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Drug resistant epilepsy

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Drug resistant epilepsy (DRE) is a distressing problem for patients and doctors. Approximately 20-60% of epilepsy cases become resistant to antiepileptic drugs (AEDs). DRE is defined as failure to achieve seizure freedom after trials of two tolerated AEDs. Causes of apparent DRE include misdiagnosis and non-adherence. Treatment options for true DRE include further AED trials, epilepsy surgery, vagus nerve stimulation, and ketogenic diet. Resective surgery offers the highest chance of remission, especially for temporal lobe epilepsy where seizure freedom rates can be over 90%.

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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).
Drug resistant epilepsy
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.
Drug resistant epilepsy
Drug resistant epilepsy
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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Drug resistant epilepsy

  • 1. DRUG RESISTANT EPILEPSY DR MOHAMMAD A.S. KAMEL CONSULTANT NEUROLOGIST
  • 2. Distressing problem for patient and the doctor
  • 3.  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
  • 4.  Intractable.  Medically refractory.  Pharmacoresistant epilepsy
  • 5. 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.
  • 6. 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 .
  • 7. 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).
  • 8.  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).
  • 9. 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)
  • 10. 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.
  • 11. 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
  • 12. 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 .
  • 13. Factors contributing to the biological basis of DRE with illustrative examples  A)Disease biology (independent of the host).  B)Drug biology.  C)Patient characteristic.
  • 14. 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.
  • 15.  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).
  • 16. 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)
  • 17. 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).
  • 19. 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.
  • 20. 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).
  • 21. 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.
  • 24. 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
  • 25. 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
  • 26. 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.
  • 27.  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)
  • 28. Responsive neurostimulation (FDA approved randomized control trial 37.9% reduction in seizures versus 17.3% seizure reduction in controls) . .
  • 29. 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.
  • 30. 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)
  • 31. t-VNS approved in the European union.
  • 32. 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 .