management of drug-resistant epilepsy management of drug-resistant epilepsy drug-resistant epilepsy (dre), also known as refractory epilepsy or pharmacoresistant epilepsy, is diagnosed when there failure of adequate trials of two tolerated and appropriately chosen and used antiepileptic drugs (aeds) (whether as monotherapies or in combination) to achieve sustained seizure freedom. the probability that the next medication will achieve seizure freedom drops with every failed aed. for example, after two failed aeds, the probability that the third will achieve seizure freedom is around 4%. drug-resistant epilepsy is commonly diagnosed after several years of uncontrolled seizures, however, in most cases, it is evident much earlier. approximately 30% of people with epilepsy have a drug-resistant form. management of drug-resistant epilepsyother namesrefractory epilepsyspecialtyneurology when 2 aed regimens have failed to produce sustained seizure-freedom, it is important to initiate other treatments to control seizures. next to indirect consequences like injuries from falls, accidents, drowning and impairment in daily life, seizure control is critical because uncontrolled seizures -specifically generalized tonic clonic seizures- can damage the brain and increase the risk for sudden unexpected death in epilepsy called sudep. the first step is for physicians to refer their dre patients to an epilepsy center. diagnostic evaluation prolonged eeg/continuous video eeg/ epilepsy monitoring unit monitoring one of the first steps in management of drug resistant epilepsy is confirming the diagnosis by eeg. typically patients are admitted to hospital for prolonged eeg monitoring. typically patients are taken off their antiseizure medications so that the evolution of seizure symptoms and there relation with changes in electrical activity of brain can be determined; while minimizing adverse consequences of seizures as far as possible. additional maneuvers to provoke seizures are also frequently performed, like sleep deprivation, photic stimulation, hyperventilation. this study can take 3–14 days. length of study depends of factors like baseline seizure frequency, number and type of seizure medication patient is taking prior to study, institutional protocols etc. the goal is to record 3-4 typical seizures, though in some cases more or less seizures may need to be recorded. after this evaluation some patients may be determined to have non-epileptic causes of their symptoms, eg syncope, psychogenic nonepileptic seizures, cardiac arrhythmia etc. for patients who are confirmed to have epilepsy, this testing helps confirm the type of epilpesy- generalized vs focal. in case of focal epilepsy, this evaluation provides crucial information to determine the area of brain where seizures begin. information from seizure symptoms and their evolution over the course of the seizure as well changes on eeg in relation to the symptoms is used to hypothesize the likely area of the brain responsible for seizure symptoms (symptomatic zone) and by extrapolation the area where seizure likely starts (seizure onset zone). in some specific cases, prolonged eeg may be done as an outpatient or ambulatory study where patient goes home with eeg set-up. this type of monitoring is usually limited to 2–3 days and patients are not taken off their medications. neuroimaging mri of brain is the most common neuroimaging modality to be used in evaluation of epilepsy. a 3 tesla mri is generally recommended, as opposed to scanning on lower magnet strengths. mri for evaluation of epilepsy often include t1 and t2 images with small voxel size, that are optimized to appreciate gray-white matter differentiation and oblique coronal images along the axis of hippocampus. identification of lesions like focal cortical dysplasia, mesial temporal sclerosis, microencephalocele, heterotopia require thorough review of images by trained clinicians as the changes can be very subtle and easily missed if not specifically evaluated for. there is active research to develop newer ways of processing information from mri to better identify subtle structural lesions that can be associated with seizures. there is also ongoing quantitative analysis of standard mri images to identify subtle lesions and use of stronger magnetic fields, like 7tesla mri, for better delineation of anatomical details. positron emission tomography scan using dg is often used in evaluation of drug resistant epilepsy as well. its use in epilepsy evaluation is based on the idea that areas of brain responsible for seizure onset also have persistent metabolic dysfunction. so they do not use glucose at the same rate as normal healthy brain. areas involved in seizure onset or early propagation are expected to have lower glucose uptake, hence, lower radiotracer uptake, compared to other parts. other ligands like 11c-flumazenil, 11c-alpha-methyl-l-tryptophan, 11c-methionine, have also been used, mostly on research basis to help identify areas of seizure onset. pet-mri involves coregisteration of pet and mri images to better identify areas of cortex with relative hypometabolism. spect scan is another radiotracer based imaging technique that uses oxygen radio-isotope to assess blood flow. this imaging is performed during inpatient video eeg monitoring. the tracer is injected in patient's vein as soon as a seizure starts with the idea that areas of brain associated with seizure onset will have increase blood flow at seizure onset, hence, will show increase uptake of the tracer if injected at an appropriate time. imaging is performed after seizure is over and patient is medically stable to be taken to the scanner. post hoc analysis to assess areas showing significant increase in blood flow at seizure onset, compared to resting state, is used to identify areas of onset and early propagation. a major limitation with this technique is early identification of seizure onset for injection of radiotracer to be given well before the seizure discharge has spread widely. neuropsychological testing this includes a battery of tests to assess higher mental functions like memory, executive function, language functions, overall iq etc. if there is poor performance in measures of specific cognitive domains like verbal memory, naming, visuo-spatial orientation; it may point to areas of brain that are dysfunctional and likely related to seizure onset. this testing could also indicate poor performance on most measures and suggest more widespread dysfunction in the brain. besides helping assess the likely area of seizure onset, this testing also informs about cognitive risks from epilepsy surgery. language lateralization if epilepsy surgery is being considered, often a test is performed to determine the hemisphere of brain that is dominant for language and memory function. this helps inform about potential risks to language and memory with surgery. there are two main tests available for this objective- wada test and fmri. wada test has been one of the most commonly used tests around the world since the 1960s. this is an invasive procedure that requires neurointerventionalists, neuropsychologists, neurophysiologists, eeg technologists, anesthetists among the team members. a catheter is threaded from wrist or groin into the carotid artery and then the middle cerebral artery. an injection of sodium amytal is then given to temporarily anesthetize 2/3rd of the cerebral hemisphere on one side. neuropsychological testing is done to assess language and memory function of the other hemisphere. once patient is fully recovered from the injection on first side, the catheter is withdrawn and threaded up the other middle cerebral artery for transient anesthesia in the other hemisphere and testing of the hemisphere injected first. this testing informs the "reserve" for memory and language function in each hemisphere and potential for decline in these with resective surgery on a given side. in some cases additional testing with selective injection of posterior cerebral artery (that supplies the mesial temporal region including hippoampus) can be done to assess potential change in function with loss of these mesial structures on either side. wada is increasingly being replaced by fmri which is a noninvasive test. functional mri or fmri measure the change in blood flow and oxygenation in different parts of the brain, in response to an activity. different tasks or paradigms are presented to a patient while they are in an mri scanner. these tasks are designed to make the patient think of words, meaning of words, read, listen to language stimuli etc and hence, activate areas involved in different language functions while continuous scanning is being done. post processing of the images helps identify areas that are activated during different language tasks. other tests meg surgery in epilepsy surgery, a distinction can be made between resective and disconnective procedures. in a resective procedure the area of the brain that causes the seizures is removed. in a disconnective procedure the neural connections in the brain that allow the seizures to spread are disconnected. in most cases epilepsy surgery is only an option when the area of the brain that causes the seizures - the so-called epileptic focus can be clearly identified and is not responsible for critical functions such as language. several imaging techniques such as magnetic resonance tomography and functional techniques like electrocorticography are used to demarcate the epileptic focus clearly. lobe resection temporal lobe epilepsy (tle) in which the epileptic focus is in the temporal lobe, is one of the most common types of epilepsy in adolescents and adults. hence temporal lobe resection, during which the whole temporal lobe or just a part of the temporal lobe for example the hippocampus or the amygdala is removed, is the most common epilepsy surgery procedure. between 40 and 60% of patients that undergo temporal lobe resection are continuously seizure free the surgery itself is very safe with a mortality of 0%. the risk for neurologic complications from a temporal lobe resection is around 3 to 7% lesionectomy if the source of seizures is a lesion, for example a scar tissue from a brain injury a tumor or malformed blood vessels, this lesion can be removed surgically in a lesionectomy. corpus callosotomy corpus callosotomy is a palliative procedure for specially severe cases of epilepsy. this corpus callosum is a large bundle of nerve fibers that connects both brain halves with each other. to prevent the spreading of seizures from one brain hemisphere (brain half) to the other the corpus callosum can be split. this procedure is mostly carried out on patients with so-called drop attacks that come with a very high risk of injury and in which the epileptic focus is not clearly delimitable. it is very rare that a corpus callosotomy causes seizure freedom however in half of the patients the dangerous drop attacks are less severe. after a corpus callosotomy among others there is the risk that language is temporarily or permanently impaired. the younger a patient is at the time of the corpus callosotomy, the better the prognosis. functional hemispherectomy this procedure is a modern adaptation of the radical hemispherectomy in which one brain hemisphere is removed to prevent the spread of seizures from one brain hemisphere to the other. in the functional version only a part of the hemisphere is removed but the connections to the other brain hemisphere are cut through. this procedure is only performed on a small group of patients under the age of 13 that have severe damage or malformation of one hemisphere, patients with sturge weber syndrome or patients with rasmussen's encephalitis. the functional hemispherectomy can achieve long-term seizure freedom in over 80% of patients however often at the price of hemiplegia and hemianopsy. the death rate is around 1 to 2% and 5% of patients develop a hydrocephalus that needs to be treated with a shunt. multiple subpial transection multiple subpial transection (mst) is a palliative procedure that is considered when an epileptic focus can be identified but cannot be removed because it is in a functionally relevant brain region- a so-called eloquent region. in an mst nerve fibers are disconnected so that seizures cannot spread from the epileptic focus into the rest of the brain. between 60 and 70% of patients experienced a seizure reduction of over 95% after an mst and the risk for neurologic deficits is around 19%. vagus nerve stimulation vagus nerve stimulation (vns) involves implanting a pacemaker-like generator below the skin in the chest area that intermittently sends electrical impulses to the left vagus nerve in the neck. the impulses are mediated to the brain by the vagus nerve and thereby help to inhibit electrical disturbances that cause seizures. the antiepileptic effect of vagus nerve stimulation increases over several months: after two years around half of vns patients experience a reduction of their seizures by at least 50% and after 10 years the average seizure reduction is around 75% furthermore, in most patients mood (vns has a significant anti-depressent effect and is approved