound

References

CHAPTER 80 Future focal treatment approaches to epilepsy

Introduction

Focal treatment principles

Focal drug delivery

The epileptic focus

The trigger site

Propagation pathways

Other focal drug delivery approaches

Seizure-stimulated drug release

Focal cooling

Genetic approaches to treatment

Viral vectors

Neuronal grafting

Transplantation of genetically engineered cells

New therapeutic approaches for focal epilepsy

Optogenetics

Chemical genetic attenuation

Conclusion

Acknowledgements

References

CHAPTER 81 Epilepsy surgery in countries with limited resources

Introduction

The need for epilepsy surgery in countries with limited resources

Challenges to implement epilepsy surgery programmes

Simplification of presurgical evaluation protocols in surgically remediable epilepsies: conceptual advances and the impact on epilepsy surgery in countries with limited resources

Patients with MTLE-HS can be evaluated non-invasively, and often without the need for ictal recordings

Lesionectomy plus electrocorticography-guided corticectomy can successfully treat most medically refractory epilepsies due to neocortical and limbic tumours

Surgical decisions in children with severe epilepsies associated with large unilateral lesions are usually straightforward

The stepwise approach and the minimal requirements for epilepsy surgery

Present state of epilepsy surgery in resource-limited countries

The Brazilian experience

Epilepsy surgery in other countries in Latin America

Epilepsy surgery in resource-limited countries in Asia

Epilepsy surgery in Africa

Surgical treatment gap

Temporal trends in epilepsy surgery in resource-limited countries

Surgical outcome in resource-limited countries

Is epilepsy surgery cost-effective in resource-limited countries?

Are minimum requirements for performing epilepsy surgery changing?

A final word on education, early identification of refractory seizures and the value of epilepsy surgery

Conclusions

References

Index

EULA