Difficult to Treat Epilepsy: A Management Primer for Non-Neurologists

Dr. Prithika Chary*

Department of Neurology and Neuroscience, Kauvery Hospital, Chennai

Email: drprithikachary@gmail.com

Epilepsy is a disorder of recurrent seizures with serious implications especially when seizures are frequent, severe and of long duration.

Such patients have difficult to treat epilepsy and can present a challenge in diagnosis and treatment. More significantly the epilepsy grossly impairs quality of life and has psychosocial implications and carries high morbidity and risk of mortality (SUDEP – Sudden Unexpected Death in Epileptic Persons).

Recent classification of the epilepsies by the ILAE (International League against Epilepsy) has defined refractory or drug resistant epilepsy as failure of adequate trials of two tolerated, appropriately chosen and used antiepileptic drug schedules (whether as monotherapies or in combination) to achieve sustained seizure freedom. This definition can be further refined when new evidence emerges.

Despite several attempts at various definitions a common ground is not present to decide when a patient fits the criterion of refractory or drug resistant epilepsy, in my practice I choose to have a broader category as difficult to treat epilepsy.

Such patients have severe epilepsy (their seizures are variable in semiology but often severe and prolonged or very frequent). The more disabling the seizures are the more impact and risk to life they cause. Such patients are often unable to lead even average normal lives and may even be dependent on others for their activities of daily living.

In my practice therefore I do not adhere too strictly to seizure count, number of drugs used or prolonged duration of active seizures to consider detailed evaluation and accurate diagnosis and a fair trial of appropriate medical, surgical, dietary and neurostimulation treatments, life style and mindset changes to believe that improvement is possible and enable them to attain a better quality of life despite limitations.

If the epilepsy is interfering with the daily life of the patient for more than 6 to 12 months, I categorize them as difficult to treat and subject them to systematic evaluation and investigation to identify a remediable lesion. The goal is always to reduce or stop seizures as far as possible, with medical or surgical treatment.

When lesion or epileptogenic zone localization is not present, the epilepsy is still more difficult to control.

Such patients are usually on polytherapy and may be having severe limitation of quality of life due to both the seizures and the medication.

What then are the options of management for such patients with difficult to treat epilepsy.

Outlined below is a primer on managing patients with “difficult to control” epilepsy


The first step is to ensure that the patient really does have epilepsy.

Proper history taking is invaluable and prevents misdiagnosis.

Out of patients referred as drug resistant or refractory epilepsy to specialist epilepsy centres around 2–70% do not have epilepsy. When reviewed by an epilepsy specialist usually around 23% do not have epilepsy. The commonest conditions misdiagnosed as epilepsy are syncopal attacks and psychogenic causes of epilepsy.

The commonest errors in diagnosis occur because of incomplete history taking, misinterpretation of the interictal EEG and inappropriate drug choice because of ignorance about the classification of epilepsy resulting in suboptimal management.

Education of general practitioners, neurologists in training and general neurologists is necessary to improve this scenario which impacts the life of the patient and his family negatively and exerts a service and monetary burden on the healthcare system.

The next step is to explore if noncompliance or triggers in lifestyle could account for the apparent drug resistance.

Since drug intake is over several years and causes considerable psychosocial difficulties, noncompliance is common and specific enquiry by the physician at each visit is important. Triggers such as sleep deprivation, missing meals, undue emotional or physical stress, overuse of technology, high ambient temperature exposure can also increase number of seizures.

Once the diagnosis of epilepsy is confirmed and peripheral factors as above are excluded, it is necessary to peruse the past investigations and plan new ones as necessary.


At least two interictal EEGs within the previous two years which shows epileptogenic activity may assist localizing the seizure in conjunction with home videos of the seizure to study ictal semiology. A properly taken EEG of 20 minutes or more is useful. If a recent seizure occurred, an EEG taken as soon as possible will provide valuable information.

All patients with more than two seizures a month, for more than two years, taking more than two anticonvulsants should undergo a video EEG. If seizures occur daily or several times a week, a drug deprived, sleep deprived video EEG of 6–24 hours may suffice to identify and classify the seizure. Longer duration of recording will be necessary for less frequent seizures.

In the more severe cases, where the scalp EEG is non-localising, intracranial electrodes or stereo EEG is done.

A careful study of the ictal semiology and correlation with the simultaneous EEG helps to classify the epilepsy and identify the epileptogenic zone.


Ideally a three tesla MRI brain with MR spectroscopy using the epilepsy imaging protocol and thin slices is the neuroimaging of choice. Rarely, a CT brain may also be needed especially for calcific lesions.

A plain study easily identifies temporal lobe pathology (DNET tumors, Mesial temporal sclerosis, Hippocampal atrophy, etc.), focal cortical dysplasia, and vascular lesions like cavernoma, etc. In symptomatic epilepsy, additional contrast studies also have to be done.

Though this extent of imaging is adequate in most patients, if the information obtained is confusing or not localizable, additional ictal SPECT and ictal or interictal PET is indicated.

Neuropsychological evaluation

The neuropsychological evaluation of a patient with difficult to treat epilepsy is done to identify areas of lobar dysfunction and to localize speech and other functions of eloquent cortex, especially if resective epilepsy surgery is planned. Also, it helps to identify comorbid psychiatric disturbances.

It has to be done by a clinical psychologist with experience in seeing such patients.

If the ictal semiology, video EEG, MRI, SPECT, PET and neuropsychological all localize to the same brain region this is known as concordance and such a patient may be suitable for epilepsy surgery. However, if the dysfunctional area is in eloquent cortex, the surgical option may have to reassessed.

As all patients with difficult to treat epilepsy may not benefit from epilepsy surgery, they have to be managed with drug treatment and possible additional dietary measures and stimulation devices.

Drug treatment

Classification of the seizure type is primary to drug selection, because the response depends on the right drug being used for the right type of seizure.

The mechanism of action of the drug is another consideration. Drugs with different mechanisms of action, or drugs with synergistic action when given together as polytherapy, increase the chances of a positive outcome with minimal or manageable side effects.

Choice of drug is also influenced by sex and age of the patient, associated comorbidities, known allergies and intolerances, affordability and access to healthcare.

Details of drug selection is beyond the scope of this article.

Epilepsy surgery

Epilepsy surgery is curative in patients with difficult to treat epilepsy if there is clear concordance between the ictal semiology, EEG, MRI, other neuroimaging, and the neuropsychological evaluation.

In properly selected cases amenable to resective surgery seizure reduction by more than 50% and complete cessation of seizures is seen in as high as 70% of patients. A small number are able to become drug free in 1–2 years post-surgery.

Unfortunately, epilepsy surgery is still an underused treatment option for patients with “difficult to treat epilepsy”

It is recommended especially in children that patients are referred for a presurgical evaluation within two years if their seizures are not controlled and occur more than twice a month despite AEDs given as polytherapy.

Details of epilepsy surgery are beyond the scope of this article.

In general, epilepsy surgery is of two types, resective and palliative. Resective procedures include anterior temporal lobectomy, amygdalohippocampectomy, hemispherectomy, excision of DNET and vascular tumors and focal cortical dysplasia, lobar resections, etc. Palliative procedures include anterior callosotomy, and subpial transection

Dietary treatment

The ketogenic diet is a very old dietary treatment used for severe seizures in children since the 1920’s. It has had a resurgence in the recent past and is useful in children and adults as a supplementary treatment option.

It is a high fat, low carbohydrate, moderate protein diet. Calories may also be restricted to 80–90%. The actual mechanism of action is unclear.

The classic KD consists of a 4:1 ratio of grams of fat to grams of protein plus carbohydrate combined; 90% of the calories in the diet come from fat.

Lower ratios such as 3:1 may be used in younger children.

This diet should be tried for at least three months and if a seizure reduction of more than 50% is seen, it can be continued for two years.

Because of the relative unpalatability of the diet for prolonged use, adaptations have been made

The MCT diet – better tolerated, 10–20% less fat and a little more allowance of carbohydrate

The modified Atkins diet – carbohydrates restricted to 10–20 g per day, and unlimited proteins with use of fat is encouraged.

Lower ratio diets are also used to improve compliance


Neurostimulation acts as a modulatory therapy in difficult to control epilepsy. They are mostly palliative treatments but play a role to improve quality of life in these patients.


Vagal nerve stimulation is particularly useful in patients with severe, frequent seizures who are unsuitable for epilepsy surgery. It works by sending small, regular pulses to the vagal nerve and this lessens or arrests seizures.

Acute Trigeminal stimulation has been found to reduce seizures in acute seizure models.

Acute deep brain stimulation (DBS) in various thalamic nuclei and medial temporal lobe structures has recently been shown to be efficacious in small pilot studies.

Responsive neurostimulation where direct stimulation of the seizure generating zone is done is showing promise for the future.

In this an advanced implantable device capable of using three algorithms is intended to detect ictal electrographic patterns and to trigger timely interference with ongoing ictal activity in a closed-loop fashion is implanted.


Patients with difficult to treat epilepsy constitute 30% of all patients with epilepsy. While the psychosocial impact of having epilepsy is experienced by all patients, these patients suffer more from the seizures themselves, and from the intensity of the treatments they require to just acquire a minimal quality of life. It is worth focusing on these patients to determine their chances of getting better. In patients suitable for resective surgery the change in their lives can be dramatic and permanent.

As an epileptologist, I recommend that these patients are referred within 2–3 years of uncontrolled seizures to improve their chances of improvement.


This article has been written to fulfill the intention of Purple Day celebrated world over on 26th March to increase awareness about epilepsy


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