Epilepsy Flashcards
Periodic slow wave complex
Subacute sclerosing panencephalitis
Periodic slow waves
CJD
A generalized periodic pattern with a 1-Hz frequency is a characteristic finding of Creutzfeldt-Jakob Disease (CJD).
Spikes
Spikes: 20-70msec
Sharp waves
70-200msec
Often with slow wave 150-350msec
May represent hyperpolarization due to secondary inhibition in large neuronal population
Teratogenicity in women with epilepsy
Prevalence of major congenital malformations: ranges from 4% to 10%. This corresponds to a two- to four-fold increase from the expected prevalence in the general population.
- Can be attributed, at least in part, to exposure to AEDs.
- Has been demonstrated even in the offspring of women with epilepsy not taking any AEDs during pregnancy.
Highest risk of cleft lip and palate, neural tube malformations, and congenital heart disease?
During the first trimester
Folate supplementation
A daily dose of 0.4 mg/d of folate supplementation is recommended for all women of childbearing age, and a folate dose of up to 4 to 5 mg/d is recommended for all women with epilepsy taking AEDs.
Temporal lobe epilepsy
Temporal lobe epilepsy is often characterized by automatisms, altered consciousness, déjà vu phenomena, complex partial seizures, and olfactory hallucinations.
The fencer’s pose
The fencer’s posture is associated with frontal lobe epilepsy and 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 MOA
Gabapentin is neither an enzyme inducer nor inhibitor, so it has less potential interactions with other medications. It can be used as adjunctive therapy for partial seizures with or without secondary generalization. It is not used as monotherapy, given the availability of other more efficacious antiepileptic agents. Gabapentin can worsen generalized epilepsy, especially myoclonic epilepsy. The mechanism by which gabapentin exerts its anticonvulsant action is unknown. Its principal proposed mechanism of action, however, is through an interaction with the alpha2-δ subunit of presynaptic L- type voltage-regulated calcium channel. This subunit was recently identified as the specific binding site of gabapentin, as well as pregabalin, in the mammalian brain; binding of gabapentin and pregabalin may result in modulation of presynaptic neurotransmitter release. 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). Notably, this is in contrast to pregabalin, which has a linear absorption and, thus, has higher bioavailability. Gabapentin is renally excreted, and essentially no metabolism occurs before excretion. The most common side effects of gabapentin include fatigue, headache, nausea, dizziness, and ataxia. There are no significant drug interactions or idiosyncratic reactions. The other medications listed interact with the metabolism of various other drugs.
Ketogenic diet
The ketogenic diet has been reported to be effective in refractory cases of epilepsy in childhood, even when multiple antiepileptic trials have failed. 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.
Febrile seizure
It is estimated that about 3% to 5% of children aged 5 months to 5 years have simple FS. Ninety percent of these events occur in the first 3 years of life.
Risk factors for having a simple FS include family history of FS, prolonged neonatal intensive care unit stay, developmental delay, and day care. Incidence does not increase in proportion to increase in temperature. No risk factors are found in 50% of children with an FS.
One-third of patients have at least one additional seizure.. The risk of afebrile epilepsy after FS is increased in children with developmental delay, abnormal neurologic examination, complex FS (defined later), and a family history of afebrile seizures. There is a <5% risk that patients with a simple FS will develop epilepsy. It is estimated that approximately 15% of patients with epilepsy have a history of FS.
Simple vs complex febrile seizures
Simple FSs are characterized by the following: <15 minutes in duration, generalized seizure, lack of focality, normal neurologic examination, no persistent deficits, and negative family history for seizures.
Complex FSs occur in approximately 20% of FSs and are characterized by the following: >15 minutes in duration, focal features, abnormal neurologic examination, seizure recurrence in <24 hours, and postictal signs (Todd’s paralysis), and are more likely to be due to meningitis, encephalitis, or an underlying seizure disorder.
After reviewing the potential risks and benefits of available effective therapies for short- and long-term prophylaxis, the American Academy of Pediatrics concluded (in its clinical practice guideline on long-term management of children with FS) that neither continuous nor intermittent anticonvulsant therapy is recommended for children with one or more simple FS.
Generalized epilepsy with febrile seizures plus (GEFS+)
The most frequently reported mutation is in SCN1A, which encodes the pore-forming α- subunit of the sodium channel and comprises four transmembrane domains. In contrast to febrile seizures (FS), which occur most commonly between 6 months and 5 years of age, the phenotype of “febrile seizures plus” includes patients in whom FSs continue past the defined upper limit of age. GEFS+ may also be associated with afebrile generalized tonic-clonic (GTC) seizures. One-third of patients have other seizure types as well.
The pattern of inheritance is usually complex, a_lthough initial genetic discoveries first identified an autosomal dominant familial pattern_. Mutations of a number of ion channel genes have been identified in GEFS+ kindreds. These include sodium channel (SCN) subunits (SCN1A, SCN1B, and SCN2A) and GABAA receptor subunit genes (GABRD and GABRG2). The result is increased sodium channel a ctivity or impaired GABA activity, ultimately leading to increased cortical hyperexcitability. The electroencephalogram (EEG) usually shows generalized spike–wave or polyspikes.
Rasmussen’s syndrome
Rasmussen’s syndrome is a rare, but severe, inflammatory brain disorder characterized by progressive unilateral hemispheric atrophy, associated progressive neurologic dysfunction (hemiparesis and cognitive deterioration), and intractable focal seizures (epilepsia partialis continua). Imaging reveals slowly progressive development of focal cortical atrophy, which correlates to the clinical findings.
It has been postulated that antibodies to glutamate receptor-3 (GLUR3) may play a pathogenic role, although the available data are conflicting and the specificity of GLUR3 antibodies in the pathogenesis of Rasmussen’s encephalitis has been challenged.
The focal cortical atrophy is progressive and eventually spreads to the surrounding cortical areas in the same hemisphere, and thus, the best treatment option for the patient’s intractable seizures is the surgical approach with hemispherectomy.
Progressive myoclonic epilepsy
Most progressive myoclonic epilepsies (PMEs) are due to either lysosomal storage disorders and/or mitochondrial disorders. They are characterized by progressive cognitive decline, myoclonus (epileptic and nonepileptic), and seizures (tonic–clonic, tonic, and myoclonic), and may be associated with ataxia or movement disorders.
Examples include Lafora body disease, Unverricht– Lundborg syndrome, neuronal ceroid lipofuscinosis, myoclonic epilepsy with ragged red fibers (MERRF), and sialidosis.
Treatment: Valproic acid is often the first-line treatment of myoclonic epilepsy. Caution is advised with use of valproic acid in patients with mitochondrial mutations, such as POLG gene mutations, because fulminant hepatic failure may result. Other treatments include clonazepam, levetiracetam, topiramate, and zonisamide.
Lamotrigine is sometimes used, but caution is advised because it rarely may worsen myoclonic seizures. Gabapentin, pregabalin, carbamazepine, and vigabatrin are also known to exacerbate some myoclonic epilepsies.
Fosphenytoin vs phenytoin
Fosphenytoin is an IV prodrug of phenytoin. It is composed of a disodium phosphate ester that is water soluble and less alkaline than phenytoin. It does not include propylene glycol and ethyl alcohol as a solvent vehicle as is the case with IV phenytoin.
Fosphenytoin can be loaded at a faster rate, but because the fosphenytoin needs to be converted into phenytoin in plasma, the rate of rise of serum levels is approximately equal to that of phenytoin. Compared to phenytoin, fosphenytoin is not associated with purple glove syndrome; it can be given more rapidly intravenously, its administration is associated with a lower occurrence of cardiovascular side effects, such as hypotension, and it 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. The most common side effects of IV fosphenytoin include pruritus, as well as the other less problematic and typical phenytoin side effects, such as dizziness, nystagmus, and drowsiness.
AEDs that exacerbate myoclonic epilepsy
Typically focal except for LTG/Phenytoin- CBZ, Gabapentin, Pregabalin, Vigabatrin, LTG (+Phenytoin)
Absence seizures
3-Hz spike and wave is characteristic for absence epilepsy. The other options are benign EEG patterns unassociated with seizures (also known as normal variants). Absence epilepsy has a peak age around 6 years and more often affects girls (70%). These patients are generally normal neurologically. Absence epilepsy is characterized by multiple daily spells lasting a few seconds. They begin and end abruptly and interrupt whatever activity is being carried out. During a seizure, there will often be a blank stare; automatisms such as lip smacking, nose rubbing, and picking at clothes may also be present, especially with longer episodes. These seizures are classically provoked by hypoglycemia and hyperventilation. Mild ictal jerks of eyelids, eyes, and eyebrows may occur at the onset of the seizure. 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. First-line treatment includes ethosuximide (which acts via T-type calcium channel inhibition). Valproic acid, lamotrigine, topiramate, and zonisamide are also used. VPA and lamotrigine are used when there are concurrent GTCs.
Notably, the use of lamotrigine has been associated with aggravation of absence seizures on rare occasions. It is important to note that GABAB receptors promote activation of T-type calcium channels. Therefore, some GABAergic drugs can exacerbate absence seizures.
PDR frequencies
β >13 Hz
α 8 to 13 Hz
θ 4 to 7 Hz
δ <4 Hz
Triphasic waves
Triphasic waves are 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.
Metabolic encephalopathy
AEDs that exacerbate absence seizures
Carbamazepine, Gabapentin, LTG, and Phenytoin have all been associated with aggravation of absence seizures and even absence status epilepticus in children with absence epilepsy.
Underlined→absence status
AEDs and OCPs
Many enzyme-inducing antiepileptics (phenytoin, carbamazepine, phenobarbital, oxcarbazepine, and topiramate at doses >200 mg/d) increase metabolism of oral contraceptives. Antiepileptic medications with minimal oral contraceptive interaction include valproic acid, levetiracetam, zonisamide, topiramate (at doses <200 mg/d), gabapentin, pregabalin, and tiagabine
JME
Onset is typically between 8 and 24 years (peaks in teens). Development is typically normal. Boys and girls seem to be equally affected. Myoclonic seizures constitute the most frequent seizure type. These are usually described as large- amplitude and bilateral simultaneous myoclonic jerks. Myoclonic seizures are 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 loss of consciousness, although myoclonic seizures can occasionally be followed by a GTC seizure. Most patients have infrequent GTC seizures, which usually also occur on awakening. Some patients with JME also have typical absence seizures. The EEG reveals generalized 4- to 6-Hz polyspike and wave discharges interictally. Ictally, trains of spikes are seen, which are commonly triggered by photic stimulation (during EEG recordings). The first- line treatment is with valproic acid. Second-line treatments include 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.
Other AEDs that worsen myoclonic sis: LTG, CBZ, Gabapentin, Pregabalin, and Vigabatrin
Benign childhood epilepsy with centrotemporal spikes
Rolandic epilepsy
Spikes are felt to be generated in the base of the rolandic fissure.
Benign childhood epilepsy with centrotemporal spikes (benign rolandic epilepsy of childhood) is fairly common and accounts for about 25% of childhood seizures. Onset is usually between 2 and 13 years of age, and the condition typically resolves in the mid- teenage years. Seizures are characterized by focal motor, sensory, or autonomic manifestations involving predominantly the face, mouth, throat, or extremities, although secondary generalization can occur. T_hese are seizures that classically occur nocturnally (70% only in sleep, 15% only awake, and 15% both). The EEG is characterized by the presence of 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. Normal development, physical examination, and brain imaging are the rule, though there are exceptions. Seizures respond well to certain antiepileptic medication and carbamazepine is usually considered the first line of therapy in the United States. It is important to note that it is often not necessary to treat with AEDs unless seizures are prolonged or frequent; some advocate waiting for two or more seizures to occur before initiating treatment. If antiepileptic medications are started, they can generally be stopped after adolescence. (Only 10% continue to have seizures 5 years after onset.)
Hypsarrhythmia and infantile spasms
Hypsarrhythmia is characterized by abnormal interictal high- amplitude slow waves on a background of irregular multifocal spikes. These waves and spikes have 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 occur during the first year of life (typically 3 to 8 months) and are discussed further in question 45. They are characterized by sudden tonic extension or flexion of limbs and axial body, often occurring in clusters, and especially shortly after awakening. West’s syndrome is a triad of infantile spasms, hypsarrhythmia, and psychomotor arrest or regression. This disorder often occurs because of pre/peri/postnatal insults, tuberous sclerosis, cerebral dysgenesis, and others. Treatment with ACTH is generally first line. Other treatments include corticosteroids, vigabatrin, clonazepam, levetiracetam, topiramate, pyridoxine, and valproic acid. Vigabatrin has been associated with retinal toxicity.
Phenytoin
Inducer
Phenytoin is used for the treatment of partial and/or generalized tonic-clonic seizures (primary or secondary).
Its primary mechanism of action is inhibition of voltage-dependent neuronal sodium channels.
It undergoes predominantly liver metabolism, although there is also minimal renal metabolism. Patients who are in low serum protein disease states (such as liver failure, etc.) need to be followed with free phenytoin levels because of less available protein for binding, making the total levels unreliable.
It is important to understand that phenytoin exhibits nonlinear (zero- order) kinetics, as the metabolic pathways responsible for its metabolism become saturated. This means that when the dose of phenytoin is increased beyond a certain point, its plasma concentration at steady state will no longer increase in a proportionate manner. Rather, small dose changes may result in a large/toxic increment in plasma concentrations. In general, phenytoin approaches zero-order kinetics at total levels of >10 to 15 μg/mL, and small dose increments can potentially cause largeincreases in the serum level.
Idiosyncratic reactions caused by phenytoin include aplastic anemia, Stevens–Johnson syndrome, and hepatic failure. Other side effects include thrombocytopenia, lymphadenopathy, gingival hyperplasia, acne, coarse facial features (also called “phenytoin facies,” from hypertrophy of subcutaneous facial tissue), hirsutism, purple glove syndrome (with intravenous administration), nystagmus, ataxia, dysarthria, diplopia, nausea, dizziness, and drowsiness. Phenytoin can also cause folate deficiency and increased vitamin D metabolism, resulting in premature osteoporosis. Chronically, its use has been associated with a usually mild peripheral neuropathy and with cerebellar but not cortical atrophy. Acutely, the IV form can cause phlebitis, pain, burning, hypotension, and cardiac conduction abnormalities. Phenytoin is a liver enzyme inducer, so it can increase metabolism of many other drugs.
Calculating loading dose for Phenytoin and Depakote (similar)
There are variations of calculating loading and correcting doses of phenytoin. A general simple formula for calculating a supplementing (or loading) IV bolus of phenytoin is as follows: (target total phenytoin level − current total phenytoin level) × (kilogram body weight × volume of distribution). The therapeutic range for phenytoin is 10 to 20 μg/mL. The range for volume of distribution for phenytoin is 0.5 to 1 L/kg, with an average of 0.8 L/kg often used. If we insert the numbers from the case into the formula, the calculation will be as follows: (15 − 10) × (75 × 0.8) = 300 mg. An accurate reassessment of new levels can be obtained by checking free and total levels approximately 2 hours after the IV load.
The correcting IV bolus for valproic acid is as follows: (target total valproic acid level − current total valproic acid level) × (kilogram body weight × volume of distribution). The therapeutic range for valproic acid is 50 to 100 μg/mL. The range for volume of distribution for valproic acid is 0.1 to 0.3 L/kg, with an average of 0.2 L/kg often used. If we apply this formula to the case, the result is as follows: (100 − 70) × (70 × 0.2) = 420 mg.
VPA
Inhibitor
Valproic acid has broad-spectrum antiseizure activity and is commonly used in partial GTC, absence, myoclonic, and tonic seizures, as well as infantile spasms. Its mechanism of action is by sodium and T-type calcium channel antagonism, and it also works as an agonist at the GABAA receptor. It primarily undergoes liver metabolism and is a hepatic enzyme inhibitor. Side effects include cognitive and gastrointestinal complaints. Infrequently, it can cause increased liver enzymes and, rarely, idiosyncratic fatal hepatitis (most common in those <2 years of age). Chronically, it can cause weight gain, hair thinning, polycystic ovarian syndrome, acne, menstrual irregularities, tremor, pancreatitis, and thrombocytopenia. Cerebellar atrophy occurs with long-term phenytoin use but not with valproic acid.
VPA and LTG
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.
CBZ
Inducer
Carbamazepine is used for partial or secondarily GTC seizures, although it is important to remember that it can rarely worsen some generalized epilepsies (including myoclonic and absence epilepsies), similar to phenytoin.
Its primary mode of action is via blockade of sodium channels, which leads to a decrease/prevention of repetitive firing in depolarized neurons. Side effects include dizziness, vertigo, fatigue, drowsiness, diplopia, nystagmus, rash, headache, nausea, vomiting, elevated liver function tests, hyponatremia, and ataxia. Serious idiosyncratic reactions include Stevens–Johnson syndrome, leukopenia, and aplastic anemia.
Carbamazepine undergoes liver metabolism with renal excretion of metabolites, so caution is advised with kidney or liver failure. Carbamazepine is also a hepatic enzyme inducer and undergoes autoinduction. The dose must be titrated up gradually to allow tolerance to develop to its CNS side effects, to avoid early toxicity, and to achieve an optimal therapeutic level as carbamazepine “autoinduces” the hepatic enzymes responsible for its own metabolism. _If carbamazepine is started at too high of a dose, or titrated too fast, the result would be elevated carbamazepine levels with accompanying toxicity early on, as the hepatic enzymes responsible for carbamazepine’s metabolism have not been fully activated (autoinduced) ye_t. It is, therefore, important to remember that carbamazepine’s 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. Therefore, carbamazepine would not be a good option if quick control of new-onset, frequent seizures was desired. Of note, oxcarbazepine does not undergo autoinduction and can be titrated faster.
Valproic acid inhibits the metabolism of the pharmacologically active 10,11-carbamazepine epoxide (the principal metabolite of carbamazepine_). 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._
OXC
Oxcarbazepine is a structural derivative of carbamazepine and is reduced to 10-monohydroxy-carbamazepine and unlike carbamazepine does not undergo oxidation to epoxide. Carbamazepine on the other hand is oxidized to 10,11-carbamazepine epoxide, which is the principal metabolite of carbamazepine. It is important to remember that t_he 10,11- carbamazepine epoxide is pharmacologically active and responsible for many of the side effects seen with carbamazepine use. Because of these differences, oxcarbazepine has less side effects, overall, as compared to carbamazepine. Oxcarbazepine has less liver enzyme induction, no autoinduction (and can thus be titrated more rapidly), and is used for the same seizure types as carbamazepine, having the same mechanism of action, metabolic pathways, and side effect profile._ Approximately 30% of patients who have a history of a rash with carbamazepine will also develop a rash when exposed to oxcarbazepine.
Benzodiazepines MOA
Benzodiazepines are broad-spectrum antiepileptic medications used most commonly for partial GTC, absence, and myoclonic seizures, as well as status epilepticus. They work as GABAA agonists. Binding to the GABAA receptor leads to subsequent activation of chloride channels and, as a result, hyperpolarization of the neuronal membrane and decreased neuronal excitability. Benzodiazepines, in general, undergo liver metabolism and renal excretion of their metabolites.
LTG and metabolism
Oral contraceptives and hormone replacement therapy increase lamotrigine clearance and, thus, decrease serum lamotrigine levels. This effect appears to be limited to contraceptives containing ethinylestradiol. Progesterone-only medications do not appear to have this effect.
During pregnancy, lamotrigine clearance may increase up to 65%, which may result in breakthrough seizures. Therefore, monitoring of lamotrigine serum levels with dose adjustments is recommended during pregnancy and after delivery.
Topamax
Inducer
Topiramate is a broad-spectrum antiepileptic used for partial GTC and absence seizures and for LGS. It has multiple mechanisms of action, including voltage-dependent sodium channel antagonism, enhancement of GABA activity through a nonbenzodiazepine site on GABAA receptors, and antagonism of AMPA/kainate glutamate receptors. It is predominantly excreted unchanged in urine with minimal liver metabolism.
Similar to zonisamide, topiramate is also a weak carbonic anhydrase inhibitor, which explains the potential risk of renal stone formation in patients treated with these agents, as well as potential benefit in idiopathic intracranial hypertension (pseudotumor cerebri is an older term). Other side effects include paresthesias, decreased appetite, weight loss, dizziness, fatigue, and cognitive complaints, such as word-finding difficulty and slowed thinking. Acute angle-closure glaucoma has been reported.
Lacosamide
Lacosamide works by selective enhancement of slow inactivation of voltage-dependent sodium channels. The result is inhibition of repetitive neuronal firing and stabilization of hyperexcitable neuronal membranes.
Lacosamide is also known to 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.
Lacosamide is Food and Drug Administration approved as an adjunct for partial- onset seizures in patients aged 17 years and older. It is available in oral and IV formulations. _It is eliminated primarily by renal excretion and has little drug–drug interaction with other antiepileptic medication_s. Dizziness and nausea are the most common side effects.
Rufinamide
Rufinamide modulates the activity of neuronal sodium channels, resulting in prolongation of the inactive state of the channel. It is Food and Drug Administration approved for the adjunctive treatment of seizures associated with LGS in pediatric patients 1 year of age and older, and in adults.
Rufinamide undergoes extensive metabolism, with only 4% excreted as parent drug. Rufinamide is 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. Plasma half-life of rufinamide is approximately 6 to 10 hours. Rufinamide shows little or no inhibition of most CYP 450 enzymes at clinically relevant concentrations, with weak inhibition of CYP 2E1. Rufinamide is a weak inducer of the CYP 3A4 enzyme.
Medial temporal seizures
Mesial temporal lobe seizures are characterized by behavioral arrest and may be preceded by an aura (a simple partial seizure), such as a rising epigastric sensation, nausea, olfactory and/or gustatory hallucinations, a sensation of fear and terror, or other emotional changes, as well as autonomic manifestations such as tachycardia, respiratory changes, face flushing, or pallor. Patients may also experience dysmnesic manifestations such as déjà vu (sensation of familiarity as if an experience has occurred before, although it has not), déjà entendu (if the experience is auditory), jamais vu (sensation that a familiar experience is new, although it is not), jamais entendu (if the latter experience is auditory), or panoramic vision (a rapid recollection of episodes from the past). During the seizure, the patient may also have automatisms, which are involuntary complex motor activities, such as nose picking, lip smacking, chewing, and picking with the hands. Typically, patients have postictal confusion, which is not present in absence seizures.
Generalized AEDs
Vicious (Valproate)
Lions (Lamotrogine)
Tigers (Topamax)
Kill (Keppra)
Zebras (Zonisamide)
(+PHB, Felbamate**)
+Phenytoin
LTG MOA
Lamotrigine is a broad-spectrum antiepileptic medication and is used for partial and GTC seizures, as well as generalized seizures of Lennox–Gastaut syndrome (LGS). It has also been used for absence and myoclonic seizures, although it is not the first line of therapy for these types of seizures. It works as a sodium channel antagonist and also inhibits glutamate release. It undergoes liver metabolism with renal excretion of metabolites (same as CBZ).
Frontal lobe seizures
Frontal lobe seizures are abrupt in onset, brief, and predominantly associated with elementary motor manifestations but may include complex automatisms. They frequently occur in sleep, often in clusters.
From SMA: This patient has seizures coming from his frontal lobe, more specifically the right supplementary motor area (SMA). The typical semiology of these seizures has been referred to as “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.
Parietal lobe seizures
Parietal lobe seizures are predominantly associated with episodic sensory symptoms, although clinical localization may be difficult as parietal discharges propagate to other brain regions.
Occipital lobe seizures
Occipital lobe seizures usually present with visual phenomena.
West’s syndrome
The triad of infantile spasms, hypsarrhythmia, and developmental arrest is known as West’s syndrome. This condition has been associated with multiple etiologies, such as hypoxic–ischemic injuries, brain malformations or structural abnormalities, congenital or acquired infections, chromosomal abnormalities, and inborn errors of metabolism. Infantile spasms are frequent in patients with tuberous sclerosis, and this condition should be considered in this setting. Every patient presenting with infantile spasms should have an appropriate, thorough workup to look for the cause, including brain magnetic resonance imaging (MRI). In close to 30% of the cases, no specific etiology is found, and these cases are considered cryptogenic.
Side-effects of treatment of infantile spasms/West syndrome
ACTH is commonly used for the treatment of infantile spasms. ACTH should be used carefully, given its potential side effects, which include hypertension, hyperglycemia, weight gain, electrolyte abnormalities, risk of infections, risk of avascular necrosis, and gastrointestinal bleeding. Vigabatrin may also be used for the treatment of infantile spasms, especially in patients with tuberous sclerosis. Vigabatrin should be used with caution as it carries the risk of retinal toxicity.
Aicardi’s disease
This patient has Aicardi’s syndrome, which is a rare genetic disorder, usually associated with an X-linked dominant pattern of inheritance. Aicardi’s syndrome is characterized by the presence of infantile spasms, chorioretinal lacunae, and agenesis of the corpus callosum. Being an X-linked dominant disorder, it is encountered predominantly in girls, as the mutation is lethal in males. This syndrome is associated with various nonspecific ocular malformations, such as cataracts, microphthalmia, retinal detachment, and hypoplastic papilla. The presence of chorioretinal lacunae is pathognomonic for this syndrome. The EEG shows multiple epileptiform abnormalities, such as burst suppression pattern with asynchrony between the two hemispheres and a disorganized background.
Doose’s syndrome
AKA myoclonic–astatic epilepsy.
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. Seizures are predominantly generalized with myoclonic or astatic components, in which the patient loses postural tone and falls, sometimes resulting in injuries. There may be other seizure types, such as absence, GTC, and tonic seizures, and/or nonconvulsive status epilepticus. The EEG demonstrates interictal bilateral synchronous irregular 2- to 3-Hz spike and wave complexes along with parietal rhythmic theta-activity. Myoclonic seizures are associated with irregular spikes and polyspikes. There may be a genetic predisposition, and a family history of epilepsy or abnormal EEGs is frequent.
Although many patients remain normal, some have severe developmental delay and intractable seizures, and the prognosis may be variable. 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.
Dravet’s syndrome
This patient has Dravet’s syndrome or severe myoclonic epilepsy of infancy. This is a severe epilepsy syndrome, in which the patient has frequent seizures and various seizure types. The typical initial presentation is a febrile seizure (FS) in the first year of life; later, these patients develop other seizure types, including myoclonias, atypical absences, and tonic and tonic–clonic seizures, which could be generalized and/or unilateral.
Given the initial presentation with an FS, the diagnosis may be delayed. Males are more affected than females, and there may be a family history of epilepsy or abnormal EEGs.
In fact, 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. The EEG may be normal initially in the interictal period, later showing generalized spike–wave complexes as well as focal and multifocal spikes. 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. Treatment options include valproic acid, topiramate, zonisamide, and ketogenic diet. Importantly, treatment with phenobarbital, phenytoin, carbamazepine, and lamotrigine may exacerbate the seizures.
Ohtahara’s syndrome
This patient has Ohtahara’s syndrome, also known as early infantile epileptic encephalopathy. This is a 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. The EEG typically shows a burst suppression pattern that is present during wakefulness or sleep. 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.
Benign myoclonic epilepsy of infancy
This patient has benign myoclonic epilepsy of infancy (BMEI). This condition affects males more than females, between the ages of 4 months and 3 years. It is characterized by the presence of 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. During a myoclonic seizure, the EEG shows generalized spikes and waves or polyspikes and waves. The interictal EEG is normal. Neuroimaging is usually normal. Seizures respond well to valproic acid, and 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.
Benign neonatal seizures
This patient has benign neonatal seizures. In this syndrome, full- term, otherwise healthy, newborns develop seizures around day 5 of life (also referred to as “fifth day fits”), which are 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. The EEG is normal but may demonstrate the “theta pointu alternant” pattern, characterized by discontinuous, asynchronous, unreactive theta-activity with intermixed sharp waves. 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.
Benign neonatal seizures and benign familial neonatal seizures should be diagnoses of exclusion, and workup to rule out symptomatic seizures is indicated. Benign familial neonatal seizures is an autosomal dominant disorder, characterized by seizures in the first few days of life, which resolve spontaneously within few weeks. Genetic linkage studies have mapped two disease loci, both associated with mutations in voltage-gated potassium channels, in the genes KCNQ2 on chromosome 20 and KCNQ3 on chromosome
8.
Panayiotopoulos syndrome
In early-onset childhood occipital epilepsy or Panayiotopoulos syndrome, t_he seizures begin between 4 and 8 years of age (with a peak incidence at 4 to 5 years) and are characterized by tonic eye deviation and vomiting_. Visual auras are reported during wakefulness, characterized by elementary or complex visual hallucinations and illusions. Partial or generalized tonic-clonic seizures may occur during sleep; in fact, in the majority of children, seizures occur predominantly or exclusively in sleep. The EEG shows high-voltage occipital spikes in 1- to 3-Hz bursts, which disappear with eye opening and reappear with eye closure or darkness. Treatment is generally not required. The prognosis is good, and this condition resolves within several years.
EEG frequencies
