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Seizure, Epilepsy and Drug Refractory Epilepsy

seizures epilepsy drug refractory epilepsy

What is Seizure?

A seizure is a transient occurrence of symptoms and/or signs due to abnormal excessive or synchronous neuronal activity in the brain. A seizure does not necessarily mean that a person has epilepsy, unless the criteria for diagnosis of epilepsy are met. Epileptic seizures fall broadly into the following types:

  1. Focal onset seizures
  2. Generalized onset seizures
  3. Unknown onset seizures

What is Epilepsy?

Epilepsy is a disease of the brain defined by any of the following conditions:

  • At least two unprovoked seizures occurring more than 24 hours apart
  • One unprovoked seizure and a probability of further seizures similar to the general recurrence risk (at least 60%) after two unprovoked seizures, occurring over the next 10 years
  • Diagnosis of an “epilepsy syndrome”

The classification of epilepsy involves classification at three levels – the seizure type, epilepsy type and epilepsy syndrome. Epilepsies are classified as:

  1. Generalized epilepsy
  2. Focal epilepsy
  3. Combined generalized and focal epilepsy
  4. Unknown epilepsy

Can Epilepsy be Resolved/Cured?

Yes. Epilepsy is considered to be resolved –
  • For individuals who had an age-dependent self-limited epilepsy syndrome but who are now past the applicable age, (or)
  • For those who have remained seizure-free for the last 10 years, with no seizure medication for the last 5 years.

What is the Burden of Epilepsy?

About 50 million people in the world suffer from epilepsy and every year 16 to 51 new-onset epilepsy cases occur per 100,000 people.(1) In majority of patients, a single antiepileptic drug (AED) suffices to control epileptic seizures, which may be withdrawn after a seizure-free period of 2 years.(2) Some patients, however, do not become completely free of seizures despite adequate compliance.(3,4) People with age of epilepsy onset <10 years, those with focal epilepsy usually have higher disability due to epilepsy. Persistent epileptic seizures in these patients, in addition to having deleterious effects on health including sudden death, are also associated with psychosocial, behavioural, cognitive, and financial consequences.(5-7)

What is Drug Refractory Epilepsy?

International League against Epilepsy defines “Drug-resistant epilepsy” as a failure of adequate trials of two (or more) tolerated, appropriately chosen, and appropriately used AED regimens (whether administered as monotherapies or in combination) to achieve freedom from seizures.(8)

Seizure freedom is defined as freedom from all types of seizures for 12 months or three times the pre-intervention inter-seizure interval, whichever is longer.

Overall approximately 20% of patients with primary generalized epilepsy and 35% of those with focal epilepsy will fall into category of drug refractory epilepsy.(9,10)

Who are at Risk for Developing Drug Refractory Epilepsy?

People with Epilepsy who have a high frequency of seizures in the early phase of the disorder and those with presence of known cause (often structural) of epilepsy like Focal cortical dysplasia, cortical malformations, hippocampal sclerosis. There are certain genetic and neuro-metabolic conditions as well which have high predisposition for developing drug refractory epilepsy.

What is Pseudoresistance?

Individual with Epilepsy persists to have seizures due to inadequate/inappropriate treatment of underlying disorder, drug default or poor compliance with medications. This phenomenon can occur in several situations of which misdiagnosis of epilepsy is the commonest. The following are the causes for pseudo-resistance:

  1. Incorrect diagnosis of epilepsy
  2. Incorrect syndrome diagnosis of epilepsy
  3. Inadequate dosage of drug
  4. Poor compliance
  5. Lifestyle factors such as drug abuse
  6. Certain sensory stimuli specific to the type of epilepsy such as hot water bath in hot water epilepsy, etc.

Is Treatment Available For Drug Refractory Epilepsy?

Yes. Treatment for Drug refractory epilepsy is a staged strategy.

  1. The initial and most important step is to rule out the possibility of Pseudo resistance.
  2. Identification of correct diagnosis and epilepsy syndrome
  3. Using the proper drug dosage and appropriate polytherapy, as per need
  4. Ensure drug compliance
  5. Identification of structural pathology
  6. Early evaluation for surgical treatment such as Anterior Temporal Lobectomy with Amygdala Hippocampectomy, Lesionectomy, Functional Hemispherotomy, Callosotomy.

Latest Developments in Drug Therapy

In the past 5 years, several new drugs were introduced Viz. Rufinamide for Lennox-Gastuat syndrome, Vigabatrin for infantile spasms and as adjuvant for complex partial seizures, Stiripentol for Dravet’s syndrome. Retigabine, Birvaracetam and Parampanel are approved as adjunctive treatment for refractory focal seizures.(11,12) Recently, the therapeutic use of steroids has been shown to reduce seizure burden in many epileptic pathologies, which may result from improved drug distribution into the brain. Dexamethasone is known as a potent anti-inflammatory drug, but also exerts powerful “blood brain barrier (BBB) repair” potency.

Take Home Point:

Despite the fact that Epilepsy causes a significant disability to individual and is one the leading causes of global burden, with proper evaluation and initiation of appropriate drugs at adequate dosage, epilepsy can be controlled resulting in significant improvement in the quality of life and lifespan of the individual.

References:

  1. Banerjee PN, Filippi D, Allen Hauser W. The descriptive epidemiology of epilepsy-a review. Epilepsy Res 2009;85(1):31–45
  2. Callaghan N, Garrett A, Goggin T. Withdrawal of anticonvulsant drugs in patients free of seizures for two years. A prospective study. N Engl J Med 1988;318(15):942–946
  3. Chang H-J, Liao C-C, Hu C-J, Shen WW, Chen T-L. Psychiatric disorders after epilepsy diagnosis: a population-based retrospective cohort study. PLoS One 2013;8(4):e59999
  4. Picot MC, Baldy-Moulinier M, Daurès JP, Dujols P, Crespel A. The prevalence of epilepsy and pharmacoresistant epilepsy in adults: a population-based study in a Western European country. Epilepsia 2008;49(7):1230–1238
  5. Mohanraj R, Norrie J, Stephen LJ, Kelly K, Hitiris N, Brodie MJ. Mortality in adults with newly diagnosed and chronic epilepsy: a retrospective comparative study. Lancet Neurol 2006;5(6):481–487
  6. Lawn ND, Bamlet WR, Radhakrishnan K, O’Brien PC, So EL. Injuries due to seizures in persons with epilepsy: a population- based study. Neurology 2004;63(9):1565–1570
  7. McCagh J, Fisk JE, Baker GA. Epilepsy, psychosocial and cognitive functioning. Epilepsy Res 2009;86(1):1–14
  8. Kwan P, Arzimanoglou A, Berg AT, et al. Definition of drug resistant epilepsy: consensus proposal by the ad hoc Task Force of the ILAE Commission on Therapeutic Strategies. Epilepsia 2010;51(6):1069–1077
  9. Cascino GD. Intractable partial epilepsy: evaluation and treatment. Mayo Clin Proc 1990;65(12):1578–1586
  10. Reutens DC, Berkovic SF. Idiopathic generalized epilepsy of adolescence: are the syndromes clinically distinct. ? Neurology 1995;45(8):1469–1476
  11. Ryvlin P, Werhahn KJ, Blaszczyk B, Johnson ME, Lu S. Adjunctive brivaracetam in adults with uncontrolled focal epilepsy: results from a double-blind, randomized, placebo-controlled trial. Epilepsia 2014;55(1):47–56
  12. French JA, Krauss GL, Steinhoff BJ, et al. Evaluation of adjunctive perampanel in patients with refractory partial-onset seizures: results of randomized global phase III study 305. Epilepsia 2013;54(1):117–125

dr sumedha maturu 1

Dr. Mohan V. Sumedha Maturu

Dr. Mohan V. Sumedha Maturu

   MD Gen. Medicine, DM Neurology
  Consultant Neurologist
   Medicover Hospitals, Visakhapatnam

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