seizure disorders patty ghazvini, pharmd., cgp associate professor of pharmacy practice florida a&m...

Seizure Disorders Patty Ghazvini, PharmD., CGP Associate Professor of Pharmacy Practice Florida A&M University

Case Presentation My son had his first seizure at 21 years old. His seizures are horrible; they last around 15 minutes, and he has a postictal period anywhere from 1-10 or so hours. During these postictal periods, he arches his back and moans or cries or sometimes screams. He also tends to hurt himself. He had 40 stitches in both his hands after a seizure this last summer. He is having seizures, what seems to us, in a pattern. He will have them almost to the day every other month. The doctors say he isn't a "text book" epileptic. They don't know how to medicate him. He has been on Keppra for almost three years. They just decided to finally try another med last week and he will be starting Dilantin. He had a terrible allergic reaction to Depakote. We are really hoping that the Dilantin will give him a break for at least longer than a month.

Definitions Seizure an uncontrolled paroxysmal discharge of the CNS that interferes with normal function. Epilepsy repeated occurrence of any of the various forms of seizures. Prodrome mood or behavior changes that precedes a seizure. Aura localized symptom that be the first part of a seizure Tonic A sustained muscular contraction Clonic- intermittent muscular contractions and relaxation

Seizures Can cause involuntary changes in body movement, sensation, awareness, or other functions Sudden attacks of involuntary movements or convulsions, brief losses of awareness Auras precede an impending seizure; patient may just not feel right or may have other symptoms: abnormal smell, taste or visual symptoms Postictal symptoms headache, confusion, generalized muscle ache, drowsiness, incontinence

Incidence Between 0.3-0.7% of the US population >200,000 Americans have a seizure more than once a month Generalized seizures are more common in children; partial seizures are more common in adults. Incidence of partial seizures remains constant at 20 per 100,000 population from infancy until age 65 years when it increases sharply.

Pathophysiology Initially a small number of neurons will fire abnormally, however, there is a break down of normal membrane conductance and inhibitory mechanisms which leads to the spread of the excitability either to a local area or widespread generalized area. Dramatic increase in metabolic needs. The brain will consume more oxygen than the vasculature can supply which can lead to brain damage.

Factors Leading to Membrane Instability Ion channel abnormalities Abnormal Potassium conductance Defective voltage sensitive ion channels Deficiency in membrane sodium potassium pumps Increase in Neurotransmitters that enhance excitability Acetycholine, glutamate, norepinephrine, histamine, aspartate. Deficiency in Inhibitory Neurotransmitters Dopamine, GABA Abnormalities in serum pH can lead to seizures due to the fact that normal neuronal activity depends on adequate supplies of glucose, electrolytes, oxygen and amino acids.

Videos on Seizures http://www.youtube.com/watch?v=CDccC hHrgRA http://www.youtube.com/watch?v=CDccC hHrgRA http://www.youtube.com/watch?v=6NcqQ kKjqTI&feature=relmfu http://www.youtube.com/watch?v=6NcqQ kKjqTI&feature=relmfu

Classification of Seizures Generalized seizures (absence, myoclonic, generalized tonic-clonic) - widespread regions of the brain Partial (focal) seizures - originate in a localized area of the cerebral cortex Further, seizures can be divided into simple or complex seizure depending on whether consciousness is altered

Generalized Seizures Absence patients are usually unaware of a lapse in concentration or awareness Myoclonic single, rapidly recurrent, bilaterally shock-like jerks to the face, trunk and extremities Tonic Clonic (grand mal) - vision, taste, smell, or sensory changes, hallucinations, or dizziness before the seizure; muscle rigidity, followed by violent muscle contraction, and loss of consciousness. * Other symptoms that occur during the seizure may include: - Biting the cheek or tongue - Clenched teeth or jaw - Loss of urine or stool control (incontinence)

Partial Seizures Originate in single area of one hemisphere. May progress to generalized seizures Simple Last 10-20 seconds. Consciousness is not impaired Presence of automatisms Complex Consciousness is lost Lasts 1-2 minutes May experience an aura More likely to progress to generalized seizures.

Absence Seizures Characterized by short frequent lapses in Consciousness Motor and speech activity Last 5-20 seconds Typically present in children ages 4-8 Occur more frequently in girls than boys. Child will typically present with history of decline in school work.

Myoclonic Seizures Bilateral synchronous single jerk of the extremities. Typically occurs in the arms Most often occurs while falling asleep or waking up.

Tonic-Clonic Seizures Sudden loss of consciousness Contractions Perioral cyanosis Loss of bladder control Post ictal state Deep sleep Headache Lasts 30-60 minutes

Atonic Seizures Sudden loss of muscle tone and subsequent falling or dropping to the floor unprotected. Drop attacks

Infantile Spasms Characterized by Recurrent brief myoclonic seizures lasting ~ 2 seconds. Flexion, extension or a mixed pattern involving the trunk, neck and limbs Unknown cause Male predominant May be a family history Presents during the first year of life Prognosis is poor Can be misdiagnosed as the colic because the seizures cause flexion at the waist.

Lennox-Gestaut Syndrome Presents in preschool age children Mixture of seizure types Myoclonic, generalized, tonic-clonic, absence, partial, atonic High seizure frequency Difficult to control High incidence of status epilepticus 40-80 % will be severely mentally retarded.

Status Epilepticus Any seizure lasting more than 5 minutes or two or more discrete seizures between which there is incomplete recovery of consciousness. Pediatric neurological emergency May occur as a result of acute cerebral insult or as the first manifestation of a ongoing seizure disorder. Early treatment is essential The longer the seizure persist the more difficult it is to control and the higher the mortality.

Evaluation of Seizures and Epilepsy History Medical history Physical examination

History of the event Descriptive information of a spell - Prodrome - Loss or alteration of consciousness - Characteristics of motor movements - Automatism - Tongue laceration, urinary or fecal incontinence - Duration of event - Postictal symptoms - Confusion - Duration - Postictal focal neurologic deficits

Medical History Medical and surgical history Current medication use Family history of seizures in affected family members Social history: alcohol and substance abuse

Electroencephalography (EEG) Samples electrical activity of the brain Only test of functional excitability of the brain Neuronal discharges are characterized by spikes and sharp waves. Recording obtained over 20-30 minutes, patient is encouraged to sleep.

Goals of Therapy Suppress seizures completely without causing intolerable side effects Initial treatment with and AED achieves these goals in 70% of patients Prognosis for seizure control in the other 30% is less favorable and may require numerous trials of AEDs, either as monotherapy or combination.

Anticonvulsants First generation- - Phenytoin (Dilantin) - Carbamazepine (Tegretol) - Valproic Acid (Depakote) - Phenobarbital - Ethosuximide (Zarontin) - Benzodiazepines (Clonazepam, Lorazepam, Diazepam, Clorazepate

Anticonvulsants (2 nd Generation) Felbamate (Felbatol) Gabapentin (Neurontin) Lamotrigine (Lamictal) Topiramate (Topamax) Tiagabine (Gabitril) Levetiracetam (Keppra) Vigabatrin (Sabril) Rectal Diazepam (Diastat) Oxcarbazepine (Trileptal) Fosphenytoin (Cerebyx)

Overview Older AEDs such as carbamazepine, valproic acid, and phenytoin remain the first line therapy in most seizure types. Exception is absence seizures Ethosuximide is the drug of choice New AED are generally used as add on therapy for children who have refractive seizures. Dosages are adjusted according to patient response and/or serum concentrations

Overview Anticonvulsants are thought to carry an increased risk of suicidal ideation and behavior Patients and caregivers should be informed of the increased risk of suicidal thoughts and behaviors and should be advised to immediately report the emergence or worsening of depression, the emergence of suicidal thoughts or behavior, thoughts of self-harm, or other unusual changes in mood or behavior.

Differences between the Generations First generation - Lack of tolerability in some patients due to side effects - Neurotoxicity - Teratogenicity - Therapeutic monitoring - Drug interactions Second generation - Improved tolerability - Multiple mechanisms - Less weight gain - Fewer endocrine effects - Less drug interactions

Limitations with 1st Generation Anticonvulsants Enzyme Induction/Inhibition Cognitive impairment Metabolic Products CBZ-epoxide, hyperammonaemia Hematological Disorders bone marrow depression, thrombocytopenia Cosmetic Side Effects

2nd Generation Anticonvulsants No required therapeutic monitoring Fewer Drug Interactions Adjunct therapy & monotherapy; Indicated for partial seizures with or without generalization Orally administered Not used for Status Epilepticus Used Outside of the Box

Partial Seizures First Line Therapy Carbamazepine or Oxcarbazepine Given as monotherapy Second Line Therapy Phenytoin or Depakote Given as monotherapy or in combination with a first line agent. Adjunct Therapy Gabapentin, Lamotrigine, Topiramate Should be used after failure with preferred agents

Absence Seizures First Line Therapy Valproic Acid, Ethosuximide Second line therapy Clonazepam, Lamotrigine

Myoclonic Seizures First Line Therapy Valproic Acid Second Line Therapy Lamotrigine Third Line Therapy Phenytoin, Carbamazepine, Oxcarbazepine Adjunct Therapy Clonazepam, Ethosuximide

Tonic-Clonic, Atonic Seizures First Line Agents Carbamazepine, Valproic Acid, Oxcarbazepine Second Line Agent Phenytoin Third Line Agents Lamotrigine, Topiramate Atonic Seizures Valproic Acid or Clonazepam

Pharmacotherapy

Phenobarbital (Luminal) Drowsiness Confusion Agitation Elevated hepatic enzymes Anxiety Constipation

Carbamazepine ( Tegretol ) MOA: limits the influx of sodium ions Therapeutic Serum Concentrations 4-12 mg/L Administration The solution should be given 3-4 times a day Tablets may be given 2-4 times a day Do not mix the solution with other medications it may decrease the effect. Suspension will produce a higher peak level than tablets at the same dose Start suspensions at the lower dosage range and titrate slowly to avoid ADE. Side Effects Hyponatremia, sedation, rash, blood dyscrasias, hepatotoxicity, photosensitivity

Oxcarbazepine ( Trileptal ) MOA: B lock Na+ channels inhibiting repetitive neuronal firing and stabilizing neuronal membranes Cross hypersensitivity can occur with carbamazepine ( 20-35%) Monitor sodium levels in person who receive other medications that also alter sodium levels. Suspension is stable for 7 weeks after opening the bottle Side Effects Sedation, ataxia, nausea, hyponatremia

Valproic Acid ( Depakote ) MOA: increases GABA availability and action Therapeutic Serum Concentrations 50 100 mg/L Should not be used in children < 2 years. Increased risk of developing fatal hepatotoxicity Do not substitute Depakote ER for Depakote May take with food. Do not administer with carbonated drinks Do not give the tablet with milk Depakote Sprinkles may be sprinkled on food and swallowed immediately. Do not chew or crush. Side Effects Hepatotoxicity,, Tremors, Hyperammonemia, alopecia, weight gain, thrombocytopenia, pancreatitis.

Phenytoin ( Dilantin ) MOA: Increases efflux or decreases the influx of sodium across the cell membrane. Therapeutic Serum Concentrations Neonates 8-15 mg/L Children 10-20 mg/L Use with caution in neonates Capsules and suspension contain Sodium Benzoate and may cause gasping syndrome. Food may affect absorption depending on formulation. High fat meals decrease the rate of absorption of Dilantin Kapseals and decreases the bioavailability of generic extended release phenytoin sodium. Administer at the same time with regard to meals Separate the doses of other medications or tube feedings by 2 hours. Side Effects Ataxia, sedation, cognitive impairment, visual disturbances,hirsutism

Gabapentin ( Neurontin ) MOA: GABA agonist activity Neuropsychiatric ADEs have occurred in pediatric population Hostility, aggressive behaviors Do not discontinue abruptly; taper over at least one week Oral Solution must be refrigerated Side Effects Somnolence, ataxia, dizziness, weight gain

Lamotrigine ( Lamictal ) MOA: affects voltage regulated sodium channels and inhibits the presynaptic release of glutamate and aspartate Potential to cause rash (Steven-Johnson Syndrome); risk factors are Young age, concurrent VPA therapy, high initial dose, rapid titration Occurs as a result of a toxic arene oxide intermediate metabolite which is produced through the P450 pathway

Topiramate ( Topamax ) MOA: Thought to block sodium channels, potentiate GABA and inhibit the activation of glutamate. May cause an ocular syndrome characterized by acute angle closure glaucoma Typically occurs within 1 month of initiation of therapy. Advise patients to report any blurred vision to physician immediately May cause kidney stones Parents should report any pain upon urination Tablets may be crushed, mixed with water and administered immediately Sprinkle capsules should not be chewed.

Zonisamide (Zonegran) Approved for adjunctive treatment of partial seizures in adults with epilepsy Blocks sodium channels, thereby stabilizing neuronal membranes Used off-label in children Adverse effects: hypothermia and oligohydrosis, kidney stones

Felbamate ( Felbatol ) MOA: regulates Na, enhances GABA Asssociated with aplastic anemia and hepatotoxicity. Currently FDA recommends that it only be used in patients who have failed therapy with all other AEDs and who have such severe epilepsy that the benefits outweigh the risk. Weekly or biweekly monitoring of CBC and Liver Function tests are recommended with use.

Tiagabine (Gabitril) Indicated for the adjunctive treatment of partial seizures Inhibits the reuptake of GABA, the major inhibitory neurotransmitter in the CNS. Side Effects: mostly GI (diarrhea, nausea, abdominal pain)

Levetiracetam (Keppra) FDA-approved as adjunctive therapy for adults and children 4 years of age and older with partial seizures FDA-approved for adults and children 6 years of age and older with primary generalized tonic-clonic seizures FDA-approved for adults and adolescents greater than 12 years of age with myoclonic seizures.

Vigabatrin (Sabril) Structural analog of GABA and was designed to inhibit the metabolism of GABA First drug to be FDA approved for the treatment of infantile spasms Also FDA-approved for adjunctive therapy in the treatment of adults with refractory complex partial seizures. Due to the risk of permanent vision loss, vigabatrin is only available through a restricted distribution program called SHARE.

Clonazepam (Klonopin) Benzodiazepine Treats myoclonic, atonic and absence seizures resistant to other drugs SE: drowsiness, ataxia Withdrawal symptoms can occur after abrupt discontinuation

Pregabalin (Lyrica) Binds to voltage-gated calcium channel and results in a decrease in the release of several excitatory neurotransmitters More potent than gabapentin Minimal CNS side effects; no drug interactions May cause weight gain and edema FDA approved for fibromyalgia

Rectal Diazepam (Diastat) Approved for use in the treatment of increased seizure activity in patients taking other antiepileptic drugs Diastat AcuDial supplied as a prefilled syringe with either 10mg or 20mg for single-dose administration by the caregiver.

Treatment of Refractory Epilepsy Epilepsy Surgery Electroconvulsive Therapy Vagus Nerve Stimulation Ketogenic Diet

Status Epilepticus Continuous or intermittent seizures lasting more than 5 minutes, without full recovery of consciousness between seizures. Therapeutic principles: time is brain If a treatment fails, there should be no interval between the end of a failed protocol and the initiation of next therapy

First-Line Therapies Benzodiazepines IV diazepam (0.2 mg/Kg given at 5mg/min) and lorazepam (0.1 mg/kg given at 2 mg/min) Phenytoin limitation is the rate at which it can be delivered Fosphenytoin prodrug of phenytoin; can be infused at rates faster than phenytoin; less vascular irritation; can be given IM

Other First-Line Therapies Valproate Phenobarbital Works on the GABA receptors; causes profound respiratory depression and hypotension

Refractory Status Epilepticus Failure of adequate amounts of two IV drugs to stop seizures. Add enough anticonvulsant to reach a high therapeutic or low toxic serum anticonvulsant concentration Should be no hesitation to depress respiration and intubate, but severe arterial hypotension should be avoided since it will curtail cerebral blood flow.

Refractory Status Epilepticus Midazolam continuous infusion due to short duration of action; less hyptonsion Propofol GABA agonist; immediate suppression of seizure activity Anesthetic Barbiturates Pentobarbital and thiopental

Seizure First Aid Remain calm Put pillow under head, turn person on their side, and loosen tight clothing DO NOT put anything in mouth DO NOT restrain the person Clear the area

New Drugs? Rufinamide (Banzel) approved for treatment of seizures associated with Lennox-Gestaut syndrome in patients 4 years of age and older Lacosamide (Vimpat) IV or PO use as add-on therapy in adults with partial- onset seizures.

Role of the Pharmacist Improve compliance - Education - Refer to patient support groups - Reinforce importance of treatment - Provide written instructions

seizure disorders patty ghazvini, pharmd., cgp associate professor of pharmacy practice florida a&m...

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