EPILEPSY

EPILEPSY
Rahnas K. THH, Sujith Varma National College of Pharmacy, Manassery, Calicut INTRODUCTION Epilepsy is a worldwide health problem. The word 'epilepsy' comes from the Greek word, meaning 'to seize'.*' Epilepsy affects approximately 1% of the worldwide population and is the second most common neurological disorder after stroke.6

Epilepsy is a chronic disorder characterized by recurrent, unprovoked seizures. A seizure is a single event of disturbed neurological function, affecting motor, sensory, autonomic or psychic function caused by excessive synchronized firing of neurons. In both medical and scientific parlance, the term seizure disorder is often used synonymously with epilepsy.

Epilepsy is a chronic condition that has considerable impact on the life of each individual patient. The pharmacist can play a vital role in the use of anti epileptic drugs. The treatment goal of epilepsy is to make the patient be completely seizure free without significant side effects. The ability of the patient to tolerate a given AED is an important part of successful AED therapy.

Adverse drug reactions of anti epileptic drugs are a major problem & have significant economic impact on health care system. Pharmacists are in an ideal situation to detect report & manage adverse drug reactions through daily contact with patients.

Patient compliance can be improved by providing patient education leaflets & medication reminder charts.The major barrier towards treatment failure in epilepsy is patient noncompliance which could be due to:

Inability in refilling prescription Taking an incorrect dose Taking the medication at the wrong time. Forgetting to take one/more doses. Stopping the medication too soon, [without prescriber's knowledge]

DEFINITION Epidemiology

At a conservative estimate 50 million people worldwide have epilepsy. WHO suggest that as many as 1 in 20 people may have an epileptic seizure during their lives and at least 1 in 200 people will have epilepsy. The annual incidence ranges from 20 to 70 cases perl 0000. The incidence is highest in the first 10 years of life and declines thereafter through the age of 50 until the elderly years, when the incidence increases again, due to cerebrovascular diseases But patients with milder epilepsy may also not be receiving ongoing medical care and so may be missed in epidemiological surveys. In India, the prevalence rate is about 5 to 6 per 1000, which means approximately more than 45 lakh Indians suffer from this disease regardless of the social or economic status.

ETIOLOGY

Idiopathic Hereditary Trauma Cerebrovascular disease Congenital Infections

Brain tumour

Degenerative CNS diseases Illicit drug use Alcohol withdrawal Metabolic disorders

Uremia Hypoglycemia Hyponatraemia Hypocalcaemia Hypomagnesaemia Renal failure Hepatic failure

Drugs that can cause seizures 1. Antimicrobials

Lactam and related compounds Quinolones Isoniazid

PATHOPHYSIOLOGY
The hallmark of epilepsy is a rather rhythmic and repetitive hyper synchronous discharge of neurons, either localized in an area of the cerebral cortex or generalized throughout the cortex. Seizures are caused by a perturbation in the normal balance of excitatory and inhibitory influences within the brain.

Synchronized high frequency bursts of action potentials are the initiating event of a seizure. These bursts are caused by an influx of extra cellular calcium followed by opening of voltage dependent sodium channels. This depolarization phase is followed by hyper polarization phase that is mediated by the inhibitory neurotransmitter y-amino butyric acid or by potassium channels. Most AEDs suppress seizures by altering ion flux through membrane channels or by altering neurotransmitter activity within the CNS. Classification

Seizures are classified as being generalized or partial on the basis of their clinical and electroencephalographic features. It's necessary to determine which AED is most likely to be effective. Generalized seizures are those that appear to begin in both hemispheres of the brain where as partial seizures localized in one hemisphere. International Classification of Epileptic Seizures

Partial seizures [local or focal] o Simple partial seizures Motor symptoms Somatosensory or special sensory symptoms Auto-iomic symptoms Psychic symptoms

II.

Antivirals

Acyclovir Ganciclovir

III.

Psychotropics

Anti depressants Antipsychotics Lithium

IV.

Radiographic contrast agents

V. VI.

Theophylline Class IB antiarrhythmic agent VII. Drug of abuse

Amphetamine Cocaine Methyl phenidate

VIII.

Sedative- Hypnotic drug withdrawal

Alcohol Barbiturates Benzodiazepines

IX.

Miscellaneous

Cyclosporin Tramadol

CLINICAL MANIFESTATION

I.

Generalized tonic-clonic seizures (grand mal) Begin with tonic (rigid) flexion of the extremities followed by extension, during which air is forced from the larynx to produce ah audible cry, usually lasts 15-20 seconds. Followed by the clonic (jerking) phase, during which there are spasms of the trunk and extremities and often biting of the tohgue, lasts 20 to 30 seconds. Followed by a postictal state, during which the patient may sleep or awaken confused and disoriented. Recovery within a period of 15 to 30 minutes. Increase in B.P., heart rate, incontinence of urine or feces, cyanosis may occur.

II.

Absence seizures (Petit mal)

Occurs primarily during childhood.

Abrupt interruption of consciousness followed by a fixed stare and automatisms (lip smacking, chewing, grimacing). No loss of postural tone. Duration - less than 45 seconds.

III.

Atonic seizures Sudden loss of muscle tone, causing the person to collapse to the ground. Recovery is quick.

IV.

Myoclonic seizures Jerking movements of a single or multiple muscle groups. Complex partial seizures [with impairment of consciousness] o Progressing to impairment of consciousness with no other features. o With features as in simple partial seizures. o With automatisms. Partial seizure that evolves to generalized seizures. o Simple partial seizures evolving to generalized seizures. o Complex partial seizures evolving to generalized seizures. o Simple partial seizures evolving to complex partial seizures to generalized seizures.

II.

Generalized seizures [convulsive or non-convulsive]

Absence seizures o Typical seizures [impaired consciousness only] o A-typical absence seizure. Myoclonic seizures. Clonic seizures. Tonic seizures Tonic-clonic seizures. Atomic seizures.

III. V.

Unclassified epileptic seizures Simple partial seizures

Discharge remains localized and consciousness is fully preserved.

VI.

Complex partial seizures

Characterized by impaired consciousness. Aura present. Average duration - 2 minutes.

Automatisms common (lip smacking, buttoning or unbuttoning of clothing or wandering behavior).

Trigger factors for seizures

Sleep deprivation. o Alcohol. o Recreational drug misuse. o Physical and mental exhaustion - stress. o Flickering light. o Intercurrent infections and metabolic disturbances. o Uncommonly - loud noises, music, reading, hot baths

DIAGNOSIS

Patients should be evaluated thoroughly after their first seizure. It is imperative that the physician obtains a complete patient history, including details of birth, childhood, family history, and medication regimen; a thorough medical history, including illnesses of the nervous system; and a thorough history of drug and alcohol use. A detailed description of the seizures is important to distinguish seizure types. Significant information includes the following: events that occurred during the seizure nature of the onset of the seizure presence of triggers (e.g., flickering light, sleep deprivation, dehydration) time of day of the seizure whether the seizure occurred during wakefulness or sleep whether awareness returns immediately or there is a prolonged period of confusion.

TREATMENT

Accurately diagnose the patient's seizure type & epilepsy syndrome. Select optimal am epileptic dw-B-ieropw Wsecl o sctztfre t^pe, epilepsy syndrome, patient's age - sex & concomitant medical conditions. Adjust anti epileptic drug therapy to attain complete control of seizures Monitor for clinical & laboratory evidence of adverse effects of drug therapy Minimize the use of poly drug therapy & sedating anti epileptic drugs whenever possible. Address patient concerns regarding the effect of seizures & anti epileptic drugs on daily activities, employment & social interactions. Recognize when patient should be referred to a comprehensive epilepsy center for evaluation of other therapeutic modalities such as surgery, vagus nerve stimulation or ketogenic diet.

Anti epileptic drug therapy is the mainstay of epilepsy treatment. The aim of therapy is to reduce the frequency of recurrent seizures & to minimize the adverse effects preferably with a single medication and a dosing schedule that is easy for the patient to follow. The ultimate goal of treatment for epilepsy is no seizure, no side effect with an optimal quality of life.

The choice of AEDs based on:o Seizure classification. o Age & sex of the patient. o Efficiency of the agent. o Adverse effects. o Pharmacokinetic properties. o Expense. o Convenience o! administration

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Thorough physical and neurological examinations also are performed. Laboratory studies of blood and urine help identify liver and kidney dysfunction, which may (1) augment adverse effects of antiepileptic drugs and (2) rule out or identify certain underlying causes. These results

also establish a baseline for monitoring kidney and liver function while the patient is on antepileptic medication. The kidney and liver metabolize most of these medications. Differential Diagnosis

It is important to identify and treat any injury or disease process that may be producing seizures, such as

head trauma, infection (e.g., encephalitis, meningitis), and drug intoxication or withdrawal.

Conditions that produce symptoms similar to those that occur during seizures must be ruled out, such as the following: Breath-holding spells: bluish tint to the skin (cyanosis), loss of consciousness, loss of muscle tone Meniere's disease: vertigo, visual phenomena, speech impairment, altered consciousness Migraine: aura, loss of consciousness, nausea, photophobia, muscle weakness. Movement disorder: tics, chorea, tremor. Syncope: sudden loss of muscle tone and posture, loss of consciousness, vertigo, nausea, muscle spasm

ELECTROENCEPHALOGRAM (EEG) EEG is a diagnostic test used to investigate a seizure disorder. It identifies abnormal electrical activity in the brain, provides information about the type of seizure disorder, and locates the area of seizure focus.

Some of the findings on EEG are specific to particular disorders and subtypes of epilepsy. Activity during a seizure can be identified by a pattern on the graph, called epileptiform, which indicates epilepsy. Correlating this type of data with clinical symptoms of seizures often helps make an accurate diagnosis. Additionally, the EEG recording between seizures is often abnormal

in patients with epilepsy. The EEG measures electrical activity in the brain through small electrodes that are placed on the scalp on both sides of the head. If the results are normal, the test is repeated after the patient is subjected to seizure triggers, such as sleep deprivation, flashing light, and hyperventilation. Continuous, 24-72 hour EEG and video monitoring may be performed at home to obtain a record of seizure activity.

Magnetic Resonance Imaging (MRI scan) or (CT scan or/ CAT scan) are performed when a lesion or other structural cause, such as stroke or tumor, is suspected

Computed tomography (CT) scan, also called computerized axial tomography (CAT) scan, is used to create cross-sectional images of structures in the body. In this procedure, x-rays are taken from many different angles and processed through a computer to produce a three-dimensional (3D) image called a tomogram.

Computed tomography is used to detect abnormalities such as blood clots, cysts, fractures, infections, and tumors in internal structures (e.g., bones, muscles, organs, soft tissue). The procedure also may be used to guide the placement of instruments within the body (e.g., to perform a biopsy).

CT scan may be used to examine structures in the abdomen and pelvis (e.g., liver, gallbladder, pancreas, spleen, intestines, reproductive organs), in the chest (e.g., heart, aorta, lungs), and in the head (e.g., brain, skull, sinuses). It also can be used to detect abnormalities in the neck and spine (e.g., vertebrae, intervertebral discs, spinal cord) and in nerves and blood vessels.

CT scan is a noninvasive procedure and is usually performed on an outpatient basis (i.e., does not require overnight hospitalization). The amount of radiation used in a CT scan is low, and the procedure is considered to be safe. However, CT scans should be used with caution in women who are pregnant, especially during the first trimester. Other diagnostic tests (e.g., ultrasound) may be used during pregnancy.

A contrast agent (e.g., iodine-based dye, barium solution) may be administered prior to CT scan to allow organs and structures to be seen more easily. Contrast agents can be administered through a vein (IV), by injection, or taken orally. Patients usually are instructed not to eat or drink for a few hours prior to contrast injection or IV because the dye may cause stomach upset Patients may be required to drink an oral contrast solution 1-2 hours before CT scan of the abdomen or pelvis.

Contrast dye may cause a rash, itching, or a feeling of warmth throughout the body. Usually, these side effects are brief and resolve without treatment. Antihistamines may be administered to help relieve symptoms.

A severe anaphylactic reaction (e.g., hives, difficulty breathing) to the contrast dye may occur. This reaction, which is rare, is life threatening and requires immediate treatment. Patients with a prior allergic reaction to contrast dye or medication and patients who have asthema, emphysema, or heart disease are at increased risk for anaphylactic reaction. Epinephrine, corticosteroids, and antihistamines are used to treat this condition.

Rarely, contrast dye may cause kidney failure. Patients with diabetes, impaired kidney function, and patients who are dehydrated are at higher risk for kidney failure.

Before undergoing a CT scan, patients must remove all metallic materials (e.g., jewelry, clothing with snaps, zippers) and may be required to change into a hospital gown that will not interfere with the x-ray images. Patients lie on a movable table, which is slipped into a doughnutshaped computed tomography scanner. The procedure usually takes from 30 to 90 minutes to perform.

To provide clear images, patients must remain as still as possible during CT scan. The technician is able to see the patient and communicate through an intercom system throughout the

procedure. At certain points during a CT scan of the chest or abdomen, the technician may ask the patient not to breathe for a few seconds. Spiral or helical scanners are newer machines that provide faster and more accurate CT scans. These machines often are used in cases of severe trauma and injury. A radiologist (physician results of a CT scan. TDM is indicated At the onset of therapy of establish a baseline. If seizure control is poor, or sudden changes in seizure control occur. If toxicity is suspected. If poor or non-compliance is suspected. To monitor the time scale of drug interactions. When changing AED therapy or other treatment changes that are known to affect the AED.

who

specializes

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imaging

procedures)

interprets

the

Frequency of monitoring varies: - stabilized patient may check only once or twice a year, a number of newer AEDs do not require TDM. HI. Withdrawal of AED therapy The following patient profile yields the greatest chance of remaining seizure free after drug withdrawals are:

Complete medical control of seizures for 1 to 5 years. Single seizure type either partial or generalized. Normal neurological examination including intelligence. Normal EEG.

In general, patient who remains free of seizures for 2 years or more may be considered candidates for AED withdrawal. The risk of seizure recurrence is highest during the period of AED reduction and within the first year after drug withdrawal.* Guidelines for anticonvulsant therapy Start with one first line drug Start with low dose; gradually increase to effective control of seizures or until side-effects, Check compliance o Availability of drug. o Concurrent medical condition Monotherapy is preferred to polytherapy because: o Lower cost of medication.

o o
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Reduced potential for ADR & drug interactions. Improved medical compliance.

If single therapy fails, switch . to polytherapy. Sedating AEDs [Phenobarbital & benzodiazepines] should be avoided.* TDM is very useful to optimizing seizure control & avoiding drug toxicity. Good seizure control can sometimes take a long time to achieve, at least 3 years.

In the early 198O's, the primary drugs used for epilepsy were Phenobarbital, phenytoin, carbamazepine and valproic acid. New AEDs are generally second-line drugs except lamotrigine & oxcarbazepine. Vigabatrin, gabapentin, felbamate, tiagabine, topiramate & zonisamide are the newer ones. Selection of AEDs.

I. Initiation of Therapy AEDs should be introduced slowly, starting with a small dose & then increased incrementally to an initial maintenance dosage II. Adjusting and monitoring There is great inter patient variability in the dose-response relationship for all of the AEDs that are in common use. The published therapeutic ranges of serum drug concentrations are only an appropriate guide for determining the proper dose for a given patient.

Guidelines for doses of AEDs in adults

Drug

Indication

Target Starting Common Standard [ No: of plasma dose daily dose maintenance doses/ conc. (mg) (mg) dose (mg) day g/ml

Carbamazepine

Partial/generalized tonicclonic seizures

200

600

400-2000

1-4 6-12

Phenytoin

Partial/generalized tonicclonic/status cpilepticus

200

300

100-700

1 or 2

10-20

Valproic acid

All-generalized seizures/partial seizures

500

1000

' 500-3000

50-100

Partial/generalized tonicPhenobarbital clonic,myoclonic,c Ionic or tonic seizures/s.e.

600

120

60-240

10-40

Pt.vc.4one

P arti al/general i zed tonic-clonic.s Absence seizures

250 500 1

500 1000 4

250-1500 500-2000 2-8

5-12 10-100 None

Clonazepam

Myoclonic/general ized t-c.s/s.e.

S.E-

- Status epilepticus

If first drug fails, start second line drug whilst gradually withdrawing first. Try three agents singly before using combinations (beware of interactions). Do not use more than two drugs in combination at any one time. If above fails, consider whether occult structural or metabolic lesion is present & whether seizures are truly epileptic

Non-pharmacological therapies include ketogenic diet, vagus nerve stimulator & surgery. AEDs choice based on seizure classification Partial seizuresGeneralized

tonic-clonic seizuresAbsence seizuresMyoclonic seizuresDrug of choiceCarbamazepineValproateEthosuximideValproate PhenytoinCarbamazepineValproate PhenytoinAlternativesPrimaryValproatePhenobarbitalClonazepamClonazepam GabapentinPrimidone Lamotrigine Vigabatrin Phenobarbital PrimidoneSecondaryClorazepateAcetazolamide FelbamateROLE OF PHARMACY Patient Care Epilepsy is a chronic condition that has considerable impact- on the life of each individual patient. So patient counseling aims to enhance patient's understanding of their illness; safe & effective use of medication etc. It's also ve proce & essential to involve the patient's family & carers in the educational pteecs% regarding their disease condition, nuriications and on daily activities. Counseling Points During seizures - First Aid Move person away from danger (fire, water, machinery, furniture)

After convulsions cease, allow the patient to lie down or sit comfortably. Ensure airway is clear. Do not insert anything in mouth (tongue- biting occurs at seizure onset & cannot be prevented by observers) Loosen the tight clothes or neck- wear. It convulsions continue for more than 5 minutes or recur without person regaining consciousness , summon urgent medical attention. Person may be drowsy & confused for some 30-60 minutes, so should not be left alone until fully recovered.

Regarding medication

Use same brand consistently. Take the drug with food or milk to minimize G.I. distress. Stress good"oral hygiene to minimize overgrowth & sensitivity of gums. Always wear a medical identification card or bracelet. Avoid alcohol & smoking habits. Stick to the prescribed medication. Report ADR immediately

Drug

Doserelated

Idiosyncratic

carbamazepine

Diplopia,Headache,Dizziness, Nausea, Drowsiness,Neutropenia,Hypo natremia

Morbillilbrm rush, teratogenicity, Agranulocytosis, Aplast.A, S.J syndrome, hepatotoxicity

phenytoin

Nystagm u s, Gum hypertrophy,Ataxia, Depress ion,Drowsy,Nausea,Me galobl.A.

Acne, Hirsuitism,blood dyscriasis, Lupus like syndrome, rash

Tremor, Wt.gain,Nausea,Vomiti Valproic acid ng,Dyspepsia Alopecia,Peripheral edema

Acute pancreatitis, hepatotoxic, thrombocytopenia, Teratogenic, encephalopathy

Phenobarbital Fatigue,Depression,lnsomnia

Maculopapular rash, exfoliation, hepatotoxic, teratogenic

primidone

Fatigue,Depression,Psychosis,^ decreased libido,hnpotence

Rash, Agranulocytosis, teratogenic, Thrombocytopenia Rash, erythema multiforma,

ethosuximide

Nausea, Vomiting,Anorexia,Ag itation Drowsiness.Headache

S.J. syndrome, Lupus syndrome, Aplastic .A. Rash, Thrombocytopenia

clonazepam

Fatigue,sedation,Drowsiness,D izziness

S.J - Steven Johnson Syndrome

A- Anaemia

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Minor side effects such as mild sedation, slight changes in cognition or imbalance will typically resolve within a few days. Avoid driving, swimming, operating machines and other hazardous activities.(drug may cause drowsiness)Pregnancy & Epilepsy

EPILEPSY IN PREGNANCY

Preconception Counseling

The patient should be informed of dangers of uncontrolled seizures to the Emphasis should be on single drug therapy. If the patient has been seizure free for 3years, withdrawal should be considered. Put the patient on folic acid supplements. If the patient has been on AED for less than 3years then it should be continued.

Counseling during Pregnancy

AED should never be stopped during pregnancy AED monitoring should be done regularly to maintain the lowest effective dose. Regular scanning of the fetus should be done to check for malformation. Vitamin K should be started in the last month of pregnancy.

Management during Lactation Period

The dose of AED should be reduced & brought to preconception level. Encourage breast-feeding. Phenobarbitone can cause drowsiness in babies, so dose should be reduced. Mothers should take proper rest & should avoid fatigue. Vitamins & calcium supplements should be added to the mothers diet. To reduce the vitamin K deficiency in infants, lmg Vitamin K I.M should be given :it birth

Epilepsy is a chronic neurological disease characterised by recurrent spontaneous seizures. A seizure is a sudden onset of symptoms and clinical manifestations caused j by sudden abnormal bursts of electrical brain activity that disrupt brain functions. I Epileptic seizures may arise from different brain regions and can cause abnormal v- motor activity, sensory changes, mood changes and unconsciousness

Life Style Adjustment

Avoidance of precipitating factors like stress, exercise, alcohol, altered sleep schedules and missed meals. Through proper education, effective AED therapy & life style adjustments an epileptic patient can lead a life that is not severely restricted by their disorder.

Although epilepsy is a common disorder, it is still a very misunderstood condition. Continuous advances in research gives more hope to patients. People with epilepsy can have normal & productive lives because of the numerous treatment options that are available. Pharmacists are key to provide the patient with proper counselling, monitoring of medication profiles & stressing the importance of patient compliance.

1. Simpson D. What is medicine management and what is pharmaceutical care? PharmaJ 2001: 266; 150. 2. G. Parthasarathi, Nyfort Hansea, Nahata Text book of clinical pharmacy practice pg; 43, 178. 1. www. Epilepsy clinic counseling, htm (Internet accessed) 2. www. Pharmacists Epilepsy-com.htm (Internet accessed)

1. Marco T Medina, Reyna M Durcon. Prevalence, incidence, and etiology of epileptics in rural Honduras, Epilepsia~46, 2005, pg: 124-131. 2. Herfindal, Gourley. Text book of Thrapeutics, Drug and Disease management, 7th edn pg: 1107. 3. Epilepsia 2005, vol-46, pg: 456. 1. R K Gupta, B M Soni. Epilepsy: Combination therapy by alternative medicine, pg: 3-4, 70-71. 2. Christopher G, Goetz. Text book of clinical neurology, 2nd edn, chapter 52, pg:1155. 3. Martin J Brodie, Marc A Dichter. Anti epileptic drugs NEJM 1996, vol-334, pg: 168-175. 4. Ashok panagariya, Bhawnasharma, Arungarg. Newer perspectives in medical management of epilepsy, Neurosciences Today 2001, vol-5, pg: 209-215 5. Roger walker, Clive Edwards. Clinical pharmacy and therapeutics 3rd edn, chapter29, pg: 465-67. 6. Kasper, Braun walk. Harissons principles of internal medicine 16 edn, vol- 2, pg:2366-67. 7. Christopher, Edwin, Nicholas. Davidsons principles and practice of medicine 19th edn, pg: 1130. 8. K K Sinha. Drug treatment of chronic epilepsy in the new millennium, Neurosciences Today 2002. vol-6, pg: 195-203. 9. A Vasudev, K. D Tripathi, V Puri. Correlation of serum and salivary carbamazepine concentration in epileptic patients - implications for therapeutic drug monitoring, Neurology India 2002, vol-50, pg: 60-62