SEIZURES AND EPILEPSY

• ACRONYMS AND DEFINITIONS

• AAN - American Academy of Neurology
• ASTMH - American Society of Tropical Medicine and Hygiene
• CBD - Cannabidiol
• EEG - Electroencephalogram
• IDSA - Infectious Disease Society of America
• IED - Interictal epileptiform discharges
• ILAE - International League Against Epilepsy
• LGS - Lennox-Gastaut syndrome
• NICE - National Institute for Health and Care Excellence
• RCT - Randomized controlled trial

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• DEFINITIONS

• 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 the 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 clonic movements

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• EPIDEMIOLOGY

• The lifetime risk of ever having a seizure is 8 - 10% [38]
• The lifetime cumulative risk of developing recurrent unprovoked seizures or epilepsy by the age of 80 years is 1.4 - 3.3%
• For patients who experience a first seizure, approximately 40 - 50% will go on to have another seizure and will meet the criteria for epilepsy [5]
• Approximately 70% of new-onset seizures in adults are focal seizures [3]

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• RISK FACTORS

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	Some classes of medications increase the risk of seizures Examples include antidepressants, tramadol, stimulants, opiate medications, muscle relaxers, methylxanthines, cyclosporine, antipsychotics, and appetite suppressants
Neurofibromatosis	Seizures are more common in patients with neurofibromatosis
Parasitic infections	Neurocysticercosis Falciparum malaria Toxocariasis Onchocerciasis
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

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• SEIZURE TYPES AND PATHOLOGY

• Generalized motor seizures
• Symptoms
• Generalized motor seizures are marked by tonic, clonic, atonic, and myoclonic motor activity
• Generalized motor seizures almost always cause impaired consciousness
• The seizures are described based on the motor movements observed and their sequence (e.g. tonic-clonic, clonic-tonic-clonic, atonic, myoclonic, myoclonic-atonic, etc.)
• Because focal seizure can progress to become generalized motor seizures, it can be difficult to distinguish between the two
• Pathology
• Seizures occur when there is abnormal excessive or synchronous neuronal activity in the brain
• Generalized motor seizures originate at some point within a bilaterally distributed network, and they spread rapidly to involve both brain hemispheres
• The abnormal neuronal activity during generalized seizures is believed to occur secondary to dysfunctional sodium and potassium ion channels present in the cell membrane of neurons
• Sodium channels allow the influx of sodium which causes neuronal depolarization and the propagation of a nerve signal. Dysfunctional sodium channels allow too much sodium to enter the cell and greater depolarization occurs which increases the risk of repetitive bursts.
• Potassium channels allow the efflux of potassium which facilitates neuronal repolarization. Dysfunctional potassium channels do not allow potassium to exit the cell fast enough. This prolongs depolarization and increases neuronal excitability. [11]



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• Generalized absence seizures
• Symptoms
• Absence seizures cause sudden impaired consciousness
• 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
• Motor symptoms are typically absent, although upward eye movement and eyelid myoclonus may be present
• Pathology
• Absence seizures are thought to occur secondary to dysfunctional neurons that relay messages between the thalamus (area of the brain that regulates consciousness and sleep) and the cerebral cortex (area of the brain that processes stimuli and directs thoughts and actions). During an absence seizure, the thalamus relays signals to the cerebral cortex in a rhythmic manner (typically seen in non-REM sleep) as opposed to a tonic manner which is normal during wakefulness. Abnormalities in T-type calcium channels and GABA receptors are thought to play a significant role in the aberrant nerve activity. [11]

• Focal seizures
• Symptoms
• Focal seizures originate in one part of the brain. Symptoms of focal seizures depend on the area of the brain affected. Focal seizures can also spread to involve both hemispheres of the brain in which case they resemble generalized seizures.
• Focal seizures may be motor or nonmotor. Motor symptoms are similar to what is seen in generalized seizures (e.g. tonic, clonic, myoclonic, atonic). If motor symptoms are present, they typically dominate.
• Non-motor symptoms may be sensory (e.g. olfactory or gustatory hallucinations), cognitive (e.g. déjà vu or depersonalization), emotional (e.g. agitation, crying, anger), or autonomic (e.g. gastrointestinal sensations, bradycardia, flushing)
• Patients may be aware during the seizure or they may have impaired awareness and loss of consciousness
• Pathology
• Focal seizures are generally thought to occur secondary to anatomical lesions in the brain. Patients with a history of head trauma or strokes are at an increased risk of focal seizures as are patients with brain masses. Temporal lobe epilepsy is the most common focal seizure disorder, and it is thought to occur secondary to hippocampal sclerosis. [11]

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• FEBRILE SEIZURES

• Prevalence
• Febrile seizures affect 2 - 5% of children and are the most common type of seizures in children less than 5 years of age [13,14]

• Definitions
• Febrile seizure - generalized seizure that occurs in a child 6 months to 5 years old with a temperature ≥ 100.4°F (38°C) who does not have a central nervous system infection
• Simple febrile seizure - a febrile seizure that lasts less than 15 minutes and does not recur within 24 hours
• Complex febrile seizure - a febrile seizure that lasts ≥ 15 minutes and/or recurs within 24 hours [13,14]

Simple febrile seizures
Workup Overview Simple febrile seizures have a generally benign and favorable prognosis The American Academy of Pediatrics makes the following recommendations for diagnostic testing in simple febrile seizures Lumbar puncture A lumbar puncture should be performed in a child with a seizure and fever who has meningeal signs and symptoms (e.g. neck stiffness, Kernig sign and/or Brudzinski sign) Lumbar puncture is an option in infants 6 - 12 months old with fever and seizure who are deficient in Haemophilus influenzae type b (Hib) or Streptococcus pneumoniae immunizations (or when immunizations cannot be confirmed) Lumbar puncture is an option in children with a seizure and fever who were pretreated with antibiotics because antibiotics may mask meningeal signs EEG EEG should not be performed in neurologically healthy children with simple febrile seizures Laboratories The following labs should not be performed routinely for identifying the cause of a simple febrile seizure: serum electrolytes, calcium, phosphorus, magnesium, blood glucose, complete blood cell count The incidence of bacteremia is the same in children < 24 months with or without febrile seizures; therefore, febrile seizures are not a marker of bacteremia Neuroimaging Neuroimaging should not be performed in the routine evaluation of children with simple febrile seizure [14]
Treatment Overview Most simple febrile seizures cease within 2 - 3 minutes For seizures that last longer than 2 - 3 minutes, treatment is recommended if available Diazepam Hospital setting: 0.5 mg/kg IV bolus at a maximum infusion speed of 5 mg/min. May repeat in 10 minutes if necessary. Home setting: 0.3 - 0.5 mg/kg rectally. It takes ∼ 3 minutes for therapeutic concentrations to reach the brain with the rectal route. See Diastat for more on dosing. [13] Other recommendations during seizures Loosen child's clothing, especially around the neck If the child is unconscious, place the child in the lateral decubitus position (lying on one' side), to avoid inhalation of saliva or vomitus Do not force opening of the mouth Observe the type and duration of the seizure Do not give any drugs or fluids orally [13] Antipyretics In trials, antipyretics have generally not been found to prevent febrile seizure recurrence, but they are still recommended for comfort measures [13] A study published in 2018 that compared rectal acetaminophen to no treatment after a febrile seizure and during the same febrile episode found that acetaminophen significantly reduced seizure recurrence [PMID 30297499]
Recurrence After a simple febrile seizure, the general risk of recurrence is 30 - 40% Maintenance therapy with anticonvulsants to prevent recurrence is generally not recommended In rare cases where febrile seizures are frequent (≥ 3 in 6 months) or severe (≥ 15 minutes long), rectal or oral diazepam at a dose of 0.3 - 0.5 mg/kg may be considered at the start of a fever and repeated in 8 hours if fever persists. 98% of febrile seizures occur within the first 24 hours of the onset of a fever. In extreme cases, prophylactic phenobarbital or valproic acid may be considered. [13] Risk factors for recurrence include the following: Age of onset < 15 months Epilepsy in a first-degree relative Febrile seizures in a first-degree relative Frequent febrile illness Low temperature at the onset of febrile seizure Risk of recurrence according to risk factors: No risk factors - 10% One to two risk factors - 25 - 50% ≥ 3 risk factors - 50 - 100% [13]
Epilepsy risk The risk of developing epilepsy after a simple febrile seizure is 1 - 1.5% which is slightly higher than the risk in the general population (∼ 0.5%) [13]

• Complex febrile seizures
• Workup
• Unlike simple febrile seizures, complex febrile seizure may be associated with a serious underlying etiology
• Lab work, EEG, neuroimaging, and hospital admission for observation are all recommended following a complex febrile seizure. Lumbar puncture should be performed if CNS infection is suspected.
• Treatment
• The treatment of complex febrile seizures depends on the underlying etiology
• In some cases, complex febrile seizures may simply be a prolonged febrile seizure, but other etiologies should be ruled out
• Risk of epilepsy
• The risk of developing epilepsy after a complex febrile seizure is approximately 4 - 15% [13]

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• STATUS EPILEPTICUS

• Definition
• Brief seizure - seizure lasting less than 5 minutes
• Prolonged seizure - seizure lasting 5 - 30 minutes
• Status epilepticus - a continuous seizure lasting > 30 minutes or two or more sequential seizures lasting > 30 minutes without full recovery of consciousness between seizures. Status epilepticus may be caused by repeated generalized tonic-clonic seizures, repeated non-motor seizures with confusion and amnesia, or repeated partial seizures without altered awareness. [16]

• Prevalence
• Status epilepticus occurs in 50,000 - 150,000 Americans each year
• Mortality from status epilepticus in children is estimated to be < 3%. In adults, mortality can be as high as 30%.

• Treatment
• The treatment of status epilepticus varies depending on the setting and resources
• Most seizures last less than 5 minutes, and seizures lasting greater than 5 minutes are likely to be prolonged. Because of this, it is recommended that treatment for status epilepticus begin after a seizure has lasted more than 5 minutes. Starting treatment after 5 minutes may prevent the adverse outcomes associated with status epilepticus.
• Treatment recommendations from the American Epilepsy Society are summarized below

• PE - phenytoin sodium equivalents
• Reference [16]

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)
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)
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)

• Studies
• Levetiracetam vs Fosphenytoin vs Valproate for Status Epilepticus in Children and Adults, Lancet (2020) [PubMed abstract]
• Levetiracetam vs Phenytoin for Second-Line Treatment of Pediatric Status Epilepticus, Lancet (2019) [PubMed abstract]
• Levetiracetam vs Phenytoin for Second-Line Treatment of Status Epilepticus in Children, Lancet (2019) [PubMed abstract]
• Levetiracetam vs Fosphenytoin vs Valproate for Status Epilepticus in Children and Adults, NEJM (2019) [PubMed abstract]

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• DIAGNOSIS

• Symptoms
• Seizure symptoms depend on the seizure type. In many cases, the patient will have no memory of the event. Obtaining an accurate description of the event often depends on a witness account.
• Most seizures last less than 5 minutes. Important seizure symptoms and history elements are presented in the table below.

• Reference [6,13]

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)

• Imaging
• Recommendations for imaging in seizure disorders vary slightly by organization
• The American Academy of Neurology recommends that all patients with a first unprovoked seizure have brain imaging with either a CT scan or MRI
• The 2016 NICE Guidelines recommend that an MRI be performed in all patients with epilepsy
• In studies, brain imaging has a yield of around 10% for significant findings which may include tumor, stroke, neurocysticercosis, and other structural lesions
• CT scans are often performed in ER settings because of convenience. MRIs are more sensitive for structural abnormalities and may be preferred in certain cases. [1,5]
• The 2016 NICE Guidelines state that MRI is preferred in the following patients:
• Patients who develop epilepsy before the age of 2 years or in adulthood
• Patients who have any suggestion of a focal onset in their history, examination, or EEG
• Patients who continue to have seizures while taking first-line antiepileptic medications [1]

Electroencephalogram (EEG)
Overview An EEG is a study that measures voltage changes across the brain that occur when neurons fire In a typical EEG, 10 - 20 electrodes are placed across the scalp. Readings from electrodes are expressed as channels. A channel is the difference in voltage between a single electrode and a reference electrode. The reference electrode can vary depending on the type of EEG and may consist of a single electrode or the average voltage from a collection of electrodes. The typical EEG recording lasts 30 - 45 minutes, although longer EEGs may be performed [6,15]
Indications AAN recommendations The American Academy of Neurology states that a routine EEG should be considered part of the workup for a first unprovoked seizure because it has substantial yield and can help determine the risk of recurrent seizure The 2016 NICE Clinical Guidelines make the following recommendations for EEGs: An EEG should only be performed to support the diagnosis of epilepsy in patients where the clinical history suggests that the seizure is likely to be of epileptic origin EEGs should not be performed in cases of probable syncope because of the possibility of false-positive results EEGs should not be used to exclude the diagnosis of epilepsy (50% of patients with a clinical seizure will have a normal EEG) EEGs should not be used in isolation to make the diagnosis of epilepsy After a first unprovoked seizure, EEGs can be used to predict risk of seizure recurrence (see Prognostic value of EEG below) Sleep and sleep-deprived EEGs are preferred when standard EEGs have not been diagnostic [1,6]
Prognostic value In seizure disorders, EEGs are obtained to look for abnormalities called interictal epileptiform discharges (IED). IEDs are sudden voltage changes that last milliseconds and are not part of the brain's normal background activity. IEDs are described morphologically as spikes, sharp waves, and spike-wave discharges. EEGs can have limited sensitivity and specificity for epilepsy. Below is some data from studies on the prognostic value of EEGs. [4,6] Prognostic value of EEG EEGs are normal in 50% of individuals with a clinical diagnosis of seizure Patients with a first seizure and IEDs on EEG have a 55% risk of recurrent seizure within 60 months Patients with a first seizure and a normal EEG have a 27% risk of recurrent seizure [6] Measures that can increase the yield of EEGs Sleep and sleep deprivation both increase the occurrence of IEDs Longer EEGs and/or repeated recordings have a higher yield EEGs recorded closer to a seizure event have a higher yield Hyperventilation and photic stimulation (flashing lights) can increase the occurrence of IEDs [4,6,15]

• Prolactin
• The hypothalamus modulates prolactin release from the pituitary through an inhibitory mechanism that is mediated through the neurotransmitter dopamine
• Seizure activity appears to alter hypothalamic inhibition of prolactin release causing elevated prolactin levels. Because of this, prolactin levels have been studied as a possible marker of seizure activity.
• The AAN issued recommendations for using prolactin levels in the diagnosis of seizure disorders in 2006. Important points from those recommendations are presented below.
• AAN recommendations on using prolactin levels in diagnosing epileptic seizures are as follows:
• Prolactin levels may be used to differentiate generalized tonic-clonic seizures and focal seizures with impaired awareness from psychogenic nonepileptic seizures
• Prolactin levels should be measured within 10 - 20 minutes after an event
• Prolactin levels typically return to baseline ≥ 6 hours after an event
• The cutoff for an elevated prolactin level in studies has typically been 2 X the baseline level. Levels > 36 ng/ml have also been used.
• Syncopal events may also cause an elevation of prolactin levels; therefore, prolactin levels cannot be used to distinguish syncope from seizures
• Prolactin levels have a high specificity and low sensitivity. This means positive values are useful (low false-positives) but negative values are not (high false-negatives).
• The sensitivity and specificity of prolactin levels measured within 10 - 20 minutes after an event are as follows:
• Generalized tonic-clonic seizures: Sensitivity 60%; Specificity 96%
• Focal seizures with impaired awareness: Sensitivity 46%; Specificity 96% [17]

• References [1,3]

Differential diagnosis for seizure-like episodes
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 See syncope for more
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.

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• FIRST UNPROVOKED SEIZURE

• Overview
• The American Academy of Neurology issued recommendations for the management of a first unprovoked seizure in 2015
• The NICE Clinical Guidelines also make recommendations regarding treatment of first unprovoked seizures


• The AAN recommends the following when managing a first unprovoked seizure
• See imaging and EEG above for recommendations on working up a first unprovoked seizure
• For patients with a first unprovoked seizure that is untreated, the risk of recurrence is approximately 26% at 6 months, 39% at 2 years, and 51% at 5 years [18]
• Factors that increase the risk of a recurrent seizure include the following: prior brain insult (e.g. trauma, stroke), abnormal EEG, abnormal brain imaging, and seizure while sleeping
• Immediate drug therapy reduces the absolute risk of seizure recurrence by about 35% within the following 2 years
• Immediate drug therapy does not alter the long-term (> 3 years) risk of seizure recurrence
• The risk of side effects from seizure medications is 7 - 31%. Side effects are generally mild and reversible.
• Based on these factors, the physician and patient should make an informed decision on whether or not to treat a first unprovoked seizure [6]


• NICE Clinical Guidelines for a first unprovoked seizure
• Drug treatment is generally recommended after a second epileptic seizure
• Drug therapy after a first seizure may be considered in the following circumstances:
• Patients with neurologic deficits
• EEG shows unequivocal epileptic activity
• Risk of recurrent seizure is unacceptably high
• Brain imaging shows structural abnormality [1]

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• TREATMENT | Anticonvulsants

• Overview
• The National Institute for Health and Care Excellence (NICE) is the only major professional organization that publishes treatment recommendations for seizures
• The International League Against Epilepsy (ILAE) published a review of antiepileptic drug efficacy in 2013
• The table below combines recommendations from NICE and ILAE for the more common seizure disorders
• In general, 60 - 70% of patients achieve seizure control with antiepileptic medications [4]

• References [1,19]

Generalized tonic-clonic seizures
NICE recommendations (children and adults) First-line: valproic acid Second-line: lamotrigine Other: carbamazepine, oxcarbazepine 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 Be aware of possible teratogenic effects of valproic acid. Lamotrigine may exacerbate myoclonic seizures. Carbamazepine and oxcarbazepine may exacerbate myoclonic and absence seizures. NOTE: A study published in 2021 found that valproate was superior to levetiracetam as initial therapy for generalized seizure disorders in children and adults [PMID 33838758] ILAE recommendations (ILAE levels) 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 Special considerations Pregnancy/breastfeeding Contraceptive recommendations Lab monitoring 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
NICE recommendations (children and adults) First-line: carbamazepine, lamotrigine Other: levetiracetam, oxcarbazepine, valproic acid Adjunctive therapy (add-on therapy): Carbamazepine, clobazam, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, valproic acid, or topiramate may be considered for adjunctive treatment Be aware of possible teratogenic and developmental effects of valproic acid. NOTE: A study published in 2021 found that lamotrigine was superior to levetiracetam and zonisamide as initial therapy for focal seizure disorders in children and adults [PMID 33838757] ILAE recommendations (ILAE levels) 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 Special considerations Pregnancy/breastfeeding Contraceptive recommendations Lab monitoring 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
NICE recommendations (children and adults) First-line: ethosuximide, valproic acid Other: Lamotrigine 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 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. ILAE recommendations (ILAE levels) Children Level A: Ethosuximide, valproic acid Level B: None Level C: Lamotrigine Level D: None Special considerations Pregnancy/breastfeeding Contraceptive recommendations Lab monitoring 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
NICE recommendations (children and adults) First-line: carbamazepine, lamotrigine Other: levetiracetam, oxcarbazepine, valproic acid Adjunctive therapy (add-on therapy): Carbamazepine, clobazam, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, valproic acid or topiramate may be used as adjunctive therapy Be aware of possible teratogenic and developmental effects of valproic acid. Carbamazepine and oxcarbazepine may exacerbate or unmask continuous spike and wave during slow sleep. ILAE recommendations (ILAE levels) Children Level A: None Level B: None Level C: Carbamazepine, valproic acid Level D: Gabapentin, levetiracetam, oxcarbazepine, sulthiame Special considerations Pregnancy/breastfeeding Contraceptive recommendations Lab monitoring 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
NICE recommendations (children and adults) First-line: valproic acid Other: lamotrigine, levetiracetam, topiramate Adjunctive therapy (add-on therapy): Lamotrigine, levetiracetam, valproic acid, or topiramate may be used as adjunctive therapy Be aware of possible teratogenic and developmental effects of valproic acid. Topiramate has a less favorable side effect profile. Lamotrigine may exacerbate myoclonic seizures. ILAE recommendations (ILAE levels) Children and adults Level A: None Level B: None Level C: None Level D: Valproic acid, topiramate Special considerations Pregnancy/breastfeeding Contraceptive recommendations Lab monitoring 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

• ILAE level definitions:
• Level A - drug has been established as effective as initial monotherapy
• Level B - drug is probably effective as initial monotherapy
• Level C - drug is possibly effective as initial monotherapy
• Level D - drug is potentially effective as initial monotherapy [19]

Pregnancy/breastfeeding recommendations
Carbamazepine (Tegretol®) Pregnancy: Carbamazepine probably does not substantially increase the risk of birth defects or developmental delay [20] Breastfeeding: Carbamazepine is found in breast milk. Most infants have had no adverse reactions, but sedation, poor sucking, withdrawal reactions and 3 cases of hepatic dysfunction have been reported [21]
Lamotrigine (Lamictal®) Pregnancy: There is insufficient evidence to determine if lamotrigine increases the risk of birth defects or developmental delay [20] Breastfeeding: Lamotrigine is found in breast milk. Many infants have had no adverse reactions, but breastfed infants should be carefully monitored for side effects such as apnea, rash, drowsiness or poor sucking, including measurement of serum levels to rule out toxicity if there is a concern [21]
Levetiracetam (Keppra®) Pregnancy: There is insufficient evidence to determine if levetiracetam increases the risk of birth defects or developmental delay [22] Breastfeeding: Maternal doses of levetiracetam up to 3500 mg daily produce low levels in milk and would not be expected to cause any adverse effects in breastfed infants, especially if the infant is older than 2 months [21]
Oxcarbazepine (Trileptal®) Pregnancy: There is insufficient evidence to determine if oxcarbazepine increases the risk of birth defects or developmental delay [22] Breastfeeding: Oxcarbazepine has been found in breast milk. Limited information indicates that oxcarbazepine would not be expected to cause any adverse effects in breastfed infants, especially if the infant is older than 2 months [21]
Phenytoin (Dilantin®) Pregnancy: Phenytoin may increase the risk of cleft palate and developmental delay [20] Breastfeeding: Because of the low levels of phenytoin in breastmilk, amounts ingested by the infant are small and usually cause no difficulties in breastfed infants when used alone except for rare idiosyncratic reactions. [21]
Topiramate (Topamax®) Pregnancy: Topiramate has been linked to an increased risk for cleft lips/palates and should be avoided during pregnancy if possible [22] Breastfeeding: Topiramate does appear to enter breast milk. Monitor the infant for diarrhea, drowsiness, irritability, adequate weight gain, and developmental milestones, especially in younger, exclusively breastfed infants and when using combinations of anticonvulsant or psychotropic drugs. [21]
Valproic acid (Depakote®) Pregnancy: Valproic acid has been linked to an increased risk of birth defects and developmental delay and should be avoided during pregnancy if possible [20] Breastfeeding: Because of the low levels of valproic acid in breastmilk and infant serum, no definite adverse reactions to valproic acid during breastfeeding have been reported. [21]

• Use with oral contraceptives
• A number of antiepileptic medications are CYP3A4 enzyme inducers and may decrease the effectiveness of combined oral contraceptives (OCPs)
• In general, pregnancy rates are still very low in women who take enzyme-inducing antiepileptics with OCPs. OCPs with a higher estrogen dose (ethinyl estradiol 0.035 - 0.050 mg) may be more effective when taken with enzyme-inducing antiepileptics (see OCP drug interactions for more) [23]
• Conversely, OCPs have been shown to reduce lamotrigine levels by as much as 50%, and they may also decrease valproic acid levels. When OCPs are combined with these antiepileptics, blood levels should be monitored closely.
• The NICE Clinical Guidelines also state that progestin-only pills and the progestin implant (Implanon®) are not recommended in women who are taking enzyme-inducing antiepileptics
• Enzyme-inducing and non-inducing antiepileptics are listed below
• CYP3A4 inducers
• Phenytoin (Dilantin®)
• Carbamazepine (Tegretol®)
• Phenobarbital
• Topiramate (Topamax®)
• Oxcarbazepine (Trileptal®)
• Felbamate (Felbatol®)
• CYP3A4 non-inducers
• Valproic acid (Depakote®)
• Ethosuximide (Zarontin®)
• Gabapentin (Neurontin®)
• Lamotrigine (Lamictal®)
• Tiagabine (Gabitril®)
• Zonisamide (Zonegran®)
• Levetiracetam (Keppra®)
• Vigabatrin (Sabril®)
• Antiepileptics affected by oral contraceptives
• Valproic acid (Depakote®) - OCPs may reduce valproic acid levels
• Lamotrigine (Lamictal®) - OCPs have been shown to reduce lamictal levels by as much as 50%

• Antiepileptics and lab monitoring
• Some antiepileptics require lab monitoring while others do not
• Lab monitoring raises the cost of treatment and requires increased patient compliance. These factors can affect drug choice.
• The table below details which antiepileptics require lab monitoring and which ones do not
• See seizure medication reference for specific recommendations on lab monitoring for each drug

• References [22,24,25]

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

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• TREATMENT | Cannabis (cannabidiol)

• Overview
• Cannabis has been used since 1800 BC to treat epilepsy. In recent years, anecdotal stories of remarkable seizure control in patients with refractory epilepsy who were treated with cannabis have renewed interest in this ancient treatment.
• Cannabinoids are a family of chemicals found in cannabis. Several cannabinoids are believed to have antiseizure activity. The two most studied are Δ⁹-Tetrahydrocannabinol (Δ⁹-THC) and cannabidiol (also referred to as CBD oil). The exact mechanism by which cannabinoids might inhibit seizure activity is not completely understood. Both Δ⁹-THC and cannabidiol have various agonist/antagonist activities at a number of receptors including cannabinoid receptor 1 (CBR₁), transient receptor potential cation channel (TRPV1-3), peroxisome proliferator-activated receptor gamma (PPAR-γ), and serotonin receptors. Cannabidiol does not have psychoactive properties while Δ⁹-THC does.
• A number of studies have now found cannabidiol to be effective in the treatment of several types of seizure syndromes. The first placebo-controlled trial to evaluate cannabidiol in treating seizures is detailed below, and two other studies are summarized below it.
• In 2018, the FDA approved Epidiolex® (99% cannabidiol and less than 0.10% Δ⁹-THC) for the treatment of seizures associated with Lennox-Gastaut syndrome and Dravet syndrome. In 2020, it was approved for use in seizures associated with tuberous sclerosis complex. [33,34]

• STUDY
  Cannabidiol vs Placebo in Lennox-Gastaut syndrome, Lancet (2018) [PubMed abstract]
• Design: Randomized, placebo-controlled trial (N=171, length = 14 weeks) in patients with treatment-resistant Lennox-Gastaut syndrome
• Treatment: Cannabidiol 20 mg/kg daily vs Placebo added on to regular seizure meds
• Primary outcome: Percentage change from baseline in monthly frequency of drop seizures
• Results:
• Primary outcome (median % decrease): Cannabidiol - 44%, Placebo - 22% (p=0.0135)
• Findings: Add-on cannabidiol is efficacious for the treatment of patients with drop seizures associated with Lennox-Gastaut syndrome and is generally well tolerated. The long-term efficacy and safety of cannabidiol is currently being assessed in the open-label extension of this trial.

• STUDY
  Cannabidiol vs Placebo in Lennox-Gastaut syndrome, NEJM (2018) [PubMed abstract]
• Design: Randomized, placebo-controlled trial (N=225, length = 14 weeks) in patients with treatment-resistant Lennox-Gastaut syndrome
• Treatment: Cannabidiol 10 or 20 mg/kg daily vs Placebo added on to regular seizure meds
• Primary outcome: Percentage change from baseline in monthly frequency of drop seizures
• Results:
• Primary outcome (median % decrease): Cannabidiol 10 mg/kg - 37%, Cannabidiol 20 mg/kg - 42%, Placebo - 17% (p<0.05 for both comparisons)
• Findings: Among children and adults with the Lennox-Gastaut syndrome, the addition of cannabidiol at a dose of 10 mg or 20 mg per kilogram per day to a conventional antiepileptic regimen resulted in greater reductions in the frequency of drop seizures than placebo. Adverse events with cannabidiol included elevated liver aminotransferase concentrations.

• Summary
• Cannabidiol is effective in reducing seizure frequency in patients with Dravet syndrome and Lennox-Gastaut syndrome
• The drug has significant side effects, but the tradeoff in seizure control will likely be worth it for most of these patients

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• KETOGENIC DIET

• Overview
• A ketogenic diet is high in fat and low in carbohydrates, causing cellular metabolism to shift from glycolysis to fatty acid oxidation that produces ketone bodies. Ketogenic diets have been used for 100 years to treat childhood epilepsy. [27]

• Mechanism of action
• The mechanism by which a ketogenic diet reduces seizure activity is not completely understood
• Proposed theories include the following:
• Ketone bodies have anticonvulsant activity
• Indirect enhancement of GABA-mediated inhibition
• Increase in noradrenergic tone which inhibits seizure activity
• Increase in polyunsaturated fatty acids (PUFA) which may inhibit sodium and calcium channels while activating potassium channels
• Increase in cerebral energy reserve which stabilizes neurons and/or causes membrane hyperpolarization
• Ketone bodies and PUFAs decrease oxidative stress and are neuroprotective [26]

• Children
• In trials, ketogenic diets have generally been found to be effective in children, with seizure reductions of > 50% in half of patients and > 90% in a third. The seizure types listed below appear to be more responsive than others.
• 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 [29]

• Adults
• Ketogenic diets are less studied in adults, but small studies have found them to be effective in this population. A review that analyzed trials in adults and adolescents with refractory seizures found that 43% of patients achieved ≥ 50% seizure reduction on a ketogenic diet; of these responders, 12% became seizure-free. Seizure type did not appear to affect efficacy, although patients with generalized epilepsy or multiple seizure types may respond better. [PMID 22004525] A randomized trial published in 2023 found that the Modified Atkins diet was beneficial in persons aged 10 to 55 (see ketogenic diet in adolescents and adults below). [30]

• Contraindications
• The ketogenic diet is contraindicated in patients who have disorders of fatty acid transport and oxidation. It is also contraindicated in patients with porphyria.
• Disorders of fatty acid transport and oxidation include carnitine deficiency, carnitine palmitoyltransferase (CPT) I or II deficiency, carnitine translocase deficiency, β-oxidation defects, and pyruvate carboxylase deficiency.
• Patients with clinical signs of these disorders should be screened before starting the diet. Clinical signs include developmental delay, cardiomyopathy, hypotonia, exercise intolerance, myoglobinuria, and easy fatigability. [29]

• Ketogenic diet types
• Different types of ketogenic diets are described in the table below. In all types, daily caloric requirements are calculated based on activity, growth requirements, and current weight. Because high-fat diets are often low in certain essential nutrients, it is recommended that all patients on a ketogenic diet receive a multivitamin with minerals and a calcium + vitamin D supplement.
• A study that compared the classic ketogenic diet to the modified Atkins diet and the low glycemic index diet in children is detailed below - diet therapies in drug-resistant epilepsy

Reference [27,28,29]

Ketogenic diet types
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®

• STUDY
  Ketogenic Diet vs Modified Atkins Diet vs Low Glycemic Index Diet in Children with Drug-Resistant Epilepsy, JAMA Pediatrics (2020) [PubMed abstract]
• Design: Randomized controlled trial (N=170 | length = 24 weeks) in children aged 1 - 15 years with ≥ 4 seizures in the last month who had not responded to 2 or more antiseizure drugs
• Treatment: Ketogenic diet vs Modified Atkins diet vs Low glycemic index diet
• Primary outcome: Median percentage change in seizure frequency after 24 weeks of dietary therapy
• Results:
• Primary outcome (percent decrease): Ketogenic diet - 66%, Modified Atkins - 45%, Low glycemic index - 54%
• The Ketogenic diet was significantly better than the Modified Atkins but not the Low glycemic index
• Findings: Neither the modified Atkins nor the low glycemic index diet met the noninferiority criteria. However, the results of this study for the low glycemic index diet showed a balance between seizure reduction and relatively fewer adverse events compared with the ketogenic diet and modified Atkins diet. These potential benefits suggest that the risk-benefit decision with regard to the 3 diet interventions needs to be individualized.

• STUDY
  Modified Atkins Diet vs Normal Diet for Drug-Resistant Epilepsy in Adolescents and Adults, Neurology (2023) [PubMed abstract]
• Design: Randomized controlled trial (N=160 | length = 6 months) in patients aged 10 - 55 with drug-resistant epilepsy, defined as two seizures/month despite using ≥ 3 appropriate anti-seizure medications at maximum tolerated doses
• Treatment: Modified Atkins diet vs Normal diet. Patients continued their medications without changes during the trial.
• Primary outcome: Greater than 50% reduction in seizure frequency
• Results:
• Primary outcome (intention-to-treat analysis): Modified Atkins diet - 26.2%, Normal diet - 2.5% (p<0.001)
• Primary outcome (per-protocol analysis): Modified Atkins diet - 45.7%, Normal diet - 3.2%
• Findings: Modified Atkins diet group demonstrated improvement in all aspects (reduction in seizure-frequency, and behavioural problems) compared to control group at the end of the study. Modified Atkins diet is an effective modality in controlling seizures, further research is required to assess its efficacy in terms of biomarkers along with descriptive metabolomics studies.

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• OTHER TREATMENTS

• Surgery
• Patients who do not gain seizure control after trying 3 antiepileptics may be candidates for brain surgery
• The most common type of epilepsy that is amenable to surgery is mesial temporal-lobe epilepsy that is marked by focal seizures with loss of awareness
• In appropriate patients, temporal lobe resection has a 60 - 70% chance of rendering the patient seizure-free
• The most common lesion found in surgical resections from patients with mesial temporal-lobe epilepsy is hippocampal sclerosis [4,11]
• A study published in the NEJM in 2017 compared brain surgery to medical therapy in children with drug-resistant epilepsy. At 12 months, 77% of the surgery-treated patients were seizure-free compared to 7% in the medical therapy group. [PMID 29069568]
• The table below shows the most common lesions found in patients with drug-resistant focal epilepsy

• Specimens from 9523 patients (6900 adults, 2623 children) who underwent epilepsy surgery
• Reference [39]

Lesions found in brain specimens in patients with drug-resistant epilepsy
Lesion	Proportion of specimens
Hippocampal sclerosis	36.4%
Ganglioglioma	10.4%
Focal cortical dysplasia type II	9%
No lesion	7.7%
Dysembryoplastic neuroepithelial tumor	5.9%
Glial scar	4.8%
Cavernous angioma	4.5%

• Vagal nerve stimulator
• A vagal nerve stimulator is a device that is used to treat refractory seizures
• The left vagus nerve carries information from the heart, lungs, pharynx, larynx, and gastrointestinal tract to the central nervous system. The right vagus nerve carries information from the central nervous system to the heart. Intermittent stimulation of the left vagus nerve has been shown to reduce seizure frequency in patients with refractory seizures.
• A vagal nerve stimulator consists of a generator that is implanted in the anterior chest wall. The generator has a lead wire that is coursed under the skin and wrapped around the left vagus nerve in the neck. The generator delivers intermittent electrical stimulation to the nerve. [Vagus nerve stimulator illustration]
• Vagal nerve stimulation has been shown to reduce seizure frequency by > 50% in 55% of children with focal or generalized epilepsy including Lennox-Gastaut syndrome. It may also be used in adults with refractory seizures that are not suitable for resective surgery. [31,32]

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• DRIVING RECOMMENDATIONS

• After a seizure, a patient should not drive until they have been seizure-free for a certain amount of time
• Most developed countries and regions have laws that govern driving privileges in patients with seizures/epilepsy. There are also laws that pertain to physician reporting of patient seizure disorders.
• In the U.S., the laws vary by state. The Epilepsy Foundation has created a webpage that details the laws for each state.
• Seizure/epilepsy driving laws by state (Epilepsy Foundation)

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• STOPPING TREATMENT

• Overview
• After a patient has been seizure-free on antiepileptics for a period of time, the question often arises as to whether therapy can be stopped
• The 2016 NICE Clinical Guidelines makes several recommendations for stopping therapy. It also provides a table that can help predict the future risk of seizures based on a patient's response to initial therapy, seizure type, length of time since last seizure, and recent EEG results.
• A study published in Lancet Neurology in 2017 looked at the long-term risk of seizures after stopping antiepileptics. Information from the study was used to formulate a risk prediction tool that is available on a website. The tool predicts the 2-, 5-, and 10-year risk of seizure recurrence in patients stopping antiepileptics based on individual factors. The tool is available at the link below


• NICE recommendations for stopping therapy
• Risks and benefits of stopping therapy should be fully understood by all parties involved (patient, caregiver, doctor)
• Patient should be seizure-free for at least 2 years
• Antiepileptic drug(s) should be tapered slowly over 2 - 3 months
• Benzodiazepines and barbiturates should be tapered over a longer period (up to 6 months or more)
• The future risk of seizure for adults can be predicted from the following table - NICE seizure remission prognosis tables


• Seizure recurrence risk prediction tool based on Lancet Neurology study
• Antiepileptic withdrawal risk calculator

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• NEUROCYSTICERCOSIS

• Overview
• Neurocysticercosis is an infection of the brain caused by the tapeworm Taenia solium. It is the most common cause of preventable epilepsy in developing nations, affecting an estimated 2 million people worldwide. T solium infection is acquired when people consume food contaminated with feces from individuals with intestinal T solium. Once ingested, T solium eggs release larvae that migrate to the brain and form cysts in parenchymal tissue. The larvae progress through four different stages described below. Live larvae are only present in the vesicular and colloidal stages, making them the only two stages amenable to treatment with anthelmintics. Most cysts are asymptomatic, but some elicit an inflammatory response that causes seizures years after the initial exposure. [37]
• Vesicular stage - contains live larvae
• Colloidal stage - larvae degenerates
• Granular-nodular stage - cyst membrane thickens
• Calcification stage - cyst calcifies

• IDSA/ASTMH 2017 neurocysticercosis treatment recommendations
• Patients with hydrocephalus or diffuse cerebral edema
• Antiparasitic therapy is not recommended. Treat with corticosteroids and surgery as indicated.


• Viable intraparenchymal neurocysticercosis in patients without elevated intracranial pressure
• 1 - 2 viable parenchymal cysticerci: albendazole 15 mg/kg/day (max 1200 mg/day) divided into 2 daily doses for 10 – 14 days with food
• > 2 viable parenchymal cysticerci: albendazole 15 mg/kg/day (max 1200 mg/day) divided into 2 daily doses for 10 – 14 days with food + praziquantel 50 mg/kg/day for 10 – 14 days
• Retreatment: retreat for parenchymal cystic lesions persisting for 6 months after the end of the initial course of therapy
• Corticosteroids: all patients should receive adjunctive corticosteroid therapy begun prior to antiparasitic drugs
• Patients with seizures: antiepileptics are recommended. In patients with few seizures prior to antiparasitic therapy, resolution of the cystic lesion on imaging studies, and no seizures for 24 consecutive months, tapering and stopping antiepileptics may be considered.
• Monitoring: repeat MRI at least every 6 months until resolution of the cystic component


• Degenerating intraparenchymal neurocysticercosis
• ≥ 2 enhancing lesions: same treatment as viable lesions (see above)
• 1 enhancing lesion: albendazole 15 mg/kg/day (max 1200 mg/day) divided into 2 daily doses for 7 – 14 days with food. Patients should also receive corticosteroids, and have repeat imaging every 6 months until resolution of cystic lesions. In patients who have been seizure free for 6 months, antiepileptics may be tapered and stopped after resolution of the lesion as long as they do not have risk factors for recurrent seizures. Risk factors for recurrent seizures include residual cystic lesions or calcifications on neuroimaging studies, breakthrough seizures, or > 2 seizures.


• Treatment of calcified intraparenchymal neurocysticercosis
• Patients should be treated with symptomatic therapy only. Antiparasitic drugs are not recommended. [40]


• Steroid dosing
• In one study (n=120), steroid dosing was dexamethasone 2 mg every 8 hours for 10 days [PMID 14724304]
• In another study (n=178), dosing was as follows:
• Weight ≥ 50 kg: prednisone 75 mg/day for 8 days, then 50 mg/day for 7 days, then 25 mg/day for 7 days
• Weight < 50 kg: prednisone 1.5 mg/kg/day for 8 days, then 1 mg/kg/day for 7 days, then 0.5 mg/kg/day for 7 days [PMID 18495737]

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• BIBLIOGRAPHY

• 1 - National Institute for Health and Care Excellence (NICE) 2016 Clinical Guidelines on Epilepsy
• 2 - ILAE Operational Classification of Seizure Types by the International League Against Epilepsy - 2016 proposal - website
• 3 - PMID 18614784 - NEJM review - initial management of Sz DO
• 4 - PMID 16581409 - Lancet review
• 5 - PMID 18025394 - AAN first Sz eval
• 6 - PMID 25901057 - AAN first unprovoked Sz recs
• 7 - PMID 15645539 - AAN new Sz drugs review
• 8 - PMID 23370205 - AHA acute CVA GL
• 9 - PMID 26022637 - AHA GL on ICH
• 10 - PMID 22556195 - AHA GL on SAH
• 11 - PMID 14507951 - NEJM epilepsy review
• 12 - PMID 19732133 - Sz risk factors
• 13 - PMID 19125841 - ILAE febrile sz GL
• 14 - PMID 21285335 - AAP febrile sz recs
• 15 - PMID 7964803 - EEG review
• 16 - PMID 26900382 - Status epilepticus GL
• 17 - PMID 16894135 - Prolactin in Sz evaluation
• 18 - PMID 15950714 - Sz recurrence after 1st unprovoked
• 19 - PMID 23350722 - ILAE sz medication review
• 20 - PMID 19398681 - AAN meds in pregnancy
• 21 - Toxnet
• 22 - Manufacturer's package insert for listed drug
• 23 - PMID 17190925 - OCPs and antiepileptics
• 24 - PMID 18397299 - Antiepileptic drug monitoring
• 25 - Clinical Pathology Laboratories website
• 26 - PMID 22787591 - Mechanism of ketogenic diet
• 27 - PMID 19535814 - Ketogenic diet review
• 28 - PMID 21514240 - Ketogenic diet review for GPs
• 29 - PMID 18823325 - Ketogenic diet recs
• 30 - PMID 22004525 - Ketogenic diet in adults and adolescents
• 31 - PMID 23986299 - AAN 2013 GL on VNS
• 32 - PMID 25284035 - VNS review
• 33 - PMID 26352816 - Cannabis review
• 34 - PMID 24595491 - Cannabis cochrane review
• 35 - PMID 14724304 - Alb + dex for NC
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