SEIZURES AND EPILEPSY




























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
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











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]







  • 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)





  • 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)


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]


  • 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
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.







  • 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.

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
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.

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


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]


  • 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




Cannabidiol vs Placebo in Drug-resistant Dravet Syndrome, NEJM (2017) [PubMed abstract]
  • A trial published in the NEJM enrolled 120 children with drug-resistant Dravet syndrome
Main inclusion criteria
  • Diagnosis of Dravet syndrome
  • Taking one or more antiepileptic drugs
  • ≥ 4 convulsive seizures during the 28-day baseline period
Main exclusion criteria
  • History of alcohol or substance abuse
  • History of cannabis use
Baseline characteristics
  • Average age - 10 years
  • Average number of antiepileptic medications currently taking - 3
  • On ketogenic diet - 8%
  • Vagus-nerve stimulator - 12%
  • Meds: Clobazam - 65% | Valproate - 59% | Vtiripentol - 42% | Levetiracetam - 28% | Topiramate - 26%
Randomized treatment groups
  • Group 1 (61 patients) - Cannabidiol 20 mg/kg/day given in 2 divided doses
  • Group 2 (59 patients) - Placebo
  • Dose was titrated up to 20 mg/kg/day over a period of 14 days
  • All medications or interventions for epilepsy, including a ketogenic diet and vagus nerve stimulation, were stable for 4 weeks before screening and were to remain unchanged throughout the trial
Primary outcome: Change in seizure frequency during the 14-week treatment period when compared to the 4-week baseline period
Results

Duration: 14 weeks
Outcome Cannabidiol Placebo Comparisons
Baseline seizure frequency 12.4/month 14.9/month N/A
Primary outcome (seizures/month) 5.9 14.1 Diff -22.8%, 95%CI [-41.1 to -5.4], p=0.01
Seizure-free patients 5% 0% p=0.08
Somnolence 36% 10% N/A
Diarrhea 31% 10% N/A
Decreased appetite 28% 5% N/A
Fatigue 20% 3% N/A
Vomiting 15% 5% N/A
Fever 15% 8% N/A
Lethargy 13% 5% N/A
Elevated liver enzymes 20% 2% N/A
Study withdrawal due to side effects 13% 2% N/A
  • There was no significant reduction in nonconvulsive seizures

Findings: Among patients with the Dravet syndrome, cannabidiol resulted in a greater reduction in convulsive-seizure frequency than placebo and was associated with higher rates of adverse events.











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®





  • 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%