Treatment resistant epilepsy

Treatment-resistant epilepsy is a type of epilepsy that doesn’t respond to standard medications.

Treatment resistant 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.

One of the first steps in management of drug resistant epilepsy is confirming the diagnosis by prolonged EEG. 

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.

Maneuvers to provoke seizures are also frequently performed, like sleep deprivation, photic stimulation, hyperventilation. 

Testing for resistant epilepsy can take 3–14 days. 

The goal is to record 3-4 typical seizures.

Some patients may be determined to have non-epileptic causes of their symptoms, eg syncope, psychogenic nonepileptic seizures, or cardiac arrhythmia.

EEG testing helps confirm the type of epilpesy- generalized vs focal. 

In the case of focal epilepsy, evaluation may 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 identify the likely area of the brain responsible for seizure symptoms.

MRI of brain is the most common neuroimaging modality to be used in evaluation of epilepsy: 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. 

Lesions like focal cortical dysplasia, mesial temporal sclerosis, microencephalocele, and heterotopia can be very subtle and easily missed if not specifically evaluated for. 

Positron emission tomography scan using [18F]DG is used in the evaluation of drug resistant epilepsy based on the idea that areas of brain responsible for seizure onset also have persistent metabolic dysfunction. 

Seizing brain cells do not use glucose at the same rate as normal healthy brain, so that areas involved in seizure onset or early propagation are expected to have lower glucose uptake, hence, lower radiotracer uptake, compared to other parts. 

SPECT scan based imaging technique uses oxygen radio-isotope to assess blood flow. 

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. 

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. 

Neuropsychological tests can assess higher mental functions like memory, executive function, language functions, and IQ.

Impaired 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. 

Treatment resistant is defined as persistent seizures after two trials with an appropriate anti-seizure medication at optimal doses, administered a single or multiple drug therapy.

Drug resistant epilepsy occurs in approximately 30 to 40% of all patients with epilepsy, but is more frequent in focal than generalized disease.

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%.

Approximately 30% of people with epilepsy have a drug-resistant form.

Identifying and avoid triggers that may be causing seizures:stress or certain foods.

The treatment plan for treatment-resistant epilepsy may vary depending on the individual’s specific circumstances.

Different medication or a combination of medications that may be more effective in controlling your seizures may be utilized.

For treatment-resistant epilepsy, a combination of medications may be used to manage seizures. Some of the medications that may be used include:

1. Felbamate

2. Topiramate

3. Lamotrigine

4. Levetiracetam

5. Zonisamide

6. Perampanel

7. Clobazam

8. Eslicarbazepine acetate

9. Rufinamide

10. Lacosamide

When 2 AED regimens have failed to produce sustained seizure-freedom, it is important to initiate other treatments to control seizures. 

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.

Other measures:

Vagus nerve stimulation (VNS)

Ketogenic diet:

Surgery may be an option for some people with treatment-resistant epilepsy, particularly if the seizures are originating from a specific area of the brain.

Before epilepsy surgery is considered, tests are  performed to determine the hemisphere of brain that is dominant for language and memory function. 

The two main tests available for this objective are the Wada test and fMRI.

The Wada test is an invasive procedure that requires neurointerventionalists, neuropsychologists, neurophysiologists, EEG technologists, anesthetists to place a catheter 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, followed by neuropsychological testing to assess language and memory function of the other hemisphere. 

The Wada test has been 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 are presented to a patient while they are in an MRI scanner, which are 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. 

In epilepsy surgery, there are 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. 

Epilepsy surgery is only an option when the so-called epileptic focus can be clearly identified and is not responsible for critical functions such as language. 

Magnetic resonance tomography and functional techniques like electrocorticography are used to demarcate the epileptic focus clearly.

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. 

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%.

If the source of seizures is a specific lesion: a scar tissue from a brain injury a tumor or malformed blood vessels, this lesion can be removed surgically in a lesionectomy.

Corpus callosotomy is a palliative procedure for specially severe cases of epilepsy. 

To prevent the spreading of seizures from one brain hemisphere 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.

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.

A radical hemispherectomy is a rare procedure when one brain hemisphere is removed to prevent the spread of seizures from one brain hemisphere to the other. 

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 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.

In Multiple subpial transection nerve fibers are disconnected so that seizures cannot spread from the epileptic focus into the rest of the brain. 

It 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.

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 (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. 

Vagus nerve stimulation has an antiepileptic effect that increases over months, and at the two-year point there around half of vagal nerve stimulator patients have a reduction in the seizures of at least 50%, and it 10 years the average seizure reduction is 75%

In most patients VNS has a significant anti-depressent effect and is approved for depression in some countries, and alertness and quality-of-life are increased significantly within the first year of vagus nerve stimulation.

VNS patients can induce an extra stimulation themselves when they notice that a seizure is approaching and a majority of seizures can be interrupted this type of on-demand stimulation.

The procedure to implant a vagus nerve stimulator is very safe.

Infection of the tissue pocket in which the generator is located that requires antibiotic treatment occurs in around 3% of patients.

The most common side effect is hoarseness or change in voice, and less often headaches and shortness of breath.

Side effects only occur during activity of the stimulation and reduce over time.

In most cases antiepileptic medications, but in many cases the dose can be reduced over time so that patients experience fewer side effects of the medication. 

In 82% of epilepsy patients the heart rate increases quickly and suddenly upon a seizure-ictal tachycardia. 

Ictal tachycardia is characteristic, distinguished it from the slow gradual increase of heart rate that occurs during physical activity. 

The earlier in the course of the seizure the stimulation occurs  the quicker the seizure end.

Generally, seizures are reduced by around 35% by stimulation.

A diet with a high fat content and a low carbohydrate content can reduce seizures. 

Decreasing carbohydrate intake diet severely forces the body to draw energy from ketone bodies that form when fat is metabolized instead of drawing its energy from sugar: ketosis changes several biochemical processes in the brain inhibiting epileptic activity. 

A  ketogenic diet for epilepsy: a ratio of fat to carbohydrates and proteins at 4:1, meaning that the fat content of the consumed food must be around 80%, the protein content must be around 15%, and the carbohydrate content must be around 5%. 

The average western diet consists of a carbohydrate content of over 50%, and after one year on the ketogenic diet seizure reduction is over 50%, and the dropout rate is around 45%.

A  fat ratio of 3: 1 instead of 4: 1 can be recommended to make meals more palatable. 

Side effects of the ketogenic diet can be constipation, tiredness and after a long term diet, in one out of 20 patients, kidney stones.

Medium-chain triglycerides (MCT) fats metabolized in the body more create more ketone bodies then from metabolizing any other fat. 

MCT ketogenic diet a modification of the ketogenic diet has nearly replaced the classic ketogenic diet in the USA. 

The MCT ketogenic diet MCT oil is added to ketogenic meals, allows the carbohydrate content to be increased to around 15 to 20%.

The success rate of the MCT ketogenic diet does not differ from the classic ketogenic diet.

A modified Atkins diet reduces seizures through ketosis: the nutrition is slightly lower than in the ketogenic diet at around 60%, the protein content is around 30% and the carbohydrate content is around 10% rendering the diet less restrictive and more compatible with the daily life compared to the ketogenic diet. 

The modified Atkins diet produces a similar or slightly lower seizure reduction to the ketogenic diet.

Deep brain stimulation of the anterior nuclei of the thalamus is approved in some countries in Europe, but has been and continues to only be used in a very few patients. 

Transcutaneous vagus nerve stimulation (tVNS) is approved in some European countries and involves externally stimulating the auricular branch of the vagus nerve in the ear. 

tVNS failed to demonstrate efficacy in a first randomized-double blinded trial.


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