DRUG RESISTANT

EPILEPSY

DR MOHAMMAD A.S. KAMEL CONSULTANT NEUROLOGIST

Distressing problem for patient and

the doctor

Spontaneous remission 20—30 %.

Remission on antiepileptic drugs 20 – 30 %.

30 -- 40 % persistent seizure under AEDS among which DRE

included.

Approximately 20% of patients with primary generalized epilepsy

and up to 60% of patients who have focal epilepsy develop drug

resistance during the course of their condition, which for many is

lifelong

Intractable.

Medically refractory.

Pharmacoresistant epilepsy

DEFINITION

A task force of the International League against Epilepsy

proposed that drug-resistant be defined as the failure of

adequate trials of two tolerated, appropriately chosen and administered antiepileptic drugs (whether as monotherapy or in

combination) to achieve seizure freedom .

They also recommended replacing the term “intractable” with “drug-resistant” epilepsy (DRE).

Frequency and severity of seizures are less commonly included in

a definition of DRE .

Even infrequent seizures can have a large impact.

EPIDEMIOLOGY

Because of unstandardized definitions as well as misdiagnoses, the

incidence and prevalence of DRE are somewhat uncertain .

Estimates of the proportion of epilepsy cases that are or become

medically resistant vary between 20 and 40 percent .

Clincal predictors that have been associated with DRE

1-High seizure density(number of seizures per time)before

treatment initiation.(Mohanraj and Brodie,2006).

2- Long history of poor seizure control(Kwan and

Brodie,2000).

3- Early onset of seizures (Ko and Holmes,1999).

4-More than one seizure type(Steffeburg et al. 1998).

5- Multiple seizures after treatment

initiation(Sillanpaa,1993).

6-Remote symptomatic etiology (e.g. history of head

trauma,infection,etc.)(Kwan and Brodie,2000).

7- Certain structural abnormalities (e.g.cortical

dysplasia,hippocampal sclerosis etc.)(Semah et al,1998).

8- Certain EEG abnormalities ,such as persistant focal

slowing(Berg et al.,2001)or high frequency of focal

epileptiform abnormalties(Ko and Holmes,1999).

9-Mental retardation (Callaghan et al.,2007).

10-Psychiatric comorbidity(Hitiris et al.,2007).

11-Abnormal neurological examination(Sillanpaa,1993).

12- History of status epilepticus (Callaghan et al.,2007).

Patterns of drug resistance (Pati and Alexopoulos,2010)

1) De novo drug resistance: with newly diagnosed epilepsy for

whom the first drug was ineffective had only an 11% probability of

future success, compared with 41% to 55% in patients who had had to stop taking the drug because of intolerable side effects or

idiosyncratic reactions.

Most patients for whom the first drug fails will be resistant to most

and often all antiepileptic drugs.( These results suggest that seizures in newly diagnosed patients are either easy to control or difficult to

control right from the start)

2)Progressive drug resistance

In some patients, epilepsy is initially controlled but then gradually

becomes refractory.

This pattern may be seen, for example, in childhood epilepsies or in

patients with hippocampal sclerosis.

3)Waxing and waning resistance

In some patients, epilepsy has a waxing-and waning pattern: I e,

it alternates between a remitting (pharmacoresponsive) and

relapsing (pharmacoresistant) course.

Patients thought to have drug-resistant epilepsy may become

seizure-free when other drugs are tried.

Changes in drug bioavailability, local concentration of the drug

in the brain, receptor changes, the development of tolerance, and interactions with new medications may be implicated,

though the exact mechanism is not understood

COMPLICATIONS OF DRE

Increased mortality rate, estimated at 1.37 per 100 person-years .

(SUDEP) is 40 times more likely among patients who continue to have seizures than in those who are seizure free .

Head injury, burns, and fractures, are seizure-related .

DRE is also associated with disability and diminished quality of life .

These complications of DRE result from the combined effects of

recurrent seizures, AED toxicity, comorbid depression, as well as

psychosocial factors such as excessive dependency .

Factors contributing to the

biological basis of DRE with illustrative examples

A)Disease biology (independent of the host).

B)Drug biology.

C)Patient characteristic.

Disease biology (independent to host) Etiology of seizures (e.g. progressive epilepsy syndromes such as

LGS,myoclonic encephalopathies).

Severity of the disease (e.g. frequent seizures early on trigger changes of cellular/molecular properties resulting in unstable network that can no longer harness seizures);”intrinsic severity "hypothesis (Rogawski and Johnson,2008).

Abnormal network plasticity and /or changes in the epileptogenic substrate/network(e.g .hippocampal sclerosis, cortical dysplasia)(Gorter and Potschka,2012).

Seizure – induced synaptic reorganization: development of epileptic circuits within and between brain regions(e.g. mossy fiber sprouting in the hippocampus leading to aberrant neuronal synchronization)(Beck and Yaari,2012).

Ion channelopathies: mutation in sodium,calicium,potassium and ligand gated channels.

Reactive autoimmunity(e.g. anti GAD antibodies,antiGM1

antibodies, antibodies against GluR3 subunit of glutamate receptor

in Rasmussen encephalitis – cause and effect relationships not

clearly established)(Kwan and Brodie,2002).

Impaired antiepileptic drug penetration: over expression of P-glycoprotein and MPR in epileptogenic tissue (capillary endothelial

cells,astrocytes of blood brain barrier and neurons);”drug transporter” hypothesis(Potschka,2010).

Altered drug target/receptors: loss of use – dependent voltage gated sodium channels from dentate granule cells in

carbamazepine – resistant patients;” drug target “hypothesis(Marchi

et al,2004).

Disrupted integrity of blood brain barrier ;”BBB” hypothesis(Marchi ,2012).

Drug biology Loss of anticonvulsant efficacy due to development of tolerance

with chronic administration :pharmacokinetic”metabolic”tolerance

due to induction of AED metabolizing enzymes or other drug- drug

interactions.pharmacodynamics”functional” tolerance may be due to loss of receptor sensitivity (Loscher and Schmidt,2006).

Restricted therapeutic/safety margin,which precludes sufficiently

high brain penetration of the active drug(Loscher and

Schmidt,2009).

Lack of antiepileptogenic”disease modifying”properties,i.e inability to halt or revers the progression of the disease with available seizure

– suppressing medications(with the exception of few AEDs such as

valproate,levetricetam and others ,where potential

antiepileptogenic activity has been observed in animal models;for instance kindling and kainite models of temporal lobe epilepsy.the

clinical relevance of these findings remains unclear)(Dudek et.al,200;Loscher and Brandt,2010)

Patient characteristics Presence of absence of genes encoding drug transporters, of which

AEDs are known substrates:e.g. genetic polymorphisms of the P-

glycoprotein encoding gene in patients with DRE (Remy and

Beck,2006).

Polymorphisms in genes encoding drug targets may result in altered

pharmacodynamics of certain AEDs :e.g. altered neuronal sodium

channels expressing a mutant auxiliary B1- subunit encode by the

SCN1B gene (which is responsible for the monogenic epilepsy

syndrome GEFS+)exhibit reduced sensitivity to phenytoin(Lucas et

el,2005).

Environmental influences (e.g. perinatal exposure to pathogens

predisposing the immature brain to acquired malformations of cortical development)(Marin – Padilla,2000).

EVALUATION

Establish the diagnosis of epilepsy.

Rule out peudoDRE.

Define the electro clinical syndrome.

Establish the etiology of epilepsy.

Evaluate the medical treatment.

Select candidate for surgery.

Causes of apparent or false DRE pseudopharmacoresistant

1)Diagnostic errors

a) Patients with nonepileptic events(e.g. syncope or psychogenic non epileptic events and inappropriately treated with multiple AED).

b) Incorrect classification of epilepsy type,leading to inappropriate drug selection (e.g.misdiagnosis of a generalized for a focal epilepsy).

c)Failure to identify an underlying causative factor (e.g. metabolic or systemic illness).

2)Treatment errors

a. Incorrect AED selection (e.g. wrong drug for type or drug interactions leading to decrease efficacy).

b. Inappropriate assessment of response or lack of response (e.g. drug interactions leading to increased side effects and decreased tolerability).

c. Inappropriate dosage (e.g. injudicious reliance on “therapeutic serum range”,blind dosage adjustments without clinical correlation,or both).

3) Non adherence to therapy

a. Poor compliance ,detrimental lifestyle, alcohol misuse,etc.

b. Inadequate patient education.

c. Intolerable side effects.

d. Prohibitive cost of medication.

TREATMENT OPTIONS

Resective epilepsy surgery is the treatment of choice for medically

resistant lesional partial epilepsy as this has the most likely chance of

producing remission.

Further AED trials, vagal nerve stimulation, and the ketogenic diet

can reduce seizure frequency and improve quality of life but are

more likely to be palliative, rather than curative, treatment options

Antiepileptic drugs Further medications trials of AEDs in mono- or polytherapy can be of

benefit in individuals with epilepsy. It is important to review past treatment trials with the patient to assess whether the dose or frequency of dosing was adequate.

Sequential drug trials have a small likelihood of inducing remission in patients who have already failed two or more AED regimens. This approach can produce remission rates estimated at 4 to 6 percent per year, or a cumulative rate of 14 to 20 percent . Among those who do not become seizure-free, a substantial reduction in seizure frequency is possible; in different series, 21 to 70 percent of patients achieve a 50 percent or greater reduction in seizure frequency .

Reduction in seizure severity may also improve patients’ quality of life . However, studies with long-term follow-up find that the benefit of

successive drug trials is not sustained in one-fourth or more.

Choosing an AED with a different mechanism of action than one not previously efficacious may maximize the benefit from subsequent drug trials

Epilepsy surgery

Resective epilepsy surgery has the best-established efficacy for

individuals with lesional temporal lobe epilepsy .

Patients with concordant abnormalities in one temporal lobe on

MRI and EEG have a rate of seizure remission as high as 90 percent .

Patients with nonlesional temporal lobe epilepsy also have a high

remission rate with surgical therapy.

The efficacy is highest in patients in whom EEG and another

imaging modality (eg, SPECT, PET) reveal a consistent location of the

epileptic focus.

Neocortical focal epilepsy also responds to resective surgery. As

with mesial temporal lobe epilepsy, rates of seizure remission are

highest in patients who have MRI lesions that are concordant

with the anatomic focus of seizure activity on EEG.

However, localization using SPECT, PET can also define a seizure focus that when surgically removed leads to seizure remission

rates that exceed 50 percent.

Pallaitive surgical treatments (lobar and multi-lobar resections, ),

corpus callosotomy(atonic attacks in LGS) ,

multiple subpial transections (seizure begin in areas in

brain that cannot be safely removed) .

Hemispherectomy(malformations of cortical development Rasmussen’s encephalitis ,sturge weber syndrome

and remote vescular insult)

Responsive neurostimulation (FDA approved

randomized control trial 37.9% reduction in seizures

versus 17.3% seizure reduction in controls) .

.

Under investigation

Deep brain stimulation (approved in the European

Union)phase III randomized controlled trial 38.8%

reduction in seizures versus 22.8% in the control group.

External trigeminal nerve stimulation is approved in the

European union for adults and children older than 9 year with

epilepsy and depression (phase II randomized controlled trial

the responder rate was 30.2% overall)

t-VNS approved in the European

union.

Ketogenic diet —

(high-fat, low protein) diet has demonstrated efficacy in children

with DRE, with more than one-third experiencing a 50 percent or

greater reduction in seizures

In two small case series of adult patients, the traditional ketogenic

diet and a modified Atkins diet reduced seizure frequency by 50 percent or more in half of patients with DRE .

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