PATHOGENESIS

• a minority of patients with apparent DRE are subsequentlyable to achieve remission and also that some patients whoseseizures are initially controlled will later relapse.

• In the latter group, medical control can be regained withsubsequent drug trials in some patients while in otherssubsequent drug trials in some patients,while in others,medical intractability is then permanent.

• These different clinical courses may represent differentmechanisms of medical intractability or pharmacoresistance

• A delayed development of intractability is most oftendescribed with epilepsy onset in childhood, particularly withepilepsy associated with mesial temporal sclerosis (MTS).

• In some individuals, MTS is a progressive condition….anevolving process involving glial proliferation and dendriticevolving process involving glial proliferation and dendriticsprouting with synaptic reorganizationmanent.

• Alterations in neural circuitry conceivably may lead to anepileptic network that becomes drug resistant over timee

• A delayed development of intractability is most oftendescribed with epilepsy onset in childhood, particularly withepilepsy associated with mesial temporal sclerosis (MTS).

• In some individuals, MTS is a progressive condition….anevolving process involving glial proliferation and dendriticsprouting with synaptic reorganizationmanent.

• Alterations in neural circuitry conceivably may lead to anepileptic network that becomes drug resistant over timee

According to Studies in animal models…

• drug-resistant temporal lobe epilepsy isassociated with:– altered expression of multidrug transporters

lt d i f AED t t– altered expression of AED targets– morphologic alterations in the hippocampus

In human…• increased P-glycoprotein activity in various brain

regions( demonstrated by PET)• polymorphism in the drug transporter gene

(ABCB1 or MDR1)

Importance ofearly aggressiveseizure treatment

• overexpression of these multidrug transportersinduced by recurrent seizures

• Other alterations…in:– AED absorption– AED metabolism,– AED receptor-binding– AED blood brain barrier permeability

COMPLICATIONS OF INTRACTABLE EPILEPSY:

� increased mortality

� Nonfatal injuries

� disability and diminished quality of life

DIFFERENTIAL DIAGNOSIS

• incorrect diagnosis of seizureclassification

• Incorrect drug choice (Carbamazepin for JME)

• Psychogenic nonepilepticseizures

• syncope• movement disorders

Apparent intractability nonepileptic paroxysmaldisorders

• Inappropriate dose• AED toxicity in association with

phenytoin, carbamazepine,tiagabine, and valproate

• Noncompliance• Lifestyle factors (recreational

drug or alcohol abuse andsleep deprivation)

• movement disorders• sleep disorders

EVALUATION

Video EEG monitoring� 25% are found to have

nonepileptic events� aid in seizure classification� used for presurgical

Seizure diaries

� have them carefullyrecord seizures

� dietary changesused for presurgicalevaluation of epilepsypatients

Neuroimaging� MRI� PET� SPECT� MSI(magnetic source

imaging)

y g

� timing of medicationintake of both AEDs andother drugs

� amount and quality ofsleep

� menstrual cycle changes

Ketogenicstim lationEpilepsAntiepileptic

TREATMENT OPTIONS

Ketogenicdiet

stimulationapproaches

Epilepsysurgery

Antiepilepticdrugs

surgery is the treatment of choice for medicallyresistant lesional partial epilepsy as this has the

most likely chance of producing remission…othersare more likely palliative,rather than curative

Antiepileptic drugs• Sequential drug trials have a small likelihood of

inducing remission in patients who have alreadyfailed two or more AED regimens. This approachcan produce remission rates estimated at 4 to 6 %per year or a cumulative rate of 14 to 20 %per year, or a cumulative rate of 14 to 20 %

• Among those who do not become seizure-free, asubstantial reduction in seizure frequency ispossible; 21 to 70 % of patients achieve a 50 % orgreater reduction in seizure frequency