Pharmacoresistant epilepsy: From pathogenesis to current and emerging therapies

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ABSTRACTAlmost one-third of people with epilepsy continue to have seizures despite appropriate antiepileptic drug treatment, placing them at considerable risk of cognitive and psychosocial dysfunction and death. We recommend early referral to an epilepsy center when seizures are difficult to control.


  • When seizures have failed to respond to two or three appropriate antiepileptic drugs, the chance of significant benefit from other drugs is 10% or less.
  • The biologic basis of pharmacoresistance is multifactorial and varies from one patient to another.
  • Social and lifestyle factors, including alcohol misuse and nonadherence to prescribed antiepileptic drugs, can contribute to or masquerade as pharmacoresistance.
  • Current options for patients with pharmacoresistant epilepsy are surgery (the best option when feasible), vagus nerve stimulation, investigational drugs or devices, and aggressive combination treatment with available antiepileptic drugs.



Although more than 10 new antiepileptic drugs have been developed in the past decade, epilepsy remains resistant to drug therapy in about one-third of patients. 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.1

Those who get no response or only a partial response to drugs continue to have incapacitating seizures that lead to significant neuropsychiatric and social impairment, lower quality of life, greater morbidity, and a higher risk of death.

Managing these patients is a challenge and requires a structured multidisciplinary approach in specialized clinics. Newer research, particularly in pharmacogenomics, holds promise of therapy that more closely suits an individual’s profile and type of epilepsy.

This article reviews recent developments in the pathogenesis and treatment of pharmacoresistant epilepsy, placing these topics in clinical context to facilitate and enhance the physician’s ability to manage it.


A US study in the early 1990s estimated that the annual cost of refractory epilepsy in adults exceeds $11,745 per person2; the cost would be considerably higher today. Another study found that costs correlate with severity of illness and that patients who have intractable seizures incur a cost eight times greater than in those whose epilepsy is controlled.3

Higher risk of death

In any given interval of time, people with pharmacoresistant epilepsy are about two to 10 times more likely to die compared with the general population.4 The risk is inversely linked to seizure control.

Sudden unexpected death in epilepsy”is the most frequent type of death in patients with pharmacoresistant epilepsy. This category excludes deaths from trauma or drowning. The death can be witnessed or unwitnessed and with or without evidence of a seizure (but not documented status epilepticus). Postmortem examination does not reveal a toxic or anatomic cause of death, and the underlying mechanisms remain unknown. However, the risk is closely associated with drug resistance (which manifests with uncontrolled convulsive seizures and need for polytherapy with antiepileptic drugs).5

Case-control studies have shown that the risk of sudden unexpected death is closely and inversely associated with seizure control; the rate is significantly higher in patients who have a higher frequency of convulsive seizures.6 In addition, freedom from seizures, achieved after successful epilepsy surgery, reduces the risk of death from all causes.7

Other causes of death in patients with epilepsy may be directly related to seizures (accidental trauma, drowning, burns) or to the underlying condition causing the seizures. Furthermore, people with epilepsy are at higher risk of suicide than the general population.


There is no uniformly accepted definition of pharmacoresistant epilepsy. Most studies defined it according to the number of antiepileptic drugs the patient had tried without success, the frequency of seizures, the duration of illness, and the period of remission. Its true definition awaits a better understanding of underlying mechanisms.

Nevertheless, a useful operational definition at present is failure to control seizures despite a trial of two or three drugs that are suitable for the type of epilepsy and have been appropriately prescribed at maximum tolerated doses. This is because the chances of controlling epilepsy decline sharply after failure of the second or third antiepileptic drug trial. In fact, some clinicians would argue against trying another antiepileptic drug in these patients, who may be candidates for surgical procedures that have high rates of success.8

Common causes of treatment failure, such as poor compliance or inappropriate selection of first-line antiepileptic drugs, should be addressed early on by the treating physician. Nonadherence to the prescribed regimen is a very common cause of uncontrolled seizures, so it is critical to maintain a good rapport with the patient and to inquire about reasons for noncompliance.

Factors that have been associated with treatment-resistant epilepsy include:

  • Early onset of seizures
  • Long history of poor seizure control
  • Having more than one type of seizure
  • Remote symptomatic etiology (eg, patients with a history of brain infection or head trauma)
  • Certain structural abnormalities (eg, cortical dysplasia)
  • Certain abnormalities on electroencephalography (EEG)
  • Cognitive disability
  • History of status epilepticus.

When to consider referral

A topic of debate is how long a patient must have active epilepsy before he or she is considered to have pharmacoresistance and should be referred to a specialist center.

Both the rate of remission and the time needed to achieve remission depend on multiple factors such as the type and etiology of the epilepsy and the definition of sustained intractability.

Importantly, the prognosis for most patients with newly diagnosed epilepsy, whether good or bad, becomes apparent within a few years of starting treatment. Although pharmacoresistant epilepsy will become refractory within 8 years in some patients, in others a second drug may not fail for more than 1 or 2 decades after diagnosis. Nonetheless, a history of a lack of a sustained seizure-free period for 12 consecutive months, in spite of two or three suitable and tolerated antiepileptic drugs, is a definite red flag for clinicians and should prompt referral to a specialist center.9,10 The National Association of Epilepsy Centers recommends referral to a specialized epilepsy center if seizure control is not achieved by a general neurologist within a period of 9 months.11

“False pharmacoresistance” (Table 1) may not be easily recognizable, and this possibility needs to be investigated in any patient presenting with difficult-to-control seizures. Up to 30% of patients referred to clinics with a diagnosis of pharmacoresistant epilepsy may have been misdiagnosed, and many can be helped by optimizing their treatment.12


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