SEIZURE AND EPILEPSY REVIEW

SEIZURE MEDICATIONS

OTHER




Term Definition
Absence seizure
  • Previously referred to as petit mal seizures
  • Absence seizures are a type of generalized seizure that cause sudden impaired consciousness. Motor symptoms are typically absent.
  • Symptoms of absence seizures include a sudden interruption of ongoing activity with a blank stare that lasts 2 - 30 seconds and has a rapid recovery. Upward eye movement and eyelid myoclonus may be present.
  • The classic pattern on an EEG for absence seizures is a "3-per-second, generalized spike wave"
  • Absence seizures are thought to occur because of abnormal neuronal messaging between the thalamus and cerebral cortex
Atonic
  • Sudden loss of muscle tone without preceding myoclonic or tonic event lasting 1 - 2 seconds
  • Affected muscle groups include, head, trunk, jaw, and limbs
Benign epilepsy with centrotemporal spikes
  • Childhood epilepsy syndrome (onset 5 - 14 years) characterized by focal motor and/or secondarily generalised seizures that typically occur during sleep. The majority of patients have focal seizures involving the face without loss of consciousness. Centrotemporal spikes are seen on EEG.
  • Seizures typically resolve around the age of 12 years. Treatment may not be necessary.
Clonic movements
  • Repetitive jerking motion caused by a rapid succession of repeated muscle contractions and relaxations
  • Clonic movements may be symmetric or asymmetric
Electroencephalogram (EEG)
  • An EEG is a recording of cerebral electrical activity
  • Certain findings on an EEG are associated with an increased risk of epilepsy
  • See EEG below for more
Epilepsy Epilepsy is defined by the presence of any of the following:
  • At least two unprovoked (or reflex) seizures occurring more than 24 hours apart
  • One unprovoked (or reflex) seizure and a probability of further seizures similar to the risk seen after two unprovoked seizures (≥ 60%). These patients have a high risk of recurrent seizure due to other accompanying risk factors (e.g. history of stroke, brain lesion, epilepsy syndrome)
  • Diagnosis of epilepsy syndrome

Epilepsy is considered to be resolved in the following cases:
  • Diagnosis of age-dependent epilepsy syndrome and patient is no longer of the applicable age
  • Seizure-free for 10 years with no seizure medications during last 5 years
Focal seizure
  • Previously referred to as partial seizures
  • Focal seizures originate in one hemisphere of the brain. They may involve sensory symptoms, motor symptoms, or both. If motor symptoms are present, they typically dominate.
  • Patients may be conscious during a focal seizure (focal aware seizure) or they may be unconscious (focal unaware seizure)
  • Focal seizures may spread to involve both hemispheres, in which case they appear similar to generalized seizures. This can make distinguishing a focal seizure from a generalized seizure difficult.
  • Focal seizures are thought to occur because of anatomical lesions in the brain
Generalized seizure
  • Generalized motor seizures were previously referred to as grand mal seizures
  • Generalized seizures can be divided into two subgroups - motor seizures and absence seizures
  • Generalized seizures originate at some point within a bilaterally distributed network, and they spread rapidly to involve both brain hemispheres. Generalized seizures almost always cause impaired consciousness.
  • Generalized motor seizures are marked by tonic, clonic, and myoclonic motor activity. Absence seizures cause a sudden loss of consciousness without motor symptoms, although eye and eyelid movements may occur.
  • Generalized seizures are thought to occur because of defects in neuronal sodium and potassium channels
Juvenile myoclonic epilepsy (JME)
  • Syndrome that typically begins between 10 - 16 years and is marked by myoclonic seizures that occur soon after waking
  • Generalized tonic-clonic seizures occur in > 85% of patients with JME and absence seizures occur in up to 40% of patients
  • EEG findings include 3–6 Hz generalized polyspike and wave activity
  • JME is a lifelong condition that typically improves with age
Lennox-Gastaut syndrome
  • Syndrome of severe, refractory seizures that begins in childhood (3 - 10 years)
  • Patients typically have multiple seizure types including atonic, tonic, tonic-clonic, and atypical absence seizures
  • EEG features include a slow spike-wave pattern and paroxysmal fast activity in sleep
  • Mental retardation is common
Myoclonus
  • Term used to describe sudden, involuntary contractions of a muscle or muscle group
  • Myoclonic contractions cause brief (< 100 ms), jerky movements that may involve any muscle group
  • Movements may be singular or occur in groups
  • Myoclonic activity is associated with polyspikes on an EEG
Reflex seizure
  • A reflex seizure is a seizure that only occurs in the presence of a trigger
  • Seizure triggers may be visual (e.g. flashes of light), auditory (sounds), olfactory (smells), or involve other senses
  • Reflex seizure syndromes are rare
Tonic movements
  • Sustained muscle contraction lasting seconds to minutes
Tonic-clonic seizure
  • Seizure marked by a tonic phase followed by a clonic movements




Reference [3,4,8,9,10,11,12]
Risk factors for seizures and epilepsy
Risk factor Comments
Alcohol withdrawal
  • Alcohol withdrawal may precipitate seizures
  • Seizures will typically occur within 7 - 48 hours of the last drink
Benzodiazepine and barbiturate withdrawal
  • Withdrawal seizures may occur within days to weeks depending on the half-life of the drug
  • Gradual tapering of the drug can help prevent withdrawal seizures
Brain masses
  • Brain masses may cause seizures and epilepsy
Central nervous system (CNS) infections
  • CNS infections increase the risk of seizures
Cerebral hypoxia
  • Cerebral hypoxia may precipitate seizures
Family history
  • Certain epilepsy syndromes are inherited
  • Examples include generalized epilepsy with febrile seizures plus, benign familial neonatal convulsions, autosomal dominant nocturnal frontal-lobe epilepsy, childhood absence epilepsy and febrile seizures, autosomal dominant partial epilepsy with auditory features
Febrile seizures
  • The risk of epilepsy is increased in children with a history of febrile seizures
  • See febrile seizures for more
Head trauma
  • Head trauma increases the risk of epilepsy
  • Approximately 9% of new-onset epilepsy in adults is secondary to head trauma
Nocturnal seizure
  • Patients who experience a nocturnal seizure are at higher risk for seizure recurrence
Hyperglycemia associated with ketoacidosis
  • Hyperglycemia associated with ketoacidosis may precipitate seizures
Hyperthyroidism
  • Hyperthyroidism may exacerbate epilepsy
Hypocalcemia
  • Severe hypocalcemia may cause seizures
Hypoglycemia
  • Severe hypoglycemia may precipitate seizures
  • The most common cause of severe hypoglycemia is diabetes medications
Hypomagnesemia
  • Severe hypomagnesemia may precipitate seizures
Hyponatremia
  • Sudden decreases in serum sodium levels may precipitate seizures
Illicit drugs
  • Crack cocaine, amphetamines, inhalants
Kidney failure
  • Patients with end-stage kidney disease are at increased risk for seizures
Lupus
  • Neuropsychiatric lupus may cause seizures
Metabolic disorders
  • Metabolic disorders are inborn errors of metabolism resulting from abnormal or absent enzymes
  • Examples include amino acid disorders, pyruvate metabolism disorders, peroxisomal disorders, and mitochondrial diseases
  • Seizures are common in these disorders
Medications
Neurofibromatosis
  • Seizures are more common in patients with neurofibromatosis
Parasitic infections
Porphyria
  • Porphyria is a condition that leads to the overproduction of heme intermediates
  • Seizures may occur in affected patients
Serotonin syndrome
  • Seizures may be seen in serotonin syndrome
Stroke
  • Stroke increases the risk of seizures
  • Following ischemic stroke, the risk of seizure is generally < 10%
  • Following hemorrhagic stroke, the risk of seizure is as high as 16% in the first week
  • Following a subarachnoid hemorrhage, the risk of stroke is as high as 20%
  • Approximately 9% of new-onset epilepsy in adults is secondary to strokes










Status epilepticus general treatment recommendations
  • Stabilize patient (airway, breathing, circulation, oxygenation, etc.)
  • Time seizure from onset
  • Initiate EKG monitoring
  • Check fingerstick blood sugar. If glucose < 60 mg/dl then
    • Adults: 100 mg thiamine IV then 50 ml D50W IV
    • Children ≥ 2 years: 2 ml/kg D25W IV
    • Children < 2 years: 4 ml/kg D12.5W IV
  • Check electrolytes, hematology, toxicology, and anticonvulsant drug levels (if applicable)
First-line medication recommendations (5 - 20 minutes)
Choose ONE of the following:
  • Intramuscular midazolam (10 mg for > 40 kg; 5 mg for 13 - 40 kg; single dose)
  • Intravenous lorazepam (0.1 mg/kg/dose, max 4 mg/dose; may repeat dose once)
  • Intravenous diazepam (0.15 - 0.2 mg/kg/dose, max 10 mg/dose; may repeat dose once)
If the 3 options above are not available, choose ONE of the following:
  • Intravenous phenobarbital (15 mg/kg/dose; single dose)
  • Rectal diazepam (0.2 - 0.5 mg/kg/dose, max 20 mg/dose; single dose)
  • Intranasal midazolam or buccal midazolam
Second-line medication recommendations (20 - 40 minutes)
Choose ONE of the following:
  • Intravenous fosphenytoin (20 mg PE/kg, max 1500 mg PE/dose; single dose)
  • Intravenous valproic acid (40 mg/kg/dose, max 3000 mg/dose; single dose)
  • Intravenous levetiracetam (60 mg/kg/dose, max 4500 mg/dose; single dose)
If the 3 options above are not available, do the following if not given already:
  • Intravenous phenobarbital (15 mg/kg/dose; single dose)
Third-line medication recommendations (40 - 60 minutes)
There is no good evidence to guide therapy in this stage
  • May repeat second-line therapy or anesthetic doses of either thiopental, midazolam, pentobarbital, or propofol (all with continuous EEG monitoring)




Symptoms during seizure (ictal)
Auras
  • Auras are actually focal seizures with awareness. If the focal seizure progresses to a generalized seizure, then the aura will precede the generalized seizure.
  • Examples of auras include the following: auditory (hearing sounds), gustatory (unusual tastes), olfactory (unusual smells), somatosensory (sensations of pressure, pain, tingling, tightness, or warmth), vestibular (dizziness, loss of balance, eye movements), visual (vision changes, hallucinations)
Vocal symptoms
  • gasping, crying out, slurred speech, garbled speech
Motor symptoms
  • Generalized motor seizures - tonic, clonic, atonic, and myoclonic movements; eye deviation
  • Generalized absence seizures - blank stare, upward eye movements, eyelid myoclonus; automatisms (repetitive motor actions such as lip smacking)
  • Focal seizures - tonic, clonic, atonic, and myoclonic movements; automatisms (repetitive motor actions such as picking at clothing, lip smacking, vocalizations, undressing, walking/running)
Respiratory symptoms
  • Change in breathing pattern, cessation of breathing, cyanosis
Autonomic symptoms
  • Pupillary dilation, drooling, change in heart rate, incontinence, pallor, vomiting
Cognition
  • Generalized motor seizures - loss of awareness
  • Generalized absence seizures - loss of awareness
  • Focal seizures - aware, impaired awareness, loss of awareness
Symptoms following a seizure (postictal)
Common symptoms after a seizure include the following:
  • No memory of seizure
  • Confusion
  • Sleepiness
  • Fatigue
  • Headache
  • Sore muscles
  • Nausea and vomiting
  • Tongue biting
  • Transient focal neurologic weakness (Todd's paresis)


Differential diagnosis for seizure-like episodes
Event Clinical features
Vasovagal syncope
  • Loss of consciousness is usually brief (< 20 seconds)
  • Lightheadedness may precede event but not aura
  • Precipitating event is usually identifiable (e.g. standing quickly, prolonged standing, emotional or painful stimuli)
  • Syncope may cause brief, myoclonic twitches of the extremities that can be confused with tonic-clonic movements
Cardiac disorders
  • Cardiac disorders can lead to syncope and loss of consciousness
  • Examples include prolonged QT syndrome, heart block, arrhythmias, aortic stenosis, mitral valve prolapse, and hypertrophic cardiomyopathy
Panic attacks
  • Panic attacks are marked by an intense sense of fear or dread
  • Hyperventilation may lead to orofacial and peripheral paresthesias
  • Shaking, twitching, blurred vision, and nausea may occur
  • Symptoms last longer than a typical seizure (> 5 minutes)
  • There is no loss of consciousness
Migraine headache
  • Migraines that involve the brainstem (basilar migraines) may mimic seizure activity
  • Symptoms of basilar migraine include aura, vertigo, dysarthria, visual changes, and altered level of consciousness
  • Basilar migraines typically cause an occipital headache and last much longer than a seizure (≥ 1 hour)
Non-epileptic attack disorder (Pseudoseizure)
  • Patients typically have other mental health disorders
  • Limb flailing is asynchronous. Pelvic thrusting is common.
  • Incontinence is uncommon
  • Prolactin level may help distinguish from epileptic seizure
Transient ischemic attack (TIA)
  • TIAs may affect ability to speak, vision, and state of awareness
  • Symptoms are usually negative (weakness, sensory deficits) as opposed to positive (tonic-clonic movements, paresthesias)
Drug intoxication or reaction
  • CNS active drugs may cause altered consciousness and other phenomena that mimic seizure symptoms
Transient global amnesia
  • Rare disorder that causes anterograde amnesia (amnesia of recent past)
  • There is no loss of consciousness or motor symptoms. Recurrence is rare.




Epilepsy treatment recommendations
Seizure type NICE recommendation ILAE recommendation
(see ILAE levels for definitions)
Special considerations
Generalized tonic-clonic seizures Recommended therapy (children and adults)
  • First-line: Valproic acid
  • Second-line: Lamotrigine
  • Other: Carbamazepine, oxcarbazepine
  • Be aware of possible teratogenic effects of valproic acid. Lamotrigine may exacerbate myoclonic seizures. Carbamazepine and oxcarbazepine may exacerbate myoclonic and absence seizures.

Adjunctive therapy (add-on therapy)
  • Clobazam, lamotrigine, levetiracetam, valproic acid or topiramate may be added if first-line therapy is ineffective
  • If there are absence or myoclonic seizures, then carbamazepine, gabapentin, oxcarbazepine, phenytoin, pregabalin, tiagabine or vigabatrin should not be used
Adults
  • Level A: None
  • Level B: None
  • Level C: Carbamazepine, Lamotrigine, Oxcarbazepine, Phenobarbital, Phenytoin, Topiramate, Valproic acid
  • Level D: Gabapentin, levetiracetam, vigabatrin

Children
  • Level A: None
  • Level B: None
  • Level C: Carbamazepine, Phenobarbital, Phenytoin, Topiramate, Valproic acid
  • Level D: Oxcarbazepine

  • Use monotherapy when possible. If initial drug fails, monotherapy with another drug may be tried.
  • Combination therapy (adjunctive therapy) should only be used when monotherapy attempts have failed
Focal seizures Recommended therapy (children and adults)
Adjunctive therapy (add-on therapy)
  • Carbamazepine, clobazam, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, valproic acid, or topiramate may be considered for adjunctive treatment
Adults
  • Level A: Carbamazepine, levetiracetam, phenytoin, zonisamide
  • Level B: Valproic acid
  • Level C: Gabapentin, lamotrigine, oxcarbazepine, phenobarbital, topiramate, vigabatrin
  • Level D: Carbamazepine, primidone
Children
  • Level A: Oxcarbazepine
  • Level B: None
  • Level C: Carbamazepine, phenobarbital, phenytoin, topiramate, valproic acid, vigabatrin
  • Level D: Clobazam, clonazepam, lamotrigine, zonisamide

Elderly
  • Level A: Gabapentin, lamotrigine
  • Level B: None
  • Level C: Carbamazepine
  • Level D: Topiramate, valproic acid

  • Use monotherapy when possible. If initial drug fails, monotherapy with another drug may be tried.
  • Combination therapy (adjunctive therapy) should only be used when monotherapy attempts have failed
  • Consider adjunctive therapy if therapy with a second first-line drug is ineffective
Absence seizures Recommended therapy (children and adults)
  • First-line: Ethosuximide, valproic acid
  • Other: Lamotrigine
  • If there is a high risk of generalized tonic-clonic seizures, use valproic acid first. Be aware of possible teratogenic and developmental effects of valproic acid.

Adjunctive therapy (add-on therapy)
  • If monotherapy with two different first-line agents fails, consider a combination of two of these three drugs: ethosuximide, lamotrigine, or sodium valproate
Children
  • Level A: Ethosuximide, valproic acid
  • Level B: None
  • Level C: Lamotrigine
  • Level D: None

  • Use monotherapy when possible. If initial drug fails, monotherapy with another drug may be tried.
  • Combination therapy (adjunctive therapy) should only be used when monotherapy attempts have failed
  • Consider combination therapy if therapy with a second first-line drug is ineffective
Benign epilepsy with centrotemporal spikes Recommended therapy (children and young people)
Adjunctive therapy (add-on therapy)
  • Carbamazepine, clobazam, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, valproic acid or topiramate may be used as adjunctive therapy
Children
  • Level A: None
  • Level B: None
  • Level C: Carbamazepine, valproic acid
  • Level D: Gabapentin, levetiracetam, oxcarbazepine, sulthiame

  • Use monotherapy when possible. If initial drug fails, monotherapy with another drug may be tried.
  • Combination therapy (adjunctive therapy) should only be used when monotherapy attempts have failed
  • Consider combination therapy if therapy with a second first-line drug is ineffective
Juvenile myoclonic epilepsy Recommended therapy (children and adults)
  • First-line: Valproic acid
  • Other: Lamotrigine, levetiracetam, topiramate
  • Be aware of possible teratogenic and developmental effects of valproic acid. Topiramate has a less favorable side effect profile. Lamotrigine may exacerbate myoclonic seizures.

Adjunctive therapy (add-on therapy)
  • Lamotrigine, levetiracetam, valproic acid, or topiramate may be used as adjunctive therapy
Children and adults
  • Level A: None
  • Level B: None
  • Level C: None
  • Level D: Valproic acid, topiramate

  • Use monotherapy when possible. If initial drug fails, monotherapy with another drug may be tried.
  • Combination therapy (adjunctive therapy) should only be used when monotherapy attempts have failed
  • Consider combination therapy if therapy with a second first-line drug is ineffective



Antiepileptic CYP3A4 activity
CYP3A4 inducers CYP3A4 non-inducers

Antiepileptics affected by oral contraceptives

Lab monitoring and antiepileptics
Drug Lab monitoring
Carbamazepine (Tegretol®)
  • Routine drug level monitoring is recommended
  • Periodic LFTs, CBC, and thyroid tests
  • HLA-B*1502 allele testing in some patients
Gabapentin (Neurontin®)
  • No lab monitoring required
Lamotrigine (Lamictal®)
  • The value of routine drug level monitoring has not been established
  • Monitoring may be helpful to evaluate toxicity, adjunctive therapy, therapy that interferes with pharmacokinetics (e.g. oral contraceptives), and dosing adjustments
Levetiracetam (Keppra®)
  • The value of routine drug level monitoring has not been established
  • The primary reasons for therapeutic monitoring are compliance and management of physiological changes
Oxcarbazepine (Trileptal®)
  • The value of routine drug level monitoring has not been established
  • Monitoring may be helpful to evaluate compliance, toxicity, adjunctive therapy, and during pregnancy
Phenobarbital
  • Routine drug level monitoring is recommended
  • LFTs periodically
Phenytoin (Dilantin®)
  • Routine drug level monitoring is recommended
Topiramate (Topamax®)
  • The value of routine blood level monitoring has not been established
  • Baseline and periodic serum bicarbonate levels are recommended
Valproic acid (Depakote®)
  • Routine drug level monitoring is recommended
  • Periodic LFTs, CBC, and coagulation tests




Reference [29]
Epilepsy syndromes where ketogenic diet is probably beneficial
Glucose transporter protein 1 (GLUT-1) deficiency
Pyruvate dehydrogenase deficiency (PDHD)
Myoclonic-astatic epilepsy (Doose syndrome)
Tuberous sclerosis complex
Rett syndrome
Severe myoclonic epilepsy of infancy (Dravet syndrome)
Infantile spasm
Reference [27,28,29]
Types of ketogenic diet
Diet Comments
Classic ketogenic diet
  • Administered as ratio of fat grams to grams of protein + carbohydrate
  • Most common is 4:1 which means 90% of calories will come from fat and 10% from protein and carbohydrate
  • May also be given as 3:1 or 2:1 when more protein is needed for growth
Medium chain triglyceride (MCT) diet
  • MCTs are more ketogenic than long-chain fatty acids. This allows for a lower proportion of fat (30 - 60%) and more protein and carbohydrates.
  • MCTs also do not require carnitine for processing so they may be an option in patients with carnitine deficiency
  • MCT diets appear to be as effective as classic ketogenic diets
  • Side effects of MCTs include abdominal discomfort, diarrhea, and cramping
Modified Atkins diet
  • Similar to the Atkins diet except that it allows fewer carbohydrates
  • Carbohydrates are initiated at 10 grams a day and gradually increased to 15 - 20 grams/day. Fat and protein are not restricted.
  • Diet may achieve better compliance since only carbohydrates are monitored
  • Small, uncontrolled trials have found the diet to be effective
Low glycemic index treatment
  • Diet is based on consuming low glycemic index carbohydrates
  • Patients may consume 40 - 60 grams/day of carbohydrates that have a glycemic index of < 50. Of the remaining calories, 60% should come from fats and 20 - 30% from protein.
  • Small, uncontrolled trials have found the diet to be effective
Ketogenic formulas
  • May be used in infants and children who are enterally-fed
  • Examples include Ketocal® (4:1 and 3:1) and Ross Carbohydrate Free®