5. Epilepsy And Sleep Flashcards
The prevalence of major congenital malformations in offspring of women with epilepsy?
4% to 10% = two-to four-fold increase from the expected prevalence in the general population.
Increased risk of congenital malformations has been demonstrated even with women with epilepsy not taking any AEDs during pregnancy.
Clearance of lamotrigine during pregnancy?
Increases substantially, so the dose may have to be adjusted during this time and breakthrough seizures can occur.
Congenital malformation with valproate?
1- Cleft lip and palate.
2- Neural tube malformations.
3- Congenital heart defects.
4- Dose-dependent cognitive adverse events.
> > The greatest risk for 1-3 is during the first trimester.
Preconceptional folate supplementation for all women with epilepsy taking AEDs? Dose?
Up to 4 to 5 mg/day is recommended to decrease the risk of neural tube defects.
0.4 mg/d for all women of childbearing age.
When does the neural tube close during pregnancy?
Weeks 3 and 4.
Side effects of topiramate?
Weight loss.
Drowsiness.
Word-finding difficulties.
Cognitive impairment.
Confusion.
Impaired memory.
Paresthesias.
Dizziness.
Nervousness.
Painful angle-closure glaucoma.
Kidney stones.
Temporal lobe epilepsy is often characterized by?
Automatisms.
Altered consciousness.
Déjà vu phenomena.
Complex partial seizures.
Olfactory hallucinations.
The fencer’s posture is associated with?
Frontal lobe epilepsy.
Indicates epileptic activation of the supplemental motor area.
It is described as external rotation and abduction of the contralateral arm from the shoulder, with head turning toward the same side of the arm posture.
Gabapentin is enzyme inducer or inhibitor?
Neither an enzyme inducer nor inhibitor, so it has less potential interactions with other medications.
Gabapentin worsens which types of epilepsy?
Can worsen generalized epilepsy, especially myoclonic epilepsy.
Gabapentin proposed mechanism of anti-seizure action?
Through an interaction with the alpha2-δ subunit of presynaptic L-type voltage-regulated calcium channel.
This subunit is the specific binding site of gabapentin, as well as pregabalin.
Binding of gabapentin and pregabalin may result in modulation of presynaptic neurotransmitter release.
Gabapentin vs Pregabalin absorption?
Gabapentin is absorbed by an active transporter in the intestine. When the transporter becomes saturated, the absorption of gabapentin becomes nonlinear (i.e., a smaller percentage is absorbed at higher doses).
Pregabalin has a linear absorption and, thus, has higher bioavailability.
Gabapentin excretion?
Is renally excreted, and essentially no metabolism occurs before excretion.
Most common side effects of gabapentin?
Fatigue.
Headache.
Nausea.
Dizziness.
Ataxia.
> No significant drug interactions or idiosyncratic reactions.
Ketogenic diet indication?
Effective in refractory cases of epilepsy in childhood, even when multiple antiepileptic trials have failed.
Ketogenic diet initiation?
It is typically initiated in the hospital by starvation for 1 to 2 days in order to induce ketosis.
This is followed by a strict diet in which 80% to 90% of calories are derived from fat.
Incidence and stats of simple febrile seizures?
- 3% to 5% of children aged 5 months to 5 years have simple FS. With a peak incidence at 18 months.
- 90% of these events occur in the first 3 years of life.
- 1/3 of patients have at least one additional seizure.
Risk factors for having a simple febrile seizure?
- Family history of FS.
- Prolonged neonatal intensive care unit stay for more than 30 days.
- Developmental delay.
- Day care.
> Incidence does not increase in proportion to increase in temperature.
No risk factors are found in 50% of children with FS.
Risk factors of having afebrile epilepsy after a febrile seizure?
- Developmental delay.
- Abnormal neurologic examination.
- Complex febrile seizure.
- Family history of afebrile seizures.
% of patients with a simple febrile seizure who develop epilepsy?
<5%
% of patients with epilepsy who have a history of febrile seizure?
15%
Simple febrile seizure; definition? characteristics?
Defined as a seizure that occurs in association with a febrile illness in the absence of CNS infection or acute electrolyte imbalance in children without prior afebrile seizures.
- <15 minutes in duration.
- Generalized seizure.
- Lack of focality.
- Normal neurologic examination.
- No persistent deficits.
- Negative family history for seizures.
% of complex febrile seizures among all febrile seizures?
20%
Complex febrile seizures characteristics?
- > 15 minutes in duration.
- Focal features.
- Abnormal neurologic examination.
- Seizure recurrence in <24 hours, or multiple times in the course of the same febrile illness.
- Postictal signs (Todd’s paralysis).
- More likely to be due to meningitis, encephalitis, or an underlying seizure disorder.
Management of febrile seizures?
> Supportive care is the general recommendation.
> Prophylaxis ASMs is generally not needed but can be considered for:
- Recurrent or prolonged seizures.
- Afebrile seizures.
- After complex FS.
- With an abnormal neurologic examination and developmental delay.
Complex febrile seizures ASM agents?
Chronic prophylaxis includes phenobarbital and valproic acid.
Short-term prophylaxis include diazepam and antipyretics, though definitive data on the use of antipyretics for the prevention of FS are lacking.
Generalized epilepsy with febrile seizures plus (GEFS+); definition and association with other seizure types?
- Is a familial syndrome.
- FSs continue past the defined upper limit of age, >5 years.
- Associated with afebrile generalized tonic-clonic (GTC) seizures.
- 1/3 of patients have other seizure types.
GEFS+; pattern of inheritance?
Is usually complex, although initial genetic discoveries first identified an autosomal dominant familial pattern.
GEFS+ genetic mutations?
- Sodium channel (SCN) subunits (SCN1A, SCN1B, and SCN2A).
- GABAA receptor subunit genes (GABRD and GABRG2).
> Most common mutation is in SCN1A.
> > The result is increased sodium channel activity or impaired GABA activity, ultimately leading to increased cortical hyperexcitability.
GEFS+ EEG?
Usually shows generalized spike–wave or polyspikes.
Rasmussen’s syndrome?
- A rare, but severe, inflammatory brain disorder characterized by progressive unilateral hemispheric atrophy.
- The focal cortical atrophy is progressive and eventually spreads to the surrounding cortical areas in the same hemisphere.
Rasmussen’s syndrome; clinical characteristics?
- Progressive neurologic dysfunction (hemiparesis and cognitive deterioration).
- Intractable focal seizures (epilepsia partialis continua).
Rasmussen’s syndrome; pathogenesis?
It’s postulated that antibodies to glutamate receptor-3 (GLUR3) may play a pathogenic role.
Rasmussen’s syndrome; treatment?
Best option for the patient’s with intractable seizures is the surgical approach with hemispherectomy.
Progressive myoclonic epilepsies (PMEs); examples?
Mostly due to either lysosomal storage disorders and/or mitochondrial disorders; examples:
- Lafora body disease.
- Unverricht–Lundborg syndrome.
- Neuronal ceroid lipofuscinosis.
- Myoclonic epilepsy with ragged red fibers (MERRF).
- Sialidosis.
Progressive myoclonic epilepsies characteristics?
- Progressive cognitive decline.
- Myoclonus (epileptic and nonepileptic).
- Seizures (tonic–clonic, tonic, and myoclonic).
- May be associated with ataxia or movement disorders.
Progressive myoclonic epilepsies; first-line treatment?
Valproic acid is often the first-line treatment of myoclonic epilepsy.
Caution is advised in patients with mitochondrial mutations, such as POLG gene mutations, because fulminant hepatic failure may result.
Other treatments for Progressive myoclonic epilepsies?
- Clonazepam.
- Levetiracetam.
- Topiramate.
- Zonisamide.
> Lamotrigine is sometimes used, but it rarely worsens myoclonic seizures.
> > Gabapentin, carbamazepine, pregabalin, and vigabatrin are also known to exacerbate some myoclonic epilepsies.
Fosphenytoin vs. Phenytoin; chemical structure?
- Fosphenytoin is an IV prodrug of phenytoin.
- Fosphenytoin is composed of a disodium phosphate ester that is water soluble and less alkaline than phenytoin.
- Fosphenytoin does not include propylene glycol and ethyl alcohol as a solvent vehicle as is the case with IV phenytoin.
Fosphenytoin vs. Phenytoin; administration?
- Fosphenytoin can be loaded at a faster rate, but it needs to be converted into phenytoin in plasma, so the rate of rise of serum levels is approximately equal to that of phenytoin.
- Fosphenytoin is not associated with purple glove syndrome; its administration is associated with a lower occurrence of cardiovascular side effects, such as hypotension.
- Fosphenytoin can be given intramuscularly.
> Purple glove syndrome may ensue when phenytoin infiltrates into the subcutaneous tissue, resulting in swelling, pain, and discoloration of the extremity because of blood vessel leakage.
Side effects of IV fosphenytoin?
- Pruritus: most common.
- The other less problematic and typical phenytoin side effects: dizziness, nystagmus, and drowsiness.
ASMs associated with myoclonic seizure exacerbation?
- Lamotrigine.
- Gabapentin.
- Carbamazepine.
- Pregabalin.
- Vigabatrin.
Valproic acid effect on hepatic enzyme?
- Hepatic enzyme inhibitor.
> Concurrent use of valproic acid with medications that undergo the same hepatic enzyme metabolism may result in dangerously elevated serum levels of these medications because their metabolism is inhibited. For example, concurrent valproic acid and warfarin use, which could result in elevated INR levels and, thus, increased bleeding risk.
3-Hz spike and wave?
Characteristic for absence epilepsy.
Absence epilepsy; patient population?
- Peak age around 6 years.
- More often affects girls (70%).
- Patients are generally normal neurologically.
Absence epilepsy characteristics?
- Multiple daily spells lasting a few seconds.
- Begin and end abruptly and interrupt whatever activity is being carried out.
Absence seizures; ictal characteristics?
- Blank stares.
- Automatisms such as lip smacking, nose rubbing, and picking at clothes [especially with longer episodes].
- Mild ictal jerks of eyelids, eyes, and eyebrows may occur at the onset of the seizure.
Absence seizures are provoked by?
Hypoglycemia.
Hyperventilation.
Absence seizure; pathogenesis?
The thalamus is implicated in the generation and sustainment of absence epilepsy with the low-threshold (T-type) calcium channels of thalamic neurons playing a central role in thalamocortical interactions.
Absence epilepsy; treatment?
- First-line treatment is ethosuximide (which acts via T-type calcium channel inhibition).
- Valproic acid.
- Lamotrigine. [associated with aggravation of absence seizures on rare occasions].
- Topiramate.
- Zonisamide.
> Ethosuximide and valproic acid are more effective than lamotrigine.
Ethosuximide is associated with fewer adverse attentional effects.
Valproic acid and lamotrigine are often the drugs of choice when there are concurrent GTC and absence seizures.
GABA-B receptors promote activation of T-type calcium channels. Therefore, some GABAergic drugs can exacerbate absence seizures.
Absence epilepsy prognosis?
- Carries a good prognosis.
- 80% of children have remission through adolescence and at least 90% eventually have remission overall.
- ASMs can often be discontinued as the child grows older, if the EEG is normal, and there have been no seizures for 1 to 2 years.
Adult EEG frequencies?
- β >13 Hz
- α 8 to 13 Hz
- θ 4 to 7 Hz theta
- δ <4 Hz delta
> The adult pattern of normal posterior dominant α-rhythm in older children and adults is usually seen by the age of 8 to 10 years.
Periodic lateralized epileptiform discharges (PLEDs)?
Unilateral or bilateral, independent, high-a amplitude, sharp, and slow-wave complexes at 0.5 to 3 Hz.
PLEDs causes?
Any destructive process such as:
- Anoxia.
- HSV encephalitis.
- Stroke.
- Tumors.
Triphasic waves?
Generalized and maximal bifrontal and consist of a prominent positive wave preceded and followed by minor negative waves at 0.5 to 2 Hz intervals.
Triphasic waves cause?
- Hepatic coma.
- Anoxia.
- Drug toxicity.
- Other toxic and metabolic encephalopathies.
ASMs associated with aggravation of absence seizures and even absence status epilepticus in children with absence epilepsy?
- Phenytoin.
- Carbamazepine.
- Gabapentin.
- Lamotrigine.
Antiepileptic medications increase metabolism of oral contraceptives?
Many enzyme-inducing antiepileptics:
- Phenytoin.
- Carbamazepine.
- Phenobarbital.
- Oxcarbazepine.
- Topiramate at doses >200 mg/d.
Antiepileptic medications with minimal oral contraceptive interaction?
- Valproic acid.
- Gabapentin.
- Pregabalin.
- Levetiracetam.
- Zonisamide.
- Tiagabine.
- Topiramate (at doses <200 mg/d).
EEG?
Run of 3-Hz spike and wave discharges typically seen with absence seizures in childhood absence epilepsy.
A paroxysmal 3-Hz spike and wave pattern emerges abruptly out of a normal background and suddenly ceases after a few seconds.
EEG?
Polyspikes in a patient with juvenile myoclonic epilepsy (JME).
JME patient population?
- Onset is typically between 8 and 24 years (peaks in teens).
- Development is typically normal.
- Boys and girls seem to be equally affected.
JME; seizures types?
- Myoclonic seizures - the most frequent seizure type.
- GTC seizures: infrequent in most patients, usually occur on awakening.
- Absence seizures.
JME; Myoclonic seizures characteristics?
- The most frequent seizure type in JME.
- Predominantly seen on awakening, and the patient often complains about being “clumsy” in the morning and frequently dropping things.
- Falls are not infrequent.
- There is typically no LOC, although myoclonic seizures can occasionally be followed by a GTC seizure.
JME EEG?
Interictal: generalized 4- to 6-Hz polyspike and wave discharges.
Ictal: trains of spikes, which are commonly triggered by photic stimulation (during EEG recordings).
JME treatment?
- First-line: Valproic acid.
- Second-line: lamotrigine, levetiracetam, topiramate, and zonisamide.
> Carbamazepine and phenytoin should be avoided because they may lead to worsening of myoclonic seizures, similar to the worsening of childhood absence epilepsy seen with these agents.
> Good control will generally require lifelong treatment and avoidance of triggers, such as alcohol intake and lack of sleep.
EEG? And characteristics?
Benign childhood epilepsy with centrotemporal spikes (benign rolandic epilepsy of childhood).
- Bilateral independent centrotemporal spikes on a normal background.
- The discharges on the two sides can either be independent or synchronized.
- They may extend beyond the centrotemporal regions.
- Although the spikes on the EEG appear in the centrotemporal area, the temporal lobe is not the generator of these spikes. Rather, they are felt to be generated in the base of the rolandic fissure.
Benign childhood epilepsy with centrotemporal spikes (benign rolandic epilepsy of childhood)?
- Accounts for 25% of childhood seizures.
- Onset is usually between 2 and 13 years of age.
- The condition typically resolves in the mid-teenage years.
- Normal development, physical examination, and brain imaging are the rule, though there are exceptions.
Benign childhood epilepsy with centrotemporal spikes; Seizures characteristics?
- Focal motor, sensory, or autonomic manifestations involving predominantly the face, mouth, throat, or extremities, although secondary generalization can occur.
- Classically occur nocturnally (70% only in sleep, 15% only awake, and 15% both).
Benign childhood epilepsy with centrotemporal spikes; EEG?
- Independent bilateral, repetitive, broad, centrotemporal interictal EEG spikes on a normal background.
- The discharges are thought to arise from the vicinity of the precentral and postcentral gyri in the lower suprasylvian region.
- The characteristic EEG spike pattern is inherited as an autosomal dominant trait with variable penetrance.
Benign childhood epilepsy with centrotemporal spikes; treatment?
- It is often not necessary to treat with AEDs unless seizures are prolonged or frequent.
- Seizures respond well to certain ARDs and carbamazepine is usually considered the first line of therapy in the US.
- If AEDs are started, they can generally be stopped after adolescence. (Only 10% continue to have seizures 5 years after onset.)
EEG?
PLEDs: Periodic lateralized epileptiform discharges.
Occur in acute lateralized pathology, such as a stroke, HSV encephalitis, rapidly expanding tumor, or any other destructive process to the brain parenchyma.
EEG? And characteristics?
Hypsarrhythmia - the most common interictal EEG correlate of infantile spasms.
> Characterized by abnormal interictal high-amplitude slow waves on a background of irregular multifocal spikes. No consistent pattern or rhythm and vary in duration and size, resulting in a chaotic-appearing EEG record.
> Hypsarrhythmia disappears ictally during a cluster of spasms and/or REM sleep.
Infantile spasms age?
Occur during the first year of life (typically 3 to 8 months).
Infantile spasms characteristics?
Sudden tonic extension or flexion of limbs and axial body, often occurring in clusters, and especially shortly after awakening.
West’s syndrome triad?
1- Infantile spasms.
2- Hypsarrhythmia.
3- Psychomotor arrest or regression.
Infantile spasms/West’s syndrome causes?
- Pre/peri/postnatal insults.
- Tuberous sclerosis.
- Cerebral dysgenesis.
- Hypoxic–ischemic injuries.
- Brain malformations or structural abnormalities.
- Congenital or acquired infections.
- Chromosomal abnormalities.
- Inborn errors of metabolism.
- 30% of the cases, no specific etiology is found, and these cases are considered cryptogenic.
Infantile spasms/West’s syndrome: Treatment?
> > ACTH is generally the first line.
Other treatments include:
- Corticosteroids.
- Vigabatrin - associated with retinal toxicity.
- Clonazepam.
- Levetiracetam.
- Topiramate.
- Pyridoxine.
- Valproic acid.
Phenytoin is used for?
Treatment of partial and/or generalized tonic-clonic seizures (primary or secondary).
Phenytoin MOA?
Inhibition of voltage-dependent neuronal sodium channels.
