Seizure and AED

AED - Goals, general principle of Medical Treatment - Whether to treat first seizure, Choosing Antiepileptic Drugs (not embedded in stone) based on mechanism of rx, General pearls of risk of Pharmacotherapy, When to Stop AED, Epilepsy and Driving

*Eliminate seizure or reduce their frequency. Antiepileptic drug therapy is symptomatic → drugs inhibit seizures, but do not provide the cure. * Avoid adverse effects *Restore psychosocial and vocational functioning* Maintain lifestyle Whether to treat first seizure (not called epilepsy yet) is controversial. Base tx on probability of second seizure Based on syndrome, etiology of seizure, anatomical defect, pt preference. Pharmacotherapy carries risk of side effects. Typically 2 or more ( epilepsy)= treatment Epilepsy syndrome, Seizure type and Likelihood/consequences of recurrence, ADR, PK, DI *GTC & partial = sodium channel agents (phenytoin, CBZ, VPA, Barbiturate (in high dose), lamictal, topiramate, laosamide, refutamide. Absence =* T-type calcium* agents ( VPA, ethosuccimide) Myoclonic = GABA-A enhancers* (VPA, barniturates (main action), BNZ, keptra, tigabine, vigabatrin) Gabapentin, pregabaline bind to *presynaptic VG Ca2+ channels* and decrease Ca thus decrese glutamate. but not for Absense seizure. Also phenytoin in high dose Pharmacotherapy carries risk of nasty side effects (30%. Treating children Brain development, learning, behavior with chronic use), *30% are refractory.* Medication noncompliance (60% ) = single most common reason for treatment failure. An AED should NOT be considered ineffective unless there have been unacceptable ADR with continued seizures. 70% will enter remission > 5 years remaining seizure free with medication. Complete control of seizures in 50% of patients; *significant improvement in 25%.* Successful therapy is greater in newly diagnosed epilepsy, family history, neurological abnormalities. 75% of seizure-free people x 2-5 yrs can be withdrawn from medications *(taper over 6 months- special PI instruction if needs quick swiching of lamictal to another rx)* If patients should meet the folloing criteria the relapse rate is < 40% 1. Seizure free for 2-5 yrs 2. History or a single type of partial seizure or GTC (Seizure free at 12 months GTC (50%) > mixed seizures (28%) > CP (25%)) 3. Normal neuro exam, Normal IQ, EEG that has normalized with tx if you learn they had a recent seizure, don't be afraid to ask if they are driving as this is potentially a public health concern. Auto insurance may not cover the patient if they have a crash while their seizures are uncontrolled, even if it was clearly not related to a seizure

Acute ADR, AED Serum Concentrations, Laboratory Monitoring - Summary, Drug interactions you MUST know

1. Osteoporosis/osteomalacia -on long term use, Interfere with Vitamin D metabolism. Calcium + D supplements; BMD testing; calcium/D levels. Phenytoin, phenobarbital, CBZ, OXCBZ, felbamate, VPA ? 2. Acute Idiosyncratic- Hypersensitivity and SJS, hepatitis, blood dyscrasias 3. Serum conc/dose related acute ADR (Common/not life threatening) -* CNS -Neurotoxic *= dizziness, blurred vision, ataxia, low concentration 4. Acute organ failure. Usually first 6 months of tx, Lab screening is not always helpful. Normal serum concentrations: patients can still experience toxicity. 5. Multiorgan Hypersensitivity Reaction -Drug reaction with eosinophilia and systemic symptoms (DRESS) with AED. 2-8 weeks between drug use and onset of sx. After d/c of drug, can still have recurrences Serious and sometimes fatal. Fever, rash, lymphadenopathy, hepatic, renal involvement. Association with reoccurrence of herpesvirus infection. Genetic incidence. 6. Like depression, suicidal ideation is high in seizure disease and also with AED Serum conc are useful to optimize therapy of some AED, pregnancy, OCP and other DI. Measured in CBZ, VPA, phenobarbital, phenytoin (due to nonlinear kinetic), ethosuccimide, lamictal. LFTs - valproate primarily, some recommend carbamazepine and zonisamide Platelet count - valproate ("dysfunctional platelets as well") WBC count - carbamazepine (FDA black box warning) usually early in treatment Serum sodium - oxcarbazepine > carbamazepine (low ADH) Serum bicarbonate - topiramate (carbonic unhydrase inhibitor) and zonisamide usually early in treatment Lamotrigine and enzyme inhibitors & inducers (especially valproic acid and CBZ) Lamotrigine and OCP Topiramate (week), AED and OCP. topiramate Doses above 200mg/day Carbamazepine and phenytoin Enzyme inducer AED ex- older agents (phenytoin, CBZ, phenobarbital. others rifamin Enzyme inhihitor AED- VPA (others- cimetidine, erythromycycin, fluoxetine, INH OCP are CYP3 A4 substrate, Warfarin is 2 C9 substrate

Management Options- primary and secondary tx, Antiepileptic medications (AED) Classification based on the seizure type, classical and newer agents, Vagal Nerve Stimulation - adv and disadvantages, Ketogenic Diet- adv and disadvantages

Antiepileptic medications (AED) - Primary tx 1. Drugs used in partial seizures (1st line- CBZ, OXCBZ, VPA, phenytoin) and generalized tonic-clonic seizures (VPA, lamotrigine, topramate) a. Classic major drugs: phenytoin, carbamazepine, valproate and barbiturates b. Newer drugs: gabapentin, pregabalin, *lamotrigine,* levetiracetam, tiagabine, *topiramate,* zonisamide, felbamate 2. Drugs used in absence seizures- Ethosuximide, VPA, clonazepam 3. Atonic/myoclonic- VPA, clonazepam 4. Other drugs used in management of seizures (many are used only as adjuct) -BNZ- diazepam, lorazepam and clonazepam, Lacosamide (Vimpat), rufinamide (Banzel), vigabatrin (Sabril), ezogabine (Potiga) Secondary Tx- 1. Surgery, 2. Vagus nerve stimulation, 3. Complementary therapy, 4. Special diet - ketogenic Vagal Nerve Stimulation (similar to a cardiac pacemaker)- Implanted device with electrode leads, generator and battery. electrical stimulation of this nerve reduced seizure frequency. Up to 50% response. Average benefit in most patients is to allow removal of one antiseizure medication, Benefit on mood. Side effects: hoarseness, cough, Pharyngitis, infection Ketogenic Diet- Ketosis reduces seizure frequency (possible mechanism of action of valproic acid). Typically used to treat kids and refractory cases. High in fat and low in carbs and proteins, Leads to acidosis and ketosis.Calories: heavy cream/butter; no sugars; vitamins are utilized. Medium Chain Triglycerides can be substituted for fats. Modified Adkins- Low Glycemic Index. Initiated as an inpatient with careful monitoring. Very strict and requires very dedicated patient and parents as well as well trained nutritional staff. Problems long term: kidney stones, bone fractures, growth issues

Considerations in Women, Pregnancy and Epilepsy also its Guidelines for Management- Before pregnancy, During pregnancy

*Estrogen = proconvulsant* (GABA inhibitory, potentials glutamate, promotes kindling) Progesterone = anticonvulsant (Potentiates GABA, decreases discharge rates) Catamenial Seizures - increase of estrogen relative to progesterone Many AED are teratogeneic, and AED *(hepatic enzyme inducers)* increase metabolism of hormones in OCP. Treatment failures in OC, Supplemental form of birth control is advised ,* Medroxyprogesterone depot, IUD are not affected*. NOTE: OC lowers lamotrigine's serum level AED that are pregnancy category D- older agents ( Phenytoin, CBZ, VPA, phenobarbitone, primidone) and Topiramate. OXCBZ is category C. VPA is Category D in seizure, but category X in migraine. Pregnancy and Epilepsy Most pregnancies (90%) in mothers with epilepsy produce normal children. Risk of cogenital malformations is 4-6% (twice that of nonepileptic women) Fetal anomalies (up to 10% of pregnancies) are multifactorial- Drug effects, Consequences of the mother's underlying diseases, Consequence of maternal seizures during pregnancy. All antiepileptic drugs carry teratogenic risks, Newer agents reported to carry less risk. Polytherapy increases risk; monotherapy with VPA has higher risk Management- Before pregnancy- Attempt AED *monotherapy* with lowest effective dose, Folate supplementation (1-5mg/day, water soluble so less chance of for toxicity), Higher doses in hx of previous pregnancy with defect and if taking VPA During pregnancy- Monitor AED serum levels to maximize seizure control, Continue folate supplementation, Consider prenatal diagnosis of fetal malformations, *Vit K (10 mg/day orally) starting at 36 weeks to prevent bleeding due to loss of vit K, with enzyme inducer AED.*. Patient Enrollment: North American Antiepileptic Drug Registry

Review glutamate,and GABA receptors, 2 kind of glutamate (excitatory) receptors, ex of Ionotropic glutamate receptors and its activation, requirements for activation of NMDA receptors and generation ESPS and ISPS

2 kind of glutamate (excitatory) receptors 1. Ionotropic glutamate receptors -Ligand-gated ion channels. Channels composed of 4 subunits. 3 subtypes, based on the action of selective agonists:1. NMDA (N-methyl-D-aspartate). 2. AMPA (α-amino-3-hydroxy-5-methylisoxasole-4-propionic acid). 3. Kainate (KA) receptors. Ionotropic glutamate receptors are permeable for Na+ only or Na+ and Ca2+ (positive charge) → receptor activation causes channel opening and membrane depolarisation = generation of *EPSPs or excitatory post synaptic potential* (neurone at the EPSP can reach threshold and generate its own AP spike). Neuron A sends excitatory projections to surrounding neurons. But neuron A also activates GABA interneurons (C), which then send inhibitory projections (ISPS) lto surrounding neurons (D). The result is that APs generated by neuron A do not activate the surrounding neurons thus prevents *synchronization* of adjacent neurons 2. Metabotropic glutamate receptors- GPCRs (G protein coupled receptors) NMDA receptors When glutamate binds to AMPA and KA Rs → immediate receptor activation and cause short duration membrane depolarization. However, when glutamate binds to the NMDA R at resting membrane potentials → no immediate R activation (the pore is blocked by Mg2+). Even though the c.hannel opening is not immediate, once its open, it producing longer lasting membrane depolarization. Requirements for the NMDA R activation and channel opening are → binding of glutamate and binding of glycine, and membrane depolarization (to overcome voltage-dependant Mg2+ blockade) Membrane depolarization is usually provided by activation of surrounding AMPA and KA Rs

EFNS 2010 guidelines for GCSE, Neurocritical Care Society 2012, Treatment for NCSE

5 min after SE BNZ (lorazepam or diazepam), right after BNZ, before even see the effects of BNZ, long acting rx like phenytoin or fosphenytoin. After 10 min, if pt is still seizing, repeat BNZ. Wait 20 min. if pt still seizing its refractory seizure and can cause brain damage, so need to give agents that can cause medically induced coma (phenobarbital, pentobarbital, midazolam, propafol). Still refractoy give valproate or levetiracetam. • Emergent Initial Therapy to all pts (in the order of preference) • Lorazepam IV or Midazolam IM (first choice) • Diazepam rectal • Phenytoin/fospheny • Phenobarbital • Valproate sodium • Levetiracetam • Urgent Control Therapy after seizure stoped. It is mainence long term therapy. • Valproate sodium (esp for peds) • Phenytoin/fospheny • Midaz (cont infu) • Phenobarbital or Levetiracetam • Refractory Therapy • Midazolam • Propofol or pentobarbital • Valproate sodium • Many other options - Levetiracetam or Phenytoin/fospheny, Lacosamide, Topiramate, Phenobarbital Try to choose non-anesthetic drugs- no need to medically induce coma in NCSE. Drug of choice- Benzodiazepine, Hydantoin Refractory seizures- Valproic acid

Define Seizures vs. Epilepsy? Describe the pathophysiologic mechanisms epileptogenesis? Mechanisms of recruitment of surrounding neurons or snchronisation? Factors that play a role in seizure activity?

A seizure is an abnormal, explosive,* disorderly discharge (electrical activity) in synchrony* from an aggregate or a group of CNS neurons (Epileptogenic focus). Based on the location of neurons, Manifested as involuntary muscle movements (shaking arms and legs, incontinence, eyes move in any direction), sensory disturbances or altered consciousness. Normal brain is capable of having a seizure under the appropriate circumstances. Seizure is More common than epilepsy. Seizures do NOT equal epilepsy. Epilepsy is Recurring seizures with no identifiable cause. At least 2 *unprovoked* seizures separated by 24 hours. 2nd most common neurologic disorder after stroke. Abnormalities in the inhibitory neurologic systems are the basis for several neurologic disorders Tremor, Chorea, Seizure. Ie, not able to maintain homeostasis. Clinical correlate of this is abnormal cortical electrical activity within the brain. Factors that play a role in seizure activity: Neurons in the epileptogenic focus show *Abnormal AP generation *(high-frequency bursts of Aps)-Due to Instability of resting potential → high frequency bursts of APs. Tx is targeted on Voltage-gated Na+ and Ca2+ channels AND (must) *Defective synaptic function*- Normally, the spread of bursts of surrounding AP inhibition and *synchronization* of adjacent neurons is prevented by intact GABA-mediated hyperpolarization process. An enhancement of excitatory synaptic activity (*glutamate generate ESPS*) or reduction of inhibitory synaptic activity (GABA) may be expected to trigger a seizure. Tx is targeted on GABAergic and glutamatergic synapse. Mechanisms of epileptogenesis Seizures are initiated by a sudden membrane depolarization within a group of neurons caused by abnormalities in Ca2+ conductance *(paroxysmal depolarization shift, PDS)* PDS then results in opening of VG Na+ channels = generation of high-frequency bursts of APs These bursts of APs then spread to surrounding neurons, causing synchronization. Normally, this spread of bursting activity and neuronal recruitment is prevented by intact surround inhibition created by GABA neurons. Decreases in GABA-mediated inhibition, because of exogenous factors, degeneration of GABA neurons, or changes at the receptor level, are major factors that aid the synchronization process Repetitive firing of neurons leads to: ↑ extracellular K+ → ↓ K+ gradient → ↓ K+-mediated hyperpolarization → spreading of seizure activity Accumulation of Ca2+ in presynaptic terminals → leads to ↑ neurotransmitter release (including glutamate) Depolarization-induced activation of NMDA receptors → causes more Ca2+ influx and further neuronal activation

Valproate - DI and ADR, monitoring and pregnancy category

ADR- Most common and transient GI symptoms: GI distress, anorexia, nausea, vomiting and heartburn CNS effects: sedation (especially if valproate combined with phenobarbital), ataxia, tremor *↑ appetite and weight, PCOS, alopecia *(hair loss since rx bind to zn and selenium. Give mineral suppliment to help) hyperammonemia (one of the metabolicte goes through Creb cycle), Encephalopathy, Pancreatitis*, Thrombocytopenia, *Impaired coagulation*, ↑ hepatic transaminases (~40% of patients in the first several months of therapy; due to bruising of liver. often asymptomatic). Rarely fulminant hepatitis (almost always fatal; especially at risk are patients under the age of 2 on multiple anti-seizure drugs) Teratogenic effects *-Neural tube defects. * FDA: VPA and derivatives are contraindicated in pregnant women for the tx of migraine headaches. Decreased IQ scores in children. Category D in epilepsy to X in Migraine Patients. Monitor: CBC, platelets, *coagulation parameters, ammonia if indicated* DI-Valproate displaces phenytoin and other drugs from plasma protein binding sites Valproate inhibits the metabolism of drugs that are substrates for CYP2C9, including phenytoin, phenobarbital and carbamazepine. Valproate can dramatically *↓ the clearance of lamotrigine*

Clinical manifestations and pathophysiologic mechanisms underlying different Primarily generalized seizures- *petit mal (typical and atypical absence seizure), tonic, atonic and myoclonic seizure*

Absence seizures (petit mal) - can be nondetectable; seconds of altered consciousness. Occur predominantly in* children.* Characterized by sudden (no aura), brief (10-30sec) lapses of consciousness *without loss of postural control*. Patients do not fall and convulse. There is no postictal confusion. There is no knowledge that an attack has occurred. Interruption of ongoing activities, blank stare, eyelids fluttering at a rate of 3/sec. Hyperventilation provokes the seizures. Can be typical (wave discharge that begins and ends suddenly) or Atypical absence seizures (often accompanied by movements and last longer and there is less abrupt lapse of consciousness compared with typical absence seizures. Usually associated with diffuse structural brain abnormalities and mental retardation. Hyperventilation does not provoke this type of seizures) tonic seizures- Characterized by sudden, without warning, brief increase or decrease in muscle tone *Atonic seizures also called drop attacks* → Usually seen in children with diffuse CNS abnormalities. complete loss of postural muscle tone and consciousness lasting 1 to 2 sec. Risk of serious injury . No postictal confusion. Myoclonic seizures- Usually coexist with other forms of generalized seizure disorder. Myoclonus is a sudden and brief muscle contraction that may involve one or more extremities or the entire body. * myoclonus occurs when falling asleep in normal people.* Pathologic myoclonus is most commonly seen in association with metabolic disorders, degenerative CNS disorders or anoxic brain injury.

Carbamazepine / Oxcarbazepine - DI and ADR and monitoring

DI- Carbamazepine ↑ rate of its own metabolism, and also *↑ metabolism (Decrease levels of )* of AED (primidone, phenytoin, ethosuximide, valproic acid, clonazepam, zonisamid, lamotrigine, tiagabine, and topiramate,) Amiodarone, antidepressants, antipsychotics, antiretrovirals, steroids, methadone, levothyroxine, warfarin, OCP Phenobarbital and phenytoin may ↑ metabolism of carbamazepine by inducing CYP3A4 Drugs to increase CBZ levels- Quetiapine, riperidone, felbamate, erythromycin, cimetidine, fluoxetine and isoniazid long-term ADR CNS and GI -include vertigo, ataxia, headache, diplopia, blurred vision, nausea & vomiting, Drowsiness (with higher doses) Less common are but serious: hypersensitivity reactions (skin rash, SJS) and blood dyscrasias *(transient leukopenia*, and rarely agranulocytosis), Transient elevation of hepatic transaminases (5-10% of cases), hepatitis, lupus, pancreatitis Retention of water → ↓ plasma Na+ concentration *(hyponatremia)*. Acute intoxication with carbamazepine can result in stupor or coma, convulsions, and respiratory depression Fetal abnormality- *cleft palate and facial issues* Carbamazepine Updated Labeling - FDA ALERT - Dangerous or even fatal skin reactions (*SJS* and toxic epidermal necrolysis), that can be caused by carbamazepine therapy, are significantly more common in patients with a particular human leukocyte antigen (HLA) allele, HLA-B 1502, ie, in patients with ancestry across broad areas of Asia, including South Asian Indians and should be screened for the HLA-B 1502 allele before starting treatment with carbamazepine. If they test positive, carbamazepine should not be started unless the expected benefit clearly outweighs the increased risk of serious skin reactions. Patients who have been taking carbamazepine for more than a few months without developing skin reactions are at low risk of these events ever developing from carbamazepine. Monitor- Sodium, LFT, CBC, serum levels of CBZ OXCBZ Less P450 induction than with carbamazepine OXCBZ Side effects: similar to carbamazepine, except that Dose related* hyponatremia occurs more commonly with oxcarbazepine than with carbamazepine. Thought to be a direct effect on renal collecting tubules (not SIADH) Mild, transient, dose related- Somnolence, headache, diplopia, nausea, tremor, ataxia Rash- 30% of pt with rash to CBZ will also react to OXCBZ

Other drugs used in management of seizures- Benzodiazepines - agents, MOA, Formulations, pregnancy category, Indication, PK, dose, DI, ADR and Summary: MOA of anti-seizure drug

Diazepam and lorazepam- Used in the management of *status epilepticus*. Diazepam is fast acting but it has high lipid solubility, so it redistribute to fat tissues and looses its conc in blood. Do don't get enough duration of action. But lorazepam is has good duration of action of 4 hrs, eventhough it is less faster than diazepam. Clonazepam- Useful in therapy of absence and myoclonic seizures in children Side effects: Drowsiness and lethargy (tolerance often develops with continued administration) Behavioral disturbances, such as aggression, hyperactivity, irritability (paradoxical disinhibiiton syndrome) 1. Anti-seizure drug-enhanced Na+ channel inactivation. Some anti-seizure drugs (shown in blue text) prolong the inactivation of the Na+ channels, thereby reducing the ability of neurons to fire at high frequencies. Note that the inactivated channel itself appears to remain open, but is blocked by the inactivation gate (1). A, activation gate 2. Enhanced GABA synaptic transmission. In the presence of GABA, the GABAA receptor (structure on left) is opened, allowing an influx of Cl-, which in turn causes membrane hyperpolarization. Some anti-seizure drugs (show in larger blue text) act by reducing the metabolism of GABA. Others act at the GABAA receptor, enhancing Cl- influx in response to GABA. As outlined in the text, gabapentin acts presynaptically to promote GABA release; its molecular target is currently under investigation. GABA molecules, GABA-T, GABA transaminase; GAT-1, GABA transporter. 3. Anti-seizure drug-induced reduction of current through T-type Ca2+ channels. Some anti-seizure drugs (shown in blue text) reduce the flow of Ca2+ through T-type Ca2+ channels thus reducing the pacemaker current that underlies the thalamic rhythm in spikes and waves seen in generalized absence seizures.

Diagnosis and Clinical manifestations of* Partial seizures*?

International Classification of Epileptic Seizures is based on clinical features of seizures and associated EEG findings . Determining the type of seizure is essential for diagnostic approach, selecting the appropriate therapy and determining prognosis. Idiopathic epilepsy must be distinguished from symptomatic epilepsy An eyewitness account (Many patients are amnesic to the event), In-depth history, Physical & neurologic examination, *Serum prolactin levels* - transient increase, Within 15 min of seizure; differentiates from pseudoseizure or psychogenic seizure, but not from syncope (GTC & ? CP) Hypoglycemia, e-lyte abnormalities, infection (CNS) Brain imaging (MRI superior to CT, determine the existence of structural abnormality of the brain, EEG- 50% of pt will be + (Measurement of electrical activity of the brain can be performed with electrodes on the scalp. EEG taken during a seizure-free interval is normal in almost half of the cases. Activating procedures are usually performed to provoke abnormalities (hyperventilation, sleep, sleep deprivation)). Tx can normalize EEG. Simple partial seizures -Cause motor, sensory, or autonomic symptoms, depend on the site of the seizure activity, without loss of consciousness Motor symptoms: repetitive movements (seizure may start with localized twitching of muscles (Frontal lobe or motor cortex) of the hand and later involves the whole arm, chewing movements, smacking of the lips etc.) Sensory: flashing lights (Occipital lobe or visual cortex), sensation of falling or vertigo (Parietal lobe or sensory cortex) Complex partial seizures (with or without automatisms)- somatosensory or focal motor sx, altered consciousness * Patient may stare,* and perform involuntary repetitive movements (automatisms), such as chewing, lip smacking, swallowing, "picking" movements of the hand. Amnesia for seizure events, Confusion following the seizure due to Involvement of medial temporal lobe Partial seizures with secondary generalization - It commonly occurs following simple partial seizures with a focus in the frontal lobe causing vague* prodromal symptoms, called aura *(a sense of fear and confusion, disturbances in memory (déjà vu) or language, altered sensations or an olfactory hallucination, smell of burning rubber). Secondary seizure produce a clonic-tonic seizure

New anti-seizure agents: Lacosamide (Vimpat), rufinamide (Banzel), vigabatrin (Sabril), ezogabine (Potiga) - MOA, Formulations, pregnancy category, Indication, PK, dose, ADR, DI, monitoring, schedule

Lacosamide and rufinamide MOA: They enhance slow inactivation of VG Na+ channels → which limits sustained repetitive AP firing characteristic of partial seizures Vigabatrin MOA: It irreversibly inhibits GABA transaminase → ↑ GABA levels Ezogabine MOA: It keeps VG K+ channels longer in an "open" position → stabilization of membrane potential → slows repetitive firing of APs Lacosamide formulations- tabs, injection; *IV * has same dosage as oral; infuse over 30-60 min. Preg Cat C Indication- *Adjunctive* therapy in the treatment of partial-onset seizures in patients with epilepsy >17 years Dose: max 200mg BID Renal mild-mod impairment no adjustment unless concomitant strong CYP3A4 &/or 2C9 inhibitors Clcr < 30ml/min: 300mg/day max Hepatic dose adjustment. further reduction if on strong CYP3A4 &/or 2C9 inhibitors Side effects-Dizziness, diplopia, blurred vision, ataxia, headache, fatigue.Nausea, vomiting LFT increase - DRESS syndrome,* Euphoria (sheducle V), Heart block,* Multiorgan hypersensitivty rxn Syncope - use with caution in pt with cardiac problems, especially prolonged PR or other conduction problems Rufinamide formulation- tabs, soln. Preg Cat C Indication-*Adjunctive* tx of Lennox-Gastaut (> 4 yr) No serum level needed CYP2E1 Inhibitor (weak); CYP3A4 inducer (weak) ADR- somnolence, dizziness, headache, nausea, ataxia, polyuria, Anemia, leukopenia, thrombocytopenia. Cardiac Arrhythmia, QT interval* shortening*, DRESS syndrome, rash, Contraindicated in familial short QT syndrome,contraindicated in patients with Familial Short QT syndrome. Make sure ECG on chart. Vigabatrin Indication-* Refractory* complex partial seizures; infantile spasms Preg Cat C Dose- > 16 yo; 500mg BID (3000mg/day). Taper: decrease by 1000mg/day weekly Serum Conc: not needed Renal dose- based on Clcr ADR-* Vision loss*. Without benefit in 2-4 weeks for infants and < 3 months for adults, stop therapy. Onset of vision loss is unpredictable; risk increases with dose and cumulative exposure. Vision loss can worsen despite d/c. Permanent bilateral concentric visual field constriction in > 30% of pt Anemia, peripheral edema, neurotoxicity, peripheral neuropathy, suicidal ideation, weight gain, tremor SHARE Program:Restricted pharmacies and prescribers; Enroll patients. Ezogabine formulations- tabs; Preg Cat C Indications: adjunct therapy for partial seizures Dose adjustment in renal and hepatic problems Significant ADR- RISKS . Retinal abnormalities and *skin changes (blue, grey)* - may be permanent. FDA recommends visual acuity testing and dilated fundus photography before treatment and every 6 months during. No monitoring of vision = no drug Dizziness, neuropsychiatric disorders (confusion, psychosis, hallucinations, Suicidal ideation), QT prolongation, urinary retention

Drugs used in absence seizures Ethosuximide (Zarontin)- MOA, Formulations, pregnancy category, Indication, PK, dose, DI, ADR

MOA: Ethosuximide reduces T-type Ca2+ currents in thalamic neurons → ↓ bursts of APs The thalamus plays an important role in generation of 3-Hz spike-and-wave rhythms characteristic for absence seizures Ethosuximide formulation- soln. Preg Cat C Indication- *Absence (petit mal) epilepsy* Children: 3-6yo Serum conc: 40-100 mcg/ml PK- No significant protein binding Metabolized by P450 enzymes (hydroxylation) CYP3A4 substrate Long half-life, 25% excreted unchanged in urine DI- Ethosuximide + valproic acid → inhibition of metabolism of ethosuximide → ↑ ETHO. steady-state concentrations It increases phenytoin levels Increases ethosuximide levels- INH, ritonavir, VPA Decreases ethosuximide levels- CBZ, phenytoin, phenobarbital, primidone, VPA Side effects- Most commonly GI complaints (anorexia, nausea and vomiting) CNS effects: drowsiness, lethargy, euphoria, ataxia, dizziness and headache Serious ADR- Blood dyscrasis, lupus, SJS, headache, behavior changes, ataxia, N/V (40%), hiccoughs, drowsiness Monitor- U/A, LFT, CBC - periodically in the event of infection

GABA analogs: Gabapentin (Neurontin) and pregabalin (Lyrica)- )- MOA, Formulations, pregnancy category, Indication, PK, dose, control schedule, caution

MOA: Even though they are structurally resemble GABA,* neither drug acts directly on GABA receptors*. Instead, gabapentin and pregabalin bind to presynaptic VG Ca2+ channels → ↓ Ca2+ entry → ↓ release of glutamate Gabapentin was designed to be a* centrally active GABA agonist,* with its high lipid solubility aimed at facilitating its transfer across the BBB. Gabapentin formulations: cap, tab. suspension; Preg Cat C Indications: Adjunct- partial seizures, so not used much for seizure.* postherpetic neuralgia, RLS, alcohol withdral Dose- 300mg TID (max 3600mg/day). Absorption is dose-dependent reduced with doses > 1200mg/day, no more lenear absorption.* Renal: Clcr, GABA analogues are not metabolized and excreted unchaged in urine No serum level monitoring required, no protein binding or DI interactions. Significant ADR- These drugs are generally well tolerated. *Pedal edema,* dizziness, fatigue, ataxia, weight gain Pregabalin is related to gabapentin Pregabalin formulation- caps; Shedule V; Preg Cat C Indications- *Adjunct* partial seizures.* Diabetic peripheral neuropathy pain, Postherpetic neuralgia, Fibromyalgia* Dose-150mg/day divided BID-TID (600mg/day - seizure max) Renal: Based on Clcr and indication specific dosage regimen. GABA analogues are not metabolized and excreted unchaged in urine Side effects: Pregabalin may cause mild euphoria (Schedule V controlled substance), *Pedal edema*, anaphylaxis, decrease platelets, weight gain, blurred vision, somnolence, CK elevationUse with glitazones increases risk of edema and heart failure. Caution in Class III or IV heart failure

Felbamate (Felbatol)- MOA, Formulations, pregnancy category, Indication, PK, dose, ADR, DI

MOA: Felbamate blocks NMDA receptors (selective for NR1-2B subtype) + potentiate GABAA receptor responses formulations: tabs, susp. Preg Cat C Indications- Because of serious side effects it is only used as a *third-line* drug in treatment of poorly controlled partial and secondarily generalized seizures in adults and children. adjunct partial with Lennox-Gastaut Dose-1200mg/day divided TID or QID (3600mg/day) Renal: reduce all dosing by 50%; no Clcr listed. Hepatic: use is contraindicated PK- CYP2E1 substrate, CYP2C19 inhibitor, CYP3A4 inducer (weak) DI-Decreases efficacy of OCP, Prescribing information must include consent form* Increases levels of CBZ metabolite, VPA, warfarin Felbamate ↑ plasma phenytoin, valproic acid and phenobarbital levels It also ↓ carbamazepine levels, but ↑ 10,11-epoxide levels ADR : (bad ADR, lastline agent)*. fatal Aplastic anemia (Onset = 2 months - first year,) and severe hepatitis (1 in 10000) Anorexia, weight loss, insomnia and purpura, somnolence, nausea, upper respir infection Monitor- LFT and bilirubin at baseline and every 1-2 weeks

Antiseizure barbiturates- Phenobarbital, Primidone (Mysoline)- MOA, Formulations, pregnancy category, Indication, PK, dose, ADR, monitoring, DI

MOA: Potentiation of synaptic inhibition through its action on GABAA receptors. Phenobarbital binds to GABAA receptors → ↑ the time the chloride channel is open → membrane hyperpolarization → inhibition of AP generation. Phenobarbital at above therapeutic levels also suppresses high-frequency repetitive AP firing in neurons in culture through an action on Na+ conductance Primidone is Metabolized into phenobarbital and phenylethylmalonamide (PEMA); all 3 compounds are active anticonvulsants Phenobarbital formulations- tabs; elixer; injection; Preg Cat D Primidone formulations- tabs, Preg Cat D Phenobarbital Indication- Generalized seizures, Partial seizures Primidone Indication-Grand mal seizures, Focal seizures, Psychomotor seizures main use is essential tremor Phenobarbital Dose: daily (200mg), Serum conc: 15-45 mcg/ml PK -pKa =7.4 → slight changes in acid-base balance can cause significant fluctuations in the ratio of ionized to un-ionized species. Up to 25% of the dose is eliminated as unchanged drug by pH-dependent renal excretion → elimination can be ↑ significantly by alkalinization of the urine Metabolized mostly by CYP2C9 (substrate) Phenobarbital *induces P450* enzymes (CYP2C and CYP3A subfamilies) and UGT (UDP-glucuronosyl-transferase) enzymes → ↑ metabolism of all drugs metabolized by these enzymes (including oral contraceptives) Primidone CYP3A4, CYP1A2 and CYP 2C9 Inducer DI- Due to induction of P450 enzymes by phenobarbital and primidone Phenobarbital + valproic acid → ↑ plasma concentration of phenobarbital (may be elevated as much as 40%) Main ADR is* sedation* (some tolerance develops over time), Nystagmus, ataxia (with higher doses) Sometimes produces irritability and hyperactivity in children and agitation and confusion in elderly Rash (~2%) SJS, TEN. lethal on overdose. So not used much Others-anemia, worsening seizures, metabolic bone disease, intellectual blunting, mood changes, behavior changes, nausea, arthritis Primidone ADR and monitoring- Anemia, agranulocytosis CBC and chem panel Q 6 months, connective tissue disorder like phenytoin.

Carbamazepine (Tegretol, Carbatrol) / Oxcarbazepine (Trileptal) - MOA, Formulations, pregnancy category, Indication, PK, dose

MOA: Similar to that of phenytoin, it binds to VG Na+ channels slowing the rate of their recovery → inhibition of high-frequency repetitive AP firing in cultured neurons It also acts presynaptically → ↓ presynaptic neurotransmission CBZ-Related chemically to the *tricyclic antidepressants.* The predominant metabolic pathway involves conversion of carbamazepine to 10,11-epoxycarbamazepine, which has anti-seizure activity. formulations- chewable tabs, suspension, tabs, XR; Preg Cat D Indication- Complex partial, generalized tonic-clonic, mixed patterns (NOT Absence seizures); not used for sezure due to ADR. But used for *trigeminal neuralgia pain* Dose -max 1200mg/day. Serum conc : 4-12 mcg/ml (for all kinds of disease and monitor) OXCBZ-A keto analog of carbamazepine. Functions as a prodrug; quickly converted into its main active metabolite, a 10-monohydroxymetabolite (MHD). formulations- tabs, suspension; Preg Cat C Indication- Monotherapy > 4 yo with partial seizures, Adjunct therapy > 2 yo with partial seizures. Switching to monotherapy guidelines in PI Serum conc: none PK CBZ - Absorption slow and erratic after oral administration Plasma protein binding ~ 75%; no significant protein binding interactions CYP3A4 substrate Carbamazepine induces multiple P450 enzymes (CYP2C9, CYP2C19, CYP3A4, CYP1A2) and UGT (UDP-glucoronosyl-transferases). *Autoinduction 3-4 weeks* PK OXCBZ-Drug inactivated by glucuronidation, followed by renal excretion

Topiramate *(Topamax can be called dopamax make people dum*) - MOA, Formulations, pregnancy category, Indication, PK, dose, DI and ADR and monitoring

MOA: Similar to those of phenytoin and carbamazepine (it reduces VG Na+ currents) In addition, topiramate activates hyperpolarizing K+ currents, enhances postsynaptic GABAA-receptor currents, and limits activation of AMPA and KA receptors Substituted monosaccharide that is structurally different from all other anti-seizure drugs Formulation-sprinkles, tabs. Preg Cat D Indications- pediatric adjunct, monotherapy >10yrs, Adjunct adults with partial, Lennox-Gastaut, tonic-clonic. PK: Little plasma protein binding, Mainly excreted unchanged in urine. As monotherapy, half life is approx 24 hours, but with enzyme induced the half-life is 15 hours. Serum levels: not needed DI- Topiramate also decreases the effectiveness of oral contraceptives (higher estrogen doses may be required), Teratogenic in animal models Side effects: Overall well tolerated May cause somnolence, fatigue, *weight loss,* headache, nervousness,* cognitive slowing or make people dum (word-finding difficulties, improve with dose reduction. Ref dose)* and confusion Metabolic acidosis, it can precipitate nephrolithiasis (or * renal calculi. topiramate is a weak carbonic anhydrase inhibitor),* hypohydrosis (don't sweat), hyperthermia, acute angle glaucoma and acute myopia Monitor-* serum bicarb *baseline and periodically

Lamotrigine (Lamictal)- )- MOA, Formulations, pregnancy category, Indication, PK, dose

MOA: Similar to those of phenytoin and carbamazepine (lamotrigine blocks sustained repetitive firing of cultured neurons by increasing the time of inactive state of VG Na+ channels) Lamotrigine also inhibits VG Ca2+ channel → ↓ release of glutamate Formulation- tabs, chewable, ODT, ER. Preg Cat C Indication- Adjunct tx for partial seizures, generalized tonic-clonic and Lennox-Gastaut seizures, *bipolar (like CBZ, VPA, trilepal) * Conversion to monotherapy in partial seizures (dose varies with CBZ, VPA, phenytoin, phenobarbital, primidone ALWAYS USE A REFERENCE DOSE chart; Follow titration in PI. refer to Bipolar.) 2 yrs and >; (2-12 yo IR formulation only) *Serum conc: 4-20 mcg/ml ( for sizure only. No conc. Required for bipolar)* If withheld for > 5 half-lives, restart according to initial dosing recommendations otherwise SJS. *Discontinuing therapy quicker to change to another rx- Decrease dose by 50%/week over at least 2 weeks or follow PI. (general rule for any drug- reduce dose 50% 1st week, then 25% next 2 week then stop). If stoping permenanantly go by D/C over 6 months like any antisiezure rx* Hepatic: dose adjustment. Half-life up to 30 hr; prolonged in renal failure PK: Completely absorbed from the GI tract and is metabolized primarily by glucuronidation

Levetiracetam (Keppra) - MOA, Formulations, pregnancy category, Indication, PK, dose, ADR, DI

MOA: The drug binds selectively to the synaptic vesicular protein SV2A. The function of SV2A is unknown, but it is likely that levetiracetam modifies the synaptic release of GABA and glutamate formulations- tabs; XR; solution; injection; Preg Cat C Indication- Adjunct partial seizures age > 4yo, Adjunct juvenile myoclonic epilepsy > 12yo, Adjunct tonic-clonic > 6yo. *migraine. Ajunct only in seizure unless, Prevention of seizure after neurosurgery like phenytoin* Dose- max 3000mg/day divided BID or XR daily Renal: dosing. 2/3 of the drug is excreted unchanged in the urine → dose adjustments are needed for patients with decreased renal function PK- Negligible protein binding Minimal drug interactions ADR- Drug is well tolerated May cause sedation, fatigue, dizziness and ataxia, behavioral disturbances, hematologic abnormalities (eosinophilia), weight loss, asthenia, *psychosis,* aggression, anger, irritability Serum conc: not necessary (10-40 mcg/ml)

Tiagabine (Gabitril)- MOA, Formulations, pregnancy category, Indication, PK, dose, DI and ADR

MOA: Tiagabine *inhibits GABA uptake* by blocking GAT-1 transporter in both neurons and glia → ↑ GABA levels at the synapse → ↑ GABA-mediated inhibition Derivative of nipecotic acid Tiagabine formulation- tabs Preg Cat C Indication-Adjunctive tx > 12 yo (adults and children), For refractory epilepsy Dose-max 56 mg, divided BID-QID. Take with food PK -Extensively bound to plasma proteins CYP3A4 substrate DI- Tiagabine + phenobarbital, phenytoin, or carbamazepine (P450 inducers) → tiagabin half-life shortened from 8 hr to 5-6 hr ADR-Somnolence, dizziness, tremor, difficulty concentrating and depression SJS, *Absence seizures, status epilepticus (tx and cause sizure),* spike-wave stupor Fatigue, difficulty concentrating, tremor, blurred vision

Zonisamide (Zonegran)- MOA, Formulations, pregnancy category, Indication, PK, dose DI and ADR

MOA: channels similar to phenytoin and carbamazepine, Prolongation of the inactivated state of VG Na+ Inhibition of the VG Ca2+ currents (T-type) Sulfonamide derivative. *Contraindicated in sulfonamide allergy* Formulation- caps, Preg Cat C Indication- *Adjunct for refractory* partial seizures > 16 yo, Dose- Daily or BID. Max = 600mg/day per PI but there is no evidence > 400mg Renal Not recommended if Clcr < 50ml/min Serum Conc: not needed PK: Low plasma protein binding Long half-life (~60 hours) Side effects: Overall well tolerated May cause drowsiness, ataxia, fatigue and GI side effects (anorexia and nausea) Agranulocytosis, aplastic anemia, SJS, TEN, *renal calculi (week carbonic unhydrase action like Topamax)* hypohidrosis/hyperthermia, metabolic acidosis, increased Scr/BUN, Monitor Renal function, Baseline and periodic *serum bicarbonate*, Suicidal thoughts (like depression, high in seizure and also with rx), depression, behavioral changes DI- Phenobarbital, phenytoin, and carbamazepine → ↓ the plasma concentration of zonisamide

Valproic acid (VPA) and sodium valproate (Depakote (DR and ER) Stavzor, Depacon (IV))- MOA, Formulations, Indication, PK, dose

MOA: similar to those of phenytoin and carbamazepine, Valproate inhibits sustained repetitive firing induced by depolarization of neurons in culture by causing a prolonged recovery of VG Na+ channels. Valproate also: ↑ the amount of GABA in the brain by stimulating the activity of GABA synthetic enzyme (glutamic acid decarboxylase) and inhibiting GABA metabolism (GABA transaminase) And also produces small reductions of T-type Ca2+ currents (reason for absence sezure in kids) * Broad-spectrum *AED (used in treatment of *absence,* myoclonic, clonic-tonic seizures and CP) also for Migraine prevention, Bipolar disorder. Valproic acid is a simple branched-chain carboxylic acid, Discovered accidentally when used as a solvent. Fully ionized at body pH → the active form of the drug is the valproate ion→ distribution in extracellular water Formulation- IR cap and syrup, DR (cap, tab, sprinkle), ER tabs, Injection. IR/Susp: divide TID (we need to keep the trough and peak steady to tx seizure); DR = BID; ER = daily Valproate-Serum Concentration- 50-125 mcg/ml (seizure go higher end or 100, for bipolar closer to 80) PK: VPA is absorbed faster, slow with depakote. VPA dissociated to Valproate (Depakote). Plasma protein binding ~90%. Valproate inhibits CYP2C9. Highly ionized Liver metabolism: β-oxidation and glucuronidation

Drugs of SE -Benzodiazepines, Hydantoins, Barbiturate, Other medications available

May need higher dose for patient on chronic benzo, All equally effective AE's: hypotension, respiratory depression, propylene glycol (an excipient in IV and used as a antifreeze in car) Lorazepam IV- Treatment of choice due to long duration of action Diazepam- High lipid solubility IV, IM, per rectal Midazolam- bolus, Followed by continuous infusion.For mechanically ventilated patients Long acting anticonvulsants. Full antiepileptic effect not immediate. Begin maintenance dose in 12 hours. Incompatible with benzos, will ppt if in the same line Cardiac monitoring mandatory ( due Na blocking in heart), Dose adjust to hypotensive effect. Phenytoin- Serum therapeutic level 10-20 mg/L 1.5 mg of fosphenytoin = 1 mg of phenytoin Fosphenytoin - Converted w/in 15 min after IV administration. 150 mg PE/min, max of 20 mg/kg Choose over hydantoin if hypersensitivity to hydantoin or cardiac conduction abnormality Phenobarbital- Initiate maintenance dose 12-24 hrs after loading dose Cardiac and respiratory monitoring mandatory (ICU) Pentobarbital- Inducing coma state with short acting drug. For mechanically ventilated patients only Propofol- after seizure controlled, Continued for 12-24 hours Valproic Acid- hyperammonemia Topiramate, Levetiracetam, Thiopental, Ketamine

Systemic complication, General Treatment, Monitoring

Metabolic- Lactic acidosis (cell death and K goes out of cell, hyperkalemia), Electrolyte imbalance (Na, K, Co2) , Hyperglycemia, then Hypoglycemia Autonomic- Hyperpyrexia, Vomiting, Incontinence, Papillary dilation Renal - Acute renal failure from rhabdomyolysis, Myoglobinuria Cardiac/Respiratory- Hypoxia, Pneumonia, Hypertension (later hypotension), Tachycardia, Arrhythmia, Output failure SE requires *immediate* intervention. Single generalized seizure with complete recovery does not require treatment Oxygenation and Circulation. Assessment and control of airways, blood pressure, pulse, hyperpyrexia Screening for underlying causes Obtain IV access, Initiate drug therapy Hypoglycemia-D50W 50ml empirically if hypoglycemia cannot be ruled out,Thiamine 100 mg (before glucose) to decrease risk of Wernicke's encephalopathy Naloxone- if opoid withdral Continuous EEG even after presumed control, Blood pressure

Review pre and post synaptic neurotransmission, & action potential, Phases neuronal AP (cardiac muscle AP is different ref slide 4,5 of set arrhythmia 6)

Neuronal signal transmission from presynaptic to post synaptic neurons and propagation of AP- first step in the chemical activity in the synapse is synthesis, transport and storage of neurotransmitters in the presynaptic axone. AP propagation changes the membrane potential in the presynaptic axone, causing Ca channel to enter through voltage gated Ca channel and trigger release of neurotransmitters. Now neurotransmitters cross the synapse and attach to post synaptic receptors and cause postsynaptic activity. Some are reuptake back to the presynaptic site by transporter and broken down by MAO. Due the propagation of AP, a brief reversal of charge across the nerve membrane occur. AP causes a All-or-none response *once the membrane potential reach threshold* and can reverse charge from -70 to +40. Phases neuronal AP (cardiac AP is different) 1. Depolarization -*Opening of VG Na+ channels → Na+ ions enter the cell* at the threshold. At this stage K start leaving the cells as well. Once membrane potential reaches +40, Na channel become *refractory (inactivated state. Na channel cannot be activated)*, and no more Na enter then repolarization starts. 2. Repolarization -*Opening of VG K+ channels* → K+ ions leave the cell *causing the membrane potential to reach resting level. Then K channel closes, Na channel resets. 3. *Hyperpolarization (mediated by GABA)* when extra K outside diffuses away to reach resting membrane potential. Now Na channel can be opened. 4. RMP (resting membrane potential)

Phenytoin and fosphenytoin - MOA, Formulations, pregnancy category, Indication, PK, dose,

Phenytoin MOA: Phenytoin blocks sustained high-frequency repetitive firing of APs At therapeutic concentrations phenytoin binds to VG Na+ channels and prolongs their inactivated state → which slows the rate of recovery of the Na+ channels → reduces the ability of neurons to fire at high frequencies. At supratherapeutic doses, phenytoin binds to Ca2+ channels → modifies the NT release from the presynaptic terminals → ↑ GABA release and ↓ glutamate release Phenytoin - The oldest nonsedative antiseizure drug. Formulations- caps, chewable tab, suspension, injection. Suspension and chewable tabs contain 8% more phenytoin than caps or injection; dosage adjustment may be needed between products Preg Cat D Indication- Complex partial seizures, Generalized tonic-clonic. *Prevention & treatment of seizures during/following neurosurgery like Keppra* Fosphenytoin -i.v. administration but if too fast cause cardiac arrhythmias. Fosphenytoin is converted into phenytoin by phosphatases in liver and red blood cells. t1/2 of 8-15 minutes. 1.5 mg of fosphenytoin = 1 mg of phenytoin. PK -Non-linear elimination kinetics → rate of phenytoin's elimination varies as a function of its concentration At very low blood levels (below therapeutic levels) → elimination follows 1st order kinetics At therapeutic levels → P450 enzymes start metabolizing phenytoin at maximum capacity (metabolism is saturable) → further increases in dosage, even very small, may produce large changes in phenytoin concentrations (zero order kinetics). Loading dose: 1000mg (400mg, 300mg, 300mg 2 hrs apart) and then start MD 24 hr later. Max PO dose is only 600/ day (300 TID). Phenytoin- Serum therapeutic level 10-20 mg/L

Phenytoin: Drug interactions, ADR (ref slide 4 set 16TPN)

Phenytoin is highly bound ~90% to plasma proteins mainly albumin. Hypoalbuminemia, uremia → ↑ amount of free drug *Valproate or sulfonamides can displace phenytoin from plasma protein* binding sites. Phenytoin is substrate of CYP2C9 and 2C10. Administration on any other drug metabolized by 2C9 or 2C10 → ↓ rate of metabolism of phenytoin → ↑ plasma phenytoin levels Phenytoin + warfarin → inhibited metabolism of warfarin Phenytoin also *induces P450 *enzymes (including CYP3A4). Phenytoin does not ↑ the rate of its own metabolism Phenytoin + oral contraceptives → ↑ metabolism of oral contraceptives (which can lead to unplanned pregnancy) Fosphenytoin When administered i.v. too fast → toxic signs are cardiac arrhythmias (Na inactivation in heart) with or without hypotension, and CNS depression Phenytoin Cerebellar-vestibular side effects, such as nystagmus at first, and ataxia at high conc. At toxic level paradoxical increase in seizure (Nystagmus = a form of involuntary eye movement consisting of a smooth drift followed by a flick back. Ataxia = a lack of muscle coordination during voluntary movements, such as walking) Less sedation than with other antiseizure drugs (only at high doses) Long-term ADR Connective tissue disorders-Gingival hyperplasia (~20%), Coarsening of facial features (caused by altered collagen metabolism), Hirsutism and acne, Cerebellar atrophy Peripheral neuropathy Osteomalacia, hypocalcemia (caused by abnormalities in vitamin D metabolism) Hyperglycemia, ↓ADH secretion Megaloblastic anemia (low folate levels), neutropenia, leukopenia Hypersensitivity reactions (skin rashes) are less common Teratogenic effects (fetal hydantoin syndrome)- Microcephaly, craniofacial and limb defects

Seizure classification based on pathophysiologic groups and Pathways of seizure propagation in Partial vs. generalized seizures/ Compare and contrast the clinical presentation of partial vs. generalized seizures/ Describe the pathophysiologic mechanisms underlying different seizure disorders

Primary Generalized seizure (*bilaterally symmetrical & diffuse onset *or without local onset) -Involve diffuse regions of the brain simultaneously or of diffuse or spread onset (generalized). Usually *originate from a subcortical brain focus* which has an extensive connection in the cortex causing abnormal *synchronization between thalamic and cortical cells. Consciousness is always lost *or impaired. a. Tonic-clonic (grand mal) (GTC)- major convulsive episodes +* loss of consciousness, without aura* b. Absence (petit mal) c. Atonic- can be nondetectable; seconds of altered consciousness d. Tonic e. Myoclonic f. Infantile spasms g. Lennox-Gastaut syndrome- difficult-to-treat form of childhood-onset epilepsy Partial-Seizure activity is restricted to discrete areas of *cerebral cortex or focal onset*(begin locally) a. Simple partial seizures *(without lack of consciousness)* - Cause motor, sensory, or autonomic symptoms. b. Complex partial seizures (CP) (with or without automatisms,* with lack of consciousness)*- Characterized by focal seizure activity accompanied by altered Consciousness or a transient loss of contact with the surroundings due to *Involvement of medial temporal lobe* (1-2 minute) c. Partial seizures with secondary generalization → paroxysmal activity *begins in the cortex (partial), but then spreads to subcortical areas* (general). Diffuse connections from the thalamus and involve deeper brain nuclei then cause the spread of activity to *both hemispheres* and can produce *clonic-tonic seizure*. it commonly occurs following simple partial seizures with a focus in the *frontal lobe (cause vague prodromal symptoms, called aura)*

Seizure classification based on cause? What causes abnormal cortical electrical activity leading to a seizure? drugs that can cause epilepsy and what are the precipitating factors of epilepsy

Primary, or idiopathic epilepsies are those without a known cause (but presumed genetic). 2/3 of the cases. Secondary, or symptomatic epilepsies are those with a clear cause involving the cortex. 1/3 of cases. 1. Focal Injury - Traumatic injury, hemorrhage, focal cerebral infection, stroke or vascular disease - Dementia of Alzheimer type 2. Systemic illness and CNS infections - metabolic disturbances (hypoglycemia, hypocalcemia, hyponatremia, hypomagnesemia hypokalemia) - High fever in kids (not epilepsy in itself) 3. Others- neoplasms, tumor, eclampsia, certain drugs such as a. Analgesics: meperidine, tramadol b. Antidepressants: TCAs, bupropion (amphitamie metabolite) c. Antipsychotic agents: clozapine d. Drugs of abuse: amphentamines, cocaine e. Sedative-hypnotic drug withdrawal: alcohol, barbiturates precipitating factors -- both endogenous (hyperventilation, sleep deprivation, hormonal fluctuations- Estrogen = proconvulsant), and exogenous (flashing lights, exposure to certain drugs)

Lamotrigine (Lamictal)- ADR and DI

Side effects- Somnolence, dizziness, ataxia, blurred or double vision, headache Nausea and vomiting, Worsening seizures Hypersensitivity reactions: hepatic/renal failure Rash , Rarely development of potentially *fatal SJS with rapid titration.* SJS comes with fever, lymph gland swelling, upperbody, chest and neck rash. Regular rash comes with macopaular rash and has a higher incidence with this rx. But hard to differenceiate with SJS. So stop rx if rash develops. FDA Warning -aseptic meningitis with lamotrigine.Headache, fever, nausea, vomiting, nuchal rigidity, rash, photophobia and myalgia. Seen Between 1 and 45 days of treatment initiation.Typically resolved after lamotrigine was withdrawn DI- *Unlike other AED, Levels of lamotrigine may be decreased by estrogen. Pt also taking enzyme inducers - no adjustment needed. Pt NOT taking enzyme inducers but taking OCP- lamotrigine doses may need increased by 2x. * metabolized primarily by glucuronidation. But Consider the impact of interacting medications on half-life of lamotrigine. Lamotrigine + phenytoin, carbamazepine or phenobarbital → ↓ plasma concentrations and half-life of lamotrigine Lamotrigine + carbamazepine → ↑ levels of 10,11-epoxy-carbamazepine Lamotrigine + valproate → valproate inhibits the clearance of lamotrigine → ↑ plasma concentrations of lamotrigine

Definition of status epilepticus (SE), Classifications based on origin of seizure, Etiology, Pathophysiology

Two or more sequential seizures without full recovery of consciousness between seizures. Or Persistent seizure activity with Loss of consciousness for five minutes or more after a witnessed seizure (impending). Life threatening emergency. Irreversible damage possible if more than 30 min of continuous seizure activity and is called refractory SE. Generalized - Generalized convulsive status epilepticus (GCSE) 75% Generalized -Nonconvulsive status epilepticus (NCSE)- Continuous EEG seizure with no motor movements Focal- Simple Focal - Complex (also part of the mixed bag of NCSE) Acute anticonvulsant withdrawal, Ineffective antiepileptic drug levels, Addicted mothers, withdrawal seizures, Magnisium or Pyridoxine deficiency, Metabolic disorder, hypoglycemia, or concurrent illness Phase I - first 30 min. Increase in epinephrine, norepinephrine, steroid. Brain is compensated Phase II - after 60 min. Begin to decompensate. Autoregulation of cerebral blood flow start to fail. Hypotensive, profound hypoglycemia, hyperthermia, hypoxia, acidosis, hyperkalemia, hyponatremia, azotemia

Clinical manifestations and pathophysiologic mechanisms underlying different Primarily generalized seizures- grand mal

grand mal -Most common type of generalized seizures. Epileptogenic focus is located in deep brain (subcortex) regions → seizure activity rapidly spreads to both hemispheres such as Corpus callosum, Thalamocortical projections. Primary generalized seizures begin abruptly *without warning (usually without an aura)* *major convulsive episodes + loss of consciousness*. Phases: tonic, clonic and postictal Initial (tonic) phase- Potential for injuries. Tonic contraction of muscles throughout the body. Lasts 15-60 seconds.* "Ictal cry" (due to respitory mucscle* contraction), falling and loss of consciousness. Contraction of the jaw muscles (biting of the tongue can occur), Breathing is suspended, cyanosis occurs, Increased sympathetic tone → HR↑, BP↑, pupils dilate Clonic phase - Produced by periods of muscle relaxation that alternate with periods of tonic muscle contraction. lasts ~ 2 minutes ( if it last longer, status epilepticus and death). The periods of relaxation progressively increase *Postictal phase -Characterized by confusion,* unresponsiveness (stupor or coma), muscular flaccidity, excessive salivation. Urinary and bowel incontinence. Patients gradually regain consciousness over minutes to hours. Postictal confusion and sleepiness. Patients complain of headache, muscle aches, and fatigue