James Fischer, Pharm.D.

Spring 1998

Drug Therapy of Epilepsy

I.Epilepsy - Pathophysiology

Definitions / Epidemiology Functional Anatomy of the Brain Pathophysiology Etiology Diagnosis Classification of Epileptic Seizures Selected Epileptic Syndromes First Aid for Seizures I.Drug Therapy

Goal of Therapy General Management of Epilepsy Principles of Antiepileptic Drug (AED) Therapy Adverse Effects Drug Interactions Specific Drug Therapy for Epilepsy I.Case Study

GOALS AND OBJECTIVES

1. Review the pathophysiology of epilepsy including etiology, diagnostic criteria, factors to consider in differentiating epilepsy from other disorders, classification of epileptic seizures and first aid measures for the patient with seizures. 2. Identify the clinical manifestations and EEG findings associated with the different types of epileptic seizures. At the conclusion of these lectures, the student should be able to classify a given patient's seizure type based on data provided concerning the clinical description and EEG results. 3. Provide an understanding of the basic principles involved in the drug treatment of epilepsy, including factors to consider in the initiation and assessment of antiepileptic drug (AED) therapy. 4. The student should be able to recommend an initial AED regimen or alteration in regimen (including dose schedule, monitoring parameters) for an epileptic patient based on information concerning patient's seizure type, medical history, previous drug therapy and pertinent laboratory data. 5. Explain the role of plasma concentration monitoring in AED therapy and be aware of the therapeutic serum concentration range for the major AED. 6. Review the adverse effects seen during therapy with the major AED. The student should be aware of the causative factors, clinical importance, prevention and/or management of these adverse effects. 7. The student should be aware of the potential drug interactions that may occur among the AED, and the mechanisms and clinical implications of these interactions.

REQUIRED READINGS
1. Fischer JH (ed). The Epilepsy Counseling Guide. MPE Communications inc., Fair Lawn, New Jersey, 1994. 2.Garnett WR. Epilepsy, in Pharmacotherapy: A Pathophysiologic Approach, 3rd ed. Dipiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM, eds. Appleton & Lange, Stamford, CT. 1997; 1179-1209.

EPILEPSY - PATHOPHYSIOLOGY I. Definitions / Epidemiology

A. Seizures are discrete, time-limited alterations in brain function - including changes in motor activity, autonomic function, consciousness, or sensation -that result from an abnormal and excessive electrical discharge of a group of neurons within the brain. The clinical manifestations of a seizure reflect the area of the brain from which the seizure begins (i.e., seizure focus) and the spread of the electrical discharge. Clinical manifestations accompanying a seizure are numerous and varied, including indescribable bodily sensations, "pins and needles" sensations, smells or sounds, fear

or depression, hallucinations, momentary jerks or head nods, staring with loss of awareness, and convulsive movements (i.e., involuntary muscle contractions) lasting seconds to minutes. Convulsions are specific type of seizures where the attack is primarily manifested by involuntary muscular contractions. B. Seizures are symptoms of a disturbance in brain function. Up to 10% of the population will experience a seizure during their lifetime. However, in the majority of these people, seizures occur either as an isolated incident or secondary to an acute reversible medical condition, such as fever, trauma, metabolic disorder, or alcohol or drug intoxication. Since seizures do not usually recur in these patients once the underlying cause has been corrected, these patients are not considered to have epilepsy and do not require long-term antiepileptic drug therapy. C. Epilepsy is defined as a condition characterized by recurrent (two or more) seizures unprovoked by any immediately identifiable cause. D. Epilepsy is the third most common neurologic disorder, following stroke and Alzheimer=s disease. Approximately 2 million people (0.5% - 1.5% of population) in the United States have active epilepsy. Each year 50 per 100,000 individuals in the United States will be diagnosed with epilepsy (125,000 new cases/year), with the highest frequency of newly identified cases occurring among children < 5 years (50100 cases/100,000) and adults >65 years of age (70-150 cases/100,000).

II. Functional Anatomy of the Brain

The material in section II. is informational only (i.e., it will not be included on test) and is included to provide a brief overview of the neuroanatomy pertaining to seizures and epilepsy. The upper and largest portion of the brain is referred to as the cerebrum. The cerebrum is comprised of grey and white matter. The outer layer of grey matter forms the cerebral cortex and consists largely of nerve cells (neurons) and supportive glial cells. White matter, comprised of myelinated nerve fibers, lies beneath the cerebral cortex. These myelinated fibers connect the cerebrum with other parts of the brain (projection fibers), the front of the brain to the back portion, different areas on the same side of the cerebrum (association fibers), and one side of the brain to the other (commissural fibers). As shown in the figure above, the cerebrum is incompletely divided into the left and right hemispheres by the medial longitudinal fissure. The left and right cerebral hemispheres are interconnected by a large fiber bundle located beneath the medial fissure, the corpus callosum. The right hemisphere controls the left side of the body and "sees" the left half of space; the left hemisphere controls the right side of the body and "sees" the right half of space. In most right-handed individuals, the left hemisphere controls language functions such as the ability to speak (frontal lobe) and understand language (temporal lobe). As shown below, each cerebral hemisphere is divided into 5 lobes: frontal, parietal, temporal, occipital, and the insula (located on the underside of brain). Specific areas in each lobe are associated with different functions. Injury or abnormal functioning of these cortical areas can cause partial seizures, with the initial symptoms of the seizure often reflecting the function of that area.

The neocortex (cortical area covering surface of brain), hippocampus, and other mesial temporal frontal areas are frequent sites of seizure onset. Subcortical areas, such as the thalamus, substantia nigra, and corpus striatum, are thought to play key roles in the spread of seizure activity and generation of generalized seizures. In the "normal" brain, inhibitory stimuli from these subcortical areas modulate excitatory neurotransmission between the cortex and other brain areas and limit the spread of abnormal electrical signals. Depression of the inhibitory activity of these areas in the brains of patients with epilepsy may facilitate the spread of seizure activity following an initial partial seizure or the generation of primary generalized seizures.

III. Pathophysiology
The onset of a seizures appears to occur when a small group of abnormal neurons undergo prolonged depolarizations associated with the rapid firing of repeated action potentials. These abnormally discharging epileptic neurons recruit adjacent neurons or neurons with which they are connected into the process. A clinical seizure occurs when the electrical discharges of a large number of cells become abnormally linked together, creating a storm of electrical activity in the brain. Seizures may then spread to involve adjacent areas of the brain or through established anatomic pathways to other distant areas. On a fundamental level, seizures can be viewed as resulting from an imbalance between excitatory and inhibitory processes in the brain. Proposed mechanisms for the generation and spread of seizure activity within the brain include abnormalities in the membrane properties of neurons, changes in the ionic micro environment surrounding the neuron, decreased inhibitory neurotransmission which is primarily by gamma-amino butyric acid (GABA), or enhanced excitatory neurotransmission which is primarily mediated by the acidic amino acid, glutamate. The different antiepileptic drugs (AEDs) act by affecting one or more of these processes. Specific mechanisms of action of the AEDs include: modulation of voltage dependent ion channels (carbamazepine, phenytoin, valproic acid), enhancement of activity of the major inhibitory neurotransmitter in the brain, GABA (phenobarbital, benzodiazepines, tiagabine), and suppression of excitatory neurotransmission (lamotrigine, felbamate).

IV. Etiology
A. In 60-70% of patients, no specific cause for their seizures can be identified. Epilepsy in these patients is referred to as being idiopathic (i.e., no definite cause). B. Infants/children: congenital malformations, perinatal injuries or hypoxia, developmental neurologic disorders, metabolic defects, injury, and infection are common causes of seizures. C. Young Adults: head trauma, brain tumors, infection, and arteriovenous malformations are common causes of seizures.

D. Elderly: cerebrovascular disease, CNS degenerative diseases, and brain tumors are common causes. E. Genetic - risk increased 2-3 times in individuals with first degree relative with epilepsy.

V. Diagnosis
A. Steps in Diagnosis of Epilepsy 1. Confirm patient has epilepsy a. Other conditions to consider in differential: pseudoseizures, syncope, breath holding spells, narcolepsy, hemiplegic migraines, drug toxicity, transient ischemia attack. b. Following factors delineate epilepsy from above: abrupt onset, genuine loss of consciousness (if not simple partial), brief duration, rapid recovery, stereotypic episodes. c. Pseudoseizures (seizures occurring on a psychogenic basis, "hysterical seizures") present a common and difficult diagnostic problem, especially since many patients may have both pseudoseizures and epilepsy. Factors differentiating pseudoseizures from epilepsy include:

1. Precipitating factors with a strong emotional or

psychological component

2. "Non-physiological" seizure patterns - violent thrashing or

flailing of all 4 limbs, particularly when movements asynchronous; preservation of consciousness despite motor activity of arms and legs; rage and directed violence as ictal events; gradual build up and prolonged resolution of seizure; lack of tongue biting, incontinence and postictal confusion.

3. Personal and family history of psychiatric disease 4. Repeatedly normal interictal EEG and lack of any response
to therapeutic levels of antiepileptic drugs

5. Definitive differentiation requires use of simultaneous video

and EEG recording 2. Correct classification of seizure type and, if possible, epileptic syndrome 3. Identification of any underlying cause B. Diagnostic Evaluation

1. History a. Medical history of patient and family history b. Description of seizure - important to obtain exact details of episode from patient and/or observer. Description should include details on:

1. Events preceding seizure: What was happening before the

seizure ? What time was it ? Does patient recognize onset of seizure by a smell, visual disturbance, sound or odd feeling ?

2. Events during the seizure: What are the initial events ? Is

consciousness lost or altered ? What kind of body movements occurred ? How long did the seizure last ? Did the person urinate or bite his/her tongue ?

3. Events after the seizure (i.e., postictal period): Is the patient

alert, drowsy, or confused ? Was there any numbness or weakness ? 4. An effort should also be made to identify any precipitating factors. Factors known to precipitate epilepsy in susceptible patients include: sleep deprivation, fever, emotional stress, lack of food, alcohol/drug withdrawal, pregnancy, menses, and various sensory stimuli (i.e., photosensitivity, television, reading, eating, music). Identification and avoidance, where possible, of these factors may assist in reducing the frequency of seizures. 2. Physical and Neurological Examination 3. Clinical Laboratory data 4. Electroencephalography (EEG) a. Measurement of fluctuations in electrical activity within brain recorded from electrodes on scalp. Role: confirm presence of epilepsy, diagnosis of seizure type, long term prognosis. b. EEG findings alone do not confirm or deny diagnosis of epilepsy. Important to correlate EEG findings to clinical events.

1. Approximately 5% of patients without epilepsy have

epileptiform discharges on their EEG.

2. Of patients with epilepsy, only about 50% have epileptiform

activity on their first EEG. c. Detection of abnormal EEG enhanced by use of multiple recordings and specific activating techniques.

1. photic stimulation, hyperventilation, sleep deprivation (these are usually performed with standard EEG exam);

2. Video-EEG monitoring: provides correlation between

clinical seizure and electrical activity in brain

3. Nasopharyngeal and sphenoidal electrodes: allows for

detection of abnormal electrical activity on underside of cortex d. EEG patterns having clinical correlations

1. 3 Hz spike and wave complex: Absence seizures 2. Slow spike and wave complex: minor motor seizures (i.e.,
atypical absence, tonic, atonic)

3. Hypsarrhythmia: infantile spasms 4. Polyspike and wave complex: myoclonic seizures

5. Neuroimaging Studies: Magnetic resonance imaging (MRI) or computed tomography are useful in identifying structural lesions in brain. MRI appears more sensitive in detecting lesions in patients with epilepsy. Consider in patients > age 18, in children with partial seizures, and in presence of abnormal neurologic findings, or focal slow-wave abnormalities on EEG.

VI. CLASSIFICATION OF EPILEPTIC SEIZURES

Seizures are classified according to their clinical features and patterns seen on the EEG. Epileptic seizures are divided into two broad categories based on the symptoms and EEG findings observed at the outset of the seizure. If the initial onset indicates involvement of both sides of the brain, the seizures are referred to as generalized seizures. If the initial onset indicates involvement of only a localized area of the brain, they are referred to as partial seizures. A. Partial Seizures - those seizures where initial onset arises from a localized area of brain. Partial seizures are caused by localized injury to brain and diagnostic evaluation for the presence of a focal lesion (i.e., tumor, vascular malformation, stroke, trauma, neurodegenerative disease) is required. However, in majority of patients, cause will remain unknown (idiopathic). Partial seizures are further subdivided based on whether consciousness is maintained (i.e., simple partial) or impaired (i.e., complex partial) during the seizure. Partial seizures are most common type experienced by adults. 1. Simple partial seizures a. No loss of consciousness; During a simple partial seizure, the patient is alert and able to respond to questions or commands and afterwards remembers what happened

during the seizure. Simple partial seizures may precede complex partial or secondarily generalized seizures, in which case they are referred to as auras. b. Clinical manifestations of simple partial seizure usually relate to the particular area of brain involved, and thus a wide variety of symptoms are possible, including motor, sensory, autonomic, and psychic manifestations. For any given patient, symptoms will be same with each seizure. c. Motor seizures generally reflect involvement of the motor or supplementary motor cortex and cause a change in muscle activity. Tonic (neck stiffening, sustained deviation of eyes to one side) or clonic (jerking) movements are most common. Abnormal movements may be restricted to one body part or spread to other muscles on same side or both sides (secondary generalization) of the body. d. Sensory seizures are often manifested by hallucinations or illusions involving one of the senses - touch (paresthesia or numbness in one or more body parts), smell (patient may smell a disagreeable odor), taste (abnormal or disagreeable taste), vision (unformed or formed visual hallucinations), and hearing (buzzing sound, ringing in ears, music, voices). e. Autonomic seizures can cause changes in heart or breathing rate, sweating, goosebumps, or strange or unpleasant sensation in abdomen, chest or head. f. Psychic seizures, arising from the limbic system and neocortical areas of the frontal and temporal lobes, affect how the patient thinks, feels, and experiences things. Manifestations of psychic seizures include feelings of fear, anxiety, depression, deja vu, jamais vu, and dissociative phenomena such as autoscopy (out of body experience). g. Duration 30 seconds or less; No postictal symptoms, although patient=s with partial motor seizures may experience a temporary numbness or weakness in the affected body part (Todd's paralysis) h. EEG findings: local contralateral discharge starting over the cortical area corresponding to symptoms j. Prognosis: good seizure control obtained in 30-50% 2. Complex partial seizures (temporal lobe, psychomotor epilepsy) a. Impairment of consciousness observed: In this context, consciousness refers to patients' ability to normally interact and respond to their environment. Thus, although patients may appear to be conscious, closer examination shows that they are unaware of their environment; fail to respond or respond inappropriately to questions; and afterward, are unable to remember the episode. Complex partial seizures involve portions of brain concerned with maintenance of consciousness and memory, and generally imply bilateral involvement of temporal or frontal lobes and limbic system.

b. Associated with initial aura (i.e., simple partial seizure) in >50% of patients; the aura is a simple partial seizure which may then progress to a complex partial (and/or generalized tonic-clonic) seizure. Most common forms of aura: fear, rising epigastric sensation, unilateral "funny feeling" or "numbness", or visual disturbances; focal twitching of face or fingers. c. Simple to complex automatisms (repetitive motor activity that is purposeless, undirected, and inappropriate) are frequently observed during complex partial seizures. Examples include repetitive chewing or swallowing, lip smacking, fumbling movements of fingers or hands, picking at clothing, mumbling, moving about aimlessly, purposeless behavior, and clumsy perseverance of a preceding motor act. d. Average duration 1 to 3 minutes e. Postictal phase - confusion, lethargy, altered behavior, amnesic for event f. EEG findings: unilateral or, frequently, bilateral discharge in temporal or frontotemporal region. g. Prognosis: good seizure control in 40-60% h. Most common seizure type seen in adult, account for up to 60% of adult epilepsies 3. Partial Seizures Secondarily Generalized - partial seizure may progress through several stages reflecting spread of discharge to different brain areas. For example, seizure may begin as simple partial (i.e., aura), progress to complex partial and subsequently become secondarily generalized (tonic-clonic). The initial clinical events of a seizure, described by patient or observer, will usually provide a reliable indication of whether seizure is partial or generalized. Sometimes, however, the focal onset may not be apparent from clinical data, due to either rapid spread of discharge or location of focus in brain area not associated with an obvious behavioral function, thus EEG findings are needed for accurate classification. B. Generalized Seizures - those seizures where first clinical changes indicate initial involvement of both hemispheres. The initial clinical event is a loss of consciousness. Various types of generalized seizures differentiated by absence or presence of specific motor activity. 1. Generalized Tonic-Clonic (Grand Mal) a. Loss of consciousness is quickly followed by a sudden fall to ground. In the tonic phase, muscles become rigid and the simultaneous contractions of diaphragm and chest muscles may produce the characteristic "epileptic cry". The patient's eyes roll up or turn to the side and the tongue may be bitten. The rigidity is replaced shortly by series of synchronous clonic movements of head, face, legs and arms. Autonomic changes also observed included: increased blood pressure, heart rate, and bladder pressure; pupillary mydriasis; hypersecretion of skin and salivary glands; cyanosis of skin.

b. Although onset may occur at any age, most commonly occurs during second decade of life. c. Average duration 2 to 5 minutes. d. Postictally, patients lethargic/sleepy lasting several minutes to hours. e. Incontinence seen in early postictal phase in approx. 35% of patients. f. In patients with primary generalized tonic-clonic seizures, seizures seen most commonly on awakening and to a lesser extent in evening when relaxing. g. Prognosis: good seizure control in 70-85%. 2. Absence (Petit Mal) a. Onset between 4 and 14 years and often resolve by age 18. b. Clinical description - Brief episodes of staring with impairment of awareness and responsive that begin without warning and end suddenly, leaving patient alert and attentive. In simple absence seizures, patient only stares. In the more common complex absence seizures, staring is accompanied by simple automatic movements such as blinking of eyes, drooping of head, or chewing. c. Duration - short (10-45 secs), patients usually unaware of occurrence. d. Abrupt recovery without after effects e. Characteristic EEG pattern of 3 per second spike and waves; may be precipitated in large percent of patients by hyperventilation. f. 25 to 50% of patients go on to develop generalized tonic-clonic (GTC) seizures. g. Development and intelligence are usually normal and long term prognosis is good, particularly in patients who do not develop GTC. h. Important in children to differentiate from complex partial seizures, since treatment and prognosis vary. In contrast to absence, complex partial seizures usually have a longer duration (minutes vs. seconds), are often preceded by aura, and typically have a brief period of postictal confusion. Also, the EEG pattern is markedly different between the two seizure types. 3 Atypical Absence a. Onset between 1 to 7 years of age b. Clinical description - similar to typical absence except that loss of responsiveness during seizure is often less complete and more gradual in onset and cessation; Also clonic, tonic and atonic components (i.e., increase or decreases in muscle tone) are more pronounced than in typical absence. Commonly seen in patients with LennoxGaustaut syndrome in conjunction with myoclonic, atonic and tonic seizures.

c. EEG findings: slow spike and wave (< 2.5 Hz) discharge and/or incompletely generalized spike-waves d. Not precipitated by hyperventilation e. Often associated with mental retardation or structural CNS damage f. Prognosis: response to therapy and long term prognosis dependent on presence of underlying neurologic deficit and/or mental retardation. Good response seen only 2030% of patients. 4. Atonic seizures a. Onset usually between age of 2 to 5 years b. Clinical description- sudden and total loss of muscle tone and posture control that causes eyelids to drop, head to nod and patient to fall to ground - "drop attack"; not necessarily associated with loss of consciousness. Must wear helmet to protect from head injury. May or may not have postictal symptoms. c. Average duration 10 to 60 seconds; brief, if any, postictal symptoms d. Other seizure types common in patients with atonic seizures. May be observed in conjunction with myoclonic seizures and atypical absence (Lennox-Gaustaut Syndrome) e. Prognosis to therapy dependent on presence of underlying neurological deficit and/or mental retardation 5. Myoclonic Seizure a. Sudden, brief shock-like jerk of a muscle or group of muscles, often occurs in healthy people as they fall asleep. Epileptic myoclonus usually causes synchronous and bilateral jerks of the neck, shoulders, upper arms, body, and upper legs. b. Myoclonic seizures occur in a variety of epilepsy syndromes. 6. Tonic seizures a. Characterized by sudden bilateral stiffening of the body, arms, or legs. Tonic seizures usually last less than 20 seconds and are more common during sleep. b. Primarily seen in younger children; commonly associated with metabolic disorder or underlying neurological deficit c. Frequently occur with other seizure types and in various epilepsy syndromes d. Duration 10-60 seconds; brief, if any, postictal symptoms Note material on handout after this point will not be covered in class and you are not responsible for this information on the test.

VII. Selected Epileptic Syndromes Epilepsy syndromes are defined by a cluster of characteristics, including seizure type, EEG, neurologic status, age at seizure onset, family history, and prognosis. While seizure type is most important determinant of drug selection, classifying the epilepsy syndrome provides information on the responsive to drug therapy, expected duration of drug therapy, and long term prognosis. A. Infantile Spasms 1. Consist of sudden flexion of the head with abduction and extension of arms, accompanied by flexion of knees and often a little grunt or cry. Spasms may also be extension rather than flexion. Spasms commonly occur in series of 2 or more. 2. Onset most commonly between 4 to 7 months of age 3. Definite etiology can be established in 60% of patients 4. Mortality rate 11-23%; developmental retardation 80-90% 5. Characterized by spasms, developmental retardation, hypsarrhythmia pattern on EEG. 6. Spasms may be flexor (jackknife), extensor or mixed flexor-extensor. 7. Unique among seizure types in responsiveness to ACTH/corticosteroids. 8. Poor treatment prognosis; spasms usually disappear by age 3 or 4, but child left profoundly handicapped, retarded, and often with Lennox-Gaustaut syndrome (see under atypical absence seizures). Patients who are normal prior to onset and who respond to therapy have slightly better prognosis. B. Febrile Seizures 1. Convulsions that occur with fever (> 38oC) in children between 6 months and 6 years of age, not secondary to an infection of brain or meninges. 2. Prevalence: 2 to 5% of all children will have a febrile seizure before 6 y/o; Peak incidence at 2 years of age. 3. Etiology: strong genetic predisposition 4. Primarily occur as generalized tonic-clonic seizures, but partial seizures occur in 10-15% of patients. 5. Prognosis: febrile convulsions usually have benign course; although 2 to 4% will go on to develop afebrile epilepsy. Intellectual dysfunction and neurologic sequelae may occur following febrile status epilepticus. 6. Factors associated with increased risk of developing afebrile epilepsy: Preexisting neurologic abnormality; family history of afebrile seizures; and a complicated initial

seizure (> 20 minutes duration 2 or more seizures in same illness, and/or focal febrile seizure). 7. Treatment

1. Symptomatic - control fever and seizures 2. Prophylactic Antiepileptic Drug Therapy - controversial;
present recommendations to consider prophylactic treatment only in patients with two or more of risk factors above; or in patients with recurrent (3 or more) febrile seizures who are under 3 years of age. Current recommendation for prophylactic therapy is the intermittent administration of rectal or oral diazepam at time of febrile episode. C. Lennox-Gastaut Syndrome: This syndrome is characterized by the triad of intractable seizures, mental and developmental retardation, and slow spike and wave pattern on the EEG. Seizures (tonic, atonic, atypical absence, myoclonic, and tonicclonic) usually begin between ages 1 and 6 years and respond poorly to antiepileptic drugs. Behavioral problems are common and probably result from the underlying neurologic injury, effects of frequent seizures and head injuries, and high-dose combinations of antiepileptic drugs. D. Benign Rolandic epilepsy. This syndrome frequently begins in children with a family history of epilepsy. The most characteristic sign is a partial motor or somatosensory seizure involving the face. Tonic-clonic seizures may also occur, especially during sleep. The seizures are infrequent (some patients require no medications), are easily controlled with antiepileptic drug therapy, and stop spontaneously by age 15. Mental development is unaffected. E. Juvenile myoclonic epilepsy: These myoclonic seizures, with or without tonic-clonic or absence seizures, usually begin shortly before or after puberty but may first occur in early adulthood. Myoclonic and tonic-clonic seizures most often occur in the early morning, shortly after the patient awakens. Mental developemnt is normal. In most patients seizures are well controlled by valproic acid alone, but the disorder requires life long therapy. VIII. FIRST AID FOR SEIZURES A. Generalized Tonic-Clonic Seizures 1. Prevent person from hurting himself or herself. Place something soft under the head, loosen tight clothing, and clear area of sharp or hard objects. 2. Do not force any objects into patient's mouth. 3. Do not restrain patient's movements. 4. Turn patient on his or her side to allow saliva to drain from mouth

5. Stay with patient until seizure ends naturally. 6. Do not pour liquids into patient's mouth or offer any food, drink or medication until fully awake. 7. Give artificial respiration if patient does not resume breathing after seizure. 8. Provide area for patient to rest until fully awakened, accompanied by responsible adult. 9. Be reassuring and supportive when consciousness returns. 10. While a convulsive seizure is not usually a medical emergency, presence of any of the following signs indicate the need for immediate medical attention:

a. Seizure lasting longer than 10 minutes or occurrence of

second seizure.

b. Difficulty in rousing at 20-minute intervals. c. Complaints of difficulty with vision d. Vomiting e. Persistent headache after a rest period f. Unconsciousness with failure to respond g. Unequal size pupils or excessively dilated
B. Nonconvulsive Seizures (Absence and Complex Partial) 1. Do not restrain patient. 2. Remove harmful objects from patient's path. 3. Calmly try to encourage patient to sit down or encourage him or her away from dangerous situations. If person does not respond to these measures, force should not be used. 4. Observe but do not approach patient who appears angry or combative. 5. Remain with patient until fully alert.

DRUG THERAPY I. GOAL OF THERAPY

A. Primary goal of drug therapy is the complete suppression of seizures in the absence

of disabling side-effects. Prognosis of epilepsy has improved in last decade, and at present about 60-70% of newly diagnosed patients can be expected to achieve complete seizure control following institution of effective monotherapy (one drug). B. When epilepsy cannot be controlled completely, the aim of treatment is to attain the best compromise between the desire to maximize seizure control and the need to keep side-effects within acceptable limits for the individual patient. C. Therapy should maintain or restore the patient=s lifestyle and ability to lead an active life. II. GENERAL MANAGEMENT OF EPILEPSY A. Appropriate diagnostic evaluation B. Identify and correct underlying cause C. Treatment of Seizures 1. Assess necessity of drug therapy

a. Drug therapy not indicated for seizures due to acute

reversible medical problem

b. Therapy not necessary for certain benign epilepsies (febrile

seizures, rolandic epilepsy) c. Following first unprovoked seizure- while some benefit may occur by initiating therapy in high risk patients, present consensus is to delay therapy until patient experiences a second unprovoked seizure. 2. Institution of appropriate antiepileptic drug therapy 3. Identify and avoid if possible any precipitating factors (i.e., alcohol, lack of sleep, emotional stress, fever, lack of food, exposure to flickering light, menstruation) 4. Evaluation for surgery or implantation of vagal nerve stimulator in patients refractory to drug therapy. D. Prevention of complications of seizures 1. Early control/termination of seizures 2. Avoidance of intolerable drug-induced adverse effects 3. Attention to and treatment of psychosocial complications

III. PRINCIPLES OF ANTIEPILEPTIC DRUG (AED) THERAPY

A. Select most appropriate drug based on:

1. Seizure Type (see Table 1) - Seizure type is the primary criteria for antiepileptic drug selection. Although not necessary for drug selection, knowledge of the epilepsy syndrome is also useful since it provides additional information including the expected responsiveness of the patient=s seizure disorder to drug therapy, expected duration of drug therapy, and long term prognosis. 2. Final selection among drugs having equal efficacy for a given seizure type should be individualized for each patient based on other factors such as potential adverse effects, convenience of administration, cost, and patient=s lifestyle. (see Individual drug monographs, Section VI). B. Optimization of therapy requires individualization of dosage. Once an agent has been selected, therapy should initiated by starting at the low end of the drug=s recommended dosage range and slowly increasing the dose until seizures are controlled or intolerable adverse effects develop. Following each dose increase, time should be allowed for the drug to come to steady-state before evaluating the patient=s clinical response at that dosage level and deciding whether further adjustments are needed. 1. Initial Dosage: AED therapy should be gradually introduced during the first month of therapy to minimize the gastrointestinal and neurologic side effects that commonly occur with initiation of AED treatment. The frequency of these side effects tends to decrease over the first few months as tolerance develops. Although seen to some extent with all the AEDs, these initiation related side effects may be especially troublesome with carbamazepine, ethosuximide, felbamate, lamotrigine, primidone, tiagabine, topiramate and valproic acid. In addition to the GI and CNS effects listed above, the occurrence of rash with lamotrigine is related to the rate of dose initiation. To minimize these initiation related side effects, these agents are usually started at subtherapeutic dosages and the dose gradually increased over several weeks to the recommended dose range. Specific initiation schedules for these drugs are provided in their monographs (see section VI). If intolerable adverse effects develop during the titration process, the dose should be reduced to the previous level that the patient tolerated and, after symptoms subside, the titration process restarted using smaller dosage increments. Since initiation related adverse effects are less problematic with gabapentin, phenytoin, and phenobarbital, therapy with these agents is generally started at dosages within the recommended dose range. 2. Before considering therapy with a given AED as a failure and switching to another drug, the following factors should be reevaluated:

a. Diagnosis of epilepsy b. Classification of seizure type and/or epilepsy syndrome c. Presence of an active lesion d. Adequate dosage and/or duration of therapy (i.e., was dose
pushed to maximal tolerated level, was adequate time

allowed for steady-state to be achieved following each dose adjustment).

e. Compliance with medication regimen (noncompliance is

most common cause of drug failure and breakthrough seizures) 3. If seizures continue, despite a maximally tolerated dose of the first AED, a second AED should be selected. Therapy with the second drug should be initiated as described above. Once the dose of the second drug has been titrated into its recommended dose range, the initial drug should then be gradually withdrawn over 1-3 weeks (more rapid if being performed as inpatient). After the first drug has been withdrawn, the dose of the second drug, taken alone (i.e., monotherapy), should then be increased until seizures are controlled or intolerable side effects develop. This process should be continued until monotherapy with two or three of the primary drugs has failed. Only after this should combination or polytherapy be considered. Factors to consider when combining drugs include the patient=s previous clinical response (i.e., seizure control, side effects) to each drug alone, mechanism of action (theoretically combining drugs having differing mechanisms of action would appear preferable), adverse effect profiles, and pharmacokinetic properties. 4. Epilepsy surgery should also be considered in patients who have failed monotherapy with the primary drugs and an initial attempt with polytherapy. C. Monotherapy Monotherapy with the AEDs is preferred for most patients. Advantages of monotherapy as compared to polytherapy (multiple drug therapy) include: equal or superior efficacy to combination drug therapy; reduced frequency of adverse effects; absence of drug interactions; lower cost; enhanced ability to correlate response, adverse effects, and abnormal lab values to specific drug; reduced risk of birth defects; and improved compliance due to simpler and less intrusive regimens D. Monitoring Therapy 1. Seizures - patients should be encouraged to keep a seizure diary and accurately record the type, duration, and time of occurrence of any seizures. In assessing therapy, the following seizure related parameters should be considered:

a. Change in seizure frequency - important to assess not only

change in absolute number of seizures, but also length of seizure-free interval

b. Change in seizure pattern or type c. Altered time of occurrence

2. Adverse Effects: patients should be educated to the type of adverse effects that may occur with the AEDs and to record in their seizure diary any adverse effects and the

time of day at which they occur. Specific adverse effects that should be monitored for include:

a. Dose-Dependent Neurological Effects - (see section V, VI) the

following should be assessed at each visit: mental status; cerebellar signs (i.e., nystagmus, balance, coordination, tremor); visual problems (blurring, double vision); cognitive function

b. Idiosyncratic/Chronic Adverse Effects: (see section V, VI)

3. Laboratory Tests a. Baseline (i.e. prior to starting therapy) lab tests should include liver function tests (SGOT, SGPT, alkaline phosphatase), serum albumin, complete blood cell count with differential, urinalysis, and serum electrolytes. b. In otherwise healthy and asymptomatic patients, routine laboratory monitoring after starting therapy is unnecessary with clinical laboratory tests only being repeated if indicated by the patient's clinical condition. For patients with abnormal baseline laboratory tests, further work up is required to evaluate their cause and follow-up monitoring performed as indicated. (i.e., for a patient with a low WBC started on carbamazepine, a CBC should be obtained every month for first 1-3 months, then quarterly for next year, and then every 6-12 months thereafter). 4. AED Plasma Concentrations: When used appropriately, AED plasma concentrations provide a useful adjunct tool to clinical monitoring to assist in optimizing therapy (particularly for carbamazepine, phenytoin, primidone, valproic acid). Because of infrequent occurrence of seizures in most patients and wide interpatient variability in AED pharmacokinetics, availability of target plasma concentrations is helpful in guiding dose adjustments. [Please note however that the final assessment of therapy is the patient=s clinical response (i.e., seizure control and side effects) not what the plasma concentration is.] AED plasma concentration monitoring also is useful in assessing medication compliance and evaluating cause of an unexpected loss of seizure control or occurrence of drug toxicity. Role of plasma concentration monitoring with newer AEDs is not established and is not currently recommended. E. Appropriate Use of AED Plasma Concentrations 1. General Guidelines for Use of AED Plasma Concentrations

a. A major problem with the use of AED plasma

concentrations is tendency of many clinicians to treat the published therapeutic ranges as a fixed range that is optimal

for every patient. It is important to remember that these ranges are derived from uncontrolled studies and at best should be viewed as a target range to initially aim for as one is attempting to optimize therapy in a given patient.

b. Considerable interpatient variability in therapeutic plasma

concentrations exists for these drugs, with many patients being controlled at levels below or above the published ranges. An important point to remember in monitoring AED plasma concentrations is that the therapeutic concentration for a specific patient is that which controls seizures without producing significant adverse effects, regardless of whether or not it is within the published therapeutic range for that drug.

c. AED plasma concentrations should be interpreted in terms

of what is occurring clinically with patient.

d. Monitoring of AED plasma concentrations should be

restricted to answering questions concerning specific clinical problems. Routine monitoring of plasma concentrations in otherwise stable patients serves no purpose except to tell you what you already know and unnecessarily increases the cost of therapy. 2. Appropriate Indications for AED Plasma Concentration Monitoring

a. Guiding dosage adjustments b. Identifying patient=s individual therapeutic range c. Determing cause of unexpected loss of seizure control or
occurrence of drug toxicity

d. Evaluating clinical consequences of addition/removal of

potential interacting drug

e. Assessment of patient compliance

3. Factors to Consider Before Obtaining AED Plasma Concentration

a. Determine reason for sampling, since this will guide when

and at what time to obtain sample

b. Should the plasma sample be reflective of steady-state ?

While not all plasma concentrations need to be at steadystate, obtaining a plasma sample prior to achievement of steady-state will not provide an accurate assessment of

patient=s clinical response to the current drug regimen and may result in inappropriate dosage adjustments. To ensure a new steady-state has been reached, plasma samples should not be obtained for at least 4-5 half lives afetr most recent dosage adjustment or change in concurrent therapy.

c. Sampling time. In most instances, sampling time should be

consistent with times of previous samples to allow an accurate assessment between changes in patient=s clinical response and plasma concentrations. Obviously exceptions to this rule exist. For example, if the indication for the plasma level is dose related toxicity, obtaining sample at time of peak concentration or occurrence of symptoms may be helpful.

d. Determine need for obtaining free (unbound) plasma drug

concentration or plasma concentration of metabolite. 4. Evaluation of AED Plasma Concentrations

a. When was last dose given ? b. Is this concentration reflective of steady-state ? (When was
drug started, when did last dosage change occur, when were regimens of any concurrent drugs last changed)

c. Is patient compliant ? d. What is patient=s clinical response to this concentration ? e. Is there an intercurrent illness or concomitant drug that
might alter plasma concentrations or clinical response to the AED ? f. What are therapeutic goals for this patient ? 5. Factors Associated with Individual Variation in Therapeutic Plasma Concentration a. Seizure Type- patients with partial seizures have been shown to require higher plasma concentrations than patients with primary generalized seizures (Lambie et al, 1976; Schmidt & Haenel, 1984).

b. Severity of Epilepsy- higher plasma concentrations shown to

be required in patients with higher pretreatment seizure frequency and patients in status epilepticus.(Lund, 1974; Schmidt & Haenel, 1984) c. Altered plasma protein binding- relationship between free

and total AED plasma concentration altered. In patients with decreased protein binding (increased free fraction), clinical response would be expected at a lower total plasma concentration than if patient's plasma protein binding were normal.

d. Active Metabolites e. Concurrent Drug Therapy: Pharmacodynamic Interactions

1). Enhancement of Concentration-Related Toxicity: Concurrent use of other AEDs (polytherapy), alcohol, antidepressant, antihistamines, antipsychotics, benzodiazepines, narcotic analgesics, and sedative hypnotics may result in the occurrence of concentration-related neurotoxicity at lower than expected plasma concentrations. 2). Drugs Antagonizing Anti-Seizure Effect of AEDs: bupropion, clozapine, imipenem-cilastin, isoniazid, reserpine, tricyclic antidepressant, theophylline and cocaine/amphetamines may lower the seizure threshhold. F. Evaluation of Patient with Chronic Active Epilepsy 1. Review diagnosis/etiology 2. Review compliance

a. Evaluation of compliance 1. Direct questioning of patient using open ended question (e.g.
"How do you take your medicine?" "Which dose is more difficult to remember?"

2. Review of refill patterns 3. Pill counts 4. AED plasma concentrations a. Approaches for Improving Compliance 1. Patient education 2. Simplification of dosage regimens 3. Flexible, patient-specific administration schedules 4. Medication calendar 5. Use of pill cups, boxes, or watch with alarm

3. Review Drug History AED history should include drugs, doses used, and clinical response in terms of any beneficial effects or adverse effects. 4. Form Treatment Plan 5. Reduction of Polytherapy

a. Assess present therapy b. Withdraw any nonessential drugs, and drugs present at
subtherapeutic plasma concentrations

c. If not present, initiate therapy with desired AED(s) and

titrate dose to therapeutic serum concentration range

d. Concurrent with above, begin reducing drugs that are

producing adverse effects or potentially toxic.

e. Once therapeutic plasma concentrations of desired drug is

achieved, remove any other AED(s) as appropriate.

f. Plan should be reassessed based on clinical response and

plasma concentration monitoring following each change in drug and/or dose.

g. Anticipate changes that may occur in pharmacokinetics of

remaining drugs as potentially interacting drugs are removed. h. Tapering Schedule for withdrawing AED therapy: To minimize any exacerbation in seizure control or the occurrence of withdrawal seizures, ensure that plasma concentrations of desired drug(s) are in the usual therapeutic range and then slowly withdrawing the unwanted drug over several days to weeks. While the exact time schedule for tapering the dose of the drug to be withdrawn will depend on the patient=s clinical condition and setting, a general recommendation would be to decrease the dose by 25% every 1 to 2 weeks. If possible the tapering process with carbamazepine, phenobarbital and benzodiazepines should be even slower than this, i.e., 25% every 2 to 4 weeks. If an exacerbation of seizures occurs during drug withdrawal, the dose should be increased to the previous level and then, after seizure control has been restored, the tapering process restarted using a more gradual schedule (i.e., decreasing the dose by a smaller amount each time and allowing a longer time between dose

decreases). G. Termination of Antiepileptic Drug Therapy 1. Need for continued AED therapy can be reevaluated when patient has been seizure free for 2 to 5 years. Once seizure free for 2 to 5 years, studies have shown that 6075% of children and 40-60% of adults may be successfully withdrawn from medication. 2. Factors favoring a low risk for recurrence of seizures after medication withdrawal include (Annegers et al, Epilepsia 1979; Emerson et al, NEJM 1981; Thurston et al, NEJM 1982; Callaghan et al, NEJM 1988; MRC Trial Group, Lancet 1991 ):

a. Minimum 2 year seizure free period b. Normal electroencephalogram c. Short duration of epilepsy prior to seizures being controlled d. Few seizures after starting AED therapy e. Controlled achieved with monotherapy f. Age of less than 16 years at onset of seizures g. Presence of absence seizures only
3. Decision should be made on individual basis considering consequences of seizure recurrence on patient=s employment, education, lifestyle, and driving priveleges. Although little data is available to indicate the optimal withdrawal rate of AED therapy or to support a relationship between withdrawal rate and seizure relapse, most investigators recommend that treatment be withdrawn gradually over a period of at least three months (Callaghan et al, NEJM 1988; Chadwick et al, Br Med J 1985). H. Patient Education The main aim of education in the patient with epilepsy is to provide the patient and/or their care givers with knowledge needed to allow their active participation in management of their epilepsy. Goals of education in these patients include providing: 1). An understanding of their disease state; 2). The goals and limitations of drug therapy; 3). How to appropriately manage their disease (i.e., observing and recording seizures and any changes in seizure activity in diary; types of adverse effects to watch for, information to record about adverse effects in diary; how and when to report any problems with adverse effects or seizure control; what to do if miss dose)

4). An understanding of the concept of a therapeutic plasma concentration range, steady-state, and relation to regular drug intake (i.e., what occurs when miss dose and how long will it take once therapy is restarted for plasma concentrations to return to previous level); 5). An understanding of the importance of compliance with their medication regimen and what measures or aides can be used to improve compliance. Also since sooner or later every patient will miss a dose, they should be instructed on how to handle missed doses. In general, if a single dose is missed, the patient should be instructed to take the missed dose as soon as possible. If two sequential doses are missed, one should be taken immediately and the other with the next regular dose. If more than two doses are missed, patients should contact their physician as the strategy in this situation will depend on patient=s clinical condition and on the AED. 6). Understanding and recognition of drug related adverse-effects and potential drug interactions (Who to contact if have questions concerning a potential drug interaction or adverse effect, What adverse effects to be aware, When to contact their health care provider); 7). For women of childbearing potential, birth control options and the risks/complications associated with pregnancy in a woman with epilepsy should be discussed (see pages 24-26 of The Epilepsy Counseling Guide).

IV. ADVERSE EFFECTS A. Dose (Plasma Concentration) Related Adverse Effects

1. These adverse effects primarily represent the toxic effects of the AEDs on the central nervous system, and include somnolence, fatigue, dizziness, vision changes (double or blurry vision), nystagmus, ataxia (incoordination), tremor, gastrointestinal disturbances, difficulty thinking, and behavioral disorders. These adverse effects are dose-related and more prominent at higher AED plasma concentrations. Although their severity and frequency may vary among agents, the concentration-related adverse effects are qualitatively similar among the different antiepileptic drugs (AEDs) and are seen in all patients if large enough doses are given. The occurrence of these adverse effects end up being the therapy limiting endpoint for most patients. 2. Due to additive neurologic effects of the AEDs, these adverse effects are more frequent and occur at lower plasma concentrations in patients receiving AED polytherapy (i.e. more than one AED). 3. The occurrence of these adverse effects, unrelated to dose, is particularly prominent during initiation of therapy (especially with carbamazepine, ethosuximide, primidone, felbamate, lamotrigine, tiagabine, topiramate, and valproic acid), but disappear as tolerance develops. For this reason, therapy with these drugs should be started with low doses and the dose slowly titrated up to the recommended maintenance over several weeks. 4. Transient neurotoxicity during the first hours following drug ingestion may relate

to an excessive fluctuation in plasma concentrations between doses and high peak plasma concentrations. These peak plasma concentration-related neurologic effects commonly result from use of inappropriate dosage intervals relative to drug=s halflife or administration of rapidly absorbed dosage formulations. 5. The occurrence and severity of these neurologic side effects can be minimized by:

a. Initiating therapy at a low dose and slowly increasing the

dose

b. Avoiding large dosage changes c. Restricting therapy to one drug when ever possible d. Adjusting the administration schedule (e.g., administration
of the largest dose at bedtime, dividing the daily dose into smaller doses given more frequently)

e. If the occurrence of these adverse effects is primarily

associated with the time of peak serum concentrations, their occurrence may be reduced by administering smaller doses more frequently or switching to a more slowly absorbed formulation.

f. Reduction in total daily dose.

6. Impairment of Cognitive Function/Behavioral Disorders

a. Impairment of cognitive function (i.e., difficulty thinking)

and behavioral disorders are the adverse effects that most significantly impact on the patient=s quality of life. Factors contributing to these problems in patients with epilepsy include the disease state, psychosocial stresses, and AED therapy. b. Adverse effects on cognitive function and behavior (i.e., hyperactivity, irritability, sleep disturbances, altered mood, depression) have been reported with all of the AEDs. The severity of these effects is increased with higher plasma concentrations and polytherapy.

c. Differential effects among the various AEDs have not been

apparent in controlled studies, with the exception of phenobarbital and the benzodiazepines. Phenobarbital appears to decreases cognitive performance to greater extent than other AEDs in both adults and children. Barbiturates have greatest effect on behavior, including hyperactivity which may be seen in 10-50% of children receiving

phenobarbital. Newer AEDs, such as gabapentin and lamotrigine, appear to have minimal effects on either cognitive function or behavior. d. Management: recognize that these adverse effects may occur with any of AEDs, restrict therapy to lowest effective dose and avoid polytherapy, particularly with barbiturates B. Idiosyncratic (Hypersensitivity) Adverse Effects 1. All of the current AEDs, with the exception of some of the newer AEDs (gabapentin, topiramate, tiagabine), have been associated with the occurrence of rare, but serious idiosyncratic reactions, including aplastic anemia, skin rash, hepatotoxicity, pancreatitis, lupus-like reaction, and exfoliative dermatitis/StevensJohnson syndrome. These reactions are generally rare (about 1 in 20,000 to 50,000 newly treated), unpredictable, non-dose related and usually occur during the first few months of therapy. 2. Previous recommendations for routine monitoring of blood and urine analyses during AED therapy were primarily designed to detect these reactions. However, because of their rare occurrence, the frequent occurrences of transient and clinically insignificant changes in lab indices during chronic AED therapy, and the fact that clinical symptoms are usually present before lab testing reveals any abnormalities; the more recent recommendations given in section III. D.3. have been adopted. 3. Most important approach to monitoring for these serious idiosyncratic effects is close clinical monitoring of the patient and education of the patient and family about the symptoms that may indicate serious adverse effects and the importance of reporting these immediately to their physician.

a. Severe dermatologic or hepatic reaction with

carbamazepine, lamotrigine, phenytoin, phenobarbital, primidone: rash and fever

b. Valproic acid induced hepatotoxicity or pancreatitis: nausea,

vomiting, lethargy, loss of seizure control, jaundice, coma

c. Aplastic anemia/granulocytopenia: abnormal bruising or

bleeding, persistent infection 4. Proposed Mechanism For Idiosyncratic Adverse Effects With Heterocyclic AED Recent studies suggest that the idiosyncratic (hepatotoxicity, rash, pseudolymphoma, aplastic anemia) and teratogenic adverse effects occurring with the heterocyclic AEDs (i.e., carbamazepine, lamotrigine, phenytoin, phenobarbital, primidone ) may result from accumulation of toxic arene oxide metabolites of these drugs. The accumulation of arene oxide metabolites results from genetic defect of drug metabolism and is enhanced by polytherapy. These AEDs are metabolized by hepatic cytochrome P-450 monoxygenase to a chemically reactive intermediate metabolite (arene oxide) which is

then rapidly detoxified by epoxide hydrolase to an inactive hydroxylated metabolite. The predisposition of certain patients to develop idiosyncratic toxicity with these drugs appears to be due to a genetic or drug-induced (i.e., valproic acid) reduction in epoxide hydrolase activity allowing accumulation of the toxic arene-oxide metabolites. Additionally enzyme induction of monoxygenases by other concurrent AED (such as carbamazepine, phenobarbital, phenytoin, primidone) serves to further increase the levels of the reactive arene oxides. 5. Skin Rash Skin rash is the most common hypersensitivity reaction with the AEDs and is seen in 5-15% of patients receiving carbamazepine, ethosuxmide, lamotrigine, phenytoin, and phenobarbital. Onset of rash is usually within first 1-3 weeks of therapy and is reversible on discontinuing the causative agent. Although a mild morbilliform rash is most common, skin reactions may rarely progress to more severe forms, such as exfoliative dermatitis, Stevens Johnson syndrome, and toxic epidermal necrolysis. The presence of fever, eosinophilia, desquamation, mucus membrane ulceration, and painful dermatitis may serve to differentiate between the benign and more serious skin reactions. Of the current AEDs, skin rash is only rarely reported with valproic acid, gabapentin, felbamate, topiramate, and tiagabine. The occurrence of skin rash with lamotrigine therapy is increased by concurrent valproic acid therapy, a high starting dose, and a rapid dose escalation schedule when initiating therapy. To minimize the occurrence of rash with lamotrigine, therapy should be started at a very low dose, particularly if already receiving valproic acid, and slowly increased into the effective dose range over 1-3 months. 6. Hepatotoxicity

a. Remember: it is not unusual (2 to 40% of patients) to see

transient elevated serum transaminases and alkaline phosphatase levels without any clinical symptoms in patients on AED (particularly children). These observations will in the vast majority of cases resolve on continued therapy and require no therapeutic intervention. It is important that these cases be differentiated from the rare but more severe hepatotoxicity observed with AED treatment: delayed hypersensitivity (seen with PHT, Pb, CBZ, Pr) and irreversible hepatic coma (VPA).

b. Delayed Hypersensitivity Reaction 1. Reported with all of the heterocyclic AEDs (i.e.,
carbamazepine, lamotrigine, phenytoin, phenobarbital, primidone). Mechanism thought to be an idiosyncratic metabolic abnormality in susceptible patients.

2. Onset in majority of patients within first 6 weeks of therapy.

3. Elevated liver enzymes accompanied by signs and symptoms of hypersensitivity: rash (86%), fever (84%), lymphadenopathy (68%), jaundice (54.5%), hepatomegaly (52%), eosinophilia (77%). (Oxley et al; 1983).

4. 38% of cases may develop fatal hepatic necrosis, multiorgan

failure, disseminated intravascular coagulation.

5. Requires discontinuation of therapy. a. Valproate Hepatotoxicity 1. Usually occurs during first 6 months of therapy.
2. Proposed mechanism: biochemical defect in fatty-acid metabolism, which is accentuated by an enhanced production of toxic valproic acid metabolites, which may be increased by concurrent therapy with enzyme-inducing AEDs, and concurrent disease states. 3. Risk factors for development of valproate hepatotoxicity include young age and use of polytherapy. Presence of other neurological disorders, biochemical diseases, or preexisting liver disease further increase risk. Highest risk of hepatic fatality is in patients < 2 years of age and on polytherapy. Risks for development of fatal hepatic failure range from 1/500 in children < 2 y/o on polytherapy to 1/37,000 for monotherapy patients.

4. Prodromal symptoms: sudden loss of seizure control,

malaise, lethargy, drowsiness, weakness, vomiting, anorexia and/or jaundice. In most cases, routine monitoring of liver function tests will be of little value in detecting onset of acute toxicity.

5. Prevention a. Avoid administering VPA as part of polytherapy regimen to

children < 3; unless either monotherapy has failed or potential benefits of polytherapy merit risk.

b. Avoid administering VPA to patients with preexisting liver

disease and/or a family history of childhood hepatic disease.

c. Administer VPA in as low a dose as possible for seizure

control

d. Avoid concomitant administration of valproate and

salicylate,

e. Monitor clinically for such symptoms as vomiting, headache,

edema, jaundice, or seizure breakthrough, especially after febrile illness. If such symptoms develop, VPA therapy should be discontinued until a definitive diagnosis is made. Patient should be made aware of these symptoms and what to do if occur, when initiated on VPA. Greater physician and patient awareness of the primary risk factors have resulted in a decrease incidence of fatal VPA hepatotoxicity from 0.93/10,000 in 1978-84 to 0.20/10,000 in 1985-86.

a. Felbamate : Acute hepatic failure with felbamate, 16 cases

reported after introduction between 1/94 to 12/94. Mechanism unknown. Has resulted in severe restrictions being placed on use of drug. 7. Aplastic Anemia/Agranulocytosis Although commonly associated with carbamazepine, serious hematological reactions (i.e., aplastic anemia and agranulocytosis) have been reported with all of the AEDs, except gabapentin, lamotrigine, topiramate, and tiagabine. The frequency of aplastic anemia with carbamazepine has been estimated at 1 in 200,000 patients. In contrast, to the extremely rare occurrence with carbamazepine and the other AEDs, thirty cases of aplastic anemia were reported with felbamate from 1/94 to 12/94, which represents an approximate frequency of 1 in 2000 patients. Routine monitoring of CBCs is usually of little value in detecting the onset of aplastic anemia. The most important approach is to clinical monitor the patient for the occurrence of any signs or symptoms indicative of a serious hematologic reaction, including bruising, bleeding, and persistent infection. C. Chronic (Systemic) Adverse Effects 1. Long-term AED therapy may lead to a variety of chronic adverse effects, including connective tissue, endocrine, GI, hematologic, and neurologic disorders. Chronic AED toxicity tends to be drug specific and is not directly related to AED serum concentration. While not usually life threatening, these chronic adverse effects may have a significant impact on the patient's quality of life. Many of these adverse effects can be avoided or minimized by appropriate preventative measures. Factors that may predispose a patient to chronic AED toxicity include a long duration of therapy, polytherapy, extended administration of high dosages, repeated or prolonged episodes of acute toxicity, poor diet or hygiene, and institutionalization. 2. Neurological

a. Chronic Cerebellar Degeneration (Encephalopathy)

1). Primarily seen in patients receiving prolonged (> 5-10y) phenytoin treatment with

high serum concentrations and/or dose. Similar syndrome also reported to rarely occur with primidone and phenobarbital. 2). Characterized by confusion, delirium, muscular hypotonia, choreoathetoid movements, orofacial dyskinesias. 3). May improve in some patients following reduction in dose and/or discontinuation of phenytoin. 4). Related to chronic degeneration of purkinje cells in cerebellum; actual role of phenytoin in this disorder controversial since most patients also have long history of uncontrolled generalized tonic-clonic seizures.

a. Peripheral Neuropathy- reported in approximately 8.5-18%

of patients receiving long term phenytoin therapy at high doses. Primarily manifested as sensory loss. May or may not improve on decreasing dose. May respond to folate supplementation. Also has been reported with carbamazepine and barbiturates. 3. Gastrointestinal a. Increased weight gain - Reported for valproic acid (VPA), primarily in children. Usually reverses with continued therapy. If not, consider reduction in caloric intake, dose reduction or discontinuation of therapy. Mechanism unknown. In the recently completed VA Cooperative study in adult epileptics, incidence of a large weight gain (>12 lbs/ 5.5 kg) with VPA was 20 % overall and 13 % after 12 months of therapy.

b. Anorexia and weight loss (>10 kg) is reported in 5-15% of

patients receiving felbamate. Mechanism unknown. Usually reversible with continued therapy. If persists, the options include attempting to increase patient caloric intake, reducing the felbamate dose, or discontinuing therapy. 4. Hematological

a. Leukopenia, thrombocytopenia and various anemias have

been reported in isolated cases with the all the AED, except gabapentin and lamotrigine. A transient and/or dosedependent leukopenia is seen in 5-10% of patient receiving carbamazepine. In most cases, this leukopenia is clinicaaly insignificant and requires no action. Presence of persistent leukopenia (WBC<3000/mm3 or neutrophils <1500/mm3) will generally respond to a reduction in the carbamazepine dose. The presence of infection with severe leukopenia or neutropenia (<3000 WBC/mm3 or <1500 neutrophils/mm3)

calls for discontinuation of carbamazepine.

b. Neonatal Coagulation Defects

1). Seen in infants born to mothers on phenobarbital, primidone, carbamazepine and/or phenytoin. Onset of this hemorrhagic disorder is usually within the first 24 hours after birth and consists of hemorrhage from atypical sites such as pleural and abdominal cavity. This is in contrast to hemorrhagic disease of the newborn which does not develop until 2 to 5 days postpartum and where bleeding is more superficial. 2). Mechanism thought to be competitive inhibition of Vitamin K metabolism in fetal liver preventing production of vitamin K dependent clotting factors. 3). Management: a). Mothers receiving antiepileptic drugs should avoid other drugs with adverse effects on hemostatic system during last trimester (i.e., aspirin, indomethacin, thiazides, promethazine). b). Consider cesarean section if difficult or traumatic delivery is expected. c). Mother receiving AED should be given oral Vitamin K1 20 mg/day the last 2 to 4 weeks of pregnancy d). Cord blood should be submitted for immediate clotting studies and fresh frozen plasma given if diminished vitamin K dependent factors are found. e). Infant should be given 1 mg IV phytonadione immediately after birth. f). The neonate should then be monitored carefully and should receive an exchange transfusion at the first sign of development of hemorrhage.

a. Megaloblastic Anemia
1). Occurs in 0.15-0.75% of epileptic patients on AED, primarily with phenytoin but also reported with Pb, Pr and CBZ. 2). Mechanism appears to be due phenytoin-induced malabsorption of dietary folate and/or induction of metabolism. 3). Readily responds to treatment with exogenous folic acid 1 to 5 mg/day. 4). Not uncommon to see subclinical macrocytosis and/or low serum folate levels without accompanying signs of megaloblastic anemia (1 to 30% of patients on phenytoin); present recommendations are not to treat these patients with folate.

a. A dose-dependent thrombocytopenia and/or platelet

dysfunction (due to inhibition of platelet aggregation) has been reported infrequently in patients on valproic acid. This side effect is probably rare or at least has little clinical

significance. Although regular monitoring is probably not warranted, a baseline platelet count should be obtained in patients starting on VPA. As a precaution, patients on VPA prior to surgery should have a platelet count and bleeding time performed. 5. Endocrine

a. Osteomalacia
1). Primarily a biochemical disorder with decreased concentrations of Vitamin D and calcium, rarely associated with the development of clinical disease. 2). Attributed to increased hepatic metabolism of vitamin D and/or inhibition of calcium absorption. Has been associated with phenytoin, phenobarbital, primidone and carbamazepine. 3). Risk factors associated with the development of clinical disease include: poor dietary intake of vitamin D, low exposure to sunlight, drug dose and duration, multiple anticonvulsants and male sex. 4). Treatment: 4000 IU vitamin D3/mm3 BSA per day for 4 months, then maintenance therapy of 1000 IU/day.

a. SIADH
1). Reported primarily in elderly patients on carbamazepine. Water retention with hyponatremia; clinically manifested as headache, mental confusion, dyspnea, and acute loss of seizure control after prolonged carbamazepine treatment. 2). Mechanism unknown; in patients in whom it occurs, it appears to be related to serum concentration and may improve with decrease in dose. Baseline urinalysis and serum sodium should be obtained in patients prior to starting carbamazepine with follow up tests done in patients with occurrence of above clinical symptoms. Often mistaken for acute carbamazepine toxicity, should be considered in elderly patients complaining of above symptoms. a. Hyperglycemia: an uncommon adverse effect reported for phenytoin; related to phenytoin impairment of normal insulin response to glucose. For most epileptic patients of no clinical significance, however should be kept in mind when phenytoin being used in diabetic patients. To prevent complications in these patients, phenytoin should be used in lowest effective dose. 6. Cardiac

a. Carbamazepine: Cardiac conduction disturbances (2nd or

3rd degree A-V block) have been rarely reported with

carbamazepine. Reversible on discontinuation. Most important risk factor appears to be advanced age. Elderly patient starting on CBZ should have EKG performed before and after initiation of therapy. b. Intravenous Phenytoin: Ventricular arrhythmias, conduction disturbances, and hypotension may occur following IV phenytoin administration. Solvent, propylene gylcol, in parenteral solution appears to be contributing factor. Occurrence related both to rate of administration and patient age (i.e., more common in elderly patients). 7. Connective Tissue Disorders

a. Gingival Hyperplasia
1). Observed in up to 50% of patients on chronic phenytoin therapy. 2). Proposed mechanism: alteration of connective tissue repair process and decrease in salivary levels of IgA. Initial tissue damage may be related to accumulation of arene oxide metabolites as severity worse in patients on polytherapy. 3). Severity may be reduced by careful oral hygiene.

a. Hirsutism, acne, hyperpigmentation, and coarsening of

facial features- not uncommonly observed in children and young adults on chronic phenytoin therapy. Incidence of facial hirsutism reported up to 30% in young females.

b. Alopecia- Reported in 2-12% of patients on valproic acid;

characterized by temporary thinning of hair with curly or wavy regrowth. Has not been shown to be dose related (although some studies have reported that it occurs more commonly in patients on high doses) and usually resolves in 2-6 weeks without any adjustments in VPA therapy required. Reversible on discontinuation of drug. c. Dupuytren's Contractures: characterized by palmar nodules, frozen shoulder, generalized joint pain. Although first reported with AEDs in 1925, the 1985 VA monotherapy trial was first study to show direct association with phenobarbital and primidone therapy. Seen after at least 6 months of therapy with Pb or Pr and reversible on D/C. Incidence 5-10% with an increasing incidence longer patients on drug. 8. Teratogenicity

a. Expected incidence of congenital malformations (Browne,

1983):
o o

2-3% general population 4-5% children born to mothers with epilepsy not taking AED

6-11% children born to mothers with epilepsy taking AED; an incidence similar to that in untreated mothers has also been reported in offspring of epileptic fathers.

a. Present data does not support a specific teratogenic effect

from AED, but indicate that congenital abnormalities that occur normally in epileptic patients occur more frequently with use of AED. Present data supporting an association between AED exposure and development of malformations include: 1). higher malformation rates in children of treated mothers as compared to untreated mothers with epilepsy 2). higher AED serum concentrations found in serum of mothers with malformed children than mothers of healthy children (Dansky et al, Neurology 3:15, 1980) 3). higher malformation rates seen in infants exposed to polytherapy than those exposed to monotherapy during gestation (Lindhout et al, Epilpesia 25:77, 1984; Kaneko et al, Epilepsia 29:459,1988). Both the Lindhout and Kaneko studies indicate that the most teratogenic AED combinations are those with VPA plus one or more enzyme inducing AEDs (PHT, Pb, Pr, CBZ). 4). higher malformation rates are not seen in infants exposed to maternal seizures during gestation than in infants whose mothers had no seizures

a. With the exceptions of trimethadione and valproic acid,

recent studies do not indicate a difference among different AEDs in either the incidence or type of malformations observed.

b. Primary abnormalities seen: cardiovascular malformations

(2.0%) and cleft lip/palate (1.8%), Skeletal abnormalities (1.0%), hypospadias (0.5%), dysmorphia with developmental retardation (0.5-1%). Incidence of neural tube defect (spina bifida) has been reported as 1-2% for infants exposed to valproic acid in utero and 0.5-1% for infants exposed to carbamazepine.

c. "Fetal AED syndrome" is manifested by cranial facial

anomalies, dysmorphic nasal features, epicanthal folds, wide mouth, prominent lips, digit hypoplasia and mental retardation. Although at one time primarily associated with

phenytoin use, more recent studies show that incidence of this syndrome with phenytoin is no different than with the other AED.

d. Mechanisms of AED Teratogenicity

1). AED-induced folate deficiency 2). Binding of certain AED due to chemical properties as weak acids (i.e.,VPA) to fetal tissue 3). Increased accumulation of arene oxide metabolites of AED and/or decreased activity of epoxide hydrolase activity

a. Management of Epilepsy in Pregnancy

Refer to Prepregnancy Counseling Guidelines for Women with Epilepsy on page 25 of the Epilepsy Counseling Guide.

V. DRUG INTERACTIONS A. Pharmacodynamic Interactions 1. Enhance AED Neurotoxicty:Concurrent use of other AEDs (polytherapy), alcohol, antidepressant, antihistamines, antipsychotics, benzodiazepines, narcotic analgesics, and sedative hypnotics may result in the occurrence of concentration-related neutotoxicity at lower than expected plasma concentrations. 2. Drugs Antagonizing Anti-Seizure Effect of AEDs: bupropion, clozapine, imipenemcilastin, isoniazid, reserpine, tricyclic antidepressant, theophylline and cocaine/amphetamines may lower the seizure threshhold B. Pharmacokinetic Drug Interactions (see Tables 3A and 3B) 1. Interference with absorption 2. Reduction in plasma protein binding 3. Enhancement/Inhibition of hepatic metabolism VI. SPECIFIC DRUG THERAPY FOR EPILEPSY Note: Information listed below is based on instructor=s experience and review of literature. Indications and dosages may therefore differ from those found in drug=s FDA approved product information. A. Phenytoin (DilantinR) (PHT)

Indications: simple or complex partial seizures, primary or secondarily generalized tonic-clonic seizures, convulsive status epilepticus Mechanism: blockade or inactivation of neuronal sodium channels, possible action on calcium conductance Target Plasma Concentration Range: 10-20 mg/mL Half Life: 7-42 hours (due to non-linear kinetics dependent on plasma concentration) Time to Steady-State: 4 - 21 days Adverse Effects Concentration Dependent: nystagmus, double-vision, blurred vision, incoordination, drowsiness, dizziness, headache Idiosyncratic: aplastic anemia, granulocytopenia, hepatotoxicity, rash, exfoliative dermatitis/Stevens-Johnson, Lupus-like reaction Chronic: gum hypertrophy, acne, hirsutism, peripheral neuropathy, chronic cerebellar damage, megaloblastic anemia, osteoporosis, fetal vitamin K depletion. Dosage: Maintenance Dose-4-6 mg/kg/day (300-500 mg/day) in adults, 4-10 mg/kg/day in children. Initiation of therapy: Therapy with phenytoin can usually be initiated at the recommended maintenance dose. Generally therapy is started at a dose of 4-5 mg/kg/day (or 300 mg/day) in adults and 6-8 mg/kg/day in children < 12 years. Following initiation of therapy, steady-state is not achieved for 1-3 weeks because of wide variation in pharmacokinetics among individuals and non-linear kinetics of drug. Due to saturable hepatic metabolism, subsequent dose adjustments should be limited to 30-100mg/day increments once serum concentrations are above 7.5 ug/ml. Administer in 1-2 daily doses. Available Dosage Forms:

a. 30mg and 100 mg capsules as phenytoin sodium b. 50 mg chewable tablet, 30 mg/5ml and 125 mg/5 ml oral
suspension with amount expressed as phenytoin acid

c. 50 mg/ml phenytoin sodium injectable solution for IV use

only d. 50 mg phenytoin sodium equivalents/ml fosphenytoin sodium injectable solution for IV and IM use Advantages: first line agent for partial seizures, inexpensive, once or twice daily administration, availability of parenteral formulation Disadvantages: dose dependent kinetics, drug interactions, chronic neurologic and

cosmetic/connective tissue adverse effects B. Phenobarbital (PB) Indications: simple or complex partial seizures, primary or secondarily generalized tonic-clonic seizures, convulsive status epilepticus Mechanism: Enhance activity of GABAA (gamma-aminobutyric acid) receptor resulting in enhanced chloride conductance, depresses glutamate-mediated excitability, blocks neuronal sodium channels Target Plasma Concentration Range: 15-40 mg/mL Half Life: 60-120 hrs (adults); 40-70 hrs (children) Time to Steady-State: 8 - 24 days Adverse Effects Concentration Dependent: drowsiness, tiredness, incoordination, dizziness, headache, decreased libido/impotence, impaired cognitive function Idiosyncratic: aplastic anemia, granulocytopenia, hepatotoxicity, rash, exfoliative dermatitis/Stevens-Johnson, Lupus-like reaction Chronic: Behavioral disturbances/hyperactivity, osteomalacia/osteoporosis, Dupuytren's contractures - frozen shoulder, megaloblastic anemia, fetal vitamin K depletion. Dosing: Maintenance dose: 1-3mg/kg/day for adults (60-240 mg/day), 3-6 mg/kg/day for children. Initiation of Therapy: Phenobarbital generally initiated at dose of 0.5-1 mg/kg/day in adults (30-60 mg/day) or 3 mg/kg/day in children < 12 years. Dose can then be increased every 3 to 4 weeks by 0.5 to 1 mg/kg /day up to the maximally tolerated dose. Administered in 1-2 daily doses. Available Dosage Forms:
o o o

15 mg, 30 mg, 60 mg tablet 15 mg/5 ml elixir 200 mg/ml phenobarbital sodium injectable solution for IV and IM use

Advantages: inexpensive, once daily administration, parenteral formulation available, extremely effective in some patients, easy to use Disadvantages: adverse sedative, cognitive, or behavioral effects; connective tissue effects; potency or libido problems C. Primidone (MysolineR) (Pr)

Indications: simple or complex partial seizures, primary or secondarily generalized tonic-clonic seizures Mechanism: see phenobarbital above. Phenobarbital is active metabolite of primidone Target Plasma Concentration Range: 5-15 mg/ml primidone, 15-40 mg/ml phenobarbital (active metabolite) Half life 6-18 hours (adults); 5-11 hours (children) Time to Steady-State 1-4 days for primidone; 8-24 days for active metabolite phenobarbital Adverse Effects Concentration Dependent: drowsiness, tiredness, incoordination, dizziness, headache, decreased libido/impotence Idiosyncratic: aplastic anemia, granulocytopenia, hepatotoxicity, rash, exfoliative dermatitis/Stevens-Johnson, Lupus-like reaction Chronic: Behavioral disturbance/hyperactivity, impaired cognitive function, osteomalacia/osteoporosis, Dupuytren's contractures - frozen shoulder, megaloblastic anemia, fetal vitamin K depletion. Dosing: Maintenance Dose: 10-25 mg/kg/day in adults (750-2000 mg/day) and 10-25 mg/kg/day in children. Initiation of therapy: For adults and children > 12 years: Start at 125 mg at bedtime for 3-7 days, with the dose increased by 125 mg every 3-7 days as tolerated by patient until an initial maintenance of 250 mg t.i.d. is reached. Dose should then be adjusted in 250 mg increments every 3 to 4 weeks up to maximally tolerated dose. Administered in 2 or 3 divided doses. Maximum recommended dosage 2 gms or 25 mg/kg/day. For children < 8 years: Start at one-half adult dose and increase up to initial maintenance dose of 125 mg t.i.d. Dose should then be adjusted in maximum 125 mg/day increments every 2 to 4 weeks. Administered in 2 to 4 divided doses. Maximum recommended dosage 25 mg/kg/day. Available Dosage Forms: 50 mg and 250 mg tablets, 250 mg/5ml oral suspension Advantages: effective in some patients for partial seizures Disadvantages: frequency and severity of initiation related side effects; adverse cognitive and behavioral adverse effects; potency or libido problems D. Carbamazepine (TegretolR) (CBZ) Indications: simple or complex partial seizures, primary or secondarily generalized tonic-clonic seizures Mechanism:: blockade or enhancement of inactivation of neuronal sodium channels Target Plasma Concentration Range: 4-12 mg/ml

Half life: 10-25 hours (adults); 6-15 hours (children) Time to Steady-State: 3-5 days (Note: due to autoinduction of hepatic metabolism, time to reach steady-state after initiating therapy will be 3-5 weeks) Adverse Effects Concentration Dependent: nausea/vomiting, nystagmus, double vision, blurred vision, incoordination, drowsiness, dizziness, headache, Idiosyncratic: aplastic anemia, granulocytopenia, hepatotoxicity, rash, exfoliative dermatitis/Stevens-Johnson, Lupus-like reaction Chronic: Transient leukopenia, syndrome of inappropriate ADH secretion, osteomalacia/osteoporosis, constipation/dry mouth, megaloblastic anemia, fetal vitamin K depletion. Dosing: Maintenance dosage: 8-20 mg/kg/day (400-1800 mg/day) in adults; 10-30 mg/kg/day in children. Initiation of therapy: Dosage must be carefully and slowly adjusted according to individual requirements and response. Initiation schedule: It is important to begin therapy with a low dosage and to proceed slowly to decrease occurrence of neurological and gastrointestinal side effect seen when initiating therapy. Start therapy at a to 3 of initial maintenance dose and gradually increase over several weeks. For example, in a 75 kg patient, the initial dose would be 600 mg/day. Should therefore start at 200 mg/day and increase by 200 mg/day every week for next 2 weeks. After this, subsequent dose changes should be made in 200-400 mg increments based on clinical response. Dosing frequency dependent on age, concurrent drug therapy and dosage form. If using extended release tablets b.i.d. dosing canusually be used in all. If using plain tablet, b.i.d. dosing possible for adults receiving carbamazepine alone, however for adults on poly therapy and children < 12 years t.i.d. or q.i.d. dosing usually needed. If using chewable tablet or suspension, t.i.d. or q.i.d. dosing Available Dosage Forms: 100 mg, 200 mg, 400 mg extended release tablet, 200 mg plain tablet, 100 mg chewable tablet, 100 mg/5 ml suspension Advantages: first line agent for partial seizures and generalized tonic-clonic seizures; usually well tolerated during chronic therapy with minimal sedative, cognitive, or behavioral adverse effects; Disadvantages: transient adverse effects during initiation of therapy; no parenteral formulation; may exacerbate absence and myoclonic seizures; autoinduction of hepatic metabolism; drug interactions. E. Valproic Acid (DepakoteR, DepakeneR) (VPA) Indications: primary and secondarily generalized tonic-clonic seizures, simple or complex partial seizures, absence seizures, atypical absence, atonic, and myoclonic seizures

Mechanism: enhancement of GABA function, neuronal sodium channel blockade, inhibitng low threshhold calcium channels Target Plasma Concentration Range: 50 - 100 mg/ml Half Life: 8-18 hours adults; 4-16 hours children Time to Steady-State: 2 -4 days Adverse Effects Concentration Dependent: gastrointestinal disturbances, tremor, drowsiness, incoordination, dizziness, headache Idiosyncratic: aplastic anemia, granulocytopenia, hepatotoxicity, pancreatitis Chronic: alopecia (hair loss/thinning), weight gain, hyperammonemia, thrombocytopenia, inhibition of platelet aggregation. Dosing: Usual maintenance dose : 10-40 mg/kg/day for adults (500-2500 mg/day) & children on monotherapy, 20-60 mg/kg/day for children on polytherapy. Initiation of therapy: Valproic acid should be started at low dosages to minimize side effects: 250 mg dose (125 mg for children) after meal on the first day; gradually increase by 5-10 mg/Kg increments every 3-7 days as tolerated by patient. A daily dose of 20-60 mg/Kg may be needed for adequate seizure control. The drug is usually given in 3-4 divided doses. Twice daily dosing (b.i.d.) may be possible for adults on monotherapy. Available Dosage Forms:
o o o

250 mg capsule, 250 mg/5ml syrup 125 mg, 250 mg, 500 mg enteric coated tablet 125 mg sprinkle capsule (prolonged release form designed to be sprinkled over food Valproic acid lyophilized powder for IV administration 500 mg/5ml

Advantages: broad spectrum of efficacy; drug of choice for primary generalized epilepsies; availability of parenteral formulation Disadvantages: cost; weight gain & alopecia; potential for rare but severe hepatic toxicity in children; drug interactions; requirement for administration in 3-4 divided doses in patients receving polytherapy and children F. Ethosuximide (ZarontinR) (ETH) Indications: absence seizures Mechanism of Action: inhibition of low threshold calcium current in thalamic

neurons. Target Plasma Concentration Range: 40 - 100 mg/ml Half Life: 40 - 60 hours adults, 30 hours children Time to Steady-State: 7 - 10 days Adverse Effects Concentration Dependent: gastrointestinal disturbances, drowsiness, incoordination, headache, dizziness, hiccups Idiosyncratic: aplastic anemia, granulocytopenia, hepatotoxicity, rash, exfoliative dermatitis/Stevens-Johnson, Lupus-like reaction Chronic: Behavioral changes, Parkinsonian movements Dosing: Usual maintenance dosage: 10-20 mg/kg/d in adults and 15-40 mg/Kg/day in children. Initiation Schedule: Therapy should be started at 250-500 mg/day and increase 250mg/d each week until seizures controlled or adverse effects develop. Usual maximum daily dosage 1000 mg/d in children < 6 y/o and 1500 mg/day in children > 6 y/o and adults. Daily dose may be given in 1 or 2 divided doses. Twice daily dosing may be beneficial in reducing the occurrence of nausea and vomiting. Available Dosage Forms: 250 mg capsule, 250 mg/5ml syrup Advantages: first line therapy for absence seizures with out risk of rare but serious hepatotoxicity as with valproic acid; relatively well tolerated by most patients; inexpensive; once or twice daily administration possible Disadvantages: only effective for absence seizures, no parenteral formulation, fairly high frequency of gastrointestinal disturbances G. Felbamate (FelbatolR) (FBM) Indications: simple and complex partial seizures, primary and secondarily generalized tonic-clonic seizures; partial and generalized seizures associated with Lennox-Gastaut Syndrome (which would include absence, atypical absence, atonic seizures). Due to occurrence of aplastic anemia in 30 pts and acute liver failure in 14 pts during first year after approval, presently recommended that use be restricted to patients whose seizures are severe enough to justify the risk of developing aplastic anemia (incidence approx. 1 in 2000) and liver failure. Mechanism: possible antagonist at glycine modulatory site on the NMDA-glutamate receptor. Target Plasma Concentration Range: not established Half Life: 11- 20 hours

Time to Steady-State: 3-5 days Adverse Effects Concentration Dependent: Headache, fatigue, drowsiness, dizziness, nausea, anorexia, insomnia Idiosyncratic: aplastic anemia, acute hepatic failure Chronic: weight loss Dosing: Maintenance dose: 1800-3600 mg/day in adults, 15-45 mg/Kg/day children. Initiation Schedule: Due to drug interactions with the other AEDs and the frequent occurrence of troublesome initiation related side effects, the following titration schedule is recommended for initiating felbamate: 600-1200 mg/day in adults or 15 mg/kg/day in children (in 3-4 divided doses) for first 1-2 weeks , with subsequent increases of 600-1200 mg/d or 5-15 mg/kg/day in children every 1-2 weeks as tolerated up to maximum of 3600 mg/d (45 mg/kg/day). Due to drug interactions, the doses of any concurrent AEDs should be reduced by 20-30% when adding felbamate and with subsequent dose increases. Available Dosage Forms: 400 mg, 600 mg tablet; 600 mg/5 ml syrup Advantages: broad spectrum of efficacy; proven effectiveness for Lennox-Gastaut syndrome; Disadvantages: rare fatal aplastic anemia/hepatitis; drug interactions with other AEDs; initiation related adverse effects in particular headache; cost; H. Gabapentin (NeurontinR) (GBP) Indications: Simple and complex partial seizures, primary and secondarily generalized tonic clonic seizures Mechanism: unknown Target Plasma Concentration Range: > 2 mg/ml Half Life: 5 - 7 hours (normal renal function, half life will decrease with decreasing renal function) Time to Steady-State: 1-2 days Adverse Effects Concentration Dependent: drowsiness, incoordination, dizziness, fatigue, double vision Idiosyncratic: None reported to date Chronic: None reported to date (anecdotal reports of weight gain in some patients)

Dosing: Maintenance dose: 900 - 4800 mg/day in adults, 15-35 mg/kg/day in children. Initiation of Therapy: Therapy in adults started at 300mg on day one and increased by 300 mg every day to the initial maintenance dose of 900 mg/day (given in three divided doses). Subsequent increases of 600 -900 mg/day should then be made based on clinical response to maximum dose of 4800 mg/d (given in three divided doses). Initial maintenance dose should be reduced in the elderly and renally impaired based on their creatinine clearance: creatinine clearance of 30-60 ml/min: 300 mg B.I.D; 1530 ml/min: 300 mg Q.D.; < 15 ml/min: 300 mg Q.O.D. Children may be started on initial maintenance dose of 10-15 mg/kg/day (given in three divided doses) and increased in 5-10 mg/kg/day increments as tolerated up to maximum of 35 mg/kg/day. Available Dosage Forms: 100 mg, 300 mg, 400 mg capsules Advantages: low frequency/severity of neurological adverse effects; no idiosyncratic/chronic adverse effects; eliminated unchanged by kidney; no pharmacokinetic interactions; ease of use- ability to rapidly titrate up to maximum tolerated dose Disadvantages: cost; dose-dependent bioavailability; three times daily administration; I. Lamotrigine (LamictalR) (LMT) Indications: simple and complex partial seizures, primary and secondary generalized tonic-clonic seizures, absence, atypical absence, atonic, myoclonic seizures. Seizures associated with Lennox-Gaustaut syndrome. Mechanism: Inhibits sodium channels similar to carbamazepine and phenytoin, but in contrast to these agents may preferentially decrease depolarization -induced release of excitatory amino acids such as glutamate. Target Plasma Concentration Range: Not Established Half Life: 29 hours (monotherapy), 15 hours (concurrent therapy with enzyme inducing AEDs), 60 hours (concurrent therapy with valproate) Time To Steady-State: 5-12 days Adverse Effects Concentration Dependent: drowsiness, incoordination, dizziness, double vision Idiosyncratic: Rash, Stevens-Johnson, Exfoliative dermatitis, hepatotoxicity Chronic: None reported Dosing: Maintenance dose: 300-500 mg/d in adults or 5-15 mg/kg/day in children receiving concurrent carbamazepine, phenobarbital or phenytoin therapy given in 2 divided doses; 50-150 mg/d for adults or 1-8 mg/kg/day for children receiving monotherapy or concurrent valproic acid given in 1-2 divided doses. Initiation Schedule: To reduce the frequency of skin rash, it is recommended to start therapy

with the following slow titration schedule: for patients receiving concurrent carbamazepine, phenobarbital, or phenytoin: 50 mg q.d. in adults or 2 mg/kg/day in children for the first 2 weeks, then 50 mg b.i.d. in adults or 5 mg/kg/day in children for next 2 weeks, with subsequent increases of 100 mg/day in adults or 5 mg/kg/day in children every 1-2 weeks based on clinical response to a maximum dose of 500 mg/day in adults or 15 mg/kg/day in children; for patients receiving monotherapy or concurrent enzyme inducing drug (carbamazepine, phenytoin, phenobarbital) along with valproic acid: 25 mg every other day in adults or 0.5 mg/kg/day in children for first 2 weeks, then 25 mg q.d. in adults or 1 mg/kg/day in children for 2 weeks with subsequent increases of 25-50 mg/day in adults or 1 mg/kg/day in children every 2 weeks based on clinical response to a maximum dose of 150 mg/d in adults or 8 mg/kg/day in children. For patients receiving concurrent valproic acid therapy: 12.5 mg every other day in adults or 0.2 mg/kg/day in children for first 2 weeks, 12.5 mg q.d. in adults or 0.5 mg/kg/day in children for 2 weeks with subsequent increases of 12.5-25 mg/day in adults or 0.5 mg/kg/day in children every 2 weeks based on a clinical response to a maximum dose of 100 mg/day in adults or 5 mg/kg/day in children. Available Dosage Forms: 25 mg, 100 mg, 150 mg, 200 mg tablets Advantages: broad spectrum of efficacy; relatively low incidence of neurologic toxicity; once or twice daily administration; Disadvantages: need to initiate therapy with slow titration schedule; cost; high frequency of skin rash and rare but serious dermatologic reactions (exfolliative dermatitis/Stevens-Johnson Syndrome); drug interactions

J. Tiagabine (GabitrilR) Indications: simple and complex partial seizures, secondary generalized tonic-clonic seizures. Mechanism: selectively inhibits neuronal and glial reuptake of GABA, thus prolonging time GABA remains in synapse to exert pharmacological effect Target Plasma Concentration Range: Not Established Half Life: 5-8 hours (monotherapy or polytherapy without enzyme inducers), 2-4 hours (concurrent therapy with enzyme inducing AEDs), 1216 hours in patients with hepatic impairment Time To Steady-State: 1-2 days Adverse Effects Concentration Dependent: dizziness, asthenia (lack of energy), somnolence, depression, nervousness/irritability, tremor, difficulty with concentration or attention

Idiosyncratic: None reported Chronic: None reported Dosing: Maintenance dose: 32-56 mg/day given in 2-4 divided doses (frequency of neurologic adverse effects lower when divided into 3-4 daily doses) for adults receiving concurrent therapy with one of the enzyme inducing AEDs (carbamazepine, lamotrigine, phenytoin, phenobarbital); dose range not well defined for patients on monotherapy, those receiving concurrent therapy with a non-enzyme inducing AED (valproic acid, gabapentin), or in children. Initiation Schedule: to minimize neurological adverse effects therapy should be initiated slowly. In adults receiving concurrent therapy with an enzyme inducing AED, initiate therapy at 4 mg once per day given at bedtime and then increase dose every week by 48 mg/day based on clinical response up to maximum dose of 56 mg/day. After dose exceeds 8 mg/day, daily dose should be given in 3-4 divided doses. Administration with meals is also recommended to slow absorption and minimize toxicity from high peak plasma concentrations. No specific dosage recommendations are available for adults in whom concurrent AED therapy consists of only non-enzyme inducing drugs or receiving tiagabine monotherapy. Clinical experience and tiagabine=s pharmacokinetic properties suggest that these patients will require lower doses and a slower titration schedule (i.e., start at 4 mg/day and then increase by no more than 4 mg/day every 2 weeks up to maximum of 28-32 mg/day). No dosage recommendations are available for children. Available Dosage Forms: 4 mg, 12 mg, 16 mg, 20 mg tablets Advantages: selective mechanism of action, no effect on pharmacokinetics of other AEDs, generally well tolerated when therapy initiated; no idiosyncratic or chronic adverse effects reported to date. Disadvantages: initiation related neurologic adverse effects; need to initiate therapy with slow titration schedule; cost; short half life requiring t.i.d. or q.i.d. dosing; K. Topiramate (TopamaxR) Indications: simple and complex partial seizures, secondary generalized tonic-clonic seizures. Possible effective for primary generalized seizures including primary generalzied tonic-clonic, absence, atypical absence, atonic, tonic seizures. Mechanism: voltage dependent blockade of sodium channels, enhances

GABA mediated inhibition by binding to unique site on GABA receptor complex, blocks AMPA subtype of glutamate receptor, weak carbonic anhydrase inhibitor.. Target Plasma Concentration Range: Not Established Half Life: 20-30 hours (monotherapy or polytherapy without enzyme inducers), 12-15 hours (concurrent therapy with enzyme inducing AEDs), 59 hours in patients with creatinine clearance < 30 ml/min/1.73 m2 Time To Steady-State: 4-7 days Adverse Effects Concentration Dependent: dizziness, mental slowing, somnolence, incoordination, confusion, impaired concentration/cognitive function, paresthesias (tingling in fingertips, toes), anxiety, depression. Paresthesias are an unusual side effect for an AEDs and probably relates to drug being a weak carbonic anhydrase inhibitor. Idiosyncratic: None reported Chronic: weight loss; 1.5% of patients develop kidney stones; males between 21-54 y/o and/or patients with family history or previous personal history of kidney stones have increased risk for development of kidney stones with topiramate. These patients should be counseled on importance of maintaining adequate fluid intake when started on topiramate. Dosing: Usual maintenance dose: 200 mg/day to 600 mg/day in adults with normal renal function. No dosage recommendations available for children. Initiation Schedule: To minimize the neurologic and cognitive adverse effects that may occur at initiation, dosage of topiramate should be titrated up slowly. Start therapy at 50 mg/day and increase dose every 1-2 weeks by 50 mg/day as tolerated by patient up to the recommended daily dose of 200- 600 mg/day. In patients who have tolerated and shown a partial response at these lower dosages, subsequent titration up to a maximum of 1000 mg/ day may be attempted. Daily dose should administered in two divided doses. For renally impaired patients, dosage recommendations are to use one-half of the dosage recommended above for patients with normal renal function. Available Dosage Forms: 25 mg, 100 mg, 200 mg tablets Advantages: efficacy for partial seizures appears slightly greater than for other new AEDs; no idiosyncratic adverse effects reported to date; twice

daily administration Disadvantages: initiation related neurologic adverse effects; frequency and severity of cognitive impairment and behavioral problems greater than with other new AEDs; need to initiate therapy with slow titration schedule; cost; drug interactions (inhibits hepatic metabolism of phenytoin, enhances hepatic metabolism of estrogen component of oral contraceptives, and decreases digoxin plasma concentrations) Table 1 Drugs of Choice for Specific Seizure Types
Seizure Type Simple or Complex Partial First-Line Drugs Second-Line Drugs Others Alternatives Phenobarbital Primidone Tiagabine Topiramate Clonazepam Felbamate Topiramate+ Tiagabine+ Clonazepam Felbamate+

Carbamazepine Gabapentin Phenytoin Valproic Acid Lamotrigine

Primary or Secondarily Generalized Carbamazepine Gabapentin+ Tonic-Clonic Valproic Acid Lamotrigine+ Phenytoin Phenobarbital Primidone Absence Atypical Absence, Atonic, Myoclonic Ethosuximide Valproic Acid Valproic Acid Lamotrigine* Clonazepam Lamotrigine* Clonazepam
+

Felbamate* Ethosuximide Ketogenic Diet

Not approved for primary generalized tonic-clonic seizures * Not approved in U.S. for these indications TABLE 2

TARGET PLASMA CONCENTRATION RANGE AND AVERAGE DOSAGE RECOMMENDATIONS FOR THE ANTIEPILEPTIC DRUGS

DRUG PHENYTOIN

TARGET PLASMA RANGE (mG/ML) 10-20

DAILY DOSE 4-6 mg/kg/day (adults) 4-10mg/kg/day(children)

NUMBER OF DAILY DOSES 1- 2

CARBAMAZEPINE

4-12

8-20 mg/kg/day (adults) 10-30mg/kg/day (children)

2-3 2-4

PHENOBARBITAL

15-40

1-3 mg/kg/day (adults) 3-6 mg/kg/day (children)

1-2

VALPROIC ACID

50-100

10-40 mg/kg/day (adults+children monotherapy) 20-60 mg/kg/day (childrenpolytherapy)

2-3 2-4

PRIMIDONE *

5-15

10-25mg/kg/day (adults) 10-25mg/kg/day (children)

2-4

ETHOSUXIMIDE

40-100

15-30 mg/kg/day (adults) 20-40mg/kg/day (children)

1-2

FELBAMATE

Not Established

1800-3600mg/day (adults) 15-45mg/kg/day (children)

2-4

GABAPENTIN

>2

900-4800mg/day (adults) 15-35mg/kg/day (children)

LAMOTRIGINE

Not Established

50 -500 mg/day (adults) 1-15mg/kg/day (children)

1 -2

* Primidone=s active metabolite is phenobarbital, phenobarbital plasma concentrations must be monitored in patients receiving primidone.

Drug Interactions: Drugs That Alter the Serum Concentrations of the Antiepileptic Drugs (AEDs)
AED AED Serum Concentrations Decreased by the Listed Drug

AED Se

Mechanism Reduced Oral Absorption Displacement from Protein Binding Sites Induction of Hepatic Metabolism

Inh

Carbamazepine

Phenobarbital1 Phenytoin1 Primidone1

De

Ery

Fe Phenytoin Antacids Enteral Feedings Aspirin Phenylbutazone Tolbutamide Valproic Acid3 Carbamazepine1 Ethanol (chronic) Phenobarbital1 Primidone1 Rifampin

Am

Chlo

Etha

Fe Flu

Phenobarbital

Carbamazepine1 Ethanol (chronic) Phenytoin1

Chlo

Valproic Acid

Aspirin3

Carbamazepine Phenytoin Phenobarbital Primidone

Felbamate

Carbamazepine Phenytoin

Valproic

Gabapentin Topiramate

Antacids Carbamazepine Phenytoin Phenobarbital

Tiagabine

Valproic Acid

Carbamazepine Phenytoin Phenobarbital

Lamotrigine

Carbamazepine Phenytoin Phenobarbital Primidone

Variable interaction, AED serum concentration may increase, decrease, or not change
1

Serum concentrations of active metabolite carbamazepine epoxide increased;carbamazepine serum concentrations may increase, decrease, or not change
2

Dual interaction, serum concentrations may increase, decrease, or not change

3

Drug Interactions: Drugs Whose Serum Concentrations are Altered by the Antiepileptic Drugs (AEDs)
AED Serum Concentrations of Listed Drug Decreased By AED

Mechanism Displacement from Protein Binding Sites Carbamazepine Induction of Hepatic Metabolism

Clonazepam Doxycycline Ethosuximide Felbamate Lamotrigine Oral Contraceptives Phenytoin1 Phenobarbital1

Primidone1 Theophylline
Tricyclic Antidepressants

Tiagabine topiramate Valproic Acid Warfarin

Phenytoin

Carbamazepine1 Corticosteroids Cyclosporine Digitoxin Doxycycline Felbamate Folic Acid Haloperidol Lamotrigine Meperidine

Methadone Oral contraceptives Phenobarbital1 Primidone1 Quinidine Theophylline Tiagabine topiramate Valproic Acid Vitamin D Warfarin

Gabapentin Tiagabine Phenobarbital Carbamazepine1 Oral Contraceptives

Chlorpromazine Corticosteroids Cyclosporine Doxycycline Lamotrigine

Phenytoin1
Tricyclic Antidepressants

Tiagabine topiramate Valproic Acid Warfarin

Valproic Acid

Phenytoin3 Tiagabine

Felbamate

Topiramate

oral contraceptives digoxin

Lamotrigine

Valproic Acid oral contraceptives (?)

Epilepsy Patient Case K.S. K.S. is a 28 y/o female (5'6"; 55 kg) who is being seen today in the Neurology Clinic for an initial workup of a seizure disorder. She is employed as a music teacher at a north suburban high school. Seizure History:

Patient has had no history of seizure-type episodes until approximately 9 months ago when she experienced a first episode of "blacking out". Patient has had three more episodes during the 9 months, with the last episode a week ago being accompanied by a "grand mal" seizure. Seizure Description: Patient describes episodes as beginning with a choking sensation in her throat prior to losing consciousness. After regaining consciousness, patient remains confused for 15-20 minutes. A coworker who has witnessed 2 of the seizures describes them as beginning with K.S.'s right arm extending out and up. "The patient then appears to be reaching or grasping for objects that are not there." The patient does not respond to verbal communication during this time. The episode lasts approximately 1-2 minutes after which the patient is confused. With the latest episode after extension of the right arm, patient fell to floor with stiffening of her arms and legs, followed by shaking of all limbs for 30 seconds. EEG (interictal): Isolated spikes over the left temporal region PMH: Noncontributory, except for two episodes of febrile seizures at age 4. PE/Neuro: WNL, ECG:NSR, BP 110/65 Study Points: 1. What type of seizures is K.S. experiencing ? Are there any further tests that you would suggest as part of the diagnostic work-up? Complex partial; during last seizure also experienced a secondarily generalized tonic-clonic seizure. Symptoms consistent with complex partial seizure: initial aura or simple partial seizure (choking sensation in throat, right arm extending up and out) followed by loss of awareness (i.e., patient did not respond to verbal communication)and automatisms (reaching or grasping for objects). Also consistent with a complex partial seizure were the duration (1-2 minutes), amnestic for episode, postictal confusion, and EEG findings. Additional tests/information to obtain: Would want to perform MRI to

rule out focal lesion such as brain tumor or vascular malformation, baseline serum chemistries and CBC with differential, serum and urine pregnancy test, medication history, family history, social history (i.e., alcohol, drug use), and evaluation of any precipitating factors (stress, lack of sleep). 2. Which antiepileptic drug would be most appropriate to use for K.S. ? How should therapy be initiated and what parameters (lab, clinical) would you monitor ? Drugs of choice for patient's seizure type are phenytoin and carbamazepine. Carbamazepine would probably be preferable in this patient due to connective tissue adverse effects seen with phenytoin (i.e., hirsutism, acne, gingival hyperplasia). Maintenance dose for carbamazepine is 10 mg/kg/day (7-15 mg/kg/day). To decrease severity of initiation related neurological and gastrointestinal side effects, therapy should be started at 1/3-1/4 this dose. An example regimen would 200 mg q.d. for 1st week, then 200 mg b.i.d. for 2nd week, and 200 mg t.i.d. for third week using plain tablets (note: if using extended release tablets could give dose during third week as 300 mg b.i.d. Because of job, twice a day dosing with extended release tablets may be preferable.). At this point, should wait for drug to reach initial steady-state and assess patient's response. Remember due to carbamazepine's autoinduction of hepatic enzymes, this may take 3 to 5 weeks after initiating therapy. So obtaining a carbamazepine serum concentration before this time would probably be of little value. Obtain baseline labs, including: liver function tests, complete blood cell count with differential, urinalysis, and serum electrolytes. If labs normal and patient asymptomatic, no need for further lab monitoring. Once therapy started, monitor seizure control (instruct patient to keep calendar)- including frequency, type and time of occurrence; adverse effects- dose-dependent neurological adverse effects (sedation, dizziness, fatigue, nystagmus, ataxia, visual changes, difficulty thinking); idiosyncratic reactions (skin rash, hepatotoxicity, hematological disorders) and chronic toxicity (see handout). Also once steady-state is reached monitor carbamazepine serum concentrations. 3. In educating K.S. about the selected AED, what issues would you discuss ? What other points should be brought up with K.S. during your counseling session ?

A). Explain about seizure disorder B).Importance of keeping seizure diary to assist with determining response to therapy (specifically with this patient, tell them to keep track of any changes in seizure type or pattern, i.e. was seizure complex partial or just simple partial (i.e., the aura) or secondarily generalized tonic-clonic). C). Types of adverse effects might experience, including serum concentration dependent, idiosyncratic, and chronic adverse effects. What symptoms may indicate the onset of a severe idiosyncratic reaction (i.e., rash and fever for severe dermatological reaction or hepatotoxicty; abnormal bleeding or bruising or persistent infection for aplastic anemia or agranulocytosis) and what to do if occur. Explain that may experience initiation related sedation, fatigue, GI problems; but should disappear after first 1-2 weeks and to call if persist. D). Discuss schedule for taking medication, methods for remembering to take doses, and what to do if miss dose (i.e., if one missed dose- take immediately, if two missed doses- take one now and other with next dose, and if more than two- call. Stress importance of compliance (i.e., concepts of therapeutic plasma concentration and steady-state). E). Drug interactions: both pharmacodynamic and pharmacokinetic (see handout and Tables 3A and 3B; NOTE: for test in this course do not have to list out specific drug interactions, just describe in general sense. With exception that if enzyme inducing AED such as carbamazepine or phenytoin in woman of child-bearing potential, should note interaction with oral contraceptives). F). Since woman of child-bearing potential, should discuss concerns with pregnancy and epilepsy. See page 25 of required reading for outline of subjects to cover.

Epilepsy Patient Case B.J. B.J. is a 47 y/o man (5'10"; 93 kg) with a history of complex partial seizures since the age of 11. Patient has been receiving phenytoin 360 mg/day (160 mg Q.A.M. and 200 mg Q.P.M.) and phenobarbital 60 mg b.i.d. for approximately 10-15 years. Patient is presently experiencing 4 to 6 seizures per month. Other complaints include intermittent headaches occurring 3 to 5 days per week, sleepiness in the early afternoon, and difficulty concentrating when doing the crossword puzzle (which has

become worse over last couple years). Seizure Description: B.J. states that he is aware that seizures are beginning by smelling an unpleasant odor similar to "burning automobile tires" prior to losing consciousness. On questioning his wife, she describes the episodes as beginning with B.J. "staring off into space followed by lip-smacking and wringing of his hands." The episodes last approximately 2 to 3 minutes with B.J. sometimes regaining consciousness immediately with no problems and at other times it may take him 20-30 minutes to become totally responsive. EEG: sharp waves in both temporal areas, mild slow wave abnormality noted in left temporal area indicating slight neurophysiological disturbance Medication: Patient has received multiple medications over the last 30 years including phenobarbital, primidone, phenytoin, carbamazepine, and valproic acid. Patient has history of developing a skin rash with carbamazepine, and had no improvement on valproic acid. PMH: cerebral hemorrhage at age 2, secondary to head trauma PE/Neuro: partial right-sided hemiparesis, moderate nystagmus on lateral gaze, mild ataxia, remainder noncontributory. LAB: WBC 4200/mm3 with normal differential; SGOT 45; albumin 4.0; serum creatinine 1.1; alk phos: 65; Phenytoin serum concentration: 16 ug/ml; Phenobarbital serum concentration: 22 ug/ml. Study Points: 1. Assess the patient's present antiepileptic drug treatment regimen ? While present antiepileptic drugs are appropriate for patient's seizure type (complex partial), they are not producing a satisfactory clinical response. Patient experiencing both dose-dependent neurological adverse effects

(sedation, ataxia, nystagmus, headache, impaired cognitive function) and poor seizure control. Additional information should obtain if available: was patient ever evaluated on phenytoin alone, if so was dose of phenytoin pushed to maximum tolerated level, and was dose of valproic acid pushed to maximum tolerated level 2. What changes would you recommend to B.J.'s AED regimen ? Patient should be switched from present polytherapy regimen to monotherapy regimen. One acceptable option here would be to withdraw phenobarbital and attempt to optimize therapy with phenytoin alone. However based on fact that patient is showing signs of cognitive impairment, a better choice would probably be one of the new drugs, such as gabapentin. The rational for this is the lower neurotoxicity profile seen with gabapentin as compared to older agents, the lack of any drug interactions, and its occasional effectiveness in patients who have been unresponsive to the older antiepileptic drugs. However, I want to stress that the first option (i.e., phenytoin alone) would be an acceptable answer, especially if history has shown that had not been pushed to maximum dose on phenytoin alone in past. At this point, a plan for switching patient from phenytoin polytherapy to gabapentin monotherapy regimen should be developed. Please note that this is only a starting plan. After each change in drug and dose, patient should be evaluated and plan modified as necessary based on clinical response. Plan: Begin gabapentin therapy (300mg on day one, 300 mg b.i.d. on day 2, and 300 mg t.i.d. on day 3) with eventual titration to a dose of 600 mg t.i.d. within 2 to 3 weeks. Once patient at this dose of gabapentin, begin withdrawing phenobarbital in 15 mg increments every 2 to 3 weeks. After phenobarbital withdrawn, begin withdrawing phenytoin initially in 30-60 mg increments every 2 weeks and then once phenytoin serum concentrations < 7.5 ug/ml in 100 mg increments. As discontinuing phenobarbital and phenytoin, should make additional dosage adjustments of gabapentin based on clinical response to maintain or improve seizure control up to maximum dosage of 4800 mg/day. Monitor: Prior to beginning gabapentin, obtain baseline clinical laboratory tests which should include a serum creatinine determination with gabapentin. Besides standard monitoring (i.e. changes in seizures and adverse effects as outlined for patient KS in previous case), would want to monitor for occurrence of withdrawal seizures as removing current drugs

(especially phenobarbital) and for pharmacokinetic drug interactions by obtaining phenytoin and phenobarbital plasma concentrations at steadystate following each dosage change of these drugs. Because phenobarbital is an enzyme inducer, may see rise in phenytoin serum concentrations as phenobarbital is withdrawn and hepatic enzymes become "deinduced". Patient education about withdrawal seizures, adverse effects to watch for, and importance of compliance are especially important to ensure cooperation of patient and success of this switch over in therapy.

3/14/94 Two months after initial visit. Patient reports 3 seizures during the last 2 months. Patient states that he feels less tired than before, but that headaches and difficulty in concentrating are unchanged. Neuro exam: unchanged from above. Present medications: Gabapentin 600 mg t.i.d.; phenytoin 360 mg/d and phenobarbital 30 mg b.i.d. What recommendations concerning B.J.'s AED regimen would you make at this point ? At this point, seizure frequency appears unchanged and symptoms of toxicity have decreased. Because of multiple changes in drug therapy that are going on, it is to early to assess whether switch over is going successfully or not. Would continue with current plan. 4/15/94 B.J. notifies you that he had three seizures over the weekend with the last one occurring approximately 24 hours ago. Wife states that seizure lasted longer than usual and that patient was extremely tired afterwards. In addition to these, patient has had four other seizures since last visit. Patient would appear to be experiencing withdrawal seizures from the discontinuation of phenobarbital. If not serious (i.e, patient in no immediate danger of harming himself during seizures and not having generalized tonic-clonic seizures), would attempt to wait for couple of days and see if he improves. Important to keep in close contact with patient and family until seizures improve. If serious or feel potential to become serious (i.e status epilepticus or acute repetitive seizures), options would include: adding back phenobarbital and attempting to withdraw at slower rate when seizures stabilize in future, or increasing dose of gabapentin (preferable option) or phenytoin. 7/15/94 Patient seen in clinic today after receiving last dose of phenobarbital 2 months ago. B.J. reports 4 seizure during the last 2 months. Although patient states that headaches had initially disappeared

with the withdrawal and discontinuation of the phenobarbital, they began reappearing about 2 weeks ago at the same intensity as in the past. Additionally, patient states that he has felt "dizzy off and on throughout the day for last week." Neuro Exam: mild nystagmus on lateral gaze; moderate ataxia. Present Medications: Gabapentin 800 mg t.i.d., Phenytoin 360 mg/day Possible dose-dependent neurological toxicity secondary to increased phenytoin plasma concentrations. As discussed above, removal of enzyme inducer (i.e., phenobarbital) may result in increase in phenytoin plasma concentrations. Check phenytoin plasma concentration. Once toxicity is reduced, attempt further titration of gabapentin dose to optimize seizure control and then consider withdrawal of phenytoin.
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