Seizures Evaluation & Management

Sections

Overview
Seizure Categorization
Lateralizing Signs
Nomenclature
Seizure Causes
Common Epilepsy Syndromes
Status Epilepticus
Epilepsy Management

Seizures & Epilepsy

Overview

Here, we'll learn an overview of seizures and epilepsy. To begin, start a table.

Key Definitions

Seizure

• A seizure is an acute, transient neurological event (typically less than 5 minutes in duration) caused by abnormal (excessive or synchronous) electrical discharges within the brain.

Epilepsy

• Epilepsy is the syndrome of recurrent, unprovoked seizures.
  • As we'll discuss elsewhere, provoked seizures can occur from conditions like intracranial hemorrhage or metabolic causes; whereas; unprovoked seizures do not have a triggering cause.

Status Epilepticus

• From a nomenclature standpoint, we use the term "prolonged seizure" for a seizure lasting longer than 5 minutes and the term "status epilepticus" for seizure activity lasting longer than 30 minutes or to describe recurrent seizures without without intervening recovery.

SUDEP

• SUDEP (Sudden Unexplained Death in Epilepsy) occurs in roughly 1 in 1,000 seizure patients per year and its frequency is largely dependent on the severity of the epilepsy (ie, seizure frequency). Although the pathophysiological mechanism of SUDEP is not yet fully elucidated, it is helpful to know that SUDEP is not simply secondary to a cardiac dysrhythmia.
• In documented cases of SUDEP, there is observable respiratory apnea with coincident heart rate slowing followed by complete cardiopulmonary failure. The hypothesized underpinnings of SUDEP are beyond our scope here. For a detailed hypothesis, read: The mechanism of sudden unexplained death in epilepsy: A mini review SUDEP.
• Note that mortality from seizures is more commonly secondary to the physical trauma from seizures (motor vehicle accidents, non-motor vehicle related traumas, drowning, etc...) than from SUDEP, itself.

Key Epidemiology

Next, let's address some key epidemiology.

Seizure Prevalence

• Anywhere from 5 to 10% of people will have a seizure at some point in their life; most often in early childhood or late adulthood.
  • Not everyone who has a seizure will have a violent, convulsive event, however. Seizure semiology is broad and varied. Seizures can manifest as something small and focal, such as a strange feeling or visual illusion of flashing lights or something big and generalized, such as violent stiffening and shaking activity with a loss of consciousness.

Epilepsy Prevalence

• Anywhere from 1 to 4% of people have epilepsy; different organizations and societies provide widely varying estimates.
  • The World Health Organization (WHO) and Centers for Disease Control (CDC) an epilepsy prevalence of ~ 1% whereas the American Epilepsy Society reports a figure of ~ 4%.

Seizure Categorization

Onset Pattern

Next, let's categorize seizures based on their onset pattern.

Focal (aka Partial)

• Draw a brain and show that focal (aka partial) onset seizures originate from networks within one hemisphere (typically in a discrete region).

Generalized

• Then, draw another brain, and show that generalized onset seizures originate from networks that involve both hemispheres.

Focal to Generalized (aka Secondarily Generalized)

• Show that a focal seizure can subsequently involves both hemispheres: we call this a focal to bilateral seizure (aka secondarily generalized seizure).

Focal

• Indicate that in focal onset seizures, awareness (ie, consciousness) can be impaired (aka complex partial seizures) or preserved (aka simple partial seizures).
  • Note, that in generalized seizures, by definition, awareness is almost always impaired.
• Then, indicate that, clinically, focal seizures can have either motor or non-motor features.
  • At the end, we'll learn some helpful localizing features of focal seizures.

Generalized

• Now, divide generalized seizures into: Motor & Non-Motor seizures.
• Indicate that the major types of motor seizures we'll address are:
  • Tonic-clonic
  • Myoclonic
  • Atonic
• And the major non-motor seizure type is:
  • Absence

Tonic-Clonic

Detailed Semiology

Pre-ictal

• Note that there is often a pre-ictal sensory prodrome that can last minutes to hours.
  • The ictal phase refers to the seizure, itself: the event.

Tonic Phase

• During the tonic phase, there is tonic stiffening: show that the back and neck are arched.
• The EEG rhythm is a 10 Hz tonic (fast frequency), low amplitude waveform.

Clonic Phase

• During the clonic phase, there is rhythmic jerking (convulsions) of the face, arms, and legs.
• The EEG rhythm is 4 Hz (slower frequency) spike-and-wave activity.

Apnea

• During the ictal phase, there is often apnea with frothing at the mouth, choking sounds, and cyanosis (a blue appearance to the skin), which can mimic a cardiac arrest.

Post-ictal Relaxation

• After the event, post-ictal, there is post-ictal relaxation, which involves a stupor with possible bladder or bowel incontinence and deep, slow respirations.
• There is post-ictal slowing, with only a few wave cycles per second.

Lateralizing Signs

In regards to seizure laterality, indicate the following important signs:

Versive Movements

• Versive motor movements refers to contralateral turn of the head and/or eyes (away from the seizure).
• Show a seizure emanating from the right hemisphere.
• Show that the eyes exhibit forced eye deviation to the left: the side opposite (contralateral) to the side of seizure.

Todd's Paralysis

• Todd's paralysis refers to a post-ictal (post-seizure) weakness in the side of the body opposite to the seizure.
• During post-itcal slowing, the brain is slow and suppressed, so naturally the corresponding side of the body is limp and weak.

Stroke Mimickers

• Naturally, then, these signs can be important mimickers of stroke. In stroke:
  • The eyes can drift toward the side of the stroke: they look at the healthy side of the body (this is the opposite direction from in seizure wherein they look away from the seizure).
  • There is weakness on the side opposite of the stroke, similar to a Todd's paralysis.

Additional Signs

Some commonly discussed, albeit less reliable lateralizing signs, include the:

• Figure 4 Sign
  • The arm contralateral to the seizure is extended at the elbow with the wrist in flexion and the fist is clenched.
  • The ipsilateral limb is in elbow flexion.
• Fencing Posture
  • The arm contralateral to the seizure is raised and semi-extended above the head, as if holding a fencing foil.
  • The head is turned toward the raised arm while the ipsilateral arm is semi-flexed at at the patient's side.

Localization

Temporal Lobe

• Temporal lobe seizures often manifest with sensory auras, automatisms, or speech arrest (or another form of cognitive impairment).
• Sensory Auras:
  • Epigastric rising
  • Inappropriate fear
  • Olfactory hallucinations
  • Deja Vu
• Autonomic features
  • Wide variety of sympathomimetic, gastrointestinal, and respiratory symptoms

Frontal Lobe

• Frontal lobe seizures tend to be stereotyped and nocturnal. They are easily confused for psychogenic seizures or a movement disorder (especially because there is often NO loss of awareness or postictal phase).
• Additional Features:
  • Manifestations of frontal lobe seizures range from emotionally-driven, fearful hallucinations to motor activity: tonic-clonic movements and the more complicated positions described previously (figure 4 sign, fencing posturing, etc…).

Parietal Lobe

• Parietal lobe seizures tend to cause somatosensory auras, which we could predict given the role of the parietal lobe in sensory processing.
• Note, however, that parietal lobe seizures are notoriously poorly localizing and they will commonly propagate to more regions with more readily obvious manifestations, such as the frontal lobe or the occipital lobe, before they are recognized.

Occipital Lobe

• Occipital lobe seizures often produce elemental visual phenomena, such as flashing lights or geometric shapes, much like migraine auras.

Insular Cortex

• Insular cortical seizures characteristically manifest with symptoms involve the GI system and throat, such as vomiting, hypersalivation, dysarthria or strange thoracoabdominal sensations.

Nomenclature

2017 ILAE (International League Against Epilepsy) classification system

Seizure Description

Although the following terms are still widely used, the 2017 ILAE classification system has made the following updates:

• Partial seizures referred to focal seizures
• Complex partial seizures referred to seizures of focal onset that resulted in loss of awareness.
• Simple partial seizures referred to focal seizures with NO loss of awareness.
• Secondarily generalized seizures referred to seizures of focal onset that ultimately generalized; these are now called focal to bilateral tonic-clonic seizures.

Epilepsy Syndromes

• Although, we still widely use the term "idiopathic generalized epilepsies," but the 2017 nomenclature now employs the term "genetic epilepsies" (akin to "genetic myopathies", which we discuss in the neuromuscular disorders section). * Importantly, genetic epilepsies do NOT have to be inherited, they can occur due to de novo mutations.
• As well, they do NOT require genetic testing to make a diagnosis of genetic epilepsy, especially since the genetic mutation is often assumed and not yet known.

Seizure Causes

Common & Notable Causes of Seizures

Elsewhere, we learn the causes of seizures in great depth. Our goal, here, is simply to develop a reliable, working knowledge of common and notable causes of seizures. We will present some basic underpinning pathophysiological principles that help distinguish these causes (consider that the true mechanisms underlying seizures are, again, beyond our scope, here).

Vascular/Trauma/Tumor

First, let's think through Vascular, Trauma, and Tumor causes of seizure.

• Hemorrhage, Ischemic Infarct, PRES/Eclampsia.
  • Acute hemorrhage causes seizure due to iron and mass effects. Think of a lobar hemorrhage dysregulating surrounding neurons through pressure and think of a subdural hematoma irritating cerebral cortical neurons due to heme components.
  • Old ischemic stroke injury (infarct) can trigger seizure through neuronal asynchrony (just like any neuronal scarring).
  • PRES (posterior reversible leukoencephalopathy) and eclampsia cause seizures from a complicated mixture of hypo- and hyper- perfusion along with vasogenic and cytotoxic edema.
• Trauma and Mass.
  • Trauma produces an acute and chronic risk of seizures.
  • Mass lesions, much like a lobar hemorrhage cause pressure-inducing changes on surrounding neurons that can trigger misfiring.

Infectious/Autoimmune

• Encephalitis, Neurocysticercosis, Systemic infection (eg, UTI)
  • For encephalitis, think about HSV, anti-Hu, NMDA Receptor encephalitis, as well as ADEM (acute disseminated encephalomyelitis). HSV and anti-Hu characteristically have a predilection for the anterior, medial temporal lobes, which makes them highly epileptogenic.
  • Neurocysticercosis (taenia solium) is the most common cause of epilepsy, worldwide. The seizures stem from the accumulation of cysts within the brain. Cyst formation occurs when patients swallow the eggs from feces of a person who has intestinal tapeworm.
  • Systemic infection (eg, UTI) is an especially common trigger in the elderly.

Metabolic/Anoxic

• Low or High Glucose.
  • Either hypoglycemia or hyperglycemia can cause seizures.
• Low Sodium (Na+), Magnesium (Mg2+), or Calcium (Ca2+)
  • Alterations of electrolyte gradients across cell membranes affect neuronal excitation and synchronicity, but other mechanisms are also at play.
  • In acute hyponatremia (to levels less than 120 mEq/L), there is swelling of glial cells and neurons (to a lesser extent).
  • In regards to hypocalcemia, it's easy to remember its potential for seizures when we consider the Chvostek's and Trousseau's signs of neuromuscular hyperexcitability that occur latent tetany from reduced ionized calcium levels. Chvostek's sign refers to hemifacial twitch or spasm when we tap on the facial nerve anterior to the ear. Trousseau's sign, refers to carpopedal spasm (wrist flexion/thumb adduction/finger extension) following prolonged hyperinflation of a blood pressure cuff.
  • We can recall the role of hypomagnesemia in seizures when we consider the role of magnesium as a calcium channel antagonist; thus reduction in magnesium causes disinhibition of voltage-gated calcium channels. Magnesium is the primary treatment in seizures secondary to eclampsia, likely secondary to its vasodilatory effects.
• Anoxia.
  • Acute anoxia or chronic hypoxic-anoxic injury can produce seizures.

Iatrogenic

• Medication Noncompliance
  • This is an incredibly important cause of seizures in epileptic patients, and it reinforces the need to pay attention to any side effects or costs that may be preventing a patient from filling and taking their medications. Remember that the risk of death from seizures is highly related to seizure frequency.
• Tramadol (Ultram) and Buproprion (Wellbutrin)
  • These are two of the more common medications to induce seizures but many medications are known to reduce the seizure threshold. We include them amongst a list of common medication causes of seizures below.

Common Medications that Increase Seizure Risk

Antidepressants

• Buproprion, venlafaxine, and tricyclic antidepressants.
  • Buproprion, venlafaxine, and certain tricyclic antidepressants increase noradrenergic activity, which results in CNS activation.
    Analgesics
• Tramadol and meperidine
  • Tramadol is a widely used analgesic because of its safety profile, however, it is a common iatrogenic cause of seizures.
  • Meperidine, which metabolizes to normeperidine, which causes CNS activation and seizures.
    Antibiotics
• Carbapenems (eg, imipenim), isoniazid (INH), and fluoroquinolones (especially trovafloxacin). - Carbapenems are known GABA antagonists (GABA stabilizes membranes via chloride channels, so its antagonism is destabilizing) and they are NMDA agonists (NMDA activitates calcium channels the presynaptic terminal, which induces cell activation).
  • Fluoroquinolones displace GABA from receptors.
    Miscellaneous
• Amphetamines (like the activating antidepressants can cause CNS overactivation and seizures), diphenhydramine, cyclosporine (an immunosuppressant), and theophylline (an asthma medication less commonly used today).

Social

• Alcohol (& Benzodiazepine) Withdrawal, Illicit Drugs, Sleep Deprivation.
  • Alcohol withdrawal is an incredibly common cause of seizures. Benzodiazepine withdrawal is less common but highly epileptogenic.
  • Illicit drugs, especially cocaine and methamphetamine, are also highly epileptogenic.
  • Sleep deprivation, especially in epileptics, is an important modifiable social factor for seizures.

Pediatric

• Finally, include a section specific for pediatric seizures: Hypoxic Injury, TORCH infections, and include febrile seizures (which is its own topic).
  • Hypoxic ischemic encephalopathy is an incredibly common cause of seizures in newborns and later in childhood.
  • As are the TORCH infections, which, stands for: Toxoplasmosis, Others (Syphilis, Hepatitis B), Rubella, Cytomegalovirus (CMV), Herpes Simplex Virus (HSV).
  • Febrile seizures are convulsions associated with an elevated temperature greater than 38 degrees Celsius in children 6 months to 5 years of age; they occur in 2 to 4 % of children younger than 5 years old and are slightly more common in males. We subdivide febrile seizures into simplex and complex febrile seizures. They are more commonly due to viral infections than bacterial (HHV-6 being the most commonly associated viral illness), they tend to occur early in the illness, and no explicit work-up is mandated but rather testing is patient-specific.
  • Note that the following conditions exclude a possible diagnosis of febrile seizures: CNS infection or inflammation, systemic metabolic abnormalities, a history of nonfebrile seizures.

Common Epilepsy Syndromes

Childhood absence epilepsy (CAE)
See: Childhood Absence Epilepsy (CAE)

• Absence seizures (aka petit mal seizures) manifest with a blank stare; patients appear to be daydreaming or zoning out. They are the major seizure manifestation in childhood absence epilepsy (CAE), which typically occurs between 4 to 8 years of age, affects girls more than boys, and can involve 100s of seizures in a day.
• These patients may exhibit rhythmic facial movements or motor automatisms. Notably, there is no postictal confusion; patients can pick right back up where they left off with an activity.
• It is essential to distinguish absence seizures from an attentional disorder, as these patients can be mistakenly diagnosed with a learning disability. Children with absence seizure often appear to be "daydreaming" or "staring off" in school.
• The EEG demonstrates runs of well-organized 3 Hz generalized high-voltage rhythmic spike-and-wave discharges.
  • See: 3 Hz Generalized Spike-Wave Discharges

Juvenile absence epilepsy (JAE)

• For reference, juvenile absence epilepsy (JAE) is another generalized epilepsy syndrome, which we can think of (albeit a simplification) as a mixture of childhood absence epilepsy and juvenile myoclonic epilepsy:
  • it occurs at 9 – 13 years of age
  • it involves absence and myoclonic seizures that tend to occur shortly after awakening.

Myoclonic - juvenile myoclonic epilepsy (JME)
See: Juvenile Myoclonic Epilepsy (JME)

• Myoclonic seizures, manifest with brief, shock-like muscle jerks and are an important component of juvenile myoclonic epilepsy (JME), which begins in adolescence (12 – 18 years old).
• They are often mistaken for a movement disorder. The jerks are symmetric, irregular, shock-like, jerks of the shoulders and arms, most notably, which can cause the person to drop items, but can also affect the legs, which can cause falls. They typically occur in the morning upon awakening.
• The EEG demonstrates polyspikes, which correlate with the myoclonic jerks, and characteristic disorganized, 4 – 5 Hz polyspike and wave discharges.
  • See: Polyspike-and-Wave Complexes
  • See: Status Myoclonus
• These discharges have a strong photoparoxysmal response, so flashing lights are used during EEG to elicit these discharges.

Atonic - Lennox-Gastaut

• Atonic seizures cause as loss of tone (drop attacks) and are an important feature of Lennox-Gastaut syndrome, which involves multiple seizure types, including atonic seizures and cognitive dysfunction. It peaks at ~ 4 years of age.
• They manifest with brief loss of muscle tone in the postural muscles or head. They can be hard to distinguish from syncope, which also involves a sudden loss of tone.
• For reference, there are slow (1.5 – 2 Hz ) spike-and-wave discharges.

Status Epilepticus

Definition

Status epilepticus refers to seizure activity lasting longer than 30 minutes or recurrent seizures without intervening recovery. Note, however, that we do not wait 30 minutes for patients to develop status epilepticus, instead we initiate our status management at 5 minutes (as described below).

Classifications

First let's divide forms of status epilepticus into:
Convulsive Status – Repeated generalized tonic-clonic seizures with post-ictal depression.
Non-Convulsive Status – Continuous seizure activity with cognitive changes (aka "epileptic twighlight").
Repeated partial seizures – repeated focal seizures: repeated focal symptoms or signs.

Mortality

It's important to know that convulsive status is associated with a high probability of mortality. In children, on average, it is 3% whereas in adults it is, on average, 30%. However, this large depends on the underlying cause of the seizures, as well as the patient's age, and the duration of the status epilepticus.

Because the underlying etiology for the seizures that is the major contributor to this poor prognosis, if there is no serious underlying morbidity, we should never "give-up" on a patient no matter how long the duration of the status epilepticus, as the seizures can persist for weeks and patients can still have a good outcome if the underlying etiology resolves or is treated.

Management Algorithm

We initiate this treatment algorithm after five minutes of continuous generalized seizure activity.

Stabilization Labs

• Oxygen
• ECG
• Fingerstick glucose.
  • At the very least, treat for glucose less than 60 mg/dl.
  • Remember to give thiamine 100 mg IV prior giving 50 ml of D50 IV in suspected alcoholics or patient's susceptible to Korsakoff syndrome.

First Phase (5 – 20 minutes)

Give any of the following (all of these are roughly equivalent in efficacy):
Lorazepam, max 8 mg IV
Diazepam, max 30 mg IV
Midazolam, max 10 mg IM

If benzodiazepines aren't an option, give:
Phenobarbital, max 15mg/kg IV

Second Phase (> 20 minutes)

Give any of the following (all of these are roughly equivalent in efficacy):
Levetiracetam, max 4,500 mg IV
Fosphenytoin, max 1,500 PE IV (PE = phenytoin equivalents)

• fosphenytoin is preferred over phenytoin.
  Valproic acid, max 3,000 mg IV

Third Phase (> 40 minutes)

Additional first or second phase medications.
Be on the lookout for lacosamide 400 mg IV to be incorporated into this protocol in the future.

Epilepsy Management

There are numerous drugs used in the management of epilepsy. Here, let's divide them into those that impact or are impacted by the cytochrome P450 system and those that are not.

P450-related

Divide the P450-related drugs into those that are affected by P450 and those that induce or inhibit it.

Affected by P450 Metabolism

Benzodiazepines

• As mentioned, benzodiazepines are the first-line treatment for status epilepticus.
• A key side effect is respiratory suppression, so status epilepticus patients often have to be intubated.
• The different benzodiazepines undergo a variety of different phase 1 and phase 2 types of drug metabolism.

Ethosuximide

• Ethosuximide is first-line in absence seizures but it is limited to this seizure type.
• Indicate the oft-used mnemonic "SUX" because of its numerous side effects.
  • We can remember these side effects with the acronym: EFGHIJ, which stands Ethosuximide can cause Fatigue, Gastrointestinal distress, Headaches, Itching (as well as urticaria), and the J stands for Stevens Johnson syndrome – a rare but potentially life-threatening rash.
  • Note that we most commonly associate Stevens Johnson syndrome with lamotrigine.
• Like the benzodiazepines, its level is affected when there are changes to major drug metabolism mechanisms, especially cytochrome P450 changes.

Lamotrigine

• Lamotrigine is a broad-spectrum AED.
• Its primary side effect is drug-rash (most worrisome being Stevens Johnson syndrome (SJS)), which is often dose-related.
  • The risk of SJS increases substantially with rapid escalation in the drugs dosing, so it must be titrated slowly.
• Lamotrigine is highly affected by medications that act on drug metabolism, especially UGT-mediated glucuronidation.
  • Thus, the titration schedule is highly affected by concomitant antiepileptic drugs which affect UGT metabolism, such as valproic acid.

Inducers of P-450 Metabolism

Carbamazepine

• Carbamazepine is indicated for focal seizures.
• One of its major side effects is blood dyscrasias (leukopenia and thrombocytopenia).
• It is an inducer of drug metabolism, including both P450 and UGT-mediated (Uridine diphosphate glucuronosyltransferase enzyme-mediated) degradation (glucuronidation).

Phenobarbital

• Phenobarbital is used for focal seizures.
• It is first-line therapy in neonates (although other medications are now also being used).
• It has numerous side effects, including sedation, but we indicate its withdrawal potential, most notably: there is significant psychological and physiological dependence from the down-regulation of GABA that occurs from chronic phenobarbital use. Thus, it requires an incredibly slow wean schedule to avoid substantial rebound anxiety when the medication is stopped.
• It can cause cardiorespiratory depression, like the benzodiazepines, so these systems must be closely monitored.
• It's a major drug metabolism inducer; it is known to act on a wide variety of cytochrome P450 isoforms (including CYP2C9 and 2C19) as well as other forms of drug biotransformation, including UGT-degradation.

Phenytoin

• Phenytoin is indicated for focal seizures.
• As mentioned, it is one of the key second-line therapies for status epilepticus.
• It has numerous side effects, including nystagmus and ataxia; gingival hyperplasia and hirsutism; megaloblastic anemia; and the potential for teratogenicity, which is referred to as fetal hydantoin syndrome.
• It's a major drug metabolism inducer, as well, and also acts on numerous cytochrome P450 isoforms.

Topiramate

• Topiramate is a broad-spectrum AED that is more commonly used in migraine prophylaxis than seizures.
• One key side effect is kidney stones.
• Many other potential side effects exist including, rarely, secondary angle-closure glaucoma; weight loss in part due to making carbonated beverages taste lousy; numbness and tingling of the hands and feet (it's a carbonic anhydrase inhibitor); and teratogenicity – an increase in oral cleft defects.
• Although it is partially renally-excreted, it is also a cytochrome P450 inducer and undergoes significant P450 degradation.
  • It's important to note that because topiramate is a P450 inducer, it can reduce the efficacy of oral contraceptives (as can the other P450 inducers). We mention this, here, because, as discussed, topiramate is widely prescribed to women of childbearing age for migraine prophylaxis.

Inhibitor of P450 Metabolism

Valproic acid (VPA)

• Valproic acid is a broad-spectrum AED.
• One of its key side effects is hepatotoxicity.
• Very importantly, it is highly teratogenic in the first trimester, as it is a key cause of AED-associated neural tube defects.
• It is a major drug metabolism inhibitor (it inhibits a wide variety of biotransformation systems, including various cytochrome P450 isoforms and also UGT-mediated degradation (which is an especially important interaction with lamotrigine).
  • Note that it's the only inhibitor in our AED list. Other less commonly used AEDs that are inhibitors of drug metabolism are: felbamate, rufinamide, and stiripentol.

Non-P450 Related (Modern)

Levetiracetam

• Levetiracetam is a broad-spectrum AED.
• Its major side effect is psychiatric issues: emotional irritability and suicidality.
• Note that all seizure medications are considered to have the potential for suicidality and thus all patients must be counseled about this possibility no matter which AED they are prescribed.
• Indicate that, similar to gabapentin, it is primarily eliminated via renal excretion, so it's unaffected by changes in drug metabolism systems.
• Brivaracetam shares the same mechanism as levetiracetam but is far more selective for synaptic vesicle protein 2A (SV2A).

Lacosamide

• Lacosamide is used to treat focal seizures.
• Indicate that, rarely, can cause arrhythmia, so should be used with caution in patients with an underlying proarrhythmic condition or in those taking medications that affect cardiac conduction or cause PR prolongation.
• It can easily cause dizziness, especially within the first half-hour after taking it and especially when taken with other sodium channel blockers.
• Indicate that it is eliminated by demethylation and it's unaffected by P450 or UGT-mediated degradation.
  • It is renally excreted so one might expect to have to make adjustments to the dose in renal failure; however it seems to have many elimination pathways, so moderate changes in renal function do not appear to significantly affect the blood level of the drug. Only in severe renal failure, does the dose need to be reduced.

Gabapentin

• Gabapentin is used to treat focal seizures.
• Its major limitation in seizure management is its inferior efficacy and its tendency to cause sedation.
• It is an important treatment in neuropathic pain (note that many pain and headache medications were originally used as seizure drugs).
• And it is unaffected by changes to drug metabolism systems because it is renally-excreted: it does not undergo major drug biotransformation – but is renally-excreted unchanged.
  • Thus, changes in the P450 system does not affect its metabolism but renal failure does alter its excretion (and thus will increase effective blood levels).

Vigabatrin

• Vigabatrin is used in refractory focal seizures.
• A major side effect of vigabatrin is the potential for blindness.
• It is renally-excreted so it is unaffected by changes in drug metabolism mechanisms.