Epilepsy Flashcards

Question

Benign childhood epilepsy with centrotemporal spikes

Answer 1

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.)

Answer 2

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.

Answer 3

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.

Answer 4

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.

Answer 5

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.

Answer 6

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.

Answer 7

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._

Answer 8

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.

Answer 9

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.

Answer 10

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.

Answer 11

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.

Answer 12

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.

Answer 13

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.

Answer 14

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.

Answer 15

**V**icious (**V**alproate) **L**ions (**L**amotrogine) **T**igers (**T**opamax) **K**ill (**K**eppra) **Z**ebras (**Z**onisamide) *(+PHB, Felbamate**)* +Phenytoin

Answer 16

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).

Answer 17

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.

Answer 18

Parietal lobe seizures are predominantly associated with episodic sensory symptoms, although clinical localization may be difficult as parietal discharges propagate to other brain regions.

Answer 19

Occipital lobe seizures usually present with visual phenomena.

Answer 20

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.

Answer 21

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.

Answer 22

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.

Answer 23

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._

Answer 24

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.

Answer 25

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.

Answer 26

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.

Answer 27

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.

Answer 28

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._

Answer 29

Late-onset childhood occipital epilepsy or Gastaut type occurs in older children at a mean age of 8 years (between the ages of 4 and 13 years) and consists of brief seizures with visual manifestations, followed by hemiclonic convulsions and in some cases a postictal migraine. The EEG is similar to that seen in Panayiotopoulos syndrome. 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.

Answer 30

This patient has Lennox-Gastaut Syndrome (LGS). This syndrome is characterized by the triad of seizures of multiple types, EEG with diffuse slow (1.5 to 2 Hz) spike–wave complexes, and cognitive– developmental impairment. The onset is between the ages of 1 to 8 years, with most children presenting at the age of 3 to 5 years. Less than half of these 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. Patients with LGS will develop various seizure types, including atypical absence, tonic, atonic, myoclonic, and tonic– clonic seizures. 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.

Answer 31

This patient has Landau–Kleffner syndrome, also known as acquired epileptic aphasia. This syndrome is characterized by an acquired aphasia associated with epileptiform abnormalities on EEG and seizures of various types. The age of onset is between 2 and 11 years, with a peak onset between 5 and 7 years; these children may 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. The seizures are of various types, including atypical absence, myoclonic, tonic, and tonic–clonic. Furthermore, a small minority of patients do not have a history of clinical seizures. The EEG demonstrates multifocal cortical spikes, predominantly in the _temporal and parietal lobes, most frequently bilaterally_. Antiepileptic agents such as valproic acid and lamotrigine are usually effective in controlling the seizures. Recovery of speech on the other hand is variable, with some patients having significant improvement but others not. Corticosteroids have been tried with variable success.

Answer 32

This patient has autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE). These seizures begin in childhood and frequently persist into adult life. Patients with ADNFLE present with bizarre episodic behaviors in the context of hypermotor seizures, that is, hyperkinetic seizures with prominent motor phenomena, such as thrashing and jerking. _These 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. Because of the unusual appearance of these seizures, they are often mistaken for psychogenic nonepileptic seizures (“pseudoseizures”) or sleep-related disorders. The interictal EEG is usually normal, and the diagnosis is based on capturing the seizures on video EEG. These seizures usually respond well to carbamazepine or oxcarbazepine. _Mutations in the genes that encode subunits of the nicotinic acetylcholine receptors, CNRNA4 and CHRNB2, have been detected_.

Answer 33

Electrical status epilepticus during slow-wave sleep (ESES) presents in children between ages 1 and 12 years (peak around 4 to 5 years) with psychomotor impairment and multiple seizure types that occur more often during sleep. The diagnosis is made with the EEG showing slow spike–wave complexes occurring during non- REM sleep occupying at least 85% of the slow-wave sleep time. This disorder has been linked to Landau–Kleffner syndrome (see question 54). Although there is an overlap between these two syndromes, children with ESES present with a more global regression and seizures that may be more difficult to treat.

Answer 34

Eyes and head version, characterized strictly by a forced and involuntary movement leading to an unnatural position of the head toward one side, are associated with a seizure focus in the contralateral hemisphere and more specifically in the frontal region in the frontal eye fields and motor areas anterior to the precentral gyrus. The association of version with the contralateral hemisphere is more robust if the version occurs immediately prior to the secondarily GTC phase. A case of asymmetric tonic posturing during a seizure is characteristic of seizures arising from the SMA. In the "figure of 4 sign,” in which the extended arm is contralateral to the seizure focus. Therefore, this patient’s seizures originate in the left SMA. Another example is the fencer’s posture, with external rotation and abduction of the arm from the shoulder, with head turn toward the same side of the arm posture; the arm posture is contralateral to the seizure focus. Unilateral dystonic hand/arm posture during a seizure has important lateralizing value in temporal lobe epilepsies, suggesting that the seizure arises from the temporal lobe contralateral to the dystonic upper extremity. The suggested hypothesis is that the discharges originate in the hippocampus and the amygdala, spreading via the fornix and through the basal ganglia, more specifically the ventral striatum, pallidum, and anterior cingulate gyrus. Patients with dystonic posture of one upper limb and automatisms in the opposite upper limb have seizures originating in the temporal lobe ipsilateral to the automatisms.

Answer 35

Phenytoin is a widely used medication for seizures. However, due to its narrow therapeutic index, nonlinear kinetics, and multiple interactions with other medications, toxicity can occur in patients treated with this medication. Phenytoin can be given orally or intravenously. It binds extensively to albumin (almost 90%); _only unbound phenytoin is pharmacologically active_. Medications (such as sulfamethoxazole) that displace phenytoin from albumin may increase free levels, producing manifestations of toxicity. Phenytoin is metabolized by hepatic cytochrome (CYP) P450 enzymes to inactive metabolites, which are then excreted in the urine. Phenytoin follows zero-order kinetic metabolism (discussed in questions 26 to 28). There is a long list of medications that could potentially interact with the metabolism of phenytoin, either increasing or decreasing its serum levels. _Fluconazole and trimethoprim are substrates of the same CYP 450 pathway and can, therefore, raise levels of this AED_. The clinical manifestations of phenytoin toxicity are usually neurologic in nature and, depending on the drug level, range from dizziness, nystagmus, ataxia, and other manifestations of cerebellar dysfunction, to lethargy, confusion, and coma. It is important to check both free and total levels.

Answer 36

A prior history of a complex FS is a known risk factor for subsequent development of epilepsy but is not associated with a higher recurrence recurrence risk of FS (compared to simple FS). The risk is even higher when the complex FS was very prolonged in duration (i.e., febrile status epilepticus). Other risk factors to develop epilepsy include the presence of a neurodevelopmental abnormality and/or family history of epilepsy. Importantly, a family history of FS does not predispose the patient to subsequent development of epilepsy. The evaluation of patients with FS should be targeted at assessing the cause of the seizure and ruling out CNS infections or abnormalities. The exact pathophysiology of FS remains unclear. A relationship between prolonged FS and mesial temporal lobe sclerosis has been proposed; however, this association is controversial and has not conclusively been confirmed in prospective and population-based studies.

Answer 37

Risk factors to develop a first FS include a first- or second-degree relative with a history of FS, developmental delay, neonatal nursery stay for more than 30 days, and attendance of day care. Most patients will have only one FS without recurrence and without subsequent development of epilepsy. Recurrent FS may occur, especially in the presence of recognizable risk factors, which include a family history of FS, age younger than 18 months at the time of the first FS, lower peak temperature, and shorter duration of fever prior to the FS. Simple FS or complex FS carries similar risk of recurrence.

Answer 38

Unverricht–Lundborg syndrome is one of the PMEs. This group of disorders is characterized by myoclonic epilepsy and progressive neurologic deterioration and includes Unverricht– Lundborg syndrome, Lafora body disease, MERFF, sialidosis, and neuronal ceroid lipofuscinosis. Unverricht–Lundborg syndrome, also known as Baltic myoclonic epilepsy, is an _autosomal recessive condition associated with mutations in the gene EPM1 located on the chromosomal locus 21q22.3, which encodes for cystatin B, a cysteine protease inhibitor associated with the initiation of apoptosis._ Patients with Unverricht–Lundborg syndrome present between 6 and 15 years of age with stimulus-sensitive myoclonus, which is action related and worsens over time. Eventually, they develop various seizure types, including absences, focal motor, or GTC seizures. These patients will deteriorate neurologically, presenting with ataxia, tremor, and intellectual decline. _Magnetic resonance imaging is usually normal, and EEG shows generalized spike–waves and polyspikes_. Treatment options include valproic acid, clonazepam, levetiracetam, and zonisamide. Certain AEDs may worsen the seizures, including phenytoin, carbamazepine, oxcarbazepine, vigabatrin, tiagabine, gabapentin, and pregabalin. These patients may worsen progressively, but, in some cases, the disease stabilizes over the years.

Answer 39

A mitochondrial disorder Characteristics suggestive of a mitochondrial disorder: migraines, short stature, ataxia, cognitive impairment, deafness, epilepsy, and elevated lactate. Proximal weakness suggesting a myopathy and muscle biopsy with ragged-red fibers support a mitochondrial process. Mitochondrial disorders are a heterogeneous group of disorders that can affect both the peripheral and central nervous system. Myoclonic epilepsy with ragged red fibers is a mitochondrial disorder that usually starts in the _second or third decade of life_ and _is maternally inherited (like other disorders of mitochondrial DNA). Cerebrospinal fluid studies will show elevation of pyruvate and lactate, and the serum creatine kinase may be elevated. Magnetic resonance imaging of the brain usually demonstrates cerebral atrophy. Point mutations in mitochondrial DNA have been detected in this disorder._

Answer 40

This patient has a progressive myoclonic epilepsy (PME), more specifically sialidosis. There are two types of sialidosis that can cause PME: Type I is caused by a deficiency of α-_neuraminidase_ and presents in adolescents and adults with action myoclonus and slowly progressive ataxia, tonic–clonic seizures, and vision loss. These patients do not have psychomotor or cognitive deterioration or dysmorphism, and, characteristically, the fundoscopic examination demonstrates a cherry red spot. Type II is caused by deficiency of N-acetyl _neuraminidase_ and β-galactosialidase and begins between the neonatal period and the second decade of life. These patients have myoclonus, along with coarse facial features, corneal clouding, hepatomegaly, skeletal dysplasia, and learning disabilities. The sialidoses are _autosomal recessive_, and the gene implicated is _NEU1 in chromosome 6p21.3_. The diagnosis is confirmed with the detection of high urinary sialyl oligosaccharides and by confirmation of the lysosomal enzyme deficiency in leukocytes or cultured fibroblasts.

Answer 41

This patient has Lafora body disease, which is an _autosomal recessive disorder_ associated with a mutation in the gene _EPM2A on chromosome 6q, encoding laforin, a_ ribosomal protein with undetermined function. Patients with Lafora body disease present between 12 and 17 years of age. These patients have seizures of various types, including myoclonus, atypical absences, atonic, complex partial, and _occipital seizures with transient blindness and visual hallucinations_. These patients also have dysarthria, ataxia, as well as emotional disturbance, and cognitive decline leading to dementia. T_he EEG shows an evolution, with multiple spike–wave discharges at the beginning, but progressively over months or years, the background deteriorates and multifocal epileptiform abnormalities appear, mainly in the occipital regions, in addition to generalized bursts_. _Lafora bodies are periodic-acid-Schiff–positive intracellular polyglucosan inclusion bodies found in neurons, cardiac muscle, skeletal muscle, hepatocytes, and sweat gland duct cells, making it possible to detect these bodies in skin biopsy specimens. Most patients die within 10 years of onset and the treatment remains palliative._

Answer 42

Rasmussen’s encephalitis is an inflammatory condition that affects one hemisphere and is characterized by focal seizures, often epilepsia partialis continua, hemiparesis, and progressive neurologic deterioration. This condition most frequently affects children, though adolescents and adults may also be affected. The pathogenesis is not well understood; _however, it is known that it is an inflammatory condition, and an antibody has been detected targeted against the GluR3 subunit of the AMPA receptor, which is a glutamate receptor. Magnetic resonance imaging demonstrates cortical atrophy that is progressive and focal areas of white matter hyperintensity. Histopathologic findings demonstrate perivascular cuffs of lymphocytes and monocytes, as well as glial nodules in the gray and white matt_er. The continuous neuron loss leaves areas of spongy tissue degeneration. In Rasmussen’s encephalitis, seizures are not typically well controlled with AED monotherapy and are usually intractable. Anti- inflammatory agents such as corticosteroids and other immune modulating treatments including IV immune globulin and plasmapheresis have been tried with some promise but variable success. Hemispherectomy is often needed, providing the possibility of cure of the seizures.

Answer 43

Elderly patients tend to: Absorption: 1) have lower gastric acidity, making the weakly basic drugs less easily absorbed and weakly acidic drugs more easily absorbed. 2) Gastric emptying may be slowed and intestinal villi height may be reduced, making the absorption surface smaller. Distribution: 1) Given that lean body mass decreases with aging, total body water mass decreases, making the volume of distribution of hydrophilic drugs smaller. The proportion of fat also decreases with age, reducing lipophilic drug distribution volume. Metabolism: The metabolism of drugs is also affected, and hepatic metabolism decreases, given the reduction in liver volume, hepatic flow, and bile flow. 1) Renal blood flow and glomerular filtration rate are lower in the elderly, and, therefore, renal excretion is also decreased. 2) Hepatic synthesis of protein is lower, and the free fraction of drug that binds to protein tends to increase. Therefore, the measurement of free drug levels is recommended if available for that specific drug. The therapeutic window is also smaller in elderly patients. These patients tend to have multiple comorbidities and are usually on multiple medications that could potentially interact with AEDs. Therefore, careful selection of drugs and monitoring for side effects are strongly recommended in this group of patients.

Answer 44

Valproic acid is a broad-spectrum antiepileptic agent that can be used in various seizure types. Its acts by blocking sodium channels, but it may have other mechanisms of action, including effects on GABAA receptors and T-type calcium channels. This medication is widely used; however, it has various side effects. These include weight gain, alopecia, tremor, gastrointestinal symptoms, such as nausea and vomiting, and pancreatitis. It can be hepatotoxic and even produce fulminant hepatic failure and hyperammonemia, leading to encephalopathy. It can be undesirable in women, as it may produce a polycystic ovarian syndrome with menstrual irregularities, and it is teratogenic, specifically producing neural tube defects. Valproic acid is an enzyme inhibitor and may lead to interactions with other medications, elevating the levels of many medications, including other AEDs. _Osteoporosis from vitamin D deficiency is postulated to occur from enzyme-inducing antiepileptic agents; however, vitamin D deficiency is also seen in patients taking valproic acid monotherapy._

Answer 45

This patient had a first unprovoked seizure. The International League Against Epilepsy defines this as a seizure occurring in a person older than 1 month with no history of unprovoked seizures. This definition excludes neonatal seizures, febrile seizures (FS), or seizures in the setting of an acute precipitating cause. According to practice parameter guidelines published by the American Academy of Neurology, there is good evidence to support both the use of a routine EEG and brain imaging with CT or MRI in patients presenting with a first unprovoked seizure. There is inadequate evidence to support or refute laboratory studies, lumbar puncture, and toxicology screens. However, specific clinical circumstances may support the need for these additional tests on an individual basis, such as if the patient is febrile and CNS infection is suspected, in which case a lumbar puncture would be diagnostic. The risk of seizure recurrence is influenced by various parameters. According to the 2015 practice parameter guidelines published by the American Academy of Neurology, there is strong evidence for seizure recurrence in the presence of a prior brain insult such as trauma or stroke, or an EEG with epileptiform abnormalities. There is moderate evidence for seizure recurrence when there are brain imaging abnormalities, or nocturnal seizures. Not every patient with a first unprovoked seizure needs to be treated. According to the same 2015 guidelines, there is strong evidence that seizure recurrence is greatest in the first 2 years after a first seizure (21% to 45%). The decision to treat is a complex one and depends on the risk of recurrence on the basis of the factors mentioned, the risk–benefit ratio of treatment, and other patient- specific considerations. Immediate AED therapy as compared with the delay of treatment pending a second seizure is likely to reduce seizure recurrence in the subsequent 2 years, but it may not improve quality of life. Furthermore, over the longer term (\>3 years), immediate AED therapy is unlikely to improve the prognosis for sustained seizure remission. The risk of AED adverse effects ranges from 7% to 31%, but they are predominantly mild and reversible.

Answer 46

Periodic lateralized epileptiform discharges are sharply contoured waveforms with various morphologies that appear at regular periodic intervals every 1 or 2 seconds and are lateralized to one hemisphere only or to a single region in one hemisphere. These are seen in structural brain lesions (usually in the acute or subacute setting), such as in a stroke, hemorrhage, infection (importantly, HSV encephalitis), brain abscess, or tumor, and are usually transient, disappearing with time as the patient recovers from the acute event. Typically, patients with PLEDs are encephalopathic with a diffusely slow EEG background. Usually, PLEDs are not thought to represent ongoing ictal activity and are considered among the interictal phenomena/patterns.

Answer 47

An initial dose of 0.2 mg is given, and if there is no response within 30 seconds, a 0.3-mg dose is given. If there is still no response after another 30 seconds, 0.5 mg is given every minute up to six times for a maximum total dose of 5 mg.

Answer 48

Sleep stages are separated into four stages: stage NREM1 (N1), stage NREM 2 (N2), stage NREM 3 (N3), and rapid eye movement (REM) sleep. _Stages 3 and 4 sleep, previously considered separate stages, are now combined together and called slow-wave sleep. Normal sleep consists of 4 to 6 cycles/night of non-REM (NREM) sleep, with each cycle followed by a period of REM sleep. The first REM period normally occurs around 90 minutes after sleep onset._ The sleep stages are defined electrographically by certain criteria as specified by the American Academy of Sleep Medicine scoring manual. Some characteristics of the different sleep stages are as follows: Stage N1: This stage normally occupies approximately 5% of total sleep time. It is marked polysomnographically by slow rolling eye movements, a reduction in muscle artifact, attenuation of the occipital dominant α-rhythm, and increasing slower frequencies. Diphasic sharp waves maximal at the vertex (vertex sharp waves) and positive occipital sharp transients of sleep (POSTS) are other features. Stage N2: Typically accounts for approximately 45% of sleep time. This stage is characterized on polysomnogram by the presence of K complexes, such as the one depicted in Figure 5.12. A K-complex is a diphasic wave (with an initial upward and then a downward deflection) that is maximal over frontocentral regions. The other main feature of stage N2 is the sleep spindle, also seen in Figure 5.12 (red arrow), following the K complex (yellow arrow). K-complexes typically appear around 5 months of age. A sleep spindle is relatively high frequency (12 to 14 Hz), brief (\<2 seconds) activity that is maximal over central regions. Delta activity may be present but occupies less than 20% of this stage of sleep. Developmentally, sleep spindles first appear around 2 months of life but do not reach adult appearance until 2 years. Stage N3, or slow wave sleep, was previously separated into stages 3 and 4. It typically accounts for 20% to 25% of sleep time but decreases with increasing age. In N3, delta activity accounts for more than 20% of visually detectable frequencies. REM sleep accounts for 20% to 25% of sleep time. Alpha activity, reminiscent of that seen during wakefulness, may be seen in occipital leads. Obviously, this stage is characterized by the presence of rapid eye movements, as is seen in Figure 5.14A (yellow arrows). Other features include sawtooth waves in central regions. Normally during REM sleep, most muscles are atonic (aside from the diaphragm and extraocular muscles). REM sleep atonia is seen on polysomnography as minimal activity in surface EMG leads placed on the chin, as seen in Figure 5.14A (green arrows; discussed further in questions 92 and 93). _REM sleep accounts for up to 50% of sleep time in neonates, and the percentage of sleep spent in REM sleep then decreases with increasing age. Selective serotonin reuptake inhibitors reduce the length of time spent in REM sleep and increase REM sleep latency._ The amount of sleep required is greatest in the neonatal period and decreases across the life span. While in the average adult population, sleep requirements are typically in the range of 7 to 8 hours, this is highly variable and long sleep requirements (\>10 hours per night) and short sleep requirements (\<6 hours a night) may both occur.

Answer 49

Obstructive sleep apnea (OSA) is diagnosed on the basis of a combination of clinical features (discussed in question 87) and the apnea-hypopnea index (AHI) observed during an overnight polysomnogram. _Apneas and hypopneas are characterized by complete cessation or reduction of airflow, respectively, for at least 10 seconds. In addition, obstructive hypopneas/apneas are associated with EEG arousal and/or oxygen desaturation (of 3% to 4%, depending on the criteria being employed). The AHI is a measure of how many apneas and hypopneas, on average, occur per hour. An AHI of 5 to 15 per hour is considered mildly elevated, of 15 to 30 per hour moderately elevated, and more than 30 per hour is severely elevated. A similar index of apneas and hypopneas is the so-called respiratory disturbance index, which in addition to apneas and hypopneas also accounts for respiratory-event-related arousals._ To support a diagnosis of sleep apnea, a_pneas or hypopneas should occur five or more times per hour and last at least 10 seconds each, as detected by polysomnogram (discussed further in question 86)_. During obstructive apneas, respiratory effort is present, differentiating this condition from central sleep apnea (discussed in question 88), in which there is no respiratory effort.

Answer 50

Besides the clinical manifestations directly associated with OSA syndrome, patients with this condition are at a higher risk of cardiovascular and cerebrovascular events. Patients with OSA are at higher risk to develop cardiac arrhythmias, hypertension, cor pulmonale, as well as myocardial infarctions and strokes.

Answer 51

Management includes weight loss, avoidance of alcohol and sedatives, and use of positive airway pressure. Much less commonly, some patients may be candidates for glossopharyngeal stimulation and/or upper airway surgery.

Answer 52

This patient has central sleep apnea syndrome (CSAS) with Cheyne- Stokes breathing. This disorder is characterized by periods of absent airflow along with a cessation of ventilatory effort during sleep, alternating with periods of _a crescendo–decrescendo respiratory flow_ (tidal volume) The clinical manifestations of CSAS are similar to those of OSA, because patients will often experience insomnia, inability to maintain sleep, and excessive daytime sleepiness, as well as arousals, bradycardia or tachycardia, and desaturations during the apneas. In central apnea, there is a transient central cessation of respiratory drive, and airway obstruction does not occur. _Polysomnogram is helpful in making the diagnosis, showing episodes of apnea, in which there is no respiratory effort_. This type of sleep-disordered breathing is much less common than OSA. Comorbid heart failure is a frequent cause of CSAS. Treating the underlying heart failure may improve the sleep disorder though in some patients, positive airway pressure treatment is needed. Opioids can precipitate or worsen central apneas. Given that there is no airway obstruction, surgical interventions are not indicated.

Answer 53

Type of non-REM parasomnia, arousal disorder Arousal disorders include confusional arousals, sleepwalking, and sleep terrors. The latter three are non-REM parasomnias typically arising from slow-wave sleep or stage N3 (previously known as stage 3 and stage 4 sleep; these two stages have been combined into stage N3). Sleep terrors are more common in children, usually occurring between the ages of 5 and 7 years but can occur in adults. These events are characterized by a sudden arousal with screaming or crying, associated with autonomic and behavioral manifestations of intense fear and some degree of confusion if awakened. Sleep terrors occur in the first third of the night (a period during which stage N3 is most likely to occur). In nightmares, as opposed to sleep terrors, the patients usually remember the dream, they occur in the last third of the night, and there is less autonomic activity. When awakened from nightmares, patients are not typically confused.

Answer 54

Type of non-REM parasomnia, arousal disorder Sleep walking is a non-REM parasomnia. Parasomnias have been classified into REM parasomnias, arousal disorders, sleep–wake transition disorders, and other parasomnias. Arousal disorders include confusional arousals, sleepwalking, and sleep terrors. The latter three are non-REM parasomnias arising from slow-wave sleep or stage 3 sleep (previously known as stage 3 and stage 4 sleep; these two stages have more recently been combined into stage 3 sleep). Sleepwalking consists of a series of complex behaviors resulting in walking during sleep. This condition occurs more commonly in children but can present in adolescents and adults, and a positive family history has been reported in many cases. Sleepwalking occurs more commonly in the first third of the night, and patients have complex motor behaviors, with amnesia of the episode. These patients are difficult to arouse and may become confused and exhibit violent behavior when this is attempted. Sleepwalking is not necessarily a manifestation of narcolepsy and does not reflect REM sleep without atonia (discussed in question 92). The clinical presentation of this patient is not consistent with narcolepsy, nor with sleep terrors (discussed in question 89). Confusional arousals are a non-REM parasomnia occurring in children, in which the patient is confused following an arousal from slow-wave sleep.

Answer 55

Confusional arousals are a non-REM parasomnia occurring in children, in which the patient is confused following an arousal from slow-wave sleep.

Answer 56

This patient has had a nightmare, which is a complicated, frightening dream. Nightmares should be differentiated from sleep terrors (discussed in question 89). Patients with nightmares usually recall the dream in detail, the event occurs in _the last third of the night,_ and there is much less autonomic activity as compared to sleep terrors. When most people are awakened from nightmares, they tend to have their normal intellectual function and are not confused. Sleep terrors occur more commonly in children, and patients wake up screaming or crying, with prominent associated autonomic and behavioral manifestations of intense fear, as well as confusion on awakening. _Sleep terrors occur in the first third of the night._

Answer 57

This patient has a REM parasomnia, specifically REM sleep behavior disorder (RBD). Normally, there is atonia (loss of muscle tone) during REM sleep. RBD is characterized by at least intermittent loss of this normal REM atonia as is shown in Figure 5.14B (blue arrow) and by the appearance of complex motor activity during which the patient acts out dreams. Dream content is usually violent with associated movements (e.g., punching, kicking, and running). This can cause injuries to the patient or to the bed partner. The prevalence of RBD increases with increasing age. Over half of patients with RBD go on to develop a neurodegenerative disorder, most often α-synucleinopathies such as Parkinson’s disease, multisystem atrophy, or dementia with Lewy bodies. Of all the disorders listed in question 92, only Parkinson’s disease is an α- synucleopathy. Treatment of RBD includes interventions to minimize risk of injury (such as padding the headboard and bedside table) as well as pharmacologic agents such as melatonin and clonazepam.

Answer 58

Sleep paralysis is characterized by persistence of REM atonia in wakefulness. Clinically, it is characterized by a transient paralysis during sleep onset or on awakening; the patient is fully conscious during these events. Sleep paralysis is a feature of narcolepsy (discussed in question 95) but can be seen in normal individuals as well. REM sleep, as described in questions 83 to 85, is normally characterized by atonia in most muscles (discussed in question 92), though muscle tone in the extraocular muscles and diaphragm is maintained. Because accessory respiratory muscles are atonic, REM sleep is a period of increased risk for obstructive respiratory events.

Answer 59

Parasomnias have been classified into REM parasomnias, arousal disorders, sleep–wake transition disorders, and other parasomnias.

Answer 60

Hypnagogic hallucinations occur at sleep onset. A useful mnemonic is that the word “go” is present in the word hypnagogic, as in going to sleep. These hallucinations may be seen in normal individuals but are also associated with narcolepsy. Hypnopompic hallucinations occur on awakening from sleep. These may occur in normal individuals and in narcolepsy and do not generally suggest a primary psychotic disorder.

Answer 61

This patient has Kleine–Levin syndrome, which is a type of recurrent hypersomnia. This condition is characterized by recurrent episodes of hypersomnia that typically occur weeks or months apart. Onset is in early adolescence and the episodes can last for several days and sometimes weeks, appearing many times per year. Patients sleep for prolonged periods of time, 18 to 20 hours, often waking only to eat and void. During these episodes, patients may exhibit irritability, aggressiveness, confusion, hypersexuality, and a voracious appetite. Disturbance of social life is significant during these episodes. In between episodes, patients sleep normal amounts and behave normally. This disorder is more common in males but can occur in females, in whom episodes of hypersomnolence may occur around the time of menstruation. While idiopathic hypersomnia and narcolepsy (discussed in question 95) are marked by hypersomnolence, these are more chronic rather than the intermittent episodes seen in Kleine-Levin syndrome. Idiopathic hypersomnia is characterized by chronic excessive daytime sleepiness, in the absence of a primary nocturnal sleep disorder, or other medical condition or factor that could account for the hypersomnolence. Patients complain of hypersomnia and sleep for long periods of time, but the sleep is not refreshing. The diagnosis is made only when no other medical or psychiatric condition can explain the hypersomnia. Narcolepsy in its classic form, now called type 1 narcolepsy, is a disorder that is characterized by excessive sleepiness, cataplexy, sleep paralysis, and hypnagogic and hypnopompic hallucinations. Patients with narcolepsy suffer sleep attacks, with episodes of involuntary sleep in inappropriate circumstances. Brief episodes of sleep, or volitional naps, lasting 15 to 30 minutes are usually refreshing.

Answer 62

This patient has narcolepsy with cataplexy, now called type 1 narcolepsy. This is a disorder characterized by excessive sleepiness, cataplexy, sleep paralysis, and hypnagogic and hypnopompic hallucinations (discussed in question 93). Patients with narcolepsy suffer sleep attacks, in which the patient has an irresistible desire to fall asleep during inappropriate circumstances. These sleep attacks are short, lasting 15 to 30 minutes, and the patient feels refreshed afterward. Although cataplexy is associated with narcolepsy, not all patients with narcolepsy have cataplexy. Cataplexy is characterized by episodes of sudden loss of tone of voluntary muscles, sparing respiratory and ocular muscles. During these attacks, remove the patients may fall and be unable to move, and deep tendon reflexes are decreased or absent. Patients have preserved consciousness. Cataplectic attacks may be triggered by emotional events, such as laughter or anger. The diagnosis of narcolepsy is supported by two features on a daytime multiple sleep latency test: (i) a mean sleep latency of 8 minutes or less and (ii) REM sleep within 15 minutes of sleep onset, during at least two of four nap trials. Cataplexy may be misdiagnosed as seizures, pseudoseizures, or conversion disorder/psychogenic events. However, the triggering of episodes by emotion as well as other features including hypersomnolence should prompt consideration of narcolepsy. Sleep paralysis, transient paralysis that intrudes from REM sleep into wakefulness, is also commonly associated with narcolepsy (discussed in question 93). Gamma-hydroxybutyrate has been approved for the treatment of sleepiness and cataplexy in the United States. Other treatment options for cataplexy include tricyclic antidepressants or serotonin reuptake inhibitors

Answer 63

Narcolepsy with cataplexy (discussed in question 95) is associated with a loss of hypocretin neurons in the lateral hypothalamus, and cerebrospinal fluid (CSF) hypocretin levels are low in these patients. In contrast, in patients with narcolepsy without cataplexy, CSF hypocretin levels are normal.

Answer 64

Circadian rhythm disorders are characterized by a misalignment between the patient’s sleep pattern and the sleep pattern regarded as the societal norm.

Answer 65

In shift work sleep disorder, patients experience symptoms of insomnia or excessive sleepiness that occurs as transient phenomena in relation to work schedules. Also, given the need for social interaction with people maintaining regular working hours, individuals with shift work sleep disorder may restrict their sleeping hours, worsening the symptoms of insomnia and sleepiness.

Answer 66

In DSPS, the major sleep episode is delayed in relation to the desired, conventional bedtime, resulting in perceived sleep-onset insomnia and difficulty awakening. When these patients are able to sleep at the bedtime they are inclined to, there is no problem with falling asleep or waking up. This condition is more common in adolescents. Treatment may include chronotherapy or melatonin. The suprachiasmatic nucleus in the anterior hypothalamus is known as the circadian pacemaker and regulates biological circadian rhythms. In DSPS, circadian markers are altered: melatonin reaches maximal levels and core body temperature reaches a minimum later as compared to controls that follow sleep and wake times more consistent with societal nor

Answer 67

In chronic insomnia disorder (discussed in question 100), patients worry about being unable to sleep and focus on their insomnia, which causes frustration and further inability to fall asleep.

Answer 68

In advanced sleep phase syndrome, the major sleep episode is advanced in relation to the desired clock time, resulting in early evening sleepiness and early sleep onset, as well as early awakening time (as discussed in question 98). This condition is more common in older adults.

Answer 69

In non–24-hour sleep–wake rhythm disorder (also known as “free-running disorder”), the 24- hour light-dark cycle and the endogenous circadian rhythm are not in synchrony. This disorder typically occurs in blind individuals in whom endogenous circadian rhythm entrainment does not occur because of lack of photic input into the circadian pacemaker. Non– 24-hour sleep–wake rhythm disorder manifests with periods of perceived insomnia and daytime sleepiness, as a progressively delaying sleep–wake pattern emerges, alternating with brief asymptomatic periods. This contrasts with DSPS in which symptoms are relatively stable.

Answer 70

The suprachiasmatic nucleus in the anterior hypothalamus is known as the circadian pacemaker and regulates biological circadian rhythms. In DSPS, circadian markers are altered: melatonin reaches maximal levels and core body temperature reaches a minimum later as compared to controls that follow sleep and wake times more consistent with societal nor

Answer 71

Irregular sleep–wake rhythm disorder is marked by lack of clearly defined and consistent sleep and wake patterns, such that periods of insomnia occur during periods of desired sleep (typically at night) and hypersomnolence occurs during periods of desired wakefulness (during the day). Sleep occurs in erratic bouts throughout the 24-hour period. It is most often seen in individuals with neurodegenerative disorders, such as dementia, and in developmentally delayed children.

Answer 72

This patient has chronic insomnia disorder. Insomnia is a disorder of initiating and/or maintaining sleep that results in significant fatigue or effects on function or quality of life. In the form of insomnia often termed psychophysiologic insomnia, patients “try to fall asleep” and are extremely concerned about and focus on their insomnia. There is frustration about being unable to initiate and maintain sleep. This worry about the need for sleep prevents these patients from falling asleep adequately, creating anxiety regarding sleepless. These patients do not meet criteria for a generalized anxiety disorder.

Answer 73

Characterized by an urge to move the legs that may be associated with abnormal sensations that may be difficult to describe. The urge to move the legs is worse at rest and in the evening or nighttime, at least initially. The urge to move the legs is partially or completely relieved by movement. Patients with RLS can have sleep disturbance and insomnia. Restless legs syndrome can be primary or secondary to several conditions including iron deficiency. In general, iron supplementation should be initiated for ferritin levels less than 50 ng/mL. Many other conditions can also be associated with symptoms of leg restlessness, including folate deficiency, chronic renal failure, neuropathies, myelopathies, multiple sclerosis, diabetes mellitus, amyloidosis, cancer, peripheral vascular disease, rheumatoid arthritis, hypothyroidism, and certain drugs. Most antidepressants including selective serotonin reuptake inhibitors, tricyclic antidepressants, and serotonin-norepinephrine reuptake inhibitors are associated with precipitation or worsening of RLS symptoms. Among the antidepressants, bupropion is least likely to cause RLS symptoms. Although the pathophysiology is not completely understood, RLS has been associated with abnormalities in dopaminergic transmission. Dopamine agonists, including pramipexole and ropinirole, are useful for treatment of RLS. Other treatments include alpha-2 delta ligands (gabapentin, pregabalin) and in more severe cases, opioids.

Answer 74

Periodic limb movements (PLMs) are a polysomnographic finding in which there are recurrent limb movements during non- REM sleep, most commonly of the lower extremities. In PLM disorder, PLMs occur more than 15 times per hour and are associated with arousals and sleep fragmentation, leading to insomnia and excessive daytime sleepiness. Periodic limb movements are often seen in patients with RLS, but in this case, the most likely diagnosis on the basis of the clinical information is RLS.

Answer 75

Temporal lobe epilepsy

Answer 76

Absence epilepsy

Answer 77

Carbamazepine

Answer 78

Topamax and Zonisamide

Answer 79

Lamotrigine

Answer 80

Infantile spasms

Answer 81

Myoclonic astatic epilepsy

Answer 82

Severe myoclonic epilepsy of infancy

Answer 83

Early infantile epileptic encephalopathy

Answer 84

Triad of infantile spasms, hypsarrythmia, and psychomotor delay or regression

Answer 85

Occipital epilepsy with tonic eye deviation, octal vomiting, and visual seizures

Answer 86

Multiple seizure types, slow spike-wave complexes, and psychomotor delay or regression

Answer 87

Epilepsy with multiple seizure types and acquired aphasia

Answer 88

AD nocturnal frontal lobe epilepsy

Answer 89

Hypothalamic hamartoma

Answer 90

Contralateral frontal lobe

Answer 91

Contralateral temporal lobe

Answer 92

Unverricht-Lundborg syndrome

Answer 93

Unverricht-Lundborg syndrome

Answer 94

Laforra syndrome

Answer 95

Sialidosis

Answer 96

Myoclonic epilepsy with ragged red fibers

Answer 97

Structural abnormality. Typically seen with HSV encephalitis.

Answer 98

Stage 2 sleep

Answer 99

Central sleep apnea

Answer 100

Narcolepsy with cataplexy

Answer 101

Restless legs syndrome

Answer 102

alpha-synucleinopathies

Epilepsy Flashcards

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