Done by PharmD Students: Sarah Haroun Lama Abu Salih ...

Epilepsy Treatment Guidelines

Done by PharmD Students:

Sarah Haroun

Lama Abu Salih

Supervisor:

Dr.Eshraq Al-Abweeny

DEFINITION

Epilepsy is a common neurologic condition in which a person is

prone to recurrent epileptic seizures. There are many types of

epilepsies characterized by different seizure types, ranging in

severity and etiologies. While the specific pathophysiologic

mechanisms behind different epilepsies are complex, the

underlying general pathophysiologic process at the heart of all

epilepsies is disturbed regulation of electrical activity in the brain

resulting in synchronized and excessive neuronal discharge.

CLASSIFICATION

Epileptic seizures can manifest physically in a variety of ways and

can range from intense involuntary repetitive muscular

contractions (eg, convulsions) to subtle alterations in sensation or

consciousness. Due to the wide range of seizure types that may

present it is often difficult to describe and classify seizures.

However, in general, most seizures can be classified by their mode

of onset and can be divided broadly into two categories: (1)

generalized and (2) focal. In the broadest terms, generalized onset

seizures begin in both hemispheres of the brain, while focal onset

seizures begin in only one hemisphere of the brain. Understanding

seizure onset is important, as it is the fundamental characteristic

by which to classify seizures. Recognizing mode of seizure onset

has significant treatment and prognostic implications.

Focal Onset Seizures Focal seizures may be further characterized by whether

impairment or alteration of consciousness occurs.

Impairment of consciousness is usually defined by loss of

awareness of external stimuli or by the inability to respond to

external stimuli in a purposeful and appropriate manner.

When consciousness is not impaired and when awareness

and responsiveness are retained, such seizures are termed

focal seizures without dyscognitive features under the

newest classification system released by the ILAE in 2010.

These seizures correspond to what has historically been

termed simple partial seizures, as by definition

consciousness is not impaired.

Generalized Onset Seizures Generalized onset seizures begin in both hemispheres of the

brain and have previously been referred to as primary

generalized seizures. The ILAE now recognizes six types of

generalized onset seizures including (1) absence seizures,

(2) myoclonic seizures, (3) tonicclonic seizures, (4) clonic

seizures, (5) tonic seizures, and (6) atonic seizures. Like

secondarily generalized seizures, generalized onset seizures

typically have clinical manifestations that indicate

involvement of both hemispheres (eg, motor manifestations

are bilateral and symmetric). Recognizing the difference

between generalized onset seizures and secondarily

generalized seizures may be difficult, but certain

distinguishing features such as presence of aura and

characteristic findings on electroencephalogram (EEG) aid in

distinguishing between the two.

Diagnosis

Epilepsy is a clinical diagnosis, meaning that it is a diagnosis

made on the basis of medical signs and patient-reported

symptoms, rather than any one diagnostic test.

A person is considered to have epilepsy if they meet any of the

following conditions:

- At least two unprovoked (or reflex) seizures occurring greater

than 24 hours apart.

- One unprovoked (or reflex) 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.

Accurate diagnosis also depends on the neurologic examination

and diagnostic techniques such as electroencephalography

(EEG) and brain imaging.

CLINICAL PRESENTATION

Characteristics of Focal Seizures

Focal seizures without dyscognitive features may manifest

clinically in a variety of ways and may be further characterized by

one or more features including motor or autonomic symptoms.

Such symptoms will vary depending on where the abnormal firing

occurs. For example, seizures may manifest as alterations in

motor functions such as clonic movements (eg, twitching or

jerking) of the arm, shoulder, face, or leg indicating seizure activity

in motor pathways. Sensory or somatosensory symptoms may

also occur, such as feelings of numbness or tingling or a feeling of

déjà vu, indicating parietal or temporal lobe seizure activity. Visual

disturbances or hallucinations may also indicate seizure activity

involving the occipital lobe, while ringing or buzzing sounds in the

ears may indicate seizure activity in auditory areas of the brain.

Autonomic symptoms such as sweating, salivation, or pallor may

also occur, indicating seizure activity in autonomic areas of the

brain. In all the above examples of focal nondyscognitive seizures,

only a portion of the brain is affected during the seizure, and the

person retains consciousness, awareness, and responsiveness.

The hallmark of focal dyscognitive seizures is amnesia to the

event. Depending on the area of the brain involved, focal

dyscognitive seizures may have similar clinical signs and

symptoms as that described except with impairment of

consciousness. The patient may still be able to perform routine

tasks such as walking, although such movements are not

purposeful or planned and after the event is over the patient may

not recall their actions. The patient may also be able to respond to

questions during the seizure, although they may not respond

appropriately. The degree of alteration in awareness and

responsiveness may be so subtle that witnesses may sometimes

not be able to recognize that anything is overtly wrong. For

example, during these seizures the patient may simply display

behavioral arrest and stare off into space for a minute. They may

also display subtle automatisms such as lip smacking, chewing, or

picking at their clothing unpurposefully. On the other hand, some

patients may display extreme aberrations of behavior, and some

are even mistakenly diagnosed as having psychotic episodes.

After the seizure (postictal period), the patient may display altered

consciousness, drowsiness, confusion, or even paranoia for a

variable period of time and frequently go into a deep sleep. Focal

seizures are sometimes followed by convulsive seizures. During

convulsive or generalized tonic-clonic (GTC) seizures, the patient

experiences loss of consciousness, followed by a sudden sharp

tonic contraction of muscles with a subsequent period of rigidity

and clonic movements oftentimes described as jerking of the arms

and legs. During the seizure, the patient may cry or moan, due to

muscles in the larynx being activated. The patient may also lose

sphincter control with bladder and/or bowel incontinence or bite the

tongue. Postictally, after the patient regains consciousness, the

patient may experience confusion, drowsiness, lack of

coordination, soreness throughout the body, and amnesia for the

event.

TREATMENT

Goals of therapy:

The management of patients with epilepsy is focused on three

main goals:

Controlling seizures.

Avoiding or minimizing treatment side effects.

Maintaining or restoring quality of life.

Non pharmacological Therapy:

Diet The ketogenic diet is high in fat and low in carbohydrates

and protein. Protein and calorie intake are set at levels that

will meet requirements for growth. Most of the calories are

provided in the form of heavy cream and butter. No sugar is

allowed. Carb-free vitamins and minerals are supplemented.

Fluids are also controlled. It requires strict control and parent

compliance. Long-term effects include kidney stones,

increased bone fractures, and adverse effects on growth.

Drugs to lower the chances of kidney stones could be taken

and ketones in urine should be checked to know how well

the diet is working.

Surgery Surgery is the treatment of choice in selected patients with

refractory focal epilepsy. Epilepsy surgery is not without risk,

Learning and memory can be impaired postoperatively, and

general intellectual abilities are also affected in a small

number of patients. Patients may need to continue

antiseizure drug (ASD) therapy for a period of time following

successful epilepsy surgery, but dosage reduction may be

achievable.

Vagus nerve stimulation (VNS) The VNS device is relatively safe. It may also have a positive

effect on mood and behavior, often independent of seizure

reduction. The most common side effect associated with

stimulation is hoarseness, voice alteration, increased cough,

pharyngitis, dyspnea, dyspepsia, and nausea. Serious

adverse effects reported include infection, nerve paralysis,

hypoesthesia, and facial paresis, left vocal cord paralysis, left

facial paralysis, left recurrent laryngeal nerve injury, urinary

retention, and low-grade fever. In the VNS studies, the

percentage of patients who achieved a 50% or greater

reduction in their seizure frequency (responders) ranged

from 23% to 50% at 3 months. VNS effects are not noted

immediately and are more long term. VNS is also unlikely to

lead to seizure freedom but may allow for reduced seizure

frequency and reduced medication burden.

Pharmacologic Therapy:

There are more than 20 antiseizure drugs (ASDs) available in the

United States and worldwide for the treatment of epilepsy. Efficacy

of ASDs as monotherapy or as add-on treatment in epilepsy is

generally established through clinical trials.

Epilepsy is initially treated with antiseizure medication

monotherapy. Almost half of patients will become seizure-free with

their first anti-seizure medication trial.

In choosing an initial therapy, clinicians must weigh relative

efficacy and potential for adverse effects of each drug.

Comparative efficacy and tolerability data are limited. Comparison

trials that have been performed have not shown significant

differences among various drugs in terms of efficacy. Clinicians

must therefore formulate treatment plans based upon a

combination of drug, seizure, and patient-specific factors.

When to start antiseizure drugs

If a patient presents after a single isolated seizure, one of

three treatment decisions can be made: (1) treat, (2) possibly

treat, or (3) do not treat. These decisions are based on the

probability of the patient having a second seizure. For

patients with no risk factors, normal MRI, and normal EEG,

the probability of a second seizure is less than 10% in the

first year and approximately 21% by the end of 2 years. If

risk factors are present, the probability of seizure recurrence

is 26% in the first year and 41% by the end of the second

year.

Immediate antiseizure medication therapy is usually not necessary

in individuals after a single seizure, particularly if a first seizure is

provoked by factors that resolve. Antiseizure medication therapy

should be started in patients who are at significant risk for

recurrent seizures, such as those with remote symptomatic

seizures. Antiseizure medication treatment is generally started

after two or more unprovoked seizures, because the recurrence

proves that the patient has a substantially increased risk for

repeated seizures, well above 50 percent.

Selection of an antiseizure medication

When selecting an ASD, the following should be considered:

1. ASD effectiveness for the specific seizure type, epilepsy

or epilepsy syndrome.

2. Selection of an ASD with the most tolerable adverse

effect profile, considering patient specific factors including

age and gender.

3. Selection of an ASD that can also treat the patient’s other

comorbid conditions.

4. Ability to comply with a regimen (eg, three or four times

daily dosing) and insurance coverage, as this can affect ASD

adherence and effectiveness.

5. Interactions with other medications.

6. Need for therapeutic levels to be reached quickly (eg,

avoid ASDs which require slow titration such as lamotrigine

or topiramate).

Once an ASD has been selected, start with a low dose, and

gradually titrate to a moderate dose goal, taking into account

the patient’s response to treatment. If the patient is seizure

free with no adverse effects at a moderate therapeutic dose,

then no further increase in dose is necessary. If the patient

continues to have seizures at this moderate dose, titrating

the patient to a maximum dose is recommend. If the first

ASD monotherapy is ineffective, or if the patient experiences

intolerable adverse effects, adding a second AED and then

tapering and discontinuing the ineffective or intolerable first

ASD is appropriate. Selecting an ASD with a different

mechanism of action than the first intolerable or ineffective

ASD may increase the likelihood of success. If the second

ASD is ineffective, polytherapy may be indicated, and an

adjunctive ASD should be gradually titrated on. Selection of

an adjunctive ASD with a different or complementary

mechanism of action is the basis behind rational polytherapy

and is recommended, although there is no clear evidence in

humans to support this.

Therapeutic Considerations in the Elderly and Young

Use of ASDs in the elderly and young can pose special challenges. The elderly are often on many different medications which may con-tribute to increased sensitivity to neurocognitive effects as well as increased possibility of drug-drug interactions with ASDs that affect the cytochrome P450 (CYP450) system (eg, carbamazepine, phenytoin, and valproic acid). Hypoalbuminemia, body mass changes, and compromised renal or hepatic function that require ASD dosage adjustment. Lamotrigine is often considered the medication of choice in elderly patients with focal-onset seizures.

For neonates and infants, an increase in the total body water to fat ratio and a decrease in serum albumin affect ASD elimination half-life. Additionally, infants up to the age of 3 years have decreased renal elimination of ASDs, with neonates being the most affected. Hepatic activity is also reduced in neonates and infants, but by age 2 to 3 years, hepatic activity then becomes more robust than that seen in adults. Therefore, whereas neonates and infants require lower doses of ASDs, children require higher doses than that seen in adults. Therapeutic drug monitoring becomes especially important in the young.

Therapeutic Considerations in Women (and Men)

Exogenously, enzyme-inducing ASDs (eg, carbamazepine and topiramate and oxcarbazepine at higher doses, and possibly clobazam, felbamate, lamotrigine, and rufinamide) can cause treatment failures in women taking oral contraceptives (OCs) due to increased metabolism of ethinyl estradiol and progestin. Medroxyprogesterone depot injections and hormone-releasing intrauterine systems on the other hand, are not similarly affected by ASDs, and it is unclear if there is an effect of ASDs on the transdermal contraceptive patch or the emergency contraceptive pill. A supplemental or alternative form of birth control (eg, IUD) is advised if breakthrough bleeding occurs in woman taking certain types of ASDs (eg, enzyme-inducing ASDs) and OCs, and it has been suggested that women use twice the normal dose of emergency contraception.

Therapeutic Considerations for Pregnancy and Breastfeeding

Pregnancy and epilepsy is a particularly complex topic. The goal of treatment in pregnant women with epilepsy is to achieve the best possible control of seizure with the minimal adverse effects for both the mother and the child. Epilepsy-related complications during pregnancy include possible changes in seizure frequency, fluctuating ASD plasma levels, and possible teratogenic effects of ASDs.

Women with epilepsy who were seizure free for at least 9 months to 1 year prior to pregnancy, had a very high probability (84%-92%) of remaining seizure free during pregnancy. It should be noted, however, that if seizures are increasing during pregnancy, a commonly over-looked reason for this increase is nonadherence in a normally adherent patient, due to concerns about the potential adverse drug effects on the developing fetus.

It is recommended that ASD levels, particularly lamotrigine levels, be monitored closely during pregnancy, and to increase doses if needed over the course of the pregnancy with rapid decrease in the postpartum period. Of note, fluctuations have also been reported for phenobarbital, valproic acid, primidone, and ethosuximide, although strong evidence for this is lacking.

Adverse pregnancy outcomes associated with ASD use include an increased risk of major congenital malformations (MCMs) compared to nonepileptic women. This risk is believed to be due to ASD exposure and not maternal seizures, as infants born to women with epilepsy who do not take ASDs have the same risk of birth defects as infants born to seizure-free women (2%-3%).The most concerning effects are found with the use of valproic acid which is associated with a risk of MCMs that is 3.5 to 4 times that of offspring from nonepileptic women, especially if taken during the first trimester of pregnancy. Furthermore there is an increased risk of neurodevelopmental deficits, including effects on cognition in children exposed to valproic acid in utero. Due to these findings, it is recommended that valproate should preferably not be used in epilepsy and that withdrawal of valproate or switch to an alternative treatment should be considered in these patients.

In general, higher ASD doses, higher ASD serum concentrations, polytherapy (especially polytherapy with valproate), and a family history of birth defects appear to increase the teratogenic risk of ASDs. As such, the risk of birth defects is believed to have gone down with decreasing doses and decreasing use of polytherapy. Deciding on the most effective single-drug treatment prior to conception is vitally important. Teratogenic effects of ASD must always be considered when choosing ASDs for women of reproductive age, even when they do not plan on becoming pregnant, as many unplanned pregnancies occur and MCMs generally occur early in pregnancy before women know that they are pregnant. With proper counseling and management, more than 90% of these pregnancies will still have satisfactory outcomes. Updated practice parameters are available to aid in the counseling and management of pregnant women with epilepsy.

Teratogenic effects may possibly be prevented by adequate folate intake, although strong data are lacking. However, as the risk of MCM is possibly decreased by folic acid supplementation, prenatal vitamins with folic acid (0.4-5 mg/day) are recommended for women of child-bearing potential who are taking ASDs.

Some ASDs pass into the breast milk. ASDs with less protein binding will accumulate more in breast milk. Treatment with ASDs is not necessarily a reason to discourage breastfeeding, although ASD concentrations are measurable in breastfeeding infants. Infants born to women taking any ASD (particularly barbiturates or benzodiazepines) should be closely observed for signs of excess sedation, irritability, or poor feeding.

Serum Concentration Monitoring

Serum concentrations of the older ASDs should be viewed as a tool with which to optimize therapy for an individual patient, not as a therapeutic end point in itself. The serum concentration is a target that should be correlated with clinical response. The desired outcome is the cessation of seizures without side effects. Seizure control can occur before the “minimum” of the published therapeutic range is achieved, and side effects can appear before the “maximum” of the range is achieved. Some patients may need and tolerate concentrations beyond the maximum.

Serum levels can be useful to document lack of efficacy, loss of efficacy, noncompliance, and to determine how much room there is to increase a dose based on expected toxicity. Depending on the ASD, serum levels can also be useful in patients with significant renal and/or hepatic disease, patients taking multiple drugs, and women who are pregnant or taking OCs. Therapeutic concentration ranges have not been clearly defined for some of the second-generation ASDs.

Drug-Drug Interactions

Knowledge of ASD metabolic pathways as well as inducer or inhibitory effects on liver enzymes can aid in the optimization of ASD therapy. Pharmacokinetic interactions are a common complicating factor in ASD selection. Interactions can occur in any of the pharmacokinetic processes: absorption, distribution, metabolism, or elimination. Caution should be used when ASDs are added to or withdrawn from a drug regimen.

When to Stop Antiseizure Drugs

The ASDs used to control seizures may not need to be given for a lifetime. Polypharmacy can be reduced, and some patients can discontinue ASDs altogether. Factors favoring successful withdrawal of ASDs include a seizure-free period of 2 to 4 years, complete seizure control within 1 year of onset, an onset of seizures after age 2 but before age 35, and a normal neurologic examination and EEG. Factors associated with a poor prognosis in discontinuing ASDs, despite a seizure-free interval, include a history of a high frequency of seizures, repeated episodes of status epilepticus (SE), a combination of seizure types, and development of abnormal mental functioning.

The American Academy of Neurology (AAN) has issued guidelines for discontinuing ASDs in seizure-free patients. After assessing the risks and benefits to both the patient and society, ASD withdrawal can be considered in a patient meeting the following profile: seizure free for 2 to 5 years, a history of a single type of focal seizure or primary generalized seizures, a normal neurologic exam and normal IQ, and an EEG that has normalized with treatment. When these factors are present, the relapse rate at 1 year is expected to be 35% and 29% at 2 years. ASDs can be restarted in patients who relapse after ASD withdrawal. Seizure freedom can be regained for most patients who restart ASDs although not for all.

Antiseizure drug withdrawal should be done gradually. Some patients will have a recurrence of seizures as the ASDs are withdrawn. Sudden withdrawal can be associated with the precipitation of SE. Withdrawal seizures are of particular concern

for agents such as benzodiazepines and barbiturates, and these ASDs should be withdrawn more slowly over a period of many months.

EVALUATION OF THERAPEUTIC OUTCOMES:

Patients should record the severity and the frequency of seizures in a seizure diary, and there should be a decrease with treatment. Patients and family should be questioned regularly to determine whether patients are truly seizure free. Patients should also be monitored long term for comorbid conditions, social adjustment (including QOL assessments), drug interactions, and adherence. Periodic screening for comorbid neuropsychiatric disorders, such as depression and anxiety, is also important.

Outcomes are focusing increasingly more on optimal QOL. It is important to remember to counsel patients about ASD side effects, initiate discussion about depression, and assess their knowledge about referral of the intractable epilepsy patient for surgery.

REFERENCES:

- Joseph T. DiPiro, Robert L. Talbert, Gary C. Yee, Gary R. Matzke,

Barbara G. Wells, L. Michael Posey. Pharmacotherapy: A

Pathophysiologic Approach. 10th ed. OH, United States: McGraw-Hill

Education: 2017. 56, Epilepsy, p. 837-867.

- Steven C Schachter. Overview of the management of epilepsy in adults.

In John F Dashe (Ed.), UpToDate. Retrieved Aug 15, 2015, from

https://www.uptodate.com/contents/overview-of-the-management-of-

epilepsy-in-adults