Review Article

Address correspondence to Dr Nancy Foldvary-Schaefer, Cleveland Clinic, 9500 Euclid Complex Nocturnal Ave, Cleveland, OH 44195, [email protected]. Relationship Disclosure: Behaviors: Nocturnal Dr Foldvary-Schaefer has served on the speakers bureaus of Jazz and Pharmaceuticals and UCB; has received an honorarium for co-editing an issue of Nancy Foldvary-Schaefer, DO, MS, FAASM; Clinics; and has received Zahreddin Alsheikhtaha, MBBS, RPSGT royalty payments for authorship of a textbook on from Oxford University Press. ABSTRACT Dr Foldvary-Shaefer also Purpose of Review: This article summarizes the clinical and electrophysiologic mani- receives research support from Cleveland Medical festations of nocturnal seizures, particularly nocturnal frontal lobe (NFLE), Devices, Inc, and ResMed. parasomnias, and other disorders presenting with complex behaviors in sleep. The Dr Alsheikhtaha reports no evaluation and treatment of patients with complex nocturnal behaviors can be chal- disclosure. Unlabeled Use of lenging. While the differential diagnosis of sleep-related movements, including Products/Investigational physiologic and pathologic phenomena, is extensive, the focus of evaluation in pa- Use Disclosure: tients with complex nocturnal behaviors distinguishes between nocturnal seizures and Drs Foldvary-Schaefer and Alsheikhtaha report parasomnias. no disclosures. Recent Findings: Seizures in NFLE have a wide range of complexity and severity, * 2013, American Academy overlapping considerably with the disorders of arousal from non-REM (NREM) sleep. of Neurology. Video with EEG (VPSG-EEG) has identified key clinical features useful in differentiating these disorders. A dysfunctional arousal mechanism involving the cholinergic system is involved in the pathophysiology of the autosomal dominant form of NFLE and NREM parasomnias. The high prevalence of parasomnias in NFLE families further confounds their distinction. VPSG-EEG combines PSG with compre- hensive EEG to evaluate unexplained nocturnal behaviors when epileptic seizures are suspected. This procedure provides improved detection of interictal and ictal EEG abnormalities and time-synchronized correlation of clinical and neurophysiologic phenomena. Summary: The diagnosis of complex nocturnal behaviors is among the most difficult to establish in sleep medicine clinics and laboratories. VPSG-EEG is indicated in the evaluation of patients with complex nocturnal behaviors when routine EEG is non- diagnostic. Ongoing research is necessary to fully elucidate the pathophysiology of these disorders, which share a host of clinical manifestations.

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Supplemental digital content: Videos accompanying this ar- ticle are cited in the text as Supplemental Digital Content. INTRODUCTION ment disorders discussed elsewhere in Videos may be accessed by clicking on links provided in Characterizing the nature of complex this issue may warrant the HTML, PDF, and iPad nocturnal behaviors is one of the most consideration. The differential diagnosis versions of this article; the URLs are provided in the print difficult diagnostic challenges in sleep of complex nocturnal behaviors includes version. Video legends begin medicine. An accurate diagnosis of sleep- seizures with tonic and/or hypermotor on page 127. related events generally relies on the features, disorders of arousal from NREM correct distinction between nocturnal sleep, REM sleep behavior disorder seizures and disorders of arousal from (RBD), and sleep-related dissociative non-REM (NREM) sleep, although other disorders. Like parasomnias, nocturnal parasomnias and the sleep-related move- seizures occur during entry into sleep,

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Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited. KEY POINT within sleep, or during arousals from h TABLE 6-1 Differential Sleep is an important sleep, and have a broad range of semi- Diagnosis of modulator of EEG ology, including autonomic nervous sys- Complex Nocturnal abnormalities and tem changes, skeletal muscle activation, Behaviors seizures in patients with and seemingly purposeful, goal-directed epilepsy; non-REM sleep complex behaviors outside of con- b Sleep-Related Epilepsy activates and REM sleep inhibits epileptic sciousness. Ill-defined EEG manifesta- b Disorders of Arousal From tions and activation by Non-REM Sleep discharges and seizures. and stress are features of both nocturnal Confusional arousals seizures and parasomnias. Disorders as- sociated with complex nocturnal behav- Sleep terrors iors are generally chronic conditions b REM Sleep Behavior Disorder that lead to injury, sleep disruption, b Other Parasomnias and daytime difficulties when diagnosis Sleep-related dissociative and treatment are delayed. In this disorder article, the clinical and electrophysio- Sleep-related groaning logic manifestations of disorders pre- () senting with complex behaviors in sleep b Sleep-Related Movement are reviewed (Table 6-1). Disorders Periodic limb movement NOCTURNAL SEIZURES disorder Basic Concepts Relating to Rhythmic movement disorder Sleep and Epilepsy b Psychogenic Seizures The modulatory effects of the sleep-wake b Nocturnal Panic Attacks cycle on seizures and the EEG in epilepsy b Sleep-Related Breathing have been recognized for over a century. Disorders Neuronal networks generating wakeful- b Nocturnal Wandering ness, NREM sleep, and REM sleep give Associated With Dementia and rise to different physiologic character- Other Forms of Cognitive istics influencing the likelihood of Impairment occurrence.1,2 NREM sleep is a state of EEG synchronization and relative pres- ervation of antigravity muscle tone. expression of seizures. The activating Synchronous oscillations of cortical neu- effects of NREM sleep and sleep depri- rons that generate sleep spindles, K vation on seizure occurrence and the complexes, and tonic background slow expression of IEDs have been exten- waves during NREM sleep promote sively reviewed.3 Several epileptic disor- seizure propagation and the expression ders characterized by seizures occurring of interictal epileptic discharges (IEDs). predominately or exclusively from sleep, In contrast, REM sleep is characterized the so-called sleep-related , by EEG desynchronization and loss of have been recognized (Table 6-2; Sup- skeletal muscle tone. Desynchronization plemental Digital Content 6-1, links. of the EEG impedes seizure propagation lww.com/CONT/A30). and the expression of IEDs during REM The prevalence and natural history of sleep and wakefulness. Preservation of sleep-related epilepsies is poorly eluci- antigravity muscle tone during NREM dated. In the largest prospective study, sleep permits expression of seizure- 7.5% of 1200 patients had seizures related movements, while its absence restricted to sleep, only 11.0% of whom during REM sleep blocks the clinical developed wake seizures, typically within

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tomatogenic area may represent the TABLE 6-2 Sleep-Related Epilepsy Syndromes electrical seizure onset or the earliest spread of the electrical seizure activity b Benign focal epilepsy of from a silent area to symptomatogenic childhood with centrotemporal areas, in which case early clinical mani- spikes festations can erroneously suggest origin b Panayiotopoulos syndrome from distant areas within the activated network. b Nocturnal frontal lobe epilepsy According to a semiologic seizure Autosomal dominant classification proposed in the late 1990s, nocturnal frontal lobe epilepsy seizures are classified as auras, auto- b Lennox-Gastaut syndrome (tonic nomic seizures, dialeptic seizures (ie, seizures) having the main manifestation of alter- b Landau-Kleffner syndrome ation in consciousness independent of ictal EEG features), motor seizures, and b Epilepsy with continuous spike special seizures.5 While virtually all sei- waves in sleep zure types arise from both sleep and waking states, the type of seizures producing complex nocturnal behaviors 2 years of the first nocturnal seizure.4 For andmostlikelytobeconfusedwith a variety of reasons, the prevalence of parasomnias are motor seizures. Motor sleep-related epilepsies is likely to be seizures are differentiated as simple and underestimated. This is due in part to complex. Simple motor seizures are the broad spectrum of seizure semi- characterized by movements that are ology; in some patients, clinical features simple and unnatural, similar to those are mild and unrecognized; in others, elicited by electrical stimulation of pri- clinical features of NREM arousal disor- mary motor areas. These include myo- ders are interpreted by the patient and clonic, tonic, clonic, tonic-clonic, and observers as benign and not warranting versive seizures. Complex motor sei- medical attention. zures are characterized by relatively complex movements simulating natural Seizure Semiologic but inappropriate movements for the Classification Related to situation. Complex motor seizures are Complex Nocturnal Behaviors subclassified as hypermotor, automotor The differentiation of nocturnal seizures (ie, having distal limb or oral automatisms and parasomnias requires some knowl- as the main manifestation), and gelastic edge of the localizing value of seizure (seizures in which the main motor semiology in the focal epilepsies. Clinical manifestation is laughter). Hypermotor manifestations of focal seizures vary by seizures feature complex movements that the location and involved network of the are repetitive, high-amplitude, and high- seizure-onset zone and the speed of velocity involving the trunk and prox- propagation, producing activation or imal extremities. Consciousness is inhibition of brain regions. In the pre- usually preserved. The differential diag- surgical evaluation of patients with nosis of complex nocturnal behaviors pharmacoresistant epilepsy, the sympto- includes seizures with tonic and/or matogenic zone is the region of the hypermotor features, disorders of arousal brain responsible for the initial symp- from NREM sleep, RBD, and other para- toms of a seizure, defined by history and somnias, including sleep-related disso- video EEG (VEEG) recordings. A symp- ciative disorders, movement disorders

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Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited. KEY POINT of sleep (rhythmic movement disor- longer, attacks and coined the term h The differential diagnosis ders) (Supplemental Digital Content nocturnal paroxysmal dystonia (NPD) of complex nocturnal 6-2, links.lww.com/CONT/A31), and to describe the entity, uncertain as to behaviors includes conditions classified as normal var- whether the cases had an epileptic nocturnal seizures, iants such as benign sleep myoclonus basis. Over time, VEEG permitted the non-REM arousal of infancy (Supplemental Digital Con- recording of similar nocturnal behaviors disorders, REM sleep tent 6-3, links.lww.com/CONT/A32) having complex, often violent, motor behavior disorder, and and psychogenic movements (Supple- manifestations with electrographic other parasomnias such mental Digital Content 6-4, links. abnormalities supporting an epileptic as sleep-related lww.com/CONT/A33). origin within the frontal lobe. Thus, dissociative disorders. NPD was replaced by nocturnal frontal Nocturnal Seizures With lobe epilepsy (NFLE). Complex Behaviors Nocturnal frontal lobe epilepsy. In 1981, Lugaresi and Cirignotta de- Frontal lobe epilepsy (FLE) is the sec- scribed five patients with frequent at- ond most common focal epilepsy in tacks in light NREM sleep, characterized adolescents and adults. About 18% of by violent movements of the limbs, patients referred to tertiary care centers neck, and trunk, having dystonic and for pharmacoresistant focal seizures tonic features.6 The attacks, called hyp- have FLE,7 and patients with isolated nogenic paroxysmal dystonia, were FLE represent about 11% of all patients short in duration and lacked epilepti- whose long-term seizure-free outcome form EEG features but responded to has been reported.8 Figure 6-1 illustrates carbamazepine therapy. In a subse- frontal lobe epilepsy syndromes and quent report, the authors described the seizure semiologies produced by additional patients with similar, but activation of these areas. The distinction

FIGURE 6-1 Dorsolateral (left) and medial (right) schematics of the brain highlighting the symptomatogenic areas in nocturnal frontal lobe epilepsies. Activation of the precentral (primary motor) region produces contralateral clonic movements; premotor region activation produces tonic posturing, usually proximal, bilateral, asymmetric, and version; dorsolateral prefrontal region activation produces hypermotor behavior, complex automatisms, and version; frontal operculum region activation produces facial grimacing and salivation; activation of the ventromedial prefrontal region produces hypermotor behavior, autonomic activation, and affective changes (eg, agitation, fear). Activation of the premotor and prefrontal regions is characteristic of nocturnal frontal lobe epilepsy.

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KEY POINTS h Seizures in nocturnal of these syndromes can be challenging automatisms, such as fumbling and frontal lobe epilepsy because of the complexity of function- grasping of objects or clothing, charac- consist of hypermotor ally interconnected frontal areas and the teristic of temporal lobe seizures, may activity involving complex variability of epileptic propagation pat- be observed. Episodes typically last 10 to movements of the trunk terns. Consequently, seizures of frontal 30 seconds; longer seizures may sec- and proximal extremities lobe origin have diverse, often bizarre ondarily generalize. Characteristics of sei- that are repetitive, high manifestations. Scalp EEG is often of zures arising from the anterior cingulate amplitude, and high limited value because epileptic foci, in or orbitofrontal cortext include fear (with velocity and asymmetric particular on the mesial and basal brain or without a matching facial expression), tonic seizures having surfaceVthe origin of seizures in laughter without mirth, and autonomic dystonic, dyskinetic, and NFLEVare relatively inaccessible for manifestations, including mydriasis, fa- repetitive proximal surface electrodes; EMG and movement cial flushing, and tachycardia.14 The ictal movements that are highly stereotyped and artifacts during seizures contaminate the sequence of behaviors is rapid and in- frequent, often with EEG signal; and paradoxic lateralization cludes extrapyramidal signs, such as tonic preserved consciousness. and secondary bilateral synchrony add or dystonic posturing of the limbs and to the complexity when interpreting the choreoathetoid or ballistic movements. h Sudden, brief, and 9Y11 Sudden, brief, and asymmetric tonic asymmetric tonic EEG. posturing of one or NFLE is a heterogeneous disorder in posturing of one or more extremities, more extremities, which 90% or more of seizures occur commonly with both sides affected 12 commonly with both during sleep. Familial, sporadic, idio- simultaneously, suggests early activation sides affected pathic, cryptogenic, and symptomatic of the supplementary sensorimotor area simultaneously, suggests forms have been reported. NFLE is (SSMA).15 Classic manifestations of early activation of the characterized by complex motor behav- SSMA seizures include the fencing pos- supplementary iors, typically of the hypermotor type, ture, a position in which the contrala- sensorimotor area. involving repetitive, high-amplitude, and teral upper extremity is extended, the high-velocity movements of the trunk ipsilateral arm flexed and abducted at and proximal extremities and asym- the shoulder, and the head rotated metric tonic seizures having dystonic, contralateral to the seizure focus; the dyskinetic, and repetitive proximal move- ‘‘M2e’’ posture, consisting of contrala- ments. Seizures are highly stereotyped teral shoulder abduction, elbow flexion, and frequent with abrupt onset and and head deviation toward the affected offset, often with preserved conscious- arm; and the figure-of-four extension of ness, occurring in clusters from NREM the contralateral upper extremity across sleep stages N1 and N2. Daytime sei- the chest and ipsilateral arm flexion zures occur in approximately 30% of at the elbow. These postures are often patients. The lifetime prevalence of accompanied by vocalizations and pre- arousaldisordersisnearlyfivefold served awareness. Negative motor sei- greater in relatives of probands with NFLE zures characterized by indescribable or than controls, suggesting an intrinsic poorly localized subjective symptoms, link between parasomnias and NFLE.13 followed by repetitive involuntary vocal- Complex motor seizures in NFLE have izations, inability to speak, and arrest of hypermotor manifestations, including voluntary movements of extremities marked agitation with body rocking, with preserved awareness, can arise kicking, boxing, thrashing, pedaling, from activation of the rostral SSMA.16 bending, hitting, running, spitting, and Seizures typical for SSMA epilepsy may various types of vocalization that include arise from epileptogenic lesions in the shouting and swearing.11,12 Case 6-1 is precuneus, lateral dorsal frontal cortex, an example of NFLE with hypermotor orbitofrontal cortex, prefrontal region, seizures (Figure 6-2). Distal manual and cingulate gyrus with subsequent

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Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited. Case 6-1 A 26-year-old woman presented with a history of arousals from sleep with uncontrollable movements since 13 years of age. Episodes abruptly awakened her every night, sometimes multiple times, usually beginning as soon as she started to fall asleep. She described a feeling of panic and moved around in bed in an uncontrollable manner, grasping at the bed sheets and turning from side to side for 10 to 20 seconds. She had full recall of episodes. Rarely, similar episodes occurred when she was napping during the daytime. On several occasions, she presented to the emergency department during the night when frequent episodes prevented her from sleeping. These nights typically occurred after she was sleep deprived or surrounding menses. Treatment with lorazepam aborted the attacks. She had a normal birth and development and denied a family history of epilepsy, febrile convulsions, head trauma, and CNS infections. Over the years, she was treated with several antiepileptic drugs, including carbamazepine, lamotrigine, gabapentin, and lacosamide, without improvement. Her most recent physician recommended that she discontinue medications because the episodes continued and EEGs had always been normal, suggesting that she did not have epilepsy. Comment. This case illustrates the key features of NFLE (nocturnal frontal lobe epilepsy): seizures occurring exclusively or nearly so from sleep at any time of the night typically beginning at , multiple episodes in a given night, hypermotor activity associated with preserved awareness, and relatively short-duration attacks. Seizures that are unresponsive to medical therapy and multiple normal EEGs over time raised concern for a nonepileptic . However, approximately one-fourth of patients with NFLE have pharmacoresistant seizures, and many have normal EEG even during typical attacks. The patient had a normal 3-T MRI. Because of the high index of suspicion for NFLE, an ictal SPECT study was performed and revealed a dominant focus of hyperperfusion in the right anterior insular and adjacent deep frontal region suggestive of right hemisphere focal epilepsy. An invasive EEG investigation was planned. ictal propagation into the SSMA, under- tion clustering in a single night. Epilep- scoring the concept that the sympto- tic discharges were observed on EEG in matogenic zone may be at some four cases, and antiepileptic drug (AED) distance from the epileptogenic zone. therapy led to complete remission in More prolonged seizures lasting 30 all, suggesting an epileptic origin dis- to 180 seconds, characterized by arousal tinct from the NREM arousal disorders. and agitated walking, running, jumping, A VPSG-EEG analysis of 100 patients and pacing with variable degrees of with NFLE found seizures to have responsiveness, are observed in a minor- variable degrees of complexity and ity of patients with NFLE.12,17 First durationVranging from minor stereo- described in 1977 by Pedley and Guille- typed movements lasting a few seconds minault,17 the term episodic nocturnal to stereotyped large proximal move- wandering (ENW) was coined to de- ments with dystonic features lasting scribe sleepwalking episodes in six as long as 30 secondsVand ENW co- young adults associated with screaming existing in the same patient.12 Seizures or unintelligible vocalization; complex, during daytime wakefulness similar to often violent automatisms; and ambula- those during sleep were observed in

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FIGURE 6-2 Components of a presurgical evaluation in a 26-year-old woman with pharmacoresistant nocturnal frontal lobe epilepsy. Hypermotor seizures are characterized by abrupt arousals associated with uncontrollable movements, including grasping, thrashing, and crawling (A) with preserved awareness lasting 10 to 20 seconds and occurring multiple times per night with a scalp EEG devoid of epileptiform activity and obscured by muscle and movement artifact (B). Ictal SPECT with flush time of 12 seconds reveals a dominant focus of hyperperfusion (red) in the right anterior insular and adjacent deep frontal region (C).

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Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited. KEY POINTS 34% of patients. Mean age at onset 15q24 with mutations in the transmem- h Autosomal dominant was 14 years. A personal or family his- brane region of the neuronal nicotinic nocturnal frontal lobe tory of parasomnia was present in 34% acetylcholine receptor alpha-4 subunit epilepsy is associated and 39% of cases, respectively. Fami- (CHRNA4), beta-2 subunit (CHRNB2), with mutations in the 21 lial seizure clustering was present in and alpha-2 subunit (CHRNA2) and transmembrane region of 25% of patients. Epileptic abnormal- corticotrophin-releasing hormone.22 All the neuronal nicotinic ities were recorded on interictal EEG but one of these mutations are located acetylcholine receptor in 33%, and ictal patterns were dis- in the second transmembrane region, alpha-4 subunit cernible in 56% of cases. Only 12% of which serves as the major ion pore- (CHRNA4), beta-2 patients had frontal lobe abnormalities forming domain of the receptor. These subunit (CHRNB2), and on neuroimaging. While 17% of pa- mutations confer a gain of function with alpha-2 subunit (CHRNA2)and tients chose to forgo therapy because increased sensitivity to acetylcholine that corticotrophin-releasing they did not feel their seizures were is the proposed basis for epileptogene- hormone. incapacitating, seizures were pharma- sis through regulation of ascending h coresistant in approximately 30% of arousal pathways. While sleep-related complex motor seizures cases and consistently recurred after In the largest clinical and polysomno- have been considered AED withdrawal. Most cases of NFLE graphic study of ADNFLE involving 30 pathognomonic for treated surgically have histopathologic unrelated Italian families, 40 individuals nocturnal frontal lobe confirmation of Taylor-type focal cort- had frequent nocturnal motor seizures epilepsy, extrafrontal ical dysplasia (malformation of cortical with a wide range of complexity and origin is observed in up development associated with balloon severity, overlapping considerably with to 30% of patients, cells),18 and a significant association the parasomnias and indistinguishable most often from the between sleep-related epilepsy and from the sporadic form.23 Daytime temporal and insular Taylor-type focal cortical dysplasia in seizures were reported in 37% of cases, regions but also from pharmacoresistant cases has been and 58% of those affected reported the posterior cortex. reported.19 Therefore, patients with symptoms, including persistent nocturnal seizures despite daytime sleepiness or tiredness and dif- two or more appropriately chosen ficulty waking. Mean age at onset AEDs should be referred for surgical was 11.8 years (1.0 to 30.0 years). Day- evaluation. time EEGs were normal in 88%, but the Autosomal dominant nocturnal sleep EEG showed IEDs in 50% of frontal lobe epilepsy. In 1994, Scheffer cases. The interictal and ictal EEGs and colleagues20 introduced the term were normal in 26% of subjects. Prior autosomal dominant frontal epilepsy, misdiagnosis was common as only 18% now known as autosomal dominant of patients had been previously diag- nocturnal frontal lobe epilepsy (ADN- nosed with epilepsy. FLE), to describe clusters of brief, sleep- Other focal epilepsies. While sleep- related motor seizures with frontal lobe related complex motor seizures have semiology in members of six families, been considered pathognomonic for many of whom were misdiagnosed as NFLE, extrafrontal origin is observed in having parasomnias or psychogenic up to 30% of patients, most often from attacks. ADNFLE was the first human the temporal and insular regions but focal epilepsy to follow single-gene in- also from the posterior cortex.24 Most heritance, believed to constitute as patients with temporal lobe epilepsy many as 25% of NFLE cases. Subse- (TLE) exhibit characteristic semiology, quently, a variety of molecular defects including auras of a rising epigastric have been identified in ADNFLE fami- sensation, fear, de´ja` vu, or depersonal- lies. Linkage studies localized genes for ization evolving to behavioral arrest ADNFLE to chromosomes 20q13 and with staring and oroalimentary and limb

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automatisms (Table 6-3).25 Seizures Pure insular epilepsy typically presents restricted to sleep are uncommon in with laryngeal discomfort, retrosternal TLE, constituting 9% of cases in one or abdominal heaviness, perioral and series.26 Infrequent and nonclustered contralateral hemibody somatosensory seizures, rare family history of epilepsy, symptoms, and dysphonic or dysarthric low prevalence of childhood febrile speechfollowedbytonicactivityofthe convulsions, and a better surgical out- contralateral face and arm.28 However, come characterized 26 patients with seizures arising from the insula can nocturnal TLE compared with age- spread rapidly to adjacent areas mim- matched, nonlesional TLE with predom- icking TLE or other focal epilepsies, inantly diurnal seizures.27 or begin simultaneously in temporal,

TABLE 6-3 Seizure Symptomatology in Temporal Versus Frontal Lobe Epilepsya

Frontal Lobe Temporal Lobe Feature Epilepsy Epilepsy Onset and offset Sudden Gradual Duration Brief (G1 minute) Longer (91 minute) Occurrence Often sleep related Usually awake Seizure clusters Common Uncommon Aura type Olfactory, gustatory, Epigastric, psychic, cephalic auditory Time to motor component Early, prominent Later in ictal sequence Automatisms Uncommon Common Autonomic signs Uncommon unless Common onset in orbitofrontal or cingulum Vocalization Common Uncommon Unilateral clonic activity Common Uncommon Unilateral dystonic arm Uncommon Common posturing Asymmetric tonic posturing Common Uncommon Versive head or eyes Common Uncommon Violent motor behaviors Common Uncommon Preserved awareness Common Common if nondominant Ictal laughing Forceful, mirthless Natural, mirthful Secondarily generalized Common Uncommon seizure Tendency for status Common Uncommon epilepticus Postictal paresis Common Uncommon Postictal confusion Uncommon Common a Adapted from Unnwongse K, et al, Curr Neurol Neurosci Rep.25

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Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited. KEY POINT frontal, or parietal regions, leading to produced by a faulty arousal network h Parasomnias are difficulty in localization. (Case 6-2, Figure 6-3). These parasom- undesirable physical nias typically arise from slow-wave sleep events or experiences PARASOMNIAS in the first half of the nocturnal sleep that occur during entry Parasomnias are undesirable physical period, but may arise from other NREM into sleep, within sleep, events or experiences that occur during stages at any time during sleep, includ- or during arousals from entry into sleep, within sleep, or during ing daytime . Sleep deprivation and sleep and involve arousals from sleep.29 The word ‘‘para- recovery from sleep deprivation due to complex, seemingly somnia’’ is derived from the Greek slow-wave sleep rebound; mental and purposeful, goal-directed para meaning ‘‘alongside of’’ and the physical stress; fever; menses; envi- behaviors without Latin somnus for ‘‘sleep.’’ In contrast to ronmental stimuli; sleep disorderY consciousness. the sleep-related movement disorders producing arousals, including sleep characterized by simple movements not apnea and periodic limb movements; associated with mentation, the neurologic and psychiatric comorbid parasomnias typically involve complex, conditions; alcohol; and medications, seemingly purposeful, goal-directed particularly psychotropic drugs, can behaviors without consciousness. Be- precipitate arousal disorders. Most cause sleep and wakefulness are not affected individuals exhibit a spectrum mutually exclusive states, dysfunction in of behaviors, and a few patients have the orchestration of neural pathways features of RBD, known as parasomnia regulating wake, NREM sleep, and REM overlap syndrome. In contrast to noc- sleep produces state dissociation result- turnal seizures, episodes are not typi- ing in the ability to perform complex cally stereotyped. Disorders of arousal motor behaviors outside of conscious- have a genetic basis, although environ- ness. A recently reported example of mental factors and psychiatric illnesses state dissociation was recorded during have been implicated in their patho- an invasive EEG evaluation, in which physiology. NREM arousal disorders can sleep was recorded from hippocampal cause daytime sleepiness and psycho- and frontal association cortex contacts social impairment, including perform- simultaneous to wake EEG activity in the ance deficiency at the workplace and motor, cingulate, insular, amygdalar, and academic underachievement. Injuries temporopolar regions during a confu- arecommoninpatientswithsleep- sional arousal.30 While event stereotypy, walking and sleep terrors. Among 100 distinct onset and offset, and occurrence consecutive adults with repeated sleep- from sleep favor the diagnosis of noctur- related injury, sleepwalking and sleep nal seizures, waxing and waning clinical terrors were the most common diag- manifestations, long duration (more noses, constituting 54% of cases; the than 2 minutes), and absence of extrapy- remainder resulted from RBD (34%), ramidal features suggest parasomnias. dissociative states, and nocturnal sei- zures.31 The treatment of arousal dis- Disorders of Arousal From orders is usually limited to patient and Non-REM Sleep family education and safeguarding the In contrast to sleep-related epilepsy, few to prevent injury. Benzodia- polysomnographic studies of the arousal zepines, tricyclic antidepressants, and disorders have been published. The have been used in particularly NREM parasomnias include confusional resistant cases with variable success. arousals, night terrors, and sleepwalking, Confusional arousals. Confusional classified as distinct entities but in reality arousals (eg, sleep drunkenness, ex- representing a spectrum of behaviors cessive ) are episodes of

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KEY POINT h Arousal disorders can be mental confusion or confusional behav- of minors and adults can occur during precipitated by sleep ior during an arousal or awakening from confusional arousals. Sudden, forced deprivation and nocturnal sleep or a daytime . Re- awakening can precipitate episodes. recovery from sleep sponsiveness to environmental stimuli The prevalence of confusional arousals 29 deprivation due to is reduced, although patients appear to is over 15.0% in children and 2.9% to slow-wave sleep be awake and may exhibit goal-directed 4.2% in adults.32 Episodes in children rebound; mental and behaviors. Speech is generally slow and typically remit spontaneously, but sleep- physical stress; fever; devoid of content. Affected individuals walking often presents in adolescence menses; environmental typically appear bewildered, have little or adulthood. Confusional arousals may stimuli; sleep to no memory of the event, and may act present de novo in adulthood and can Y disorder producing out aggressively toward bystanders. be difficult to differentiate from focal arousals, including sleep Motor and autonomic system involve- seizures. apnea and periodic limb movements; neurologic ment characteristic of sleepwalking and Sleepwalking. Sleepwalking (som- and psychiatric sleep terrors is lacking. Duration is nambulism) is characterized by a se- comorbid conditions; usually a few minutes, although epi- quence of complex behaviors in sleep, alcohol; and medications, sodes as long as several hours have including ambulation that is more elab- particularly psychotropic been described. Episodes typically arise orate and seemingly goal-directed than drugs. from the first part of the sleep period; usually seen in confusional arousals. however, confusional arousals can arise Episodes begin with an arousal from during the transition from sleep to slow-wave sleep with the individual wakefulness in the morning from light looking around, appearing confused, NREM sleep. Examples of confusional before leaving the bed (Supplemental arousal are illustrated by the accompa- Digital Content 6-7, links.lww.com/ nying videos (Supplemental Digital CONT/A36). Ambulation is typically slow Content 6-5, links.lww.com/CONT/ and quiet with the eyes open, but more A34; Supplemental Digital Content agitated behaviors, including running 6-6, links.lww.com/CONT/A35). Abnor- andjumpingwithvocalizationinan mal sexual behaviors (sexsomnia) rang- attempt to escape a perceived threat, ing from masturbation to sexual assault preparing foods, eating, cleaning, and

Case 6-2 A 35-year-old man presented with his wife reporting abnormal behaviors in sleep. At 11:30 PM one night 2 months before presentation, he jumped from his third-story bedroom window, fracturing both of his legs. He vaguely recalled thinking he was escaping a house fire. While recovering in a rehabilitation facility, he was involved in an altercation with an attendant after he wandered outside his room. He was wrestled to the ground when he became agitated after being shaken awake, prompting transfer to a psychiatric ward, where he was evaluated and discharged a few days later without further treatment. His wife reported less dramatic episodes 2 to 3 times per week during which he would wander outside of his room asleep or wake up confused, typically within a few hours of sleep onset. Similar episodes had occurred in childhood. He generally would not respond during episodes and had little or no recollection of what had transpired. He reported mild daytime sleepiness and , but denied gasping or choking in sleep. His body mass index was 33 kg/m2, but his examination was otherwise normal. He wore a cast on his right leg. Continued on page 115

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Comment. This case illustrates the spectrum of complex behaviors seen in the disorders of arousal from non-REM sleep. While classified as sleepwalking, sleep terrors, or confusional arousals for nosologic purposes, these behaviors often coexist in the same patient. Most episodes occur in the first third of the sleep period, where slow-wave sleep predominates. The frequency of sleepwalking episodes varies considerably from case to case, ranging from isolated, rare occurrences to multiple episodes per night. Events may cluster for several nights, followed by remission for weeks to months. Sleepwalking and confusional arousals are commonly precipitated by sleep deprivation, emotional or physical stress, fever, comorbid psychiatric and neurologic disorders, and medications. Because of the presence of sleep-related injury and clinical suspicion of , a polysomnogram with EEG was performed in this patient and revealed moderate (apnea-hypopnea index of 28 events/h) and several unprovoked arousals from slow-wave sleep. Safeguards to secure a safe sleep environment were recommended, and the patient was instructed to avoid alcohol and sleep deprivation. Treatment with continuous positive airway pressure followed an in-laboratory titration study, resulting in a near cessation of arousal episodes. Treatment of sleep disorders producing sleep fragmentation such as obstructive sleep apnea often reduces the frequency of parasomnia episodes in both children and adults.

FIGURE 6-3 Non-REM arousal disorder. A 30-second videopolysomnograph-EEG epoch showing an adult with nonstereotyped nocturnal behaviors since childhood. The patient awoke from slow-wave sleep at approximately 1 AM (arrow), appeared confused, and tried to get out of bed. The EEG shows a delta sleep pattern without epileptiform features that becomes obscured by movement artifact. She had no recollection of the event the following morning.

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KEY POINTS h The non-REM parasomnias driving, have been reported. In other ized by sudden arousal and sitting up in include confusional cases, inappropriate behaviors are ob- bed associated with a cry or vocalization arousals, sleep terrors, served, such as urinating in a closet or and intense autonomic system activa- and sleepwalking, rearranging furniture. Episodes usually tion (Supplemental Digital Content classified as distinct terminate spontaneously with the pa- 6-8, links.lww.com/CONT/A37; Supple- entities but in reality tient waking up in a different location or mental Digital Content 6-9, links. representing a spectrum returning to bed without incident. Pa- lww.com/CONT/A38; Supplemental of behaviors produced tients appear confused and can be Digital Content 6-10, links.lww.com/ by a faulty arousal agitated or aggressive when aroused. CONT/A39; Supplemental Digital Con- system. Violent acts, including homicide and tent 6-11, links.lww.com/CONT/A40). h The presenting sexual molestation, have been reported. Tachycardia, tachypnea, diaphoresis, complaint in REM sleep Complete for the event usually facial flushing, and mydriasis are com- behavior disorder is occurs, although some patients have monly observed. Affected individuals recurrent dream-enacting partial recollection the following day. appear frightened and confused and behaviors, including The frequency of episodes varies con- are inconsolable and difficult to arouse, vocalizations and motor siderably from case to case, ranging typically with no recollection of events activity in relation to altered dream mentation. from isolated, rare occurrences to multi- the following morning. In contrast to Sleep-related injuries to ple episodes per night with clustering children, adults with sleep terrors may the affected person or for several nights, followed by pro- bolt out of bed in a violent or agitated bed partner occur in longed periods of remission. Nightly manner with some dream recollection approximately one-third episodes that cluster are rare. Sleep- after the event. Sleep terrors affect 1.0% of cases. walking affects as many as 17% of to 6.5% of children and 2.6% of adults,32 children and 4% of adults, with peak typically peaking in the early school-age prevalence between ages 8 and 12.33,34 years and remitting by adolescence. Most affected children had confusional Episodes typically last several minutes arousals at an earlier age. Sleepwalking and are followed by the patient calmly typically begins in the first decade of life and quietly returning to sleep. and remits spontaneously in late child- hood or adolescence, although onset in REM Sleep Behavior Disorder adulthood is observed. Childhood-onset RBD is the REM sleep parasomnia that sleepwalking continues into adulthood presents with complex nocturnal behav- in 20% of cases. Sleepwalking has a iors that are occasionally challenging strong genetic predisposition, with first- to differentiate from nocturnal seizures degree relatives of sleepwalkers having and at times overlap with disorders of at least a 10-fold increased likelihood of arousal. The presenting complaint in the condition compared to the gen- RBD is recurrent dream-enacting behav- eral population.33 Sleepwalking was iors, including vocalizations and motor inherited as an autosomal dominant dis- activity in relation to altered dream order with reduced penetrance in a mentation (Case 6-3)(Supplemental four-generation family with localization Digital Content 6-12, links.lww.com/ to chromosome 20q12-q13.12, the first CONT/A41).35,36 Sleep-related injuries genetic locus identified that contains to the affected person or bed partner the adenosine deaminase gene.35 In- occur in approximately one-third of hibition of adenosine metabolism in- cases (Supplemental Digital Content creases slow-wave sleep, rendering this 6-13, links.lww.com/CONT/A42). In the most likely candidate gene in link- contrast to the NREM disorders of age analysis. arousal, patients typically wake up Sleep terrors. Sleep terrors (ie, night abruptly at the end of an episode and terrors, pavor nocturnus) are character- are alert and able to recount a coherent

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Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited. Case 6-3 A 64-year-old man presented with snoring and daytime sleepiness. During the interview, he reluctantly described having vivid associated with violent movements, yelling, and swearing in sleep. He appeared embarrassed by these behaviors and expressed remorse when telling the story of how he once repeatedly punched and kicked his wife while dreaming that he was fending off an attacker. In turn, his wife stated adamantly that this behavior was highly uncharacteristic of her loving husband. Similar, though milder, episodes occurred sporadically, usually in the early morning hours from 2:00 AM to 4:00 AM. His wife once found him with blood dripping from his eyelid, bruises on his face, and the bedside table on the floor; she assumed that he had struck himself in his sleep. After an episode, he would usually wake up and provide a detailed account of his dream. His medical history was notable only for diet-controlled hyperlipidemia. He exercised regularly and avoided alcohol and drugs. His family history was notable for Alzheimer disease in his mother. Comment. Violent dream-enacting behaviors arising from sleep in an older man raise concern for REM sleep behavior disorder (RBD). A polysomnography with EMG recordings from both upper and lower extremities was performed. The study ruled out sleep apnea (apnea-hypopnea index was 4.5 events/h), although frequent periodic limb movements were seen in NREM sleep. During REM sleep, EMG was increased and limb twitching was observed, confirming the diagnosis of RBD. A thorough neurologic examination ruled out features of Parkinson disease, dementia with Lewy bodies, and multiple system atrophyVdegenerative disorders associated with RBD. Treatment with low-dose at was recommended. Home safety precautions were implemented, including the removal of potentially dangerous objects from the bedroom and placement of a cushion around the bed. Almost immediately after the patient started treatment, the frequency of his violent behaviors declined markedly. dream of being confronted, chased, or with the eyes closed. Primitive behav- attacked by unfamiliar people, animals, iors (including chewing, eating, drink- insects, or other beings. Vocalizations ing, urination, defecation, and sexual and motor behaviors are strikingly con- behaviors) that may manifest in NFLE sistent with the reported dream con- and NREM arousals disorders were only tent. Vocalizations including talking, recently reported as part of the behav- arguing, laughing, yelling, screaming, ioral spectrum of RBD.37 RBD episodes and swearing are often described as usually occur in the early morning being out of character for the individ- hours preceding the morning awaken- ual. The spectrum of motor behaviors ing, when REM sleep predominates, in RBD overlaps both with NFLE and and less commonly during the first disorders of arousal and includes repet- REM period at least 90 minutes after itive proximal movements such as ges- sleep onset. Dream-enacting episodes turing, punching, slapping, grabbing, may occur even earlier in the sleep kicking, running, and jumping, often period in patients with and performed in a self-protective manner. comorbid RBD. Episodes occur sporadi- Unlike sleepwalking, people rarely walk cally an average of once per week and out of the room, and episodes occur rarely nightly or in clusters. Typical

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duration is less than 2 minutes. Three ance should not be better explained by subtypes of abnormalities related to any other sleep disorder; medical, men- RBD have been described: (1) subclin- tal, or neurologic condition; medica- ical RBD, characterized by polysomno- tion; or substance use. graphic findings consistent with RBD in RBD usually emerges later in life, the absence of a clinical history of typically after age 50, although it can dream enactment; (2) parasomnia over- present at any age and has a striking lap disorder, comprising RBD com- male predominance. For reasons not bined with a disorder of arousal; and understood, RBD is about 9 times more (3) status dissociatus, characterized by a common in men than in women. The state of dissociation without clear sleep estimated prevalence of RBD based on stages but with REM-related behaviors a UK telephone survey of people aged 15 resembling RBD in patients with neuro- to 100 years old is 0.5%.32 The patho- logic disorders. RBD is the only para- physiology of RBD (Figure 6-5)38 re- somnia requiring polysomnographic quires bilateral pontine tegmental confirmation.29 The diagnosis of RBD lesions resulting in loss of REM atonia is made in patients with REM sleep and disinhibition of locomotor path- without atonia (RSWA) in the chin or ways, thereby facilitating dream en- limb EMG and either sleep-related actment. The condition is frequently injurious, potentially injurious, or dis- associated with the "-synucleinopathies ruptive behaviors documented by his- that include Parkinson disease, demen- tory or abnormal REM sleep behaviors tia with Lewy bodies, and multiple documented on PSG (Figure 6-4). EEG system atrophy. These disorders share abnormalities suggestive of epilepsy acommonpathologiclesioncomposed must be absent, and the sleep disturb- of abnormal aggregates of "-synuclein

FIGURE 6-4 REM sleep behavior disorder (RBD). A 30-second polysomnograph epoch showing an elderly man with RBD. The arrow indicates the point during REM sleep when augmentation of EMG activity is seen, followed within seconds by the emergence of abnormal dream-enacting behavior. Note the elevated EMG activity in the upper and lower extremity and chin EMG channels (REM sleep without atonia) with simultaneous REMs in the electrooculogram (left: E1-M2, right: E2-M1) and EEG appearance of REM sleep. SAO2 = arterial oxygen saturation.

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Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited. FIGURE 6-5 Pathophysiology of REM sleep behavior disorder. Muscle atonia during REM sleep results from pontine-mediated perilocus coeruleus inhibition of motor activity. This pontine activity exerts an excitatory influence on medullary centers (magnocellularis neurons) via the lateral tegmentum reticular tract that, in turn, hyperpolarizes the spinal motor neuron postsynaptic membranes via the ventrolateral reticulospinal tract. Modified from Avidan AY, Prim Care.38 B 2005, with permission from Elsevier. www.sciencedirect.com/science/article/pii/S009545430500028X. proteininspecificbrainnuclei.RBD exacerbating or even causing RBD. may precede the diagnosis of a degen- These include psychotropic and antide- erative disorder by up to 50 years39 with pressant medications, including selec- a mean latency of 12.7 years from the tive serotonin reuptake inhibitors, onset of RBD to the first manifestation serotonin-norepinephrine reuptake of neurodegeneration,36 serving as an inhibitorsVparticularly venlafaxineV indicator of an evolving synucleinopathy and tricyclic antidepressants. Alcohol in as many as two-thirds of cases. Pa- and drug abuse or withdrawal and tients with neurologic lesions involving caffeine can also trigger RBD. The the REM generator centers in the brain treatment of RBD centers on reducing due to stroke, multiple sclerosis, or clinical manifestations that lead to sleep- neoplasm have also been reported to related injuries.40 Modifying the sleep develop RBD. While the condition is environment to protect patients and more common in older men, its pres- bed partners from injury is advised. ence in younger patients should raise Despite the lack of randomized clinical the possibility of narcolepsy. Several trials, clonazepam is remarkably effec- drug classes have been implicated in tive in treating RBD and is considered

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KEY POINT h REM sleep behavior first-line therapy. Melatonin and prami- study, a history of sleep-related events disorder usually pexole are also effective in small series was more often reported by patients emerges later in life, and are preferred in patients with with PNES than by patients with phar- typically after age 50, dementia, gait disorders, and obstructive macoresistant epilepsy (59% versus 42 and has a striking sleep apnea (OSA). Treatment of comor- 47%). Sleep-related PNES were signifi- male predominance. bid sleep disorders, including OSA, is cantly associated with convulsive seiz- The condition is recommended as RBD-like behaviors ure semiology, AED polytherapy, social frequently associated with may be due solely to OSA, a condition security benefits, mood disorders, sui- the "-synucleinopathies, known as pseudo-RBD. cide attempts, physical abuse, and which include Parkinson fatigue. Like parasomnias, PNES are disease, dementia with Sleep-Related Dissociative characterized by waxing and waning Lewy bodies, and Disorders patterns and long duration (more than multiple system atrophy. Sleep-related dissociated disorders 2 minutes). Motor manifestations emerge at the transition from wake to include jactitation (restless tossing in sleep or shortly following awakening bed), asynchronous movements, side- with EEG evidence of wakefulness.29 to-side head movements, pelvic thrust- Most patients have psychiatric comor- ing, opisthotonic posturing, prolonged bidities, including mood disorders, post- body flaccidity, and preserved aware- traumatic stress disorder, and a history ness during bilateral motor activity. of sexual abuse. Episodes are non- Affective manifestations, vocalizations, stereotyped and feature screaming, ictal moaning and crying, emotive running, and self-mutilating, violent be- speech, ictal stuttering, and heart rate haviors that may represent a reenact- elevations may be seen in PNES, pa- ment of prior traumatic events. Driving, rasomnias, and nocturnal seizures, cooking, and eating can occur. The although postictal crying is most com- patient usually has complete amnesia moninpatientswithPNES.Ictaleye for episodes that can last from minutes closure and jaw clenching suggest to an hour or longer. Injuries are com- PNES, whereas lateral tongue bites, mon. Among 100 consecutive adults with urinary incontinence, event-related repeated sleep-related injury, 7% were injury, and myalgia support the diagno- diagnosed with dissociative states.31 Dis- sis of epilepsy. Occurrence only in the sociative disorders preferentially affect presence of observers and events trig- females. gered by emotional stress raise suspi- Psychogenic nonepileptic seizures cion for PNES. Approximately 70% of (PNES) occurring in relation to sleep PNES cases develop between the sec- may be considered a form of sleep-re- ond and fourth decades of life, usually lated dissociative disorder. PNES are in females, but children and older highly prevalent and difficult to differ- adults are also affected.43 The EEG in entiate from frontal lobe seizures, espe- PNES shows a normal waking alpha cially those arising from the mesiobasal rhythm during behavioral unresponsive- frontal regions. PNES are classically con- ness. Historical features, including sidered to arise from wakefulness, as chronic pain disorders, somatization psychological stress exceeding one’s disorder, and histrionic personality, capacity is the typical precipitant. How- have a high predictive value for the ever, 55% of patients with PNES in diagnosis of PNES. Epileptic seizures one series had seizures arising from coexist in 10% to 60% of cases. Con- pseudosleep, defined as behavioral sequently, long-term VEEG is recom- sleep associated with EEG evidence of mended in patients with abnormal wakefulness.41 In a prospective UK EEGs in whom PNES is suspected.

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Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited. KEY POINT Pathophysiologic Associations datory (eg, biting, teeth chattering), h Activation of common Between Nocturnal Frontal emotional (eg, fear, vocalizations), loco- pattern generators is Lobe Epilepsy and Parasomnias motor (eg, pedaling, crawling, wander- responsible for the Among the various types of parasom- ing, running), and copulatory (eg, pelvic overlapping semiology nias, the NREM arousal disorders appear thrusting) behaviors. of nocturnal seizures to have the strongest association with and arousal disorders. NFLE. Consequently, a common patho- EVALUATION OF PATIENTS WITH physiologic mechanism involving chol- COMPLEX NOCTURNAL inergic pathways in the ascending BEHAVIORS arousal system has been hypothesized. The diagnosis of nocturnal seizures and Various mutations in the neuronal nic- parasomnias is often achieved through a otinic acetylcholine receptor in ADNFLE comprehensive clinical history provided families suggest a molecular basis for the by the patient and bed partner or other disorder. These ion channel receptors observers that includes timing, fre- are widely distributed on neuronal and quency, semiology, and evolution of glial membranes in cortical and subcort- typical events (Table 6-4). Following ical regions of the brain, regulating the the clinical history, EEG is the primary release of acetylcholine, +-hydroxybutyric modality for the confirmation of sus- acid, and glutamate, and having a pected epilepsy and, therefore, in the modulatory effect on arousals at the evaluation of patients with complex cortical and thalamic levels. Receptor nocturnal behaviors. The yield of EEG mutations confer a gain of function with varies with the duration of the study, increased sensitivity to acetylcholine patient state, recording technique, that may lead to changes in the excit- and presence or absence of recorded ability of networks of cortical and sub- events. When the diagnosis is not con- cortical neurons preferentially affecting firmed by outpatient EEG procedures, the mesial frontal area, thereby facilitat- further evaluation in the sleep labora- ing intrinsic epileptogenesis and, at the tory or epilepsy monitoring unit may be same time, altering arousal mechanisms warranted. Additional investigations and destabilizing sleep.21 may be indicated, depending on the Activation of common pattern gener- clinical presentation and EEG findings atorsVgenetically determined or such as MRI, functional neuroimaging learned neural circuits located in the (eg, PET, ictal SPECT), and laboratory mesencephalon, pons, and spinal cord analyses, including genetic testing. Vali- that code for self-sustained patterns of dated questionnaires useful in discrim- behavior subserving innate motor inating between NFLE and parasomnias behaviors essential for survivalVis pro- may enhance the diagnostic accuracy of posed to underlie the similar semiologic the clinical history. manifestations of nocturnal seizures and parasomnias.44 During sleep states and Video Polysomnography With seizures, a temporary disruption of higher brain centers can produce ster- VPSG-EEG is indicated in the evaluation eotyped motor behaviors, including of patients with complex nocturnal be- through activation of brainstem and haviors. However, capturing a typical spinal cord common pattern genera- event can be challenging in the out- tors. A broad spectrum of clinical man- patient setting during a single night of ifestations may be observed, including recording. While a limited number of alimentary (eg, , chewing, swal- EEG channels is adequate for sleep lowing, lip smacking), defensive or pre- staging in routine PSG, the identification

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TABLE 6-4 Differentiating Nocturnal Frontal Lobe Epilepsy and Parasomnias

REM Sleep Nocturnal FrontalArousal Behavior Feature Lobe Epilepsy Disorders Disorder Age at onset Variable, typically Usually first Over 50 years first or second decade of life decade of life Sleep stage of origin Non-REM N1 or Non-REM N3 REM N2, sleep-wake transitions Timing of episodes Anytime First third of Last third of sleep period sleep period Duration of episodes 5 to 60 seconds 2 to 30 Seconds to minutes 2 minutes Frequency of episodes Nightly clusters Sporadic, rare Sporadic, rare clusters clusters Onset and offset Sudden Gradual Sudden Semiology of episodes Highly stereotyped, Not Not highly hypermotor, stereotyped, stereotyped, asymmetric variable vocalizations with tonic/dystonic complexity self-protective behaviors and dream recall Level of consciousness Usually preserved Variable Poorly responsive during episodes Postictal confusion Typically absent Present Absent Risk of injury Low High Moderate Video-polysomnography Epileptic activity Slow-wave REM sleep without with EEG findings in G50% sleep arousals, atonia rhythmic delta pattern

of epileptic abnormalities requires more evaluation of complex nocturnal behav- extensive monitoring.45 In studies com- iors. Due to the limitations of capturing paring abbreviated (4- and 7-channel) a typical event in 1 night of recording, EEG montages with 18-channel record- long-term VEEG over several days in an ings, temporal and parieto-occipital sei- epilepsy monitoring unit is preferred zures were more accurately distinguished when episodes do not occur nightly or from arousals and artifacts using 7- and every other night, primary sleep disor- 18-channel recordings, while expanded ders such as OSA are not suspected, a montages did not increase the detection history of postictal agitation or wander- of frontal lobe seizures.46,47 Therefore, ing exists, and patient cooperation is more comprehensive EEG recordings uncertain. During long-term VEEG, pa- with synchronized high-quality video tients taking AEDs can undergo super- and additional EMG in patients with vised drug withdrawal, increasing the suspected RBD are required in the yield of the study.

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Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited. KEY POINTS VPSG-EEG has several advantages from slow-wave sleep), ictal EEG fea- h Video polysomnogram-EEG over routine PSG, including the im- tures were much less useful, with only has several advantages proved ability to identify interictal and 38% of seizures associated with defini- over routine ictal EEG abnormalities and correlate tive ictal patterns. polysomnogram, clinical behaviors with neurophysiologic The stage from which nocturnal including the improved parameters. The procedure is recom- events emerge and event timing relative ability to identify mended for the evaluation of (1) com- to sleep onset provide important diag- interictal and ictal EEG plex nocturnal behaviors when the nostic information. Sleep-related sei- abnormalities and clinical history and routine EEG are in- zures usually arise from NREM sleep correlate clinical conclusive; (2) sleep-related events that and often during sleep-wake transitions behaviors with are violent or potentially injurious; (3) anytime during the sleep period. In neurophysiologic parameters. parasomnias with unusual or atypical contrast, NREM arousal disorders arise features; (4) situations with forensic predominantly from slow-wave sleep, h Complex nocturnal considerations; and (5) presumed para- usually in the first third of the sleep behaviors can be somnias or nocturnal seizures not period. RBD episodes occur from REM differentiated by the state from which responsive to conventional therapy.45 sleep preferentially in the last one-third episodes emerge. In an early study involving 122 patients of the sleep period where REM sleep Nocturnal seizures with complex nocturnal behaviors, predominates. typically arise from light VPSG-EEG provided a definite diag- non-REM sleep often nosis in 35% of cases, with epilepsy EEG Findings in Patients With during sleep-wake 48 being most common. Supportive evi- Nocturnal Seizures and transitions, while dence of sleep terrors or epilepsy was Parasomnias arousal disorders arise obtained in 35%, and the study was Nocturnal seizures. The electrographic from slow-wave sleep inconclusive in 34% of cases. Among manifestations of nocturnal seizures preferentially during the 100 consecutive adults with history of with complex behavioral manifestations first third of the sleep sleep-related injury, the procedure pro- depend on a variety of factors, includ- period, and REM sleep vided conclusive diagnostic information ing the size, location, and propagation behavior disorder episodes present from in 65% of cases and was helpful in characteristics of the ictal generator; 31 REM sleep preferentially another 26%. location and number of recording elec- during the last third of In a recent VPSG-EEG analysis of 120 trodes; and the attenuating character- the sleep period. events of 44 patients with NFLE or NREM istics of the skull and other intervening arousal disorders, 94% of events were tissues. In many cases, the EEG shows correctly classified using a diagnostic IEDs in the region harboring the decision tree based on a cluster analy- epileptogenic lesion. This is particularly sis.49 Semiologic features strongly favor- true in TLE, in which a unilateral focal ing the diagnosis of arousal disorders preponderance of IEDs predicts the included interactive behavior, failure to area of seizure origin with a probability wake after the event, and indistinct of more than 95%.50 Similarly, localized offset. Crying or sobbing, coherent ictal EEG patterns are more common in speech in sentences, and normal arousal TLEcomparedtoextratemporalepilep- behaviors, such as scratching and rub- sies (90% versus 50%) and least likely in bing the face, were also strongly sug- seizures arising from the mesial frontal gestive of an arousal disorder. In region (24%).51 contrast, hypermotor features, grunting, The EEG is often normal in patients grimacing, and dystonic posturing fa- with epileptogenic lesions arising from voredNFLE.Whilesleepstageatevent deep or midline regions or who show onset was discriminatory (82% of sei- seemingly generalized epileptic activity zuresoccurredduringsleepstageN1or due to rapid propagation to the contrala- N2, and 100% of arousal disorders arose teral hemisphere. Epileptic abnormalities

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may be restricted to the vertex and tivity. The EEG features of NREM arousal therefore missed if data are reviewed disorders are more variable and less on montages not incorporating midline definitive than those associated with electrode placements. Seizures are com- seizures and overlap with seizures aris- monly obscured by artifact due to the ing from the mesial and basal cortical prominent motor activity of nocturnal regions.53 NREM parasomnias typically frontal seizures (Figure 6-2B). In produce generalized, hypersynchro- patients with NFLE, VEEG recordings nous delta waves with superimposed typically reveal an event frequency faster frequencies without considerable dramatically exceeding estimates based evolution (Figure 6-3). The arousal on the clinical history, owing to under- itself can consist of any frequency, in- detection of frequent minor stereo- cluding rhythmic delta activity sugges- typed motor events associated with tive of a persistent sleep pattern or a arousal in the presence or absence of predominance of alpha activity more epileptiform discharges.52 The involve- widespread and less reactive than the ment of basal and mesial cortices not waking background, suggestive of par- directly accessible to scalp EEG, rapid tial wakefulness. EEG state dissociation spread of EEG activity within and out- with a posteriorly dominant alpha side these areas, and tangential orienta- rhythm and delta activity anteriorly tion of the spike source are responsible combined with vertex waves or sleep for the lower yield of scalp EEG in FLE. spindles that is consistent with light The EEG may be normal even during a sleep has been reported.49 Slow-wave seizure if the episode is brief and the sleep arousals in the absence of clinical epileptic generator is distant from the events are supportive of an arousal recording electrodes. Therefore, a nor- disorder. An increase in delta power mal EEG does not exclude the diagnosis immediately preceding arousal and in of epilepsy. slow-wave sleep percentage across the Disorders of arousal from NREM sleep period may be observed.53 Sleep sleep. Because the diagnosis of NREM deprivation for 24 hours before PSG arousal disorders can often be made and forced arousal from auditory stimuli with an adequate level of certainty induce somnambulistic episodes in based on clinical history alone, labora- sleepwalkers, thereby increasing the tory evaluation is not routinely indi- yield of testing.54 A normal PSG does cated. VPSG-EEG is recommended in not exclude the diagnosis of an arousal patients with (1) potentially injurious disorder. night behaviors or behaviors otherwise REM sleep behavior disorder. PSG disruptive to the bed partner or house- is valuable in confirming the diagnosis hold members; (2) atypical features or of RBD. PSG should be tailored in pa- features suggestive of nocturnal seiz- tients with RBD to include expanded ures, daytime consequences such as EEG and EMG monitoring of the upper sleepiness, and failure to respond to and lower limbs as motor manifesta- appropriate therapy; and (3) suspected tions may be restricted to the upper comorbid primary sleep disorders such extremities. The pathognomonic poly- as OSA, as their treatment can lead to somnographic finding in patients with a reduction in event frequency and clinical suspicion of RBD is RSWA severity. (Figure 6-4). In isolation, RSWA is some- VPSG-EEG can help to confirm the times referred to as preclinical or sub- diagnosis of arousal disorders largely by clinical RBD. REM sleep is characterized by excluding the presence of epileptic ac- primarily low-amplitude mixed-frequency

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Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited. a TABLE 6-5 The Frontal Lobe Epilepsy and Parasomnia Scale

Clinical Feature Score Age at onset At what age did the patient have Aged G55 years 0 the first clinical event? Aged Q55 years j1 Duration What is the duration of a typical event? G2 minutes +1 2Y10 minutes 0 910 minutes j2 Clustering What is the typical number of events to occur 1Y20 in a single night? 3Y5+1 95+2 Timing At what time of night do events most Within 30 minutes of sleep onset +1 commonly occur? Other times 0 Symptoms Are the events associated with a definite aura? Yes +1 No 0

Does the patient ever wander outside the Yes j2 bedroom during the events? No (or uncertain) 0

Does the patient perform complex, directed Yes j2 behaviors during events? No (or uncertain) 0

Is there a clear history of prominent dystonic Yes +1 posturing, tonic limb extension, or cramping No (or uncertain) 0 during events? Stereotypy of events Are the events highly stereotyped or variable Highly stereotyped +1 in nature? Some variability/uncertain 0 Highly variable j1 Recall Does the patient recall the events? Yes, lucid recall +1 No or vague recollection only 0 Vocalization Does the patient speak during the events and, No 0 if so, is there subsequent recollection of this speech? Yes, sounds only or single words 0 Yes, coherent with incomplete or no recall j2 Yes, coherent speech with recall +2

Total Score

a Reprinted with permission from Derry CP, et al, Arch Neurol.56 B 2006, American Medical Association. All rights reserved. archneur.jamanetwork.com/article.aspx?articleid=791451.

EEG activity, REMs, and low chin EMG of the epoch having increased chin tone.55 RSWA is identified by sustained EMG amplitude and/or excessive transient muscle activity in REM sleep with 50% muscle activity defined by the presence

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KEY POINT h REM sleep behavior of five or more 3-second epochs within contrast to seizures involving autonomic disorder is the only a 30-second epoch containing transient network activation and arousal disor- parasomnia that muscle activity at least 0.5 seconds in ders, tachycardia is uncommon in RBD. requires diagnostic duration. No minimum number of confirmation by epochs of abnormal motor activity is Other diagnostic modalities polysomnography. required to confirm the presence of The Frontal Lobe Epilepsy and Para- The pathognomonic RSWA. Recording full-blown RBD epi- somnias (FLEP) Scale has been pro- polysomnographic sodes is rare in the sleep laboratory, and posed as an adjunct to the clinical finding in patients with most cases are confirmed by the pres- history in the evaluation of complex clinical suspicion of REM ence of RSWA and minor clinical fea- nocturnal behaviors.56 The scale con- sleep behavior disorder tures, such as low-intensity vocalizations sists of 11 items addressing semiologic is REM sleep without and/or nonspecific movements lacking features developed to differentiate fron- atonia. goal-directed content. Periodic limb tal lobe seizures from NREM disorders movements in sleep, typically without of arousal (Table 6-5). A score of zero arousal, are commonly observed. In or less favors the diagnosis of an NREM

FIGURE 6-6 MRI of a 49-year-old woman with stereotyped complex nocturnal behaviors consisting of arousal with a panicked sensation, grasping and pronation, and tachycardia with preserved awareness unresponsive to antiepileptic drug therapy and long misinterpreted as a parasomnia. Numerous video EEG recordings were normal without ictal or interictal epileptiform findings. Her Frontal Lobe Epilepsy and Parasomnias Scale score of 5 (+1 for duration G2 min; +1 for 3 to 5 events in a single night; +1 for timing within 30 minutes of sleep onset; +1 for highly stereotyped events; and +1 for lucid recall) suggested a diagnosis of nocturnal frontal lobe epilepsy. A 3-T MRI revealed a hyperintensity extending from the ependymal surface of the superior margin of the right frontal horn to the overlying cortex of the ventral aspect of the superior frontal sulcus (arrow)suggestive of a malformation of cortical development. Invasive EEG recorded spikes and seizures in the depth of the superior frontal sulcus corresponding to the MRI lesion. Lesionectomy was performed, resulting in a seizure-free state for 5 years.

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Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited. parasomnia, whereas patients scoring and hypermotor behaviors that are ster- 3 or greater are likely to have NFLE eotyped for the individual subject; are (Figure 6-6). Indeterminate scores brief, typically lasting 20 to 30 seconds; require further evaluation. The scale and are associated with preserved aware- has been shown to have high positive ness without postictal confusion or (91%) and negative (100%) predictive amnesia. The absence of epileptiform values, but misdiagnosis can occur es- features on EEG in many NFLE cases pecially in cases of RBD. NFLE was re- further complicates the differentiation of liably diagnosed using the FLEP Scale these disorders. VPSG-EEG is indicated in with a sensitivity of 100% and a specif- the evaluation of patients with complex icity of 90% in the initial validation nocturnal behaviors when routine EEG study. This scale does not help in the is nondiagnostic. Ongoing research is differentiation of other types of epilep- necessary to fully elucidate the patho- tic seizures and parasomnias. physiology of these disorders, which Multiple screening questionnaires share a host of clinical manifestations. for RBD have been developed for use in situations where a diagnosis is not VIDEO LEGENDS confirmed by PSG due to absence of Supplemental Digital Content 6-1 REM sleep or where PSG is not feasible. Nocturnal frontal lobe epilepsy seizure. Video Such cases include patients with severe demonstrates a bilateral, asymmetric, tonic seizure cognitive impairment, inaccessibility to with semiology characteristic of frontal lobe (mesial) activation in a 32-year-old man with a a sleep laboratory with ample expertise, normal MRI, no interictal discharges on scalp EEG, and situations in which the cost of and a nonlocalizable scalp ictal EEG pattern. An testing is difficult to justify because of ictal SPECT shows hyperperfusion in the left medial infrequent or mild clinical manifesta- frontal lobe, so a stereo EEG evaluation is planned. tions. Two such instruments, the Mayo The patient is medically intractable, with repet- Sleep Questionnaire and the REM Sleep itive seizures at sleep-wake transition at bedtime most nights that have not responded to medi- Behavior Disorder Screening Question- cation. The seizures routinely wake him up, but naire, are reported to have a sensitivity he typically can recall what happens during the of 96% to 98% and specificity of 55% to seizure and responds immediately thereafter. 69% for confirmed PSG.35 links.lww.com/CONT/A30 B 2013 Nancy Foldvary-Schaefer, DO, MS, FAASM. CONCLUSIONS Used with permission.

The diagnosis of complex nocturnal Supplemental Digital Content 6-2 behaviors is among the most difficult Rhythmic movement disorder. Video demon- to establish in sleep medicine clinics and strates head rolling in an adult man. The stereo- laboratories. An accurate diagnosis of typed and repetitive movement artifact is sleep-related events generally relies on depicted at the frequency of 1 Hz to 2 Hz. the correct distinction between noctur- links.lww.com/CONT/A31 B nal seizures and parasomnias. While 2013 Geert Mayer, MD, PhD. Used with permission. several epilepsy syndromes arise prefer- Supplemental Digital Content 6-3 entially from sleep, NFLE is the disorder Benign sleep myoclonus in infancy. Video most difficult to differentiate from para- demonstrates benign sleep myoclonus in in- somnias. In contrast to the parasomnias, fancy, a disorder of quiet sleep. Its main character- nocturnal frontal lobe seizures typically istics include rhythmic myoclonic jerks when have an abrupt, explosive onset that drowsy or asleep (that stop in wakefulness), and a normal encephalogram during the episodes. awakens the patient from light NREM links.lww.com/CONT/A32 sleep; are accompanied by sustained B 2013 Son˘ a Nevs˘

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Supplemental Digital Content 6-4 Supplemental Digital Content 6-9 Psychogenic movements. Video shows a 56-year- Sleep terror. Video demonstrates sleep terror old woman with psychogenic movement of both in an adult woman. She screams suddenly, hands at bedtime. She is alert and has no urge to beginning from slow-wave non-REM sleep. The move her hands. The movements interfere with video segment after the event illustrates con- her sleep onset, disappear in sleep, and reoccur versation with the technologist in which the upon awakening. The movements are at times patient recalls being awakened, but has little also seen during the day in wakefulness. recollection for the event, and returns to base- links.lww.com/CONT/A33 line fairly quickly. B 2013 Marcel Hungs, MD, PhD. Used with links.lww.com/CONT/A38 permission. B 2013 Rama Maganti, MD. Used with permission.

Supplemental Digital Content 6-5 Supplemental Digital Content 6-10 Confusional arousal. Video demonstrates confu- Sleep terror. Video demonstrates sleep terror in sional arousal in an adult man. The patient has an a 46-year-old woman with a childhood history of arousal, appears confused, and gets out of bed, sleep terror who started having episodes of demonstrating automatic behavior. This is an screaminginthemiddleofthenight,towhich example of a hybrid attack in which the patient she was oblivious. If her husband was home and begins the episode with a confusional arousal and able to wake her, she sometimes reported seeing proceeds for exhibit somnambulistic behavior. spiders on the bed but often did not know what links.lww.com/CONT/A34 had happened. The terrors started the previous B 2013 Son˘aNevs˘

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Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited. Supplemental Digital Content 6-13 polygraphic overview of 100 consecutive REM sleep behavior disorder. Video dem- cases. Brain 1999;122(pt 6):1017Y1031. onstrates aggressive behavior in patients with 13. Bisulli F, Vignatelli L, Naldi I, et al. Increased REM sleep behavior disorder necessitating frequency of arousal parasomnias in families prompt safety modifications and pharmacologic with nocturnal frontal lobe epilepsy: a interventions. common mechanism? Epilepsia 2010; links.lww.com/CONT/A42 51(9):1852Y1860. B 2013 Geert Mayer, MD, PhD. Used with permission. 14. Rheims S, Ryvlin P, Scherer C, et al. Analysis of clinical patterns and underlying epileptogenic zones of hypermotor seizures. REFERENCES Epilepsia 2008;49(12):2030Y2040. 1. Shouse MN, Farber PR, Staba RJ. 15. Morris HH 3rd, Dinner DS, Luders H, et al. Physiological basis: how NREM sleep Supplementary motor seizures: clinical and components can promote and REM sleep electroencephalographic findings. components can suppress seizure discharge Neurology 1988;38(7):1075Y1082. propagation. Clin Neurophysiol 2000; 16. Ikeda A, Hirasawa K, Kinoshita M, et al. Y 111(suppl 2):S9 S18. Negative motor seizure arising from the 2. Steriade M, Contreras D, Amzica F. negative motor area: is it ictal apraxia? Synchronized sleep oscillations and their Epilepsia 2009;50(9):2072Y2084. paroxysmal developments. Trends Neurosci 17. Pedley TA, Guilleminault C. Episodic Y 1994;17(5):199 208. nocturnal wanderings responsive to 3. Foldvary-Schaefer N, Grigg-Damberger M. anticonvulsant drug therapy. Ann Neurol Sleep and epilepsy: what we know, don’t 1977;2(1):30Y35. know, and need to know. J Clin Neurophysiol 18. Nobili L, Francione S, Mai R, et al. Surgical Y 2006;23(1):4 20. treatment of drug-resistant nocturnal 4. D’Alessandro R, Guarino M, Greco G, et al. frontal lobe epilepsy. Brain 2007;130(pt 2): Risk of seizures while awake in pure sleep 561Y573. epilepsies: a prospective study. Neurology 19. Nobili L, Cardinale F, Magliola U, et al. Y 2004;62(2):254 257. Taylor’s focal cortical dysplasia increases the 5. Lu¨ ders H, Acharya J, Baumgartner C, et al. A risk of sleep-related epilepsy. Epilepsia new epileptic seizure classification based 2009;50(12):2599Y2604. exclusively on ictal semiology. Acta Neurol 20. Scheffer IE, Bhatia KP, Lopes-Cendes I, et al. Y Scand 1999;99(3):137 141. Autosomal dominant frontal epilepsy 6. Lugaresi E, Cirignotta F. Hypnogenic misdiagnosed as sleep disorder. Lancet paroxysmal dystonia: epileptic seizure or a 1994;343(8896):515Y517. Y new syndrome? Sleep 1981;4(2):129 138. 21. Hoda JC, Gu W, Friedli M, et al. Human 7. Rasmussen T. Surgery for central, parietal nocturnal frontal lobe epilepsy: and occipital epilepsy. Can J Neurol Sci pharmacogenomic profiles of pathogenic 1991;18(4 suppl):611Y616. nicotinic acetylcholine receptor beta-subunit mutations outside the ion channel pore. Mol 8. Tellez-Zenteno JF, Dhar R, Wiebe S. Pharmacol 2008;74(2):379Y391. Long-term seizure outcomes following epilepsy surgery: a systematic review and 22. Combi R, Dalpra L, Ferini-Strambi L, Tenchini meta-analysis. Brain 2005;128(pt 5):1188Y1198. ML. Frontal lobe epilepsy and mutations of the corticotropin-releasing hormone gene. 9. Jobst BC, Siegel AM, Thadani VM, et al. Ann Neurol 2005;58(6):899Y904. Intractable seizures of frontal lobe origin: clinical characteristics, localizing signs, and 23. Oldani A, Zucconi M, Asselta R, et al. results of surgery. Epilepsia 2000;41(9): Autosomal dominant nocturnal frontal lobe 1139Y1152. epilepsy. A video-polysomnographic and genetic appraisal of 40 patients and 10. McGonigal A, Chauvel P. Frontal lobe delineation of the epileptic syndrome. Brain epilepsy: seizure semiology and presurgical 1998;121(pt 2):205Y223. evaluation. Pract Neurol 2004;4(5):260Y273. 24. Proserpio P, Cossu M, Francione S, et al. 11. Unnwongse K, Wehner T, Foldvary-Schaefer Epileptic motor behaviors during sleep: N. Mesial frontal lobe epilepsy. J Clin anatomo-electro-clinical features. Sleep Med Neurophysiol 2012;29(5):371Y378. 2011;12(suppl 2):S33YS38. 12. Provini F, Plazzi G, Tinuper P, et al. Nocturnal 25. Unnwongse K, Wehner T, Foldvary-Schaefer frontal lobe epilepsy. A clinical and N. Selecting patients for epilepsy surgery.

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