5. Epilepsy And Sleep Flashcards
(202 cards)
1
Q
The prevalence of major congenital malformations in offspring of women with epilepsy?
A
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.
2
Q
Clearance of lamotrigine during pregnancy?
A
Increases substantially, so the dose may have to be adjusted during this time and breakthrough seizures can occur.
3
Q
Congenital malformation with valproate?
A
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.
4
Q
Preconceptional folate supplementation for all women with epilepsy taking AEDs? Dose?
A
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.
5
Q
When does the neural tube close during pregnancy?
A
Weeks 3 and 4.
6
Q
Side effects of topiramate?
A
Weight loss.
Drowsiness.
Word-finding difficulties.
Cognitive impairment.
Confusion.
Impaired memory.
Paresthesias.
Dizziness.
Nervousness.
Painful angle-closure glaucoma.
Kidney stones.
7
Q
Temporal lobe epilepsy is often characterized by?
A
Automatisms.
Altered consciousness.
Déjà vu phenomena.
Complex partial seizures.
Olfactory hallucinations.
8
Q
The fencer’s posture is associated with?
A
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.
9
Q
Gabapentin is enzyme inducer or inhibitor?
A
Neither an enzyme inducer nor inhibitor, so it has less potential interactions with other medications.
10
Q
Gabapentin worsens which types of epilepsy?
A
Can worsen generalized epilepsy, especially myoclonic epilepsy.
11
Q
Gabapentin proposed mechanism of anti-seizure action?
A
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.
12
Q
Gabapentin vs Pregabalin absorption?
A
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.
13
Q
Gabapentin excretion?
A
Is renally excreted, and essentially no metabolism occurs before excretion.
14
Q
Most common side effects of gabapentin?
A
Fatigue.
Headache.
Nausea.
Dizziness.
Ataxia.
> No significant drug interactions or idiosyncratic reactions.
15
Q
Ketogenic diet indication?
A
Effective in refractory cases of epilepsy in childhood, even when multiple antiepileptic trials have failed.
16
Q
Ketogenic diet initiation?
A
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.
17
Q
Incidence and stats of simple febrile seizures?
A
- 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.
18
Q
Risk factors for having a simple febrile seizure?
A
- 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.
19
Q
Risk factors of having afebrile epilepsy after a febrile seizure?
A
- Developmental delay.
- Abnormal neurologic examination.
- Complex febrile seizure.
- Family history of afebrile seizures.
20
Q
% of patients with a simple febrile seizure who develop epilepsy?
A
<5%
21
Q
% of patients with epilepsy who have a history of febrile seizure?
A
15%
22
Q
Simple febrile seizure; definition? characteristics?
A
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.
23
Q
% of complex febrile seizures among all febrile seizures?
A
20%
24
Q
Complex febrile seizures characteristics?
A
- > 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.
25
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.
26
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.
27
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.
28
GEFS+; pattern of inheritance?
Is usually complex, although initial genetic discoveries first identified an autosomal dominant familial pattern.
29
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.
30
GEFS+ EEG?
Usually shows generalized spike–wave or polyspikes.
31
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.
32
Rasmussen’s syndrome; clinical characteristics?
- Progressive neurologic dysfunction (hemiparesis and cognitive deterioration).
- Intractable focal seizures (epilepsia partialis continua).
33
Rasmussen’s syndrome; pathogenesis?
It’s postulated that antibodies to glutamate receptor-3 (GLUR3) may play a pathogenic role.
34
Rasmussen’s syndrome; treatment?
Best option for the patient’s with intractable seizures is the surgical approach with hemispherectomy.
35
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.
36
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.
37
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.
38
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.
39
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.
40
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.
41
Side effects of IV fosphenytoin?
- Pruritus: most common.
- The other less problematic and typical phenytoin side effects: dizziness, nystagmus, and drowsiness.
42
ASMs associated with myoclonic seizure exacerbation?
- Lamotrigine.
- Gabapentin.
- Carbamazepine.
- Pregabalin.
- Vigabatrin.
43
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.
44
3-Hz spike and wave?
Characteristic for absence epilepsy.
45
Absence epilepsy; patient population?
- Peak age around 6 years.
- More often affects girls (70%).
- Patients are generally normal neurologically.
46
Absence epilepsy characteristics?
- Multiple daily spells lasting a few seconds.
- Begin and end abruptly and interrupt whatever activity is being carried out.
47
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.
48
Absence seizures are provoked by?
Hypoglycemia.
Hyperventilation.
49
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.
50
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.
51
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.
52
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.
53
Periodic lateralized epileptiform discharges (PLEDs)?
Unilateral or bilateral, independent, high-a amplitude, sharp, and slow-wave complexes at 0.5 to 3 Hz.
54
PLEDs causes?
Any destructive process such as:
- Anoxia.
- HSV encephalitis.
- Stroke.
- Tumors.
55
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.
56
Triphasic waves cause?
- Hepatic coma.
- Anoxia.
- Drug toxicity.
- Other toxic and metabolic encephalopathies.
57
ASMs associated with aggravation of absence seizures and even absence status epilepticus in children with absence epilepsy?
- Phenytoin.
- Carbamazepine.
- Gabapentin.
- Lamotrigine.
58
Antiepileptic medications increase metabolism of oral contraceptives?
Many enzyme-inducing antiepileptics:
- Phenytoin.
- Carbamazepine.
- Phenobarbital.
- Oxcarbazepine.
- Topiramate at doses >200 mg/d.
59
Antiepileptic medications with minimal oral contraceptive interaction?
- Valproic acid.
- Gabapentin.
- Pregabalin.
- Levetiracetam.
- Zonisamide.
- Tiagabine.
- Topiramate (at doses <200 mg/d).
60
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.
61
EEG?
Polyspikes in a patient with juvenile myoclonic epilepsy (JME).
62
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.
63
JME; seizures types?
- Myoclonic seizures - the most frequent seizure type.
- GTC seizures: infrequent in most patients, usually occur on awakening.
- Absence seizures.
64
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.
65
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).
66
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.
67
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.
68
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.
69
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).
70
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.
71
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.)
72
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.
73
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.
74
Infantile spasms age?
Occur during the first year of life (typically 3 to 8 months).
75
Infantile spasms characteristics?
Sudden tonic extension or flexion of limbs and axial body, often occurring in clusters, and especially shortly after awakening.
76
West’s syndrome triad?
1- Infantile spasms.
2- Hypsarrhythmia.
3- Psychomotor arrest or regression.
77
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.
78
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.
79
Phenytoin is used for?
Treatment of partial and/or generalized tonic-clonic seizures (primary or secondary).
80
Phenytoin MOA?
Inhibition of voltage-dependent neuronal sodium channels.
81
Phenytoin metabolism? Kinetics?
It undergoes predominantly liver metabolism, although there is also minimal renal metabolism. Metabolized by hepatic cytochrome (CYP) P450 enzymes to inactive metabolites, which are then excreted in the urine.
Phenytoin exhibits nonlinear (zero-order) kinetics, as the metabolic pathways responsible for its metabolism become saturated.
Phenytoin approaches zero-order kinetics at total levels of >10 to 15 μg/mL, and small dose increments can potentially cause large increases in the serum level.
82
Phenytoin level with low albumin?
With low serum protein disease states (such as liver failure, etc.), follow with free phenytoin levels because of less available protein for binding, making the total levels unreliable.
83
Idiosyncratic reactions caused by phenytoin?
- Aplastic anemia.
- Stevens–Johnson syndrome.
- Hepatic failure.
84
Phenytoin side effects?
- Thrombocytopenia.
- Lymphadenopathy.
- Gingival hyperplasia.
- Acne.
- Coarse facial features (also called “phenytoin facies,” from hypertrophy of subcutaneous facial tissue).
- Hirsutism.
- Purple glove syndrome (with IV form).
- Nystagmus.
- Ataxia.
- Dysarthria.
- Diplopia.
- Nausea.
- Dizziness.
- Drowsiness.
- Folate deficiency.
- Increased vitamin D metabolism, resulting in premature osteoporosis.
- Mild peripheral neuropathy.
- Cerebellar (but not cortical) atrophy.
85
Acute side effects of Phenytoin IV form?
- Phlebitis.
- Pain.
- Burning.
- Hypotension.
- Cardiac conduction abnormalities.
86
Phenytoin effect on liver enzymes?
It is a liver enzyme inducer, so it can increase metabolism of many other drugs.
87
Calculating loading and correcting doses of phenytoin?
(target total phenytoin level − current total phenytoin level) × (kilogram body weight × volume of distribution).
> The therapeutic range is 10 to 20 μg/mL.
> The volume of distribution is 0.5 to 1 L/kg, with an average of 0.8 L/kg often used.
> An accurate reassessment of new levels can be obtained by checking free and total levels approximately 2 hours after the IV load.
88
The correcting IV bolus for valproic acid calculation?
(target total valproic acid level − current total valproic acid level) × (kilogram body weight × volume of distribution).
> The therapeutic range is 50 to 100 μg/mL.
> The volume of distribution is 0.1 to 0.3 L/kg, with an average of 0.2 L/kg often used.
89
Valproic acid used for?
Broad-spectrum antiseizure activity and is commonly used in partial GTC, absence, myoclonic, and tonic seizures, as well as infantile spasms.
90
Valproic acid MOA?
Sodium and T-type calcium channel antagonism, and it also works as an agonist at the GABA-A receptor.
91
Valproic acid metabolism?
It primarily undergoes liver metabolism.
92
Valproic acid effect on liver enzymes?
It is a hepatic enzyme inhibitor.
93
Valproic acid Side effects?
- Cognitive decline.
- Gastrointestinal complaints.
- Increased liver enzymes.
- Idiosyncratic fatal hepatitis (rarely but most common in those <2 years of age).
- Weight gain.
- Hair thinning.
- Polycystic ovarian syndrome.
- Acne.
- Menstrual irregularities.
- Tremor.
- Pancreatitis.
- Thrombocytopenia.
94
Valproic acid interaction with Lamotrigine?
Valproic acid significantly increases the half-life of lamotrigine by 24 to 48 hours.
Initiation of as little as 500 mg of valproic acid in chronic lamotrigine users may necessitate an immediate 50% reduction in the dose of lamotrigine.
95
Carbamazepine is used for?
- Partial or secondarily GTC seizures.
- It can rarely worsen some generalized epilepsies (including myoclonic and absence epilepsies), similar to phenytoin.
96
Carbamazepine MOA?
Blockade of sodium channels, which leads to a decrease/prevention of repetitive firing in depolarized neurons.
97
Side effects of Carbamazepine?
- Dizziness.
- Vertigo.
- Fatigue.
- Drowsiness.
- Diplopia.
- Nystagmus.
- Rash.
- Headache.
- Nausea.
- Vomiting.
- Elevated liver function tests.
- Hyponatremia.
- Ataxia.
98
Serious idiosyncratic reactions to Carbamazepine?
- Stevens–Johnson syndrome.
- Leukopenia.
- Aplastic anemia.
99
Carbamazepine metabolism?
It undergoes liver metabolism with renal excretion of metabolites, so caution is advised with kidney or liver failure.
100
Carbamazepine effect on liver enzymes?
It’s a hepatic enzyme inducer and undergoes autoinduction.
101
Carbamazepine autoinduction?
- Carbamazepine “autoinduces” the hepatic enzymes responsible for its own metabolism.
- So half-life decreases from 30 hours to 10 to 20 hours after the first few days to weeks of use.
- Autoinduction is completed after 3 to 5 weeks of a fixed dosing regimen.
- Plasma concentrations decrease in the first 1 to 2 months, and during this time, the dose of carbamazepine should be gradually increased.
102
Carbamazepine dose must be titrated up gradually. Why?
- Allow tolerance to develop to its CNS side effects.
- Avoid early toxicity, as the hepatic enzymes responsible for carbamazepine’s metabolism have not been fully activated (autoinduced) yet.
- Achieve an optimal therapeutic level as carbamazepine “autoinduces” the hepatic enzymes responsible for its own metabolism.
103
Carbamazepine vs Oxcarbazepine; chemical structure?
- Oxcarbazepine is a structural derivative of carbamazepine and is reduced to 10-monohydroxy-carbamazepine and unlike carbamazepine does not undergo oxidation to epoxide.
- Carbamazepine is oxidized to 10,11-carbamazepine epoxide, which is the principal metabolite of carbamazepine. 10,11-carbamazepine epoxide is pharmacologically active and responsible for many of the side effects of carbamazepine.
104
Oxcarbazepine MOA and use?
Used for the same seizure types as carbamazepine, having the same mechanism of action, and metabolic pathways.
105
Carbamazepine vs Oxcarbazepine; side effects?
- They have the same side effect profile.
- Oxcarbazepine has less side effects,as it does not undergo oxidation to epoxide.
- Oxcarbazepine has less liver enzyme induction, no autoinduction (and can thus be titrated more rapidly),
- 30% of patients who have a history of a rash with carbamazepine will also develop a rash when exposed to oxcarbazepine.
106
Valproic acid and Carbamazepine interaction?
- Valproic acid inhibits the metabolism of the 10,11-carbamazepine epoxide.
- Thus, although the carbamazepine level may be normal, the patient may experience toxicity because of elevated 10,11-carbamazepine epoxide levels.
- The 10,11-carbamazepine epoxide is not routinely measured but can be ordered specifically if there are concerns about toxicity.
107
Benzodiazepines are used for?
Broad-spectrum antiepileptic medications used most commonly for:
- Partial GTC.
- Absence seizures.
- Myoclonic seizures.
- Status epilepticus.
108
Benzodiazepines MOA?
They work as GABA-A agonists.
Binding to the GABA-A receptor leads to subsequent activation of chloride channels and, as a result, hyperpolarization of the neuronal membrane and decreased neuronal excitability.
109
Benzodiazepines metabolism?
They undergo liver metabolism and renal excretion of their metabolites.
110
Lamotrigine is used for?
It’s a broad-spectrum ASM and is used for:
- Partial seizures.
- GTC seizures.
- Generalized seizures of Lennox–Gastaut syndrome (LGS).
- Also used for absence and myoclonic seizures, although it is not the first line of therapy for these types of seizures.
111
Lamotrigine MOA?
It works as a sodium channel antagonist and also inhibits glutamate release.
112
Lamotrigine metabolism?
It undergoes liver metabolism with renal excretion of metabolites.
113
Lamotrigine side effects?
It’s typically well tolerated as long as it is introduced gradually with a slow titration.
- Dizziness.
- Blurred vision.
- Diplopia.
- Ataxia.
- Cognitive disturbances but much less common compared to many other AEDs.
114
Side effects associated with concurrent use of valproic acid and Lamotrigine or rapid lamotrigine titration?
- Stevens–Johnson syndrome.
- Toxic epidermal necrolysis.
> This risk appears to be increased in those younger than 16 years.
115
Lamotrigine and OCPs?
- Oral contraceptives and hormone replacement therapy increase lamotrigine clearance and decrease serum levels.
- This effect appears to be limited to contraceptives containing ethinylestradiol.
- Progesterone-only medications do not appear to have this effect.
116
Lamotrigine and pregnancy?
- Lamotrigine clearance may increase up to 65% during pregnancy, which may result in breakthrough seizures.
- Therefore, monitoring of lamotrigine serum levels with dose adjustments is recommended during pregnancy and after delivery.
117
Topiramate is used for?
It’s a broad-spectrum antiepileptic used for:
- Partial seizures.
- GTC seizures.
- Absence seizures.
- LGS.
118
Topiramate MOA?
- Voltage-dependent sodium channel antagonism.
- Enhancement of GABA activity through a nonbenzodiazepine site on GABA-A receptors.
- Antagonism of AMPA/kainate glutamate receptors.
- A weak carbonic anhydrase inhibitor.
119
Topiramate metabolism?
It is predominantly excreted unchanged in urine with minimal liver metabolism.
120
Topiramate as a carbonic anhydrase inhibitor?
- Similar to zonisamide, topiramate is also a weak carbonic anhydrase inhibitor.
- This explains the potential risk of renal stone formation in patients treated with these agents, as well as potential benefit in idiopathic intracranial hypertension.
121
Topiramate side effects?
- Paresthesias.
- Decreased appetite.
- Weight loss.
- Dizziness.
- Fatigue.
- Cognitive complaints: such as word-finding difficulty and slowed thinking.
- Acute angle-closure glaucoma.
- Renal stone formation.
122
Lacosamide MOA?
1- Selective enhancement of slow inactivation of voltage-dependent sodium channels.
The result is inhibition of repetitive neuronal firing and stabilization of hyperexcitable neuronal membranes.
2- Interfere with the activity of the collapsing response mediator protein-2 (CRMP-2), a cell protein involved in neuronal differentiation and axonal guidance. The nature of the interaction between lacosamide and CRMP-2 and its role in seizure control are unclear.
123
Lacosamide is used for?
FDA approved as an adjunct for partial-onset seizures in patients aged 17 years and older.
124
Lacosamide metabolism?
It is eliminated primarily by renal excretion and has little drug–drug interaction with other antiepileptic medications.
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Lacosamide side affects?
- Dizziness.
- Nausea.
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Rufinamide MOA?
Modulates the activity of neuronal sodium channels, resulting in prolongation of the inactive state of the channel.
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Rufinamide is used for?
FDA approved for the adjunctive treatment of seizures associated with LGS in pediatric patients 1 year of age and older, and in adults.
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Rufinamide metabolism?
- Undergoes extensive metabolism, with only 4% excreted as parent drug.
- Primarily metabolized via enzymatic hydrolysis of the carboxylamide group to form carboxylic acid.
- This metabolic route is not CYP 450 dependent.
- There are no known active metabolites.
- Elimination of rufinamide is predominantly via urine.
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Plasma half-life of rufinamide?
Approximately 6 to 10 hours.
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Rufinamide effects on liver enzymes?
- Little or no inhibition of most CYP 450 enzymes at clinically relevant concentrations.
- Weak inhibition of CYP 2E1.
- Weak inducer of the CYP 3A4 enzyme.
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Mesial temporal lobe aura (simple partial seizures)?
- Rising epigastric sensation.
- Nausea.
- Olfactory and/or gustatory hallucinations.
- Sensation of fear and terror, or other emotional changes.
- Autonomic manifestations: tachycardia, respiratory changes, face flushing, or pallor.
- Dysmnesic manifestations such as:
1- Déjà vu (sensation of familiarity as if an experience has occurred before, although it has not).
2- Déjà entendu (if the experience is auditory).
3- Jamais vu (sensation that a familiar experience is new, although it is not).
4- Jamais entendu (if the latter experience is auditory)
5- Panoramic vision (a rapid recollection of episodes from the past).
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Mesial temporal lobe seizures; ictal characteristics?
- Behavioral arrest.
- Automatisms (involuntary complex motor activities) such as:
1- Nose picking.
2- Lip smacking.
3- Chewing.
4- Picking with the hands.
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Mesial temporal lobe seizure; postictal?
Typically, patients have postictal confusion, which is not present in absence seizures.
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Frontal lobe seizures characteristics?
- Abrupt in onset.
- Brief.
- Predominantly associated with elementary motor manifestations but may include complex automatisms.
- They frequently occur in sleep, often in clusters.
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Parietal lobe seizures characteristics?
- Predominantly associated with episodic sensory symptoms, which include positive symptoms such as tingling or, less commonly, negative symptoms such as asomatognosia.
- In posterior parietal seizures, visual phenomena may occur.
- Although clinical localization may be difficult as parietal discharges propagate to other brain regions.
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Occipital lobe seizures characteristics?
- Usually present with visual phenomena.
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Supplementary motor area (SMA) [frontal lobe] seizures characteristics?
- Typical semiology is “fencer’s posture,” a tonic posture in which the patient exhibits deviation of the eyes and the head, as well as tonic arm extension to the side contralateral to the hemisphere where seizures are originating.
- These seizures are frequent, occurring in clusters or many times per day, and frequently arising during sleep.
- They are usually difficult to treat with medications.
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ACTH side effects?
- Hypertension.
- Hyperglycemia.
- Weight gain.
- Electrolyte abnormalities.
- Risk of infections.
- Risk of avascular necrosis.
- Gastrointestinal bleeding.
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Vigabatrin uses? And side effects?
Treatment of infantile spasms, especially in patients with tuberous sclerosis.
Vigabatrin should be used with caution as it carries the risk of retinal toxicity.
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Aicardi’s syndrome; genetics?
- X-linked dominant pattern of inheritance.
- It is encountered predominantly in girls.
- The mutation is lethal in males.
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Aicardi’s syndrome is characterized by?
- Infantile spasms.
- Chorioretinal lacunae - pathognomonic.
- Agenesis of the corpus callosum.
- Various nonspecific ocular malformations, such as:
1- Cataracts.
2- Microphthalmia.
3- Retinal detachment.
4- Hypoplastic papilla.
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Aicardi’s syndrome; EEG?
Multiple epileptiform abnormalities, such as burst suppression pattern with asynchrony between the two hemispheres and a disorganized background.
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Doose’s syndrome also known as?
Myoclonic–astatic epilepsy.
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Doose’s syndrome; age of onset?
- Typical onset is between 1 and 5 years of age.
- Children are normal prior to the onset of seizures, and many continue to have normal cognitive development.
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Doose’s syndrome; seizure types?
- Predominantly generalized with myoclonic or astatic components, in which the patient loses postural tone and falls, sometimes resulting in injuries.
- Other seizure types, such as absence, GTC, and tonic seizures, and/or nonconvulsive status epilepticus.
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Doose’s syndrome; EEG?
- Interictal bilateral synchronous irregular 2- to 3-Hz spike and wave complexes along with parietal rhythmic θ-activity [theta].
- Myoclonic seizures are associated with irregular spikes and polyspikes.
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Doose’s syndrome; genetics?
There may be a genetic predisposition, and a family history of epilepsy or abnormal EEGs is frequent.
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Doose’s syndrome; prognosis?
Although many patients remain normal, some have severe developmental delay and intractable seizures, and the prognosis may be variable.
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Doose’s syndrome;,seizure treatment?
- Valproic acid is commonly prescribed.
- Ethosuximide may help with absence seizures.
- Levetiracetam and ketogenic diet have also been reported to be beneficial in some cases.
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Dravet’s syndrome also known as?
Severe myoclonic epilepsy of infancy.
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Dravet’s syndrome; definition? Genetics?
Severe epilepsy syndrome - frequent seizures and various seizure types.
Dravet’s syndrome may lie at the most severe end of the spectrum of generalized epilepsy with febrile seizures plus (GEFS+) and may commonly be associated with a mutation in the sodium channel gene SCN1A.
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Dravet’s syndrome; initial presentation? Seizure types?
The typical initial presentation is a febrile seizure in the first year of life; later, these patients develop other seizure types, including:
1- Myoclonias.
2- Atypical absences.
3- Tonic.
4- Tonic–clonic seizures.
> which could be generalized and/or unilateral.
>Given the initial presentation with an FS, the diagnosis may be delayed.
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Dravet’s syndrome; risk factors?
Males are more affected than females, and there may be a family history of epilepsy or abnormal EEGs.
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Dravet’s syndrome; EEG?
The EEG may be normal initially in the interictal period, later showing generalized spike–wave complexes as well as focal and multifocal spikes.
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Dravet’s syndrome; prognosis?
Developmental delay is the rule and neurologic abnormalities are common.
The prognosis is poor, seizures are difficult to control, and there is sensitivity to hyperthermia.
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Dravet’s syndrome; Treatment options?
- Vialproic acid.
- Topiramate.
- Zonisamide.
- Ketogenic diet.
> Importantly, treatment with phenobarbital, phenytoin, carbamazepine, and lamotrigine may exacerbate the seizures.
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Ohtahara’s syndrome, also known as?
Early infantile epileptic encephalopathy.
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Ohtahara’s syndrome; characteristics?
Rare severe neurologic condition in which seizures begin during early infancy (between 1 day and 3 months of age).
Patients have epileptic tonic spasms occurring multiple times per day.
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Ohtahara’s syndrome; EEG?
Burst suppression pattern that is present during wakefulness or sleep.
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Ohtahara’s syndrome; prognosis?
This is a catastrophic epileptic encephalopathy with intractable seizures and a very poor prognosis.
In one series, 25% of patients died before 2 years of age.
All survivors have severe disabilities and developmental impairment.
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Benign myoclonic epilepsy of infancy (BMEI); age of onset? Gender?
Affects males more than females between the ages of 4 months and 3 years.
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Benign myoclonic epilepsy of infancy (BMEI); characteristics?
- Brief myoclonic seizures, which are easily treatable.
- These myoclonias are brief (1 to 3 seconds) and usually isolated and are more prominent during drowsiness, photostimulation, and external stimulation.
- Unlike infantile spasms, the myoclonic seizures of BMEI do not occur in long series/clusters.
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Benign myoclonic epilepsy of infancy (BMEI); EEG? Neuroimaging?
- During a myoclonic seizure, the EEG shows generalized spikes and waves or polyspikes and waves.
- The interictal EEG is normal.
- Neuroimaging is usually normal.
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Benign myoclonic epilepsy of infancy (BMEI); Prognosis?
- Seizures respond well to valproic acid.
- The prognosis is generally good with spontaneous resolution of seizures in less than a year.
- Neuropsychological outcome is favorable, although a small minority of patients may have mild cognitive–developmental delay.
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Benign neonatal seizures; characteristics?
- Full-term, otherwise healthy, newborns develop seizures around day 5 of life (also referred to as “fifth day fits”).
- Partial clonic seizures that may be unilateral and/or symmetric and may migrate to other regions of the body.
- These seizures are frequently associated with apneic spells.
- Diagnosis of exclusion, and workup to rule out symptomatic seizures is indicated.
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Benign neonatal seizures; EEG?
Typically is normal but may demonstrate the “θ pointu alternant” pattern, characterized by discontinuous, asynchronous, unreactive θ-activity with intermixed sharp waves.
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Benign neonatal seizures; treatment? Prognosis?
- Patients are neurologically normal.
- In general, there is no need for treatment with antiepileptic agents, and seizures resolve spontaneously by 4 to 6 weeks of age.
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Benign familial neonatal seizures; characteristics?
- Seizures in the first few days of life, which resolve spontaneously within few weeks.
- Diagnosis of exclusion, and workup to rule out symptomatic seizures is indicated.
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Benign familial neonatal seizures; genetics?
- Autosomal dominant disorder.
- Genetic mutations in voltage-gated potassium channels, in the genes KCNQ2 on chromosome 20 and KCNQ3 on chromosome 8.
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Panayiotopoulos syndrome; definition?
- One of the idiopathic occipital epilepsies.
- Aka Early-onset childhood occipital epilepsy.
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Panayiotopoulos syndrome; age of onset?
Seizures begin between 4 and 8 years of age (with a peak incidence at 4 to 5 years).
172
Panayiotopoulos syndrome; characteristics?
- Tonic eye deviation and vomiting.
- Visual auras during wakefulness, characterized by elementary or complex visual hallucinations and illusions.
- Partial or generalized tonic-clonic seizures occur predominantly or exclusively in sleep.
173
Panayiotopoulos syndrome; EEG?
High-voltage occipital spikes in 1- to 3-Hz bursts, which disappear with eye opening and reappear with eye closure or darkness.
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Panayiotopoulos syndrome; treatment? Prognosis?
- Treatment is generally not required.
- The prognosis is good, and this condition resolves within several years.
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Late-onset childhood occipital epilepsy or Gastaut type; definition?
One of the idiopathic occipital epilepsies.
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Late-onset childhood occipital epilepsy; agr of onset?
Occurs in older children at a mean age of 8 years (between the ages of 4 and 13 years).
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Late-onset childhood occipital epilepsy; characteristics?
Brief seizures with visual manifestations, followed by hemiclonic convulsions and in some cases a postictal migraine.
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Late-onset childhood occipital epilepsy; EEG?
Similar to that seen in Panayiotopoulos syndrome - High-voltage occipital spikes in 1- to 3-Hz bursts, which disappear with eye opening and reappear with eye closure or darkness.
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Late-onset childhood occipital epilepsy; treatment? Prognosis?
- The prognosis is variable in the Gastaut type, but most patients have a benign course.
- However, pharmacologic therapy may be needed and seizures may be difficult to control in some cases.
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Lennox-Gastaut Syndrome (LGS); triad?
1- Seizures of multiple types.
2- EEG with diffuse slow (1.5 to 2 Hz) spike–wave complexes.
3- Cognitive–developmental impairment.
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LGS; age of onset?
The onset is between the ages of 1 to 8 years, with most children presenting at the age of 3 to 5 years.
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LGS; diagnosis?
- Less than half of patients will have normal cognitive function before the onset of seizures, eventually deteriorating after the onset of seizures leading to severe psychomotor impairment.
- About 60% of the cases have an identified cause but some are cryptogenic.
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LGS; seizure types?
- Atypical absence seizures.
- Tonic seizures.
- Atonic seizures.
- Myoclonic seizures.
- Tonic–clonic seizures.
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LGS; treatment?
- Valproic acid and clonazepam are frequently used.
- Other medications that could be given include lamotrigine, felbamate, topiramate, and vigabatrin.
- Ketogenic diet may be considered.
- These seizures are often refractory to therapy.
185
Landau–Kleffner syndrome, also known as?
Acquired epileptic aphasia.
186
Landau–Kleffner syndrome is characterized by?
An acquired aphasia associated with epileptiform abnormalities on EEG and seizures of various types.
187
Landau–Kleffner syndrome; age of onset?
Between 2 and 11 years, with a peak onset between 5 and 7 years.
188
Landau–Kleffner syndrome; presentation?
- Initially present with word deafness in the setting of normal hearing.
- The disorder of language progresses and both a receptive and expressive aphasia may eventually occur.
189
Landau–Kleffner syndrome; seizures types?
- Atypical absence seizures.
- Myoclonic seizures.
- Tonic seizures.
- Tonic–clonic seizures.
- A small minority of patients do not have a history of clinical seizures.
190
Landau–Kleffner syndrome; EEG?
Multifocal cortical spikes, predominantly in the temporal and parietal lobes, most frequently bilaterally.
191
Landau–Kleffner syndrome; treatment?
- Antiepileptic agents such as valproic acid and lamotrigine are usually effective in controlling the seizures.
- Corticosteroids have been tried for speech recovery with variable success.
192
Landau–Kleffner syndrome; prognosis?
Recovery of speech is variable, with some patients having significant improvement but others not.
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Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE); age of onset?
Begin in childhood and frequently persist into adult life.
194
ADNFLE; seizure characteristics?
- Bizarre episodic behaviors in the context of hypermotor seizures [hyperkinetic seizures with prominent motor phenomena, such as thrashing and jerking].
- Seizures occur during non-REM sleep, and patients may experience sudden awakenings with motor manifestations.
- Some patients will be conscious and report auras with epigastric, sensory, or psychic components.
195
ADNFLE; misdiagnosis?
Because of the unusual appearance of these seizures, they are often mistaken for psychogenic nonepileptic seizures (“pseudoseizures”) or sleep-related disorders.
196
ADNFLE; EEG?
- Interictal EEG is usually normal.
- Diagnosis is based on capturing the seizures on video EEG.
197
ADNFLE; treatment?
These seizures usually respond well to carbamazepine or oxcarbazepine.
198
ADNFLE; genetics?
Mutations in the genes that encode subunits of the nicotinic acetylcholine receptors, CNRNA4 and CHRNB2.
199
Electrical status epilepticus during slow-wave sleep (ESES)? Age of onset?
Children between ages 1 and 12 years (peak around 4 to 5 years) with
200
ESES; characteristics?
- Psychomotor impairment and multiple seizure types that occur more often during sleep.
- This disorder has been linked to Landau–Kleffner syndrome.
201
ESES; EEG?
Slow spike–wave complexes occurring during non-REM sleep occupying at least 85% of the slow-wave sleep time.
202
ADNFLE vs. ESES?
- There is an overlap between these two syndromes, but
- ESES present with a more global regression and seizures that may be more difficult to treat.
