Evolving

concepts in
Epilepsy
INTRODUCTION &
EPIDEMIOLOGY
INTRODUCTION

• Epilepsy is a neurological disorder that is characterized by an enduring

predisposition to generate epileptic seizures and is associated cognitive,
psychological and social consequences (Fischer et al, 2017)
• An epileptic seizure is a transient behavioural change caused by abnormal excessive
or synchronous neuronal activity in the brain, and is associated with objective signs
or subjective symptoms such as loss of awareness, stiffening, jerking, a sensation
that rises from the abdomen to the chest, a smell of burnt rubber or déjà vu
IMPACT OF EPILEPSY ON
QUALITY OF LIFE
• Epilepsy affects all age
• No sex difference, however it is often underreported among females.
• It is a common and one of the most disabling neurological disorders.
• Epilepsy can substantially impair quality of life owing to seizures, comorbid mood
and psychiatric disorders, cognitive deficits and adverse effects of medications.
IMPACT OF EPILEPSY ON
QUALITY OF LIFE
• Seizures can be fatal owing to direct effects on autonomic and arousal functions
or owing to indirect effects such as drowning and other accidents.
• The accurate diagnosis of seizures is essential as misdiagnosis and
– inaccurate medication often have severe consequences.
• Although many patients have seizure control using a single medication, others
require multiple medications, resective surgery, neuromodulation devices or dietary
therapies. Also or clinical trials of newASDs
IMPACT OF EPILEPSY ON
QUALITY OF LIFE
• Epilepsy can be a significant burden for patients and caregivers.
• Adverse effects (by the condition and the medications) contribute to
– decreased quality of life.
• One-third of patients will continue to have uncontrolled seizures.

• Children and adolescents who are trying to be socially accepted have

– increased difficulty e.g.when their AED cause sedation
IMPACT OF EPILEPSY ON
QUALITY OF LIFE
• There have been different moves to reduce stigma associated with
– epilepsy
• For example, changing the nomenclature: It is strongly encouraged to
– discontinue the use of the term epileptic to reduce stigma;
• however, antiepileptic drug (AED) remains the terminology used in the literature;
however, newer literatures are beginning to use the term “Anti- seizure drugs”
(ASD)
IMPACT OF EPILEPSY ON
QUALITY OF LIFE
• For many patients, seizures can remit; however some might relapse after
– remission.
• Epilepsy is considered resolved when
• an individual is seizure free and older than the applicable age for an
– age-dependent epilepsy syndrome, or,
• when the person has remained seizure free for ≥10 years with no anti-
seizure medication for the past 5 years
IMPACT OF EPILEPSY ON
QUALITY OF LIFE
• The loss of driving privileges
• Social stigma
• Employment difficulties
• Loss of marriage, and other relationships
• Wrong diagnosis of epilepsy (common) leads to the improper use of anti- seizure
medications leading to anti-seizure-drug-associated adverse effects, including
inducing further seizures
EPIDEMIOLOGY
EPIDEMIOLOGY

• Almost 10% of people will experience a seizure during their lives.

• Epilepsy is the third leading contributor to the global burden of disease
– for neurological disorders and affects 65 million people worldwide.
• the prevalence of epilepsy is 6.4 cases per 1,000 persons and the annual incidence is
67.8 cases per 100,000 person-years
• Both prevalence and incidence are higher in low-income and middle- income
countries (LMICs) than in high-income countries, however underreported due
to stigma associated, mostly among women.
EPIDEMIOLOGY

• The incidence of epilepsy is bimodal: highest in younger age groups (for

example, in infancy and early childhood) and in older age groups (for example,
more than 50–60 years of age).

• Whereas the prevalence tends to be lowest in infants and children,

– increases in early adulthood – midlife and decreases later in life.
• The higher prevalence of Epilepsy in LMICs is believed to be partly due to a higher
frequency of traffic accidents, birth injuries and neuroinfectious disorders (such as
neurocysticercosis) that can cause epilepsy in LMICs
Incidence of epilepsy by age—composite of 12 studies in developed countries, 1988–2005.. SOURCE:
Thurman, 2011. https://www.nap.edu/read/13379/chapter/3#26
estimated number of patients in Scotland consulting a GP or practice nurse at least once in the financial year 2012/13.
https://www.isdscotland.org/Health-topics/General-practice/Gp-consultations/Health-Conditions/Epilepsy/index.asp
AETIOLOGY
PRECIPITA N TS

• Alcohol withdrawal • Metabolic abnormalities

• Fever • Photosensitivity and auditory
• Head injury and surgery – stimuli
• Sleep deprivation
• Infections
• Stress
• Drugs
CAUSES OF EPILEPSY

• Structural: stroke and brain tumours

• Genetic: SCN1A-related epilepsies),

• Infectious: bacterial or viral brain infections

• Metabolic: facilitated glucose transporter member 1 (GLUT1) deficiency
• Immune: multiple sclerosis and autoimmune encephalitis
• Unknown aetiologies
CAUSES OF EPILEPSY…

– STRUCTURAL – GENETIC OR PRESUMED GENETIC

• Neurotrauma – Multiple • Tuberous sclerosis complex –
Tuberous sclerosis complex
• De novo status epilepticus – TLE
• Spontaneous mutations – Absence epilepsy
• Stroke – Multiple
• Induced monogenic mutations – Multiple
• Blood–brain barrier damage – Multiple
• Developmental epileptic encephalopathies
• Cortical dysplasia – Multiple –
• Glioblastoma - Multiple – Infantile spasms, Dravet syndrome
• Developmental epileptic encephalopathies
–
– infantile spasm,multiple
CAUSES OF EPILEPSY…

• Other causes include primary CNS dysfunction or underlying metabolic

– derangement or systemic diseases
• Common causes:
• In children, congenital and genetic causes

• In young adult, tumours, alcohol anddrugs

• In elderly, cerebrovascular diseases
CAUSES ACCORDING TO AGE

• Neonates
• Perinatal hypoxia and ischaemia
• Intracranial haemorrhage/trauma
• Acute CNS infection
• Metabolic disturbance (hypo – glycaemia, calcaemia and magnesaemia;
pyridoxine deficiency)
• Drug withdrawal
• Developmental disorders
• Genetic disorders
CAUSES ACCORDING TO AGE

• >1 month to <12yrs

• Febrile seizures
• Genetic disorders
• CNS infection
• Developmental disorders
• Trauma
• Idiopathic
CAUSES ACCORDING TO AGE

• Adolescents (12-18yrs)
• Trauma
• Genetic disorders
• Infection
• Brain tumours
• Illicit drugs
• Idiopathic
CAUSES ACCORDING TO AGE

• 18-35yrs
• Trauma
• Alcohol withdrawal
• Illicit drug use
• Brain tumour
• Idiopathic
MORTALITY
EPILEPSY C A N BE LETHAL DUE TO THE DIRECT & INDIRECT EFFECTS
OF SEIZURES

• THE DIRECT EFFECTS:e.g. • THE INDIRECT EFFECTS:e.g.

• sudden unexpected death in epilepsy
• status epilepticus
• Accidents such as :drowning motor
vehicle accidents, falls and burns
• aspiration pneumonia,
• suicide 5-25x more in epileptics
• adverse effects of ASDs or
psychiatric drugs, such as obesity
and cardiovascular side effects
PATHOPHYSIOLOGY
PATHOPHYSIOLOGY

• The spread of electrical activity between cortical neurones is normally

restricted.

• Synchronous discharge of neurones in normal brain takes place in small groups

– only.
• During a seizure, large groups of neurones are activated repetitively and hyper-
– synchronously, there is failure of inhibitory synaptic contact between neurones.
• This causes high voltage spike-and-wave activity on EEG.
Epilepsy and inflammation in the brain. https://www.semanticscholar.org/paper/Epilepsy-and-inflammation-in-
the-brain%3A-overview-Vezzani/86351e1c5e25a373c2b3b13977efd2ec679cfa7a
CLASSIFICATION
HISTORICAL PERSPECTIVES

• For over 35 years, the terms partial and generalized seizures were used to
describe types of seizures:
• Partial (seizures starting in one area or side of the brain) and
• Generalized (seizures starting in both sides of the brain at the same time).
• Partial seizures were further classifies into
• Simple partial seizures (Person is aware of what happens during the event.)
• Complex partial seizures: (Person has some impaired awareness during the
– seizure.)
CLASSIFICATION

1. Seizures may present with a variety of symptoms, and awareness may be

– either intact or impaired.
2. Seizures are further described by the presence of motor movements, including
automatisms or other motor activity, and by nonmotor onset symptoms,
including sensory or autonomic symptoms.
CLASSIFICATION

• Seizure onset can be :

• Focal: when abnormal neuronal activity arises in one or more localized
– brain regions or hemisphere;
• Generalized: when abnormal neuronal activity begins in awidespread
– distribution over both hemispheres; or
• Of unknown onset: if the available clinical and laboratory data cannot identify
whether the onset is focal or generalized.
CLASSIFICATION

• The International League against Epilepsy (ILAE) published in the April 2017
edition of Epilepsia three companion articles on the classification of seizures and
the epilepsies,
• (These represent a long-awaited update on the original 1981 and 1989
– classifications).
• The new classification provide a modern descriptive template for epilepsy; by using
more accessible, transparent language suitable for clinicians, scientists, and patients
CLASSIFICATION

• The new classification presents three levels of terminology, involving

1. Where seizures begin in the brain
2. Level of awareness during a seizure
3. Other features of seizures – e.g. motor vs non-motor.
The management of epilepsy in children and adults by Perucca P, et al. MJA 208 (5) j19 March 2018
CLASSIFICATION
The management of epilepsy in children and adults by Perucca P, et al. MJA 208 (5) j19 March 2018
ONSET: DEFINING WHERE
SEIZURES BEGIN
• The first step is to separate seizures by how they begin in the brain.
• The type of seizure onset is important because it affects choice of seizure
medication, possibilities for epilepsy surgery, outlook, and possible causes.
ONSET: DEFINING WHERE
SEIZURES BEGIN
• Focal seizures: Previously called partial seizures, these start in an area or
network of cells on one side of the brain.
• Generalized seizures: Previously called primary generalized, these engage or
involve networks on both sides of the brain at the onset.
• Unknown onset: If the onset of a seizure is not known, the seizure falls into the
unknown onset category. Later on, the seizure type can be changed if the beginning
of a person’s seizures becomes clear.
• Focal to bilateral seizure: A seizure that starts in one side or part of the brain and
spreads to both sides has been called a secondary generalized seizures.The new term
for secondary generalized seizure would be a focal to bilateral seizure. (Now the
term generalized refers only to the start of a seizure.)
DESCRIBING AWARENESS

– Whether a person is aware during a seizure is of practical importance

– This is because it is one of the main factors affecting a person’s safety
– during a seizure.
– Awareness is used instead of consciousness, because it is simpler to evaluate.
DESCRIBING AWARENESS

• Focal aware: If awareness remains intact, even if the person is unable to talk or
respond during a seizure, the seizure would be called a focal aware seizure.This
replaces the term simple partial.
• Focal impaired awareness: If awareness is impaired or affected at any time during a
seizure, even if a person has a vague idea of what happened, the seizure would be called
focal impaired awareness.This replaces the term complex partial seizure.
• Awareness unknown: Sometimes it’s not possible to know if a person is aware or
not, for
– example if a person lives alone or has seizures only at night
• Generalized seizures: These are all presumed to affect a person’s
awareness or consciousness in some way.Thus no special terms are needed
to describe awareness in generalized seizures.
OTHER FEATURES OF
SEIZURES
• Many other symptoms may occur during a seizure.
• In this basic system, seizure behaviours are separated into groups that
– involve movement.
1. DESCRIBING MOTOR AND OTHER
SYMPTOMS IN FOCAL SEIZURES

• Focal motor seizure: This means that some type of movement occurs during the event. For
example twitching, jerking, or stiffening movements of a body part or automatisms (automatic
movements such as licking lips, rubbing hands, walking, or running).
• Focal non-motor seizure: This type of seizure has other symptoms that occur first, such as
changes in sensation, emotions, thinking, or experiences. It is also possible for a focal aware or
impaired awareness seizure to be sub-classified as motor or non-motor onset.
• Auras: The term aura, which describes symptoms a person may feel in the beginning of a seizure,
is not in the new classification.Yet people may continue to use this term. It’s important to know
that in most cases, these early symptoms may be the start of a seizure
1. DESCRIBING MOTOR AND OTHER
SYMPTOMS IN FOCAL SEIZURES

– MOTOR ONSET – NON-MOTOR ONSET

– automatisms – autonomic
– atonic – behaviour arrest
– clonic – cognitive
– epileptic spasms – emotional
– hyperkinetic – sensory
– myoclonic
– tonic
2. DESCRIBING GENERALIZED
ONSET SEIZURES

• Generalized onset seizures can be motor or non-motor.

• Generalized motor seizure:
• The generalized tonic-clonic seizure term is still used to describe seizures with
stiffening (tonic) and jerking (clonic).This loosely corresponds to “grand mal.”
Other forms of generalized motor seizures may happen. Many of these terms
have not changed, and a few new terms have been added. (see image below)
• Generalized non-motor seizure:
• These are primarily absence seizures, and the term corresponds to the old
term "petit mal." These seizures involve brief changes in awareness, staring,
and some may have automatic or repeated movements like lip-smacking.
2. DESCRIBING GENERALIZED
ONSET SEIZURES
MOTOR NON-MOTOR (ABSENCE)
– tonic-clonic – typical
– clonic – atypical
– tonic – myoclonic
– myoclonic – eyelid myoclonia
– myoclonic-tonic-clonic
– myoclonic-atonic
– atonic
– epileptic spasms
Symptoms MedicalTerm

automatic behaviors automatisms

emotions or appearance of emotions emotions
extension or flexion postures tonic
flushing/sweating/piloerection autonomic
jerking arrhythmically myoclonus
jerking rhythmically clonus
language or thinking problems, deja vu cognitive
lid jerks eyelid myoclonia
limp atonic
numb/tingling, sounds, smells, tastes visions,vertigo sensations
pausing, freezing, activityarrest behavior arrest
thrashing/pedaling hyperkinetic
trunk flexion spasm
 DIAGNOSIS
& DIFFERENTIAL
DIAGNOSES
DIAGNOSIS

• Often over-diagnosed
• Diagnosis is essentially clinical
• Description of the seizure provided by an eye witness (MOST seizures)
• Sometimes patient self especially in partial onset
• Good history and examination
• Generally no place for a therapeutic trial
 DIAGNOSIS/CASE DEFINITION
• The case definition of epilepsy, based on combined clinical and
epidemiological

– evidence, includes the following:

– Patients with two or more unprovoked or reflex seizures that are >24 hours
– apart;
– Patients with one unprovoked or reflex seizure and who have a ≥60% chance of
further seizures over the following 10 years, e.g. patients with a known
structural lesion such as stroke, severe traumatic brain injury or brain infection
– Patients with one or more seizures in the context of a well-defined epilepsy
syndrome (for example, childhood epilepsy with centrotemporal spikes)
NEUROLOGICAL DIFFERENTIAL DIAGNOSIS

Epileptic Seizures Are Often Confused With Other Physiological

Disorders A n d Psychiatric Disorders

• Benign paroxysmal positional • Periodic leg movements during sleep

vertigo
• Panic attacks
• Breath-holding attacks
• Paroxysmal dyskinesia
• Daydreaming
• Migraine • Psychogenic non-epileptic seizures

• Parasomnias (such as REM • Sleep apnoea

sleep behaviour disorder)
• Transient global amnesia. and
• Narcolepsy and/or cataplexy
• Transient ischaemic attacks
• Syncope;tics
MANAGEMENT
MANAGEMENT

• Lifestyle modification
• Education
• Drug treatment
• Surgery
LIFESTYLE MODIFICATION
Avoid Factors That Could Lower Seizure Threshold

• Stress • Hyperventilation
• Alcohol use or withdrawal • Diet & missing meals
• Dehydration • Sleep deprivation
• Drugs & drug interactions • Extreme fatigue
• Photosensitive stimuli (flashingTV • Systemic infections
– program or computer games)
LIFESTYLE MODIFICATION

• Never stop anti-epileptic drug suddenly or omit dose

• Avoid potential harmful situations
• Avoid heights & open fires
• Prefer showering to bathing
• Prefer microwave cooking to gas or electric hobs
• Avoid swimming alone
• Avoid cycling on a busy road
• Avoid solo canoeing
EDUCATION

• Understand epilepsy
• Keep a seizure chart
• Keep a pill box to facilitate daily medication
• Obtain a Medic Alert kit
• Know the name and the dose of the drugs prescribed, and the frequency
– of dosing and the necessity of regular ongoing use
• Refrain from driving
CLINICAL APPROACH:
EMERGENCY MEASURES
• ABCDE &Manage
• Airway
• FMO2,
• Left lateral position
• HGT,
• Valium 10mg/Ativan 4mg IVI stat
HISTORY

• Main complaint • Past Medical History

• HPT/IHD/AF – Cerebrovascular
• Description of seizure disease
• Duration • D M – Hypoglycaemia
• Frequency • Social history
• Prev.seizures • Alcohol – trigger
• Smoking – CVA risk
• History of trauma • Illicit drugs
• Associated symptoms • Family history of epilepsy (increased
risk of
– recurrence)
EXAMINATION

• Vitals,Saturations
• JACCOLD
• Systemic examination focusing on Neurological exam
• Exclude focal signs
• Check orientation and level of consciousness
• Check for signs of injury
SIDE ROOM/SPECIAL INVESTIGATIONS

• HGT • ECG
• FBC • CT Brain /MRI
• UEC • EEG
• CMP
• LFTs
• Individualize your patient, based on
• Toxic screen/Anti-epileptic levels – history and examination findings
PHARMACOTHERAPY
Epilepsy. By Jeannine M. Conway, PSAP 2018 BOOK 3 •Neurology/Psychiatry
ANTIEPILEPTIC DRUGS

• Principles
• Start low, go slow
• Monitor levels
• Inform of side-effects
• Refractory Epilepsy: Add second drug with different mechanism
of action
FIRST GENERATION AEDS:
EFFICACY
AED EFFICACY SPECTRUM
Valproic acid All seizure types
Benzodiazepines All seizure types
Phenobarbital Most seizure types
Carbamazepine Focal seizures and generalised tonic-clonic seizures
Phenytoin Focal seizures and generalised tonic-clonic seizures
Ethosuximide Absence seizures
Primidone Most seizure types
SECOND GENERATION AEDS:
EFFICACY
AED EFFICACY SPECTRUM
Lamotrigine Most seizure types
Gabapentin Focal seizures
Oxcarbazepine Focal seizures and generalised tonic-clonic seizures
Topiramate Most seizure types
Vigabatrin Focal seizures and infantile spasm
Pregabalin Focal seizures
Brivaracetam Focal seizures
 AED ADVERSE EFFECTS

Drug Common Serious

Carbamazepine Nausea/vomiting, ataxia, dizziness, SJS,TEN, hypersensitivity reaction,
somnolence, blurred vision, pruritus aplastic anemia/agranulocytosis, AV
heart block, hepatic failure,
hyponatremia
Gabapentin Somnolence,sedation,dizziness, ataxia, DRESS, anaphylaxis,angioedemaa
tremor, peripheral oedema, increased
weight
Lamotrigine Dizziness,ataxia,somnolence,headache, SJS,TEN, DRESS,hemophagocytic
double vision, blurred vision, lymphohistiocytosis, asepticmeningitis
nausea/vomiting
Phenobarbital Somnolence, sedation, impairedcognition, Hypersensitivity reactions
depressed affect

Epilepsy. By Jeannine M. Conway, PSAP 2018 BOOK 3 •Neurology/Psychiatry

 AED ADVERSE EFFECTS

Drug Common Serious

Phenytoin Nystagmus, ataxia, slurred speech, SJS,TEN, anaphylaxis, DRESS,
decreased coordination,somnolence, hematologic abnormalities, hepatic
confusion,dizziness, gingival hyperplasia failure

Valproate Abdominal pain, nausea, vomiting, Hyperammonaemia,

somnolence, insomnia, tremor, asthenia, thrombocytopenia,
alopecia, weight changes, blurred vision hepatic failure, pancreatitis

Ethosuximide Nausea/vomiting, loss of appetite, Agranulocytosis, aplastic anemia,

abdominal discomfort, ataxia, SJS,TEN,
dizziness, headache, somnolence DRESS, depression

Topiramate Paraesthesia, anorexia, weight loss, Metabolic acidosis, vision changes and
fatigue, dizziness, somnolence, word glaucoma, kidney stones, oligohidrosis
finding difficulty, memory impairment and hyperthermia,Hyperammonemia
Epilepsy. By Jeannine M. Conway, PSAP 2018 BOOK 3 •Neurology/Psychiatry
SPECIAL CONSIDERATIONS
 WOMEN’S HEALTH

• The highest risk of major congenital malformations is with exposure to

valproate, which has an odds ratio of 6.7–9.3,
• Exposure to carbamazepine, lamotrigine, levetiracetam, or phenytoin resulted in
a risk of major congenital malformations with odds ratios of 2–3 with a 95% CI
of 1.2–5.
• There is a greater risk with exposure to phenobarbital and topiramate (OR 4.2–
5.5; 95% CI,2.4–9.7).
• Beyond teratogenicity risk, in utero exposure to valproate results in reduced
neurocognitive abilities and low IQ.

Meador KJ, Loring DW. (2016). Developmental effects of antiepileptic drugs and the need for
improved regulations. Neurology 2016;86:297-306.
WOMEN’S HEALTH

• Pre-pregnancy planning and education are important.

• Ideally, the woman has to be seizure free for at least 9 months before
– pregnancy.
• Folic acid should be taken while trying to become pregnant or while at risk of
pregnancy, ideally for at least 1–3 months before conception.
 STUDY ON AED IN
PREGNANCY
• The same principles apply for withdrawal of AEDs in seizure-free women
as in any person with epilepsy

• This needs to be carefully planned months before conception

• In those women who continue to need treatment the aim should be to achieve
seizure control with the lowest possible dose of monotherapy. Polytherapy is best
avoided where possible

• Treatment should be optimised and where necessary the continuation of AEDs

reviewed

Review Management of women with epilepsy during pregnancy. Authors Naghme Adab /DavidW
Chadwick. 2016.https://obgyn.onlinelibrary.wiley.com/doi/pdf/10.1576/toag.8.1.020.27204
 STUDY ON AED IN
PREGNANCY…
• The choice of AED is determined primarily by the type of epilepsy
• There is accumulating evidence of a greater risk with valproate exposure in
utero for both major malformations and later development

• Safer alternatives include carbamazepine, lamotrigine

• There is clinical consensus and observational data indicating the superiority of
valproate over other AEDs for seizure control, and no justification for switching
every woman of childbearing age on valproate to an alternative drug

Review Management of women with epilepsy during pregnancy. Authors Naghme Adab /David W
Chadwick. 2016.https://obgyn.onlinelibrary.wiley.com/doi/pdf/10.1576/toag.8.1.020.27204
 CHILDREN

• A large, randomized, double-blind trial addressed the relative difference in

efficacy and tolerability between ethosuximide, valproate, and lamotrigine.
• The study included 451 children, and the primary outcome was freedom from
treatment failure, with failure defined as continued seizures or excessive drug
toxicity, evaluated at weeks 16 and 20.
• There was no difference between ethosuximide and valproate (53% and 58%
respectively, p=0.35), whereas patients taking lamotrigine were less likely to meet
the study outcome, probably because of alack of seizure control (29%, p<0.0001).
• Adverse effects were not significantly different between the drugs.

GlauserTA, CnaanA, Shinnar S,et al.Ethosuximide, valproic acid,and lamotrigine in childhood absence epilepsy:
initial monotherapy outcomes at 12 months. Epilepsia 2013;54:141-55.
NEW DRUGS ACTING
AT ‘NOVEL TARGETS
NEUROSTEROIDS

– GANAXOLONE (3-hydroxy-3-
methyl-5- pregnan-20-one) (GNX)
is the 3- methylated synthetic
analog of allopregnanolone
 GANAXOLONE

– Positive allosteric modulator of GABA-A receptors

– Pre-clinical studies demonstrated no teratogenic potential
Currently in PHASE 3 development for refractory partial onset seizures.
Doses upto1500 mg is well tolerated
S/E. somnolence, dizziness, and fatigue
– No significant drug interactions with other AEDs
– FDA Orphan Drug Designation in PCDH19 Female Epilepsy
–

Available from: https://clinicaltrials.gov/ct2/show/NCT01963208

 LOGISAMONE

– Unknown mechanism of action.

– Human studies in Phase 3
– Shown efficacy in refractory partial seizures.
– Doses upto 1500 mg were well tolerated
– 50% seizure reduction was seen in 29% , 17%, 12% receiving 1500, 1200
mg/day of Losigamone and placebo respectively when used as add on therapy
for partial epilepsy(n=467)

Xiao Y, Luo M, Wang J, Luo H. Losigamone add-on therapy for partial epilepsy.Cochrane Database Syst Rev.2012 Jun 13;6:CD009324. doi: 10.1002/14651858.CD009324.pub2.
Role of neurosteroids in epilepsy
• Neurosteroids, such as all pregnanolone, are synthesized within
the brain
• Positive allostric modulators of GABAA and have anticonvulsant
properties
• Ganaxolone- synthetic analog
• Potentiates both phasic and tonic currents and thus prevents seizures
• Evidence from animal models of kindling also shows that they may also
possess anti-epileptogenic property
Role of endogenous neuropeotides

 Somatostatin
• via SRIF1 receptors in hipocampus
• Reduce presynaptic release of glutamate
• SRIF1 agonist under development

 Neuropeptide Y
• NPY Y1 receptors present post-synaptically on glutamatergic neurons
• Increase excitability by reducing K+ currents
• NPY Y1 antagonists currently in preclinical development
 Stiripentol

– Increase γ-amino butyric acid (GABA) levels in brain tissue

– Involves at least two independent neurochemical mechanisms:
– Inhibition of synaptosomal uptake of GABA
– Inhibition of GABA transaminase
– Phase III- Childhood focal seizure
– failed to achieve primary end point
– Currently undergoing Expanded Access study for Dravet Syndrome or Sodium
Channel Mutation Epileptic Encephalopathy

Chiron C1, Tonnelier S, Rey E, Brunet ML, Tran A, d'Athis P, Vincent J, Dulac O, Pons G. Stiripentol in childhood partial epilepsy: randomized
placebo-controlled trial with enrichment and withdrawal design. J Child Neurol. 2006 Jun;21(6):496-502.
 Valrocemide

– Amide derivative of valproic acid

– MoA: Potentiation of gabanergic current by binding to GABA receptor
– Phase I : Safe, Relative bioavailabily-88 %
– Phase II : showed efficacy of Valrocemide as an adjunctive therapy in refractory
epilepsy patients
– Phase III: Presently Ongoing in patients with refractory epilepsy

Hovinga CA. Valrocemide (Teva/Acorda). Curr Opin Investig Drugs. 2004 Jan;5(1):101-6.
Voltage Gated Potassium
Channel Inhibitor: Retigabine
– Approved by FDA in 2010 as an adjunctive treatment for partial epilepsy
– Acts on the pre-synaptic voltage gated K+ channels.
– Opens the KCNQ2/3 and KCNQ3/5 channels.
– Positive allosteric modulator of GABA-A receptors.
– Dosage 300- 1200mg/d in three divided doses
– drowsiness, tinnitus and vertigo, confusion, and slurred speech.
– Occasionally tremor, memory loss, ataxia, and diplopia
– Rarely blue skin discoloration and pigment changes in the retina
 Carisbamate (RWJ 333369)

– Novel neuromodulator
– Proposed mechanism of action: Inhibit voltage gated sodium channel & modest
inhibition of voltage gated calcium channel
– Phase II study- adjunctive use in partial onset seizures showed efficacy at a well
tolerated dose
– Phase III study in 2011 for focal seizure failed to demonstrate efficacy across
the dose range assessed versus placebo.

A Study of the Effectiveness, Safety, and Tolerability of Carisbamate as Add-On Therapy in Patients With Partial Onset Seizures.
http://clinicaltrials.gov/show/NCT00740623
AMPA Receptor Antagonists:
Parampanel
– First-in-class drug, a highly selective, non competitive AMPA type glutamate
receptor antagonist
– Nov 2012: FDA approved for treatment of refractory partial-onset seizures in
patients 12 years and older
– Treatment of primary generalized tonic-clonic seizures
– Dose: 4 – 12 mg OD
– S/e- Dizziness, somnolence, fatigue
– Boxed warning about the risk for serious neuropsychiatric events like irritability,
aggression, anger, anxiety and rarely homicidal ideation
 AMPA antagonists

1. NS 1209
– Novel competitive AMPA antagonist
– Phase II study in patients with refractory status epilepticus failed to reach study end
point
2. BGG 492 (Selurampanel)
– Orally active AMPA antagonist
– Very favourable safety profile is evidence by a lack of cardiovascular, phototoxic or
teratogenicity potential
– Discontinued - Phase-II for Epilepsy

Global Journal of Medical Research: B Pharma, Drug Discovery, Toxicology and Medicine. Volume 14 Issue 4 Version 1.0 Year 2014
 Caspase 1 inhibitor

Belnacasan
– Potent and selective inhibitor of interleukin-converting enzyme/caspase-1
– Proposed involvement of inflammatory mechanisms in the generation of
epileptic discharges
– Following exposure to pro-inflammatory stimuli, the release of IL-1β in
hippocampus is reduced, thereby preventing acute seizures
– Phase II trial for refractory partial epilepsy

Xiao Y, Luo M, Wang J, Luo H. Losigamone add-oLauren Walker, Graeme JS. Inflammation and Epilepsy: The Foundations for a New Therapeutic Approach in Epilepsy? Epilepsy Curr. 2012 Jan- Feb;12(1): 8–12
n therapy for partial epilepsy.Cochrane Database Syst Rev.2012 Jun 13;6:CD009324. doi: 10.1002/14651858.CD009324.pub2.
DP-VPA (SPD 421)

– Phospholipid derivative of valproic acid

– It is a pro-drug based on Regulated activation of pro- drugs (RAP) technology, to
overcome unfavourable pharmacokinetics of valproic acid
– Multicenter phase II trials of SPD-421 as add-on therapy in the treatment of
complex partial seizures reported positive results
– Adverse effects are minimal compared to Valproate
 Bumetanide

– A loop diuretic, blocks the Na–K–2Cl co-transporter in neurons

– excessively high intracellular chloride concentration leads to
– excitatory actions of GABA that contribute to seizure generation
– Thought to reduce [Cl]i, shift the polarity of GABA-activated currents, and thus preserve the
positive (i.e., hyperpolarizing) effects of GABA-acting AEDs such as diazepam and
phenobarbital
– Preclinical studies have shown promising results
– A pilot study demonstrated reduction of seizure frequency in adult patients with temporal
lobe epilepsy
– A Phase I Study of Pharmacokinetics and Safety of Bumetanide for Neonatal Seizures is
currently ongoing

Wolfgang Lösche. Martin Puskarjov. Kai Kaila. Cation-chloride cotransporters NKCC1 and KCC2 as potential targets for novel antiepileptic and antiepileptogenic treatments. Neuropharmacology. Vol. 69,June 2013, pg.62–74
Eftekhari S et al. Bumetanide reduces seizure frequency in patients with tempo al lobe epilepsy. Epilepsia. 2013 Jan; 54(1):9-12
Naluzotan

– Orally active selective 5-HT-1A receptor partial agonist

– Proposed mechanism of epileptogenesis is reduced 5-HT-1A receptor binding
– Naluzotan acts by increasing neurotransmitter activity at 5HT- 1A receptor,
thereby reducing seizure incidence and severity
– Phase I study revealed Naluzotan as safe & well tolerated
– Currently, Phase 2 trial is ongoing in patients with epilepsy
 Intranasal formulations

– Midazolam (USL 261)

– Phase II: Single doses up to 7.5mg
– were well-tolerated with no significant adverse events
– ARTEMIS1: Phase 3 study to Evaluate the Safety and Efficacy of Intranasal
Midazolam in Patients With Seizure Clusters is currently ongoing.
– Diazepam
– Phase I study showed intranasal diazepam is safe with a bioavailability of 97%

Study to Evaluate the Safety and Efficacy of USL261 (Intranasal Midazolam) in Patients with Seizure Clusters (ARTEMIS1). http://www.clinicaltrials.gov/show
/NCT01390220. (accessed 20 Nov 2014)
Thakker A1, Shanbag P. A randomized controlled trial of intranasal-midazolam versus intravenous-diazepam for acute childhood seizures. J Neurol. 2013 Feb;260(2):470-4
 Advantages:
– Absorption from nasal mucosa within 2 – 5 minutes
– Rapid penetration into the central nervous system
– Studies reveal superiority over oral formulations for quickness of response and
ease of administration
– Feasible to administer to children & adults as well
– S/E- nasal discomfort, throat irritation, increased lacrimation, and dysgeusia

Lesley K. Humphries. Lea S. Eiland. Treatment of Acute Seizures: Is Intranasal Midazolam a Viable Option? J P ediatr Pharmacol Ther. 2013 Apr-Jun; 18(2): 79–87
 Diazepam auto injection

– Pen-like device that injects medication intramuscularly

– Phase I & II : Safe & effective at stopping acute repetitive or cluster seizures
– July 2014: Phase III in 234 patients with refractory epilepsy having acute
repetitive seizures showed diazepam AI was significantly more effective than
placebo AI at delaying the next seizure or rescue

Abou-Khalil B et al. A double-blind, randomized, placebo-controlled trial of a diazepam autoinjector administered by caregivers to patients with epilepsy who require intermittent intervention for acute repetitive seizures. Epilepsia. 2013 Nov ; 54(11): 1968-76
Drugs in pipeline

Drug MOA Status

Becampanel AMPA/kinate receptor antagonist Preclinical testing

Talampanel Same Pre clinical testing

selurampanel Same Phase II

ICA 105665 Pottasium channel opener Completed preclinical

testing
YKP3089 Pottasium channel opener Phase II

JZP 4 Stuructural analogue of Phase I

Lamotrigine
YKP3089 Sodium channel blocker &increses Phase II
presynaptic release ofGABA
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

– Cons
– cough, hoarseness difficulty in
swallowing throat discomfort
VNS candidates

Used in:
– Generalized Seizures & Lennox-Gastaut syndrome
– Patients unfit for surgery
– Those unable to tolerate anti-epileptic drugs

Disadvantages:
– Expensive
– Does not provide complete seizure remission
 Deep Brain Stimulation

– Based on stimulating widespread inhibitory pathways

– Thalamus
– Anterior Thalamic Nucleus
– Centromedian Nucleus of the Thalamus
– Pros
– Minimal invasive
– Safe, Well tolerated
– Cons
– Malfunction
– Unknown long term benefits/complications
CLOSED-LOOP LOCAL DRUG
DELIVERY
– It is an attractive possibility that localised intracerebral delivery of antiepileptic
drugs (AED) can improve the efficacy of pharmacological treatment of epilepsy,
without systemic side effects.
– Several groups are, therefore, engaged in research developing automated local drug
delivery systems, comprising of seizure detection technology coupled with
intracranial delivery of AED.
– Thus, epilepsy surgery remains a significantly underused resource. It is often
perceived as a treatment of last resort.
– Perhaps the most important advance for the future would be to increase awareness
in the general population, and education among health professionals, on the safety
and efficacy of epilepsy surgery as an early intervention in medically refractory focal
epilepsy.
REFERENCES

– Fisher, R. S. et al. (2017). Operational classification of seizure types by the International League
Against Epilepsy: Position Paper of the ILAE Commission for Classification and Terminology.
Epilepsia 58, 522–530.
– Devinsky O, et al, (2018). Epilepsy. Disease Primers Volume 3, Article Number 18024,
doi:10.1038/Nrdp.2018.24
– Brodie, M.J. et al. (2018).The 2017 ILAE classification of seizure types and the epilepsies: what do
people with epilepsy and their caregivers need to know? Epileptic Disord,Vol. 20, No. 2, April 2018
– Conway JM & Tallian KB (2018). Epilepsy. PSAP 2018 BOOK 3 • Neurology /Psychiatry
– Perucca P, et al. (2018). The management of epilepsy in children and adult. MJA 208 (5) j 19 March
2018
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