definition of intractable epilepsy and its...

Definition of Intractable Epilepsy

and its Treatment

Lin Yang, MD, PhD

Pediatric department

Second Affiliated Hospital of Xi'an Jiao Tong University

Almost 50% patients became seizure-free during first single antiepileptic drug treatment

• First single drug therapy gets the highest seizure free rate of patients with epilepsy,

when replace to the second, and the third single drug treatment, the seizure free rate

would significantly reduced.

• A prospective study，they studied 525 patients (age, 9 to 93 years) who were given a diagnosis, treated, and followed up at a single center between 1984 and 1997. to find the response to antiepileptic drugs in patients with

newly diagnosed epilepsy to identify factors associated with subsequent poor control of seizures.

• The result shows that Among 470 previously untreated patients, 222 (47 percent) became seizure-free during

treatment with their first antiepileptic drug and 67 (14 percent) became seizure-free during treatment with a second or

third drug. In 12 patients (3 percent) epilepsy was controlled by treatment with two drugs.

Kwan P. Early identification of refractory epilepsy. N Engl J Med. 2000 ;342(5):314-9

Pe

rcen

tage o

f p

atie

nts

(%

) First drug second drug

third drug two AEDs

Seizure-free

1982-2001

890 patients （age 1-93 years）

who were given a diagnosis, treated,

and followed up.

780 patients completed the follow-

up study.

Brodie MJ, Kwan P et al. Neurology (2012) 78:1548–1554.

1982-2006

1098 patients （age 9-93

years）who were given a

diagnosis, treated, and

followed up.

890 patients completed the

follow-up study.

Current status of epilepsy’s treatment

controlled 50% 50%

10% 40%

5% Not controlled 35%

others：VNS、Ketogenic diet

surgery 15%

combination therapy

multidrug therapy

monotherapy

Intractable

Epilepsy ？

Not controlled

controlled Not controlled

controlled

Defining a situation where the epilepsy is likely to be

pharmacoresistant will help in the early identification

of those patients to be referred for further evaluation

to an epilepsy service.

Mohanraj R, Brodie MJ. Eur J Neurol 2006;13:277-82

Drug resistant epilepsy defined as failure of adequate trials of two

tolerated and appropriately chosen and used AED schedules

(whether as monotherapies or in combination) to achieve sustained

seizure freedom.

*drug resistant epilepsy； medically refractory/intractable；pharmacoresistant

• Seizure freedom is defined as freedom from seizures for a minimum

of three times the longest preintervention interseizure interval

(determined from seizures occurring within the past 12 months) or

12 months, whichever is longer.

• Undetermined is defined as recurrent seizure(s) after the

intervention has been adequately applied. If a patient has been

seizure-free for three times the preintervention interseizure interval

but for

Examples of how the definition framework can be applied in different clinical scenarios

Patient history Level 1—

categorization

of treatment

outcome

Level 2—

classification

of drug

responsiveness

of epilepsy

Notes

(1) A patient had one

seizure in January

2006 and two seizures in

October 2006. After starting

treatment in

November 2006 he has

been seizure free for 30

months with no adverse

effect

One current drug

with seizure-free

outcome

Drug responsive The longest pretreatment interseizure interval was 9

months (January–October

2006). The patient has had no

seizure for more than three times

the pretreatment

interseizure interval and for more

than 12 months

(2) A 16-year-old patient

was started on valproate 2

years ago after

experiencing two seizures in

6 months, and has been

seizure-free since with mild

sedation. He reports a

history of an apparently

nonfebrile

convulsive seizure when he

was 6 years of age

One current drug

with seizure-free

outcome

Drug responsive The longest pretreatment interseizure interval was 6

months. The patient has had no

seizure for more than three times

the pretreatment interseizure

interval and for more than 12

months. The seizure that

occurred at 6 years of age (more

than 12 months prior to starting

treatment) is not relevant to

determining the responsiveness

of his current epilepsy



categorization

of treatment

outcome

Level 2—

classification

of drug

responsiveness

of epilepsy

Notes

(3) A 40-year old man was

diagnosed to have partial

epilepsy 20 years ago.

He reported ‘‘I was on

phenytoin initially for a short

period, it didn’t work and

they took me off.’’ He was

then given an adequate trial

of carbamazepine but

continued to have monthly

seizures. Levetiracetam

was added 1 year ago and

tried adequately. He now

has seizures once

every 3 months

One previous drug

with undetermined

outcome. Two

current drugs with

treatment failure

outcome

Drug resistant Outcome of phenytoin treatment

was undetermined because of

lack of sufficient data .

Nonetheless, he has failed

informative trials with two

appropriate AEDs. Treatment

with levetiracetam is considered

failed because despite reduction

in seizure frequency, seizure free

duration is



categorization

of treatment

outcome

Level 2—

classification

of drug

responsiveness

of epilepsy

Notes

(4) A patient was newly

started on

carbamazepine after two

partial seizures in 9

months. He has had no

seizures for 12 months

since

One current drug

with

undetermined

outcome

Undefined

The pretreatment

interseizure interval was 9

months. Although the patient

has had no seizure for 12

months, the duration is less

than three times the

pretreatment interseizure

interval, hence outcome to

treatment is undetermined

and drug responsiveness of

epilepsy is undefined



categorization

of treatment

outcome

Level 2—

classification

of drug

responsiveness

of epilepsy

Notes

(5) A 16-year-old girl was

started on carbamazepine a

week after she had a tonic–

clonic seizure in the

morning, with a history (not

recognized by her doctor at

the time) of jerks over the

past 3 months. The jerks

got worse after 2 months on

carbamazepine 800 mg/day.

EEG later showed

generalized polyspike and

wave discharge. She was

diagnosed to have juvenile

myoclonic epilepsy and was

switched to lamotrigine,

which was stopped after 2

weeks (dosage at the time,

50 mg/day) because of a

rash. She is now on

valproate 2g/day for 3

months,

One previous

inappropriate

drug.

One previous drug

with undetermined

outcome.

One current drug

with treatment

failure outcome

Undefined Carbamazepine is recognized to

exacerbate myoclonic seizures

and, in this case, is not

considered an appropriate

treatment for the patient’s

epilepsy syndrome.

Lamotrigine and valproate are

appropriate treatments, but

outcome in terms of seizure

control of lamotrigine is

undetermined because it was

stopped due to an adverse

effect during titration, before a

dose range usually regarded as

optimal could be reached. Thus

the patient has failed only one

drug (valproate) so far, and the

drug responsiveness of her

epilepsy remains undefined

Patient history Level 1—categorization

of treatment outcome

Level 2—

classification

of drug

responsivene

ss of epilepsy

Notes

(6) A patient is having

more than one seizure

per day for 3 months

despite adequate trials of

four appropriate

AEDs. Patient is taking

one drug currently

Three previous drugs

and one current drug with

treatment failure outcome

Drug resistant The patient has failed more than

two appropriate AEDs

(6) After adding drug X,

patient 6 has had no

seizure for 8 months

Four previous drugs with

treatment failure outcome.

One current drug with

undetermined outcome

Drug resistant

Outcome of treatment with drug X

is undetermined and the epilepsy

remains drug resistant because the

patient has not been seizure-free

for 12 months

(6) With further follow-up

patient 6 has had no

seizure for 24 months

Four previous drugs with

treatment failure outcome.

One current drug with

seizure-free outcome

Drug responsive

The patient has had no seizures for

more than three times the

pretreatment interseizure interval

and for more than 12 months

Patient history Level 1—categorization

of treatment outcome

Level 2—

classification

of drug

responsivene

ss of epilepsy

Notes

(6) Patient 6 has two

seizures within 1 month Four previous drugs and

one current drug with


Undefined The patient is no longer seizure free, treatment of drug X is failed,

but the ‘‘clock’’ is ‘‘reset’’ for

considering the epilepsy to be drug

resistant again in future after it has

been drug responsive. Thus at

present the epilepsy does not fulfill

the criteria of drug resistant (unless

the patient fails at least one further

drug after the relapse)

(6) Two more

appropriate AEDs are

added at adequate

dosage but patient 6

continues to have

seizures once per month

Four previous drugs and

three current drugs with


Drug resistant After the relapse the patient has failed more than two adequate

trials of appropriate AEDs

Etiological of intractable epilepsy

（1）Epilepsy syndrome

Ohtahara syndrome，West syndrome，Lennox- Gastaut syndrome and so on

（2）Symptomatic epilepsy

Tumor, trauma and so on

（3） Refractory epilepsy developed from idiopathic or

latent epilepsy

Risk factors for intractable epilepsy

• Have definite causes, for example: congenital metabolic

abnormalities, intracranial developmental disorders,

bleeding and brain trauma, etc.

• Had status epilepticus

• Why it is important to recognize intractable epilepsy as

early as possible.

Early recognition means early selecting of appropriate treatment,

which can improve the patient’s prognosis .

• It is possible that some of the seizures are intractable

from the beginning.

«Clinical guidelines: epilepsy» People's Medical Publishing House，2004

Therapies

for epilepsy

Medic-

ation

Neuro-

stimulation

Surgery

Diets

The goal of AED treatment in patients with epilepsy

Seizure free

no side-effects

Lowest cost

Intractable

epilepsy

the lowest frequency of seizure

tolerable side effects

interference development as little

as possible during the process of

epilepsy treatment

Rational multidrug therapy

Combination of drugs with the following characteristics

- different mechanisms or complementary medicine

- no or fewer drug-drug interactions

- different side effects

Seizure

type

First-line

drug

Add-on

therapy

To be

considered

May worsen

seizures

Tonic-

clonic

seizure

Valproic acid

Lamotrigine

Carbamazepine

Oxcarbazepine

Levetiracetam

Phenobarbital

Levetiracetam

Topiramate

valproic acid

Lamotrigine

Clobazam

Absence

seizure

Valproic acid

Ethosuximide

Lamotrigine

Valproic acid

Ethosuximide

Lamotrigine

Clonazepam

Clobazam

Levetiracetam

Topiramate

Zonisamide

Carbamazepine

Oxcarbazepine

Phenobarbital

Gabapentin

Pregabalin

Tiagabine

Vigabatrin

Myoclonic

seizure

Valproic acid

Levetiracetam

Topiramate

Levetiracetam

Valproic acid

Topiramate

Clonazepam

Clobazam

Zonisamide

Carbamazepine

Oxcarbazepine

Phenytoin

Gabapentin

Pregabalin

Tiagabine

Vigabatrin

Choice of drug therapy according to seizure types

Type First-line drug Add-on therapy To be considered May worsen seizures

Tonic or

atonic

seizures

Valproic acid

Lamotrigine

Topiramate

Rufinamide

Carbamazepine

Oxcarbazepine

Gabapentin

Pregabalin

Tiagabine

Vigabatrin

Focal

seizure

Carbamazepine

Lamotrigine

Oxcarbazepine

Levetiracetam

Valproic acid

Carbamazepine

Levetiracetam

Lamotrigine

Oxcarbazepine

Gabapentin

Valproic acid

Topiramate

Zonisamide

Clobazam

Phenytoin

Phenobarbital

Choice of drug therapy according to seizure types

Syndrome First-line treatment Other treatments

to consider

Treatments to be

avoided (may

worsen seizures)

Ohtaharaa Corticosteroids

Levetiracetam

Ketogenic diet

Zonisamide

vigabatrin

West Corticosteroids

(prednisolone/

ACTH)

Vigabatrin

Benzodiazepines

Topiramate

Zonisamide

Ketogenic diet

Carbamazepine

Choice of drug therapy according to epilepsy syndromes

a Limited evidence from case reports/series and generally poor response in the early infantile epileptic encephalopathies

Treatment of epileptic encephalopathies. CNS Drugs. 2013

Syndrome First-line

treatment

Other treatments

to consider

Treatments to be

avoided(may

worsen seizures)

Dravet Sodium valproate

Topiramate

Clobazam

Stiripentol

Ketogenic diet

Carbamazepine

Gabapentin

Lamotrigine

Oxcarbazepine

Phenytoin

Tiagabine

Vigabatrin

LGS Sodium Valproate

Lamotrigine

Topiramate

Rufinamide

Felbamate

Levetiracetam

Corticosteroids

Ketogenic diet

Benzodiazepines:

small risk of

precipitating tonic

status epilepticus

Gabapentin/oxcarbaze

pine/carbamazepine/la

motrigine:may worsen

myoclonic seizures if

prominent


Syndrome First-line treatment Other treatments

to consider

Treatments to be

avoided(may

worsen seizures)

LKS Corticosteroids Valproate

Clobazam

Sulthiame

ESES/CSWS Corticosteroids

Clobazam

Valproate

Ethosuximide

Sulthiame

Ketogenic diet

Doose/MAE Sodium valprate

Lamotrigine

Ketogenic diet

Clobazam

Rufinamide

Felbamate

Ethosuximide

Carbamazepine

Phenytoin

Vigabatrin


Ketogenic diet

Ketogenic diet could be chosen after the failure of 2-3 antiepileptic

drugs treatment

1

Normal diet

Carbohydrate

/(Protein + Fat ）

65%:35%

Proportion of nutrients in diet

Protein should meet the needs of the lowest

growth and development.（WHO）

Ketogenic diet

Fat /(Protein +

Carbohydrate ）

80%:20%

Indications of ketogenic diet

The best effects of epilepsy syndrome

Severe myoclonic epilepsy in infancy

Myoclonic atonic seizures, Infantile spasms

tuberous sclerosis

Lennox-Gastant syndrome and epilepsy with spastic seizures

First choice

Glucose transporter protein deficiency （GLUT-1）

Pyruvate dehydrogenase（PDH）deficiency

Indications of ketogenic diet

Epilepsy syndrome with better therapeutic effect

Lafora disease

acquired epileptic aphasia

subacute sclerosing panencephalitis

• Ohtahara Syndrome

• Early myoclonic encephalopathy

• Epilepsy of infancy with migrating focal seizures

• West syndrome

• Dravet syndrome

• Epilepsy with myoclonic atonic seizures

• Lennox-Gastaut syndrome

• Landau-Kleffner syndrome and epileptic encephalopathy with continuous

spikes and waves during sleep

Contraindication of ketogenic diet

Fatty acid transport and oxidation disorders

Carntine deficiency

β-oxidase deficiency

Relative contraindications

Severe malnutrition, there is no way to maintain adequate

nutrition

Can be treated by surgical treatment

Patients or family members lacking of patience, do not

cooperate with the treatment

Diets

• The ketogenic diet, modified Atkins diet and other diet has a certain efficacy

in seizure control. Ketogenic diet has the best effect, but the least well-

tolerated.

• Adverse reactions: constipation, nausea and other gastrointestinal reactions

may occur in the early stage, malnutrition may occur, needing to add

vitamins, minerals, calcium.

• The ketogenic diet mostly used in infants and children, In the early stage，

dehydration and hypoglycemia may occur, patients should be observed in

the hospital.

• The ketogenic nor Atkins diets does not increase long-term cardiovascular

disease risks.

Surgery

• Structural abnormality

resective surgery

（FCD，Rasmussen encephalitis, tuberous sclerosis, etc）

• No structural abnormality

VNS, DBS or palliative operation

Surgical treatment

• Risk-benefit assessments of surgery，is not only assess

the risk of surgery，but should also considering the

purpose of the operation （as：complete remission or

reduction of seizures ）

For example, the risk of temporal lobe resection is higher than that of nerve

stimulation, however，if the surgery is to complete remission of seizures, compared to nerve stimulation, temporal lobe resection should still be the

first choice .

Resective Surgery

• Temporal lobe resections are the safest, with a serious complication

rate of 5%, and with continually improving techniques.

• Nonlesional extra-temporal resections have a greater rate of complications

and a lower rate of seizure freedom. Invasive EEG is often used for extra-

temporal resection, and that carries its own risks .

• The most frequent adverse effects of temporal lobe surgery are superior

quadrant visual field defects (~8% for temporal lobectomies and rare for

selective resections),wound infections (~5%) , and mild verbal memory

decline with dominant resections (~8%) .

• These are usually acceptable risks, given the probability of obtaining a

seizure-free outcome.

Corpus callosotomies

• These are palliative (not aiming at seizure freedom), and are performed for

“drop seizures” and other severe motor seizures in refractory, symptomatic,

generalized epilepsy.

• The control of drop attacks with a callosotomy can be life- and injury-saving.

• Because these patients almost always have major pre-existing

neuropsychological deficits, cognitive complications are generally minimal.

Hemispherectomy

• Indications: young patients with severe epilepsy, often with

hemisphere lesions or injuries (hemiplegia and visual field defects).

• From the point of view of nerve injury, this part of the patient is

generally well tolerated.

• Surgical complications: hydrocephalus, most need to do shunt

surgery.

• With the improvement of technology, the incidence of surgical

complications decreased gradually.

• Risk-benefit evaluation, the rate of seizure free after hemisphere

resection can reach 60-65%.

Nerve stimulation

Vagus Nerve Stimulation(VNS)

• “Low risk and low return”

• Extracranial surgery, the operation risk is small, the complication is

well tolerated

• Complications: hoarse voice, cough, sound changes, etc

• Infection risk is low, it is reported to be 3%-5%

• The incidence of arrhythmia was also low

Deep brain stimulation

• Methods: intracranial electrodes stimulate brain structures that

presumed to restrict seizure activity.

• 110 patients had been with anterior thalamic nucleus stimulation ，

there were no deaths in the study. Bleeding occurred in 5 patients

(no symptoms)，infection in 14 cases.

• Deep brain stimulation is used in many countries, but the United

States does not allow.

Fisher R, Salanova et al. Epilepsia. 2010;51:899–908.

Responsive neurostimulation

• Passed U.S. FDA certification in November 2013

• Methods: the electrodes are placed in the epidural and / or brain

parenchyma, and the seizure is controlled in a closed loop manner.

• No death in 191 patients. Bleeding in 5% of the patient. No permanent

neurological impairment. 5% infection rate. 4 cases removed the equipment.

• Advantages: it can simultaneously treat 2 epileptic foci, and can provide

useful diagnostic information and record the origin of epilepsy.

Morrell MJ, RNS System in Epilepsy Study Group. Neurology 2011;77:1295–304.

Neurostimulation

• Disadvantages: MRI examination can not be performed after nerve

stimulation surgery

• There was no significant difference among effects of the three kinds

of nerve stimulation, but two kinds of intracranial nerve stimulation

have more complications, so the vagus nerve stimulation should be

the first choice.

• Patient ： LGS（76 cases）；West（19 cases）

• Method： 1.Operation: lobectomy; hemisphere

resection; callosal disconnection

2.Neural development assessed

• Follow up : 1 years

• Results

1.Engel grade I: LGS (61.5%); West (60%);

2.Good seizure outcomes, and decreased number of antiepileptic drugs;

3.Cognitive improved

Surgical outcome in children with intractable epilepsy

Conclusion: Epilepsy surgery should be considered in treating childhood

intractable EE with expectation of improvement of both seizure and cognitive

outcomes, even in cases of LGS.

We are willing to help patients with epilepsy

to have a better life

definition of intractable epilepsy and its...

Documents