Epilepsy and Paroxysmal Events

Jurriaan M. Peters

Heather E. Olson

Tobias Loddenkemper

Diagnostic Approach¹

(1) General: The common general neurology approach implies: (1) description of signs and symptoms, (2) localization, and (3) etiological investigation. Specific combinations of as well as related medical information may provide information on a possible (4) epilepsy syndrome.

(2) Temporary management: (a) Recurrent paroxysmal event of uncertain etiology is a neutral term that allows for later adjustment of the diagnosis, and often patients can be managed temporarily without a more specific diagnostic label. (b) First, do no harm. A false-positive diagnosis may be more harmful than a delayed diagnosis. A wrong diagnosis does not address the true condition, and may result in parental anxiety, patient stigmatization, and exposure to unnecessary testing and potentially harmful treatment. (c) Treatment trials with antiepileptic drugs (AED) are discouraged as they are often false-positive, as less events on AED may be due to inherent low frequency or natural evolution. Patients with frequent, threatening events of unknown etiology may be admitted for urgent diagnosis and therapy. (d) Make a clinical diagnosis. EEG and auxiliary tests have limitations.

Step 1: Structured History and Physical (What are the clinical features?)

(1) History: Analyze the event in sequence: (1) setting, (2) onset, (3) core presentation, (4) end and postictal features.¹ Describe the presentation in the patient’s or family’s own words, and obtain a history from both the patient and a witness of the event (Table 5.2).

(2) Physical examination: See Chapter 1 of this book. Skin examination by Wood’s lamp and hair examination, ophthalmologic exam, and presence of dysmorphic features may provide important clues. Check for injuries sustained during or after an event (e.g., burns from hot drinks, open fire, radiator). Activation procedures (e.g., hyperventilation) can be performed in office-based outpatient setting, provided appropriate safety measures are in place.

Step 2: Epileptic vs. Nonepileptic Event (Is it an Epileptic sz?)

Nonepileptic paroxysmal events: Key clinical features of the event assist in formulating a differential diagnosis (see Table 5.15 [by age] and Tables 5.16, 5.17, 5.18, 5.19 and 5.20 [by key feature]).

Psychogenic nonepileptic szs (PNES): Spells that resemble epilepsy but have psychogenic rather than physiologic origin. Usually somatoform
(conversion more often than somatization disorder, rarely factitious, malingering). Ten percent to thirty percent of patients with PNES also have epileptic szs. Poor prognosis of PNES with significant disability is associated with longer duration and prolonged course of symptoms and with late diagnosis and psychotherapy. Better prognosis with early diagnosis, no psychiatric comorbidity, less dramatic features (e.g., limpness rather than thrashing). In children respectfully and carefully assess for psychosocial stressors, sexual abuse, and mood disorders (Table 5.3).

TABLE 5.1 Definitions of Epilepsy and Seizures

Seizure (sz): Transient occurrence of signs and symptoms due to excessive or synchronous neuronal activity in the brain.

Epilepsy: Two or more unprovoked epileptic szs (status epilepticus and multiple szs in 24 h are both considered a single event, only febrile szs do not qualify as epilepsy).

Epilepsy syndrome: A complex of signs and symptoms that define a unique epilepsy condition. This may include sz type, age at onset, gender predominance, etiology, behavioral or cognitive comorbidity, diurnal variation or association with sleep, precipitating factors (sleep deprivation, photic stimulation), family history. A syndromic diagnosis has implications for management, developmental prognosis and epilepsy outcome, genetic testing, and heritability.

Adapted from Vendrame M, Loddenkemper T. Approach to seizures, epilepsies and epilepsy syndromes. In: Grigg-Damberger MM, Foldvary-Schaefer N. Sleep-related Epilepsy and Electroencephalography. Sleep Med Clin. 2012;7(1):59-73.¹

TABLE 5.2 Structured History and Physical Examination

History Taking: Key Elements
General	Patient: development, birth Hx, PMH (e.g., cardiac, neurologic, psychiatric, immunologic, infectious, trauma) Family: szs, febrile convulsions, tics, ADHD, behavioral problems, developmental delay, significant learning disabilities, neurological or genetic syndromes, including neurocutaneous disorders, psychiatric or mental health diagnoses, unexplained or early death, malignancies Exposures, psychosocial: insect bites, travel (e.g., malaria, cysticercosis), stressors, life events
(1) Setting	Who witnessed the sz? Who is the source of the history? Always question the patient and a witness if possible Where (environment): home, school, bed, in- or outside, cross-situational, alone or witnesses present What (activity engaged at time of onset): awake, asleep, active, sitting, standing, TV/computer When (triggers, circumstances immediately prior): feeding (timing, certain foods, missed meals), medication, drugs, alcohol, or toxins (intake, ingestion, recent change), sleep, sleep transitions, or sleep deprivation, menstruation, exercise, auditory and visual stimuli, headache, head trauma, emotions, fever, other triggers and reflex epilepsies (e.g., hot water) How: frequency, duration, time course (worsening, decreasing, stable), diurnal pattern or time of day; if clusters, interval and duration
(2) Onset	Aura: premonitory experiential sz symptom of sensory, gustatory, olfactory, auditory, abdominal, or more complex experiences, frequently providing localizing clues
	Aura	Symptom
	Somatosensory	Burning, tingling, pain, numbness
	Visual	Simple fixed objects, complex, moving
	Auditory	Sounds, voices
	Olfactory, gustatory	Smell, taste without external source (usually bad smell or taste)
	Epigastric	Rising abdominal sensation
	Déjà vu, jamais vu	Sensation of familiarity, unfamiliarity
	Derealization	Sensation out of body, seeing self “like on camera”
	Cephalic	Unspecified, unexplainable feeling in head
	Autonomic	Palpitations, (cold) sweat, shivers, piloerection, urge to urinate or defecate
	Note: Prodromal symptoms in syncope—cold sweat, lightheadedness, graying or blackening of vision “like a curtain,” palpitations, chest pain, weakness or buckling of legs, sensation of voices and sounds being distant
(3) Core presentation, evolution	Feature	Poor Descriptors	More Accurate
	Motor	Shaking, twitching, seizing, grand mal	Tonic activity/dystonic posturing (tense unnatural posture) Myoclonic movements (fast flexion, rapid relaxation) Clonic movements (recurrent biphasic, rhythmic, synchronous motor movements) Tonic-clonic (first posturing, then clonic movements) Head version (forcible slow deliberate head and eye deviation, often with clonic movements) Epileptic spasms (rapid forward hip/abdomen flexion with extension of arms, brief tonic moment, then relaxing, often clustering; more subtle or extension, or a combination can also be seen) Eye movements (nystagmus, forced sustained deviation)
	Impairment of consciousness	Out of it, zoned/blanked out, nobody home, lost it, out, gone	Unconscious, unresponsive, loss of awareness, loss of memory, attempting to answer, eye contact, response to voice, touch, or noxious stimuli, agitation or fending people off
	Fall	Fall, went down	Found down, helped to ground, slumped, buckled, partial loss of tone while sitting or standing, sudden total loss of tone and posture, forced brisk forward motion with trunk and head, injury
	Automatisms	Weird motions with hands or lips	Simple repetitive movements or natural-looking sequence of movements, including picking movements, hand washing or -rubbing, lip smacking or tongue licking, chewing
	Autonomic system	Off color, wet, sweaty	Piloerection, flushing, pallor, cyanosis, diaphoresis, vomiting, sensation of cold or feeling hot, loss of urine, fecal incontinence
	Oral, language	Making strange sounds	Gagging, choking, guttural sound, swallowing, drooling, vocalization (scream, moan, grunt, hum, mumble), verbalization (speech, gibberish), aphasia (speech impaired) or anarthria (speech motor control impaired)
	Note: Qualitative descriptors include rhythmicity, frequency, synchrony, amplitude, symmetry, quality (fast-and-slow phase or oscillatory, violent (jerks, thrashing), subtle (tremulous, trembling, shivering), sequence (body parts involved, tonic phase, clonic phase)
(4) End	Todd’s paresis		Postictal weakness of arm, leg, or face, typically resolves in 24-48 h
	Vision		Hemianopia
	Language		Aphasia or dysphasia
	Mental status		Combativeness, agitation more diagnostic than brief bewilderment or mild confusion, rapidly alert/oriented after loss of consciousness suggests syncope
	Posture		Are events position related; i.e., do they always occur while standing (syncope)?
ADHD, attention deficit hyperactivity disorder; Hx, history; PMH, past medical history; sz, seizure. Table in part based on,^1,2,39 in addition to own data.

Step 3: Localization (What regions in the brain are involved?)

Localization of sz focus assists in (1) classification and (2) etiology (e.g., focused high-resolution imaging of the temporal lobe) and (3) determining candidacy for epilepsy surgery. Semiology may reflect only the symptomatogenic zone (area of the cortex that is generating the symptoms) but epileptic activity may have originated in and spread from a “silent” cortical area.³ Different aspects from the semiology provide information about lateralization (in which hemisphere) and localization (in which area) (Table 5.4)¹.

TABLE 5.3 Psychogenic Nonepileptic Seizures—Diagnostic Considerations

A. Features suggestive of PNES (most differentiating features are in bold):

History: clinical presentation and features can be influenced bγ others, multiple normal EEGs, resistance to multiple AEDs, unusual triggers (stress, pain, specific movements, sounds, lights), antecedent of sexual trauma or conversion disorder, occur only around others or only when alone, extensive positives on review of systems, vague somatic symptoms suggesting somatization, coexistence of poorly defined diagnosis (e.g., fibromyalgia, chronic pain, fatigue), depression, anxiety, inappropriate affect or lack of concern (“la belle indifference”), or inducibility by suggestion

Semiology: Side-to-side head shaking, bilateral asynchronous movements, crying, moaning, stuttering, back arching, pelvic thrusting, presence of stuffed animals (“teddy bear sign”) in adolescent or adult patients, eye flutter or eye closing (with eyes rolling to back on passive eye-opening, aka Bell sign), prolonged spells (10-30 min), preserved awareness despite generalized motor involvement, waxing and waning pattern with fluctuating responsiveness (rather than clear onset, core presentation, and end with postictal phase in epileptic szs)

B. Features against PNES (most differentiating features are in bold): eye opening or widening, abrupt onset, arise during verified sleep (DDx panic attacks, OSAS, sleep disorder), injuries sustained, tongue bite (especially lateral), incontinence, postictal confusion, depressed mental status or agitation (more so than confusion)

C. Pitfalls⁶ and pearls: (1) Movements not suppressible by the examiner do not necessarily imply epilepsy and do not exclude PNES or movement disorders. (2) Response to pharmacologic intervention is not specific to epileptic szs; e.g., benzodiazepines will also suppress PNES or motor spasticity. (3) Rage attacks and psychosis are uncommon presentations of epilepsy, as opposed to postictal agitation and memory problems. Pearls include lateral tongue bite (highly suggestive of epileptic origin) and forced eye closure against resistance (highly suggestive of PNES)

PNES, psychogenic nonepileptic szs.

Adapted from Westover MB, Peters JM, Bromfield E. Seizures and other spells. In Greer DM, ed. Pocket Neurology. Philadelphia, PA: Lippincott, Williams & Wilkins; 2010:57-79, with permission.

TABLE 5.4 Lateralization and Localization from Seizure Semiology

Feature		Lateralization	Localization
Aura	Unilateral sensory aura	C/L	PL (Brodmann area 1-3)
	Hemifield visual aura	C/L	OL (Brodmann area 17-19, adjacent areas)
	Abdominal aura	None	Usually mesial TL
Motor	Head version	C/L	FL (Brodmann area 6 and 8)
	Clonic movements	C/L	FL (Brodmann area 4 and 6)
	Tonic activity	C/L	FL (SMA, possibly others)
	Unilateral dystonic posturing	C/L	Basal ganglia activation
	Figure-of-four (asymmetric tonic limb posturing in early tonic phase before generalization: arm flexed, other extended, head version to extended arm)	C/Lofext. arm	FL
	Fencing posture (abduction, external rotation, and partial flexion of arm at the shoulder, head and eyes “look at” the abducted arm. Other arm extends downward and backward, feet may be apart to support partially rotated trunk)	None	FL(SMA)
	Unilateral eye-blinking	I/L	Unknown
	Nystagmus	C/L	FL, PL
Impairment of Consciousness		Complex	TL, FL, B/L
Automatisms	With preserved consciousness	N/D	TL
	With impaired consciousness	D or B/L	TL, hippocampus
	With unilateral dystonic posturing	I/L	TL, BG
Autonomic	Ictal emesis/urination/defecation	N/D	TL
	Cold sensation	D	TL
Speech	Ictal speech	N/D	TL
	Ictal aphasia	D	TL, sometimes FL
	Ictal anarthria	D	Rolandic/Sylvian fissure
Postictal	Todd paresis	C/L	Brodmann 4 and 6
	Hemianopia	C/L	Brodmann 17-19, adjacent areas
	Aphasia or dysphasia	D	Language areas
B/L, bilateral; C/L, contralateral; BG, basal ganglia; D, dominant; FL, frontal lobe; I/L, ipsilateral; N/D, nondominant; PL, parietal lobe; TL, temporal lobe. Adapted from Loddenkemper T, Kotagal P. Lateralizing signs during seizures in focal epilepsy. Epilepsy Behav. 2005;7:1-17.⁴⁰

Step 4: Etiology (What is causing the clinical presentation?)

In many patients no cause can be found. In others, history, physical exam, and auxillary test may provide guidance.¹ (1) EEG: Recommended by AAN in the evaluation of a first unprovoked sz.⁴ Assists in determination of sz type, localization, potential syndrome, and estimate of recurrence risk. Activation procedures include hyperventilation, photic stimulation, and recording sleep and may provoke epileptiform discharges and increase yield of routine outpatient EEG. Routine EEG is 20 min. Ambulatory monitoring can be done at home or in-hospital with continuous video recording, up to several days in duration. Sleep, the transition to sleep, and sleep deprivation itself increase sensitivity increase by 25%. EEG performed <24 h after event increases sensitivity by 15%. EEG‘s sensitivity in predicting recurrence is 48% to 61%, specificity 71% to 91%. EEG findings should always be placed in clinical context.⁵ Interpretation in clinical context: (1) A normal EEG does not rule out epilepsy. (2) An abnormal EEG with epileptiform discharges by itself does not constitute a diagnosis of epilepsy unless a sz is captured during the recording. Up to 3.5% of normal school-aged children may have epileptiform spikes in EEG, with higher numbers in children with ADHD (6%) and autism (18%-64%). An epileptiform EEG therefore may indicate (a) a genetic trait, (b) a lowered sz threshold, or (c) a higher recurrence risk if the event in question was indeed a sz. An abnormal EEG is more predictive of epilepsy if the prior clinical suspicion of a sz is high.⁶ (3) Variations in subjective interpretation (i.e., over- or under-reading) contribute to variability in sensitivity and specificity of EEG as a test. (2) Neuroimaging: MRI is recommended by AAN in the evaluation of first unprovoked sz, to assess for underlying etiology such as structural abnormality (e.g., tumor, stroke, infection, arteriovenous malformation, cortical malformation, or cerebral dysgenesis).⁴ Persistent focal deficits and altered mental status prompt urgent imaging with CT. In classic presentations of genetic or developmental epilepsies (e.g., juvenile myoclonic epilepsy, childhood absence epilepsy, or benign Rolandic epilepsy of childhood), imaging may not be needed. (3) Laboratory studies: Basic metabolic panel includes sodium, potassium, calcium, magnesium, phosphate, and bicarbonate. Serum &urine toxicology screen. For suspected infection extend workup (e.g., to include CSF examination). In case of known epilepsy, consider AED levels. (4) Genetic testing: Please refer to later paragraphs in this chapter. (5) ECG: May be indicated to assess for QT prolongation and to rule out other cardiac causes.

Step 5: Classification¹ (Which category does this presentation fit best?)

(1) Utility: To (a) understand the sz type(s) and epilepsy of a patient, (b) localize the clinical presentation, (c) identify the potential etiology, (d) elicit related medical conditions important for the diagnosis (in part reiterative from Steps 1 to 4). Classification improves communication and allows tailored treatment and prognosis assessment. (2) Several classifications have been evaluated by the International League Against Epilepsy (ILAE) each serving different functions, e.g., practical clinical vs. research-driven applications. (3) The 1989 ILAE classification of epilepsies (Table 5.5) is still current. Strengths include ease of use and, in some cases, guidance for choice of AED. Weaknesses include the neglect of more complex conditions, genetic and structural metabolic etiologies, the limited description of sz semiology, and the assumption of a strict relationship between etiology, localization, and sz type (Steps 1-4). (4) The 2010 Revised Terminology and Concepts for Organization of Szs and Epilepsies⁷ (Table 5.6) attempts to reconcile ongoing controversies and address weaknesses of previous
schemes. It allows for further description within each category of sz type(s), localization, cause, age of onset, and comorbid conditions. Etiology is divided into (a) known genetic (without significant structural abnormalities), (b) structural/metabolic, or (3) unknown. Epilepsy syndromes and etiologies by subgroups are outlined in Tables 5.7, 5.8, 5.9, 5.10 and 5.11. (5) Ongoing critical interpretation of novel data allows for ajustment of a diagnosis and the therapeutic approach.¹

TABLE 5.5 The 1989 International League Against Epilepsy (ILAE) Classification of Epilepsies

Etiology
(a)	Idiopathic: unknown cause (with age-related onset), now often genetic epilepsies
(b)	Symptomatic: known cause
(c)	Cryptogenic: a cause is suspected but not demonstrated yet
Localization
(a)	Localization-related (focal, partial) epilepsies and syndromes
(b)	Generalized epilepsies and syndromes
(c)	Epilepsies and syndromes underdetermined whether focal or generalized
(d)	Special syndromes
Note: Still current, novel proposals have not been formally adapted. Proposal for revised classification of epilepsies and epileptic syndromes. Commission on Classification and Terminology of the International League Against Epilepsy. Epilepsia. 1989;30:389-399.⁴¹

TABLE 5.6 2010 ILAE Proposal for Classification of Epilepsies

I(a) Electroclinical syndromes with age-related onset
Neonatal period
	Benign familial neonatal epilepsy (BFNE) Early myoclonic encephalopathy (EME) Ohtahara syndrome (EIEE)
Infancy
	Epilepsy of infancy with migrating focal szs (MMPEI) West syndrome (IS) Myoclonic epilepsy in infancy (MEI) Benign (familial or nonfamilial) infantile epilepsy Dravet syndrome (SMEI) Myoclonic encephalopathy in nonprogressive disorders
Childhood
	Febrile szs plus GEFS+ Epilepsy with myoclonic atonic (previously astatic) szs (Doose syndrome) Benign epilepsy with centrotemporal spikes (BECTS) Autosomal-dominant nocturnal frontal lobe epilepsy (ADNFLE) Early-onset childhood occipital epilepsy (Panayiotopoulos syndrome) Late-onset childhood occipital epilepsy (Gastaut-type) Epilepsy with myoclonic absences (EMA) Lennox-Gastaut syndrome (LGS) Epileptic encephalopathy with continuous spike and wave during sleep (CSWS) Landau-Kleffner syndrome (LKS) Childhood absence epilepsy (CAE)
Adolescence and Adulthood
	Juvenile absence epilepsy (JAE) Juvenile myoclonic epilepsy (JME) Epilepsy with generalized tonic-clonic szs alone (EGTCO) Progressive myoclonus epilepsies (PME) Autosomal-dominant epilepsy with auditory features (ADEAF) Other familial temporal lobe epilepsies
Less-specific age relationship
	Familial focal epilepsy with variable foci Reflex epilepsies
I(b) Electroclinical syndromes with structural-metabolic cause
	Mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE with HS) Rasmussen syndrome Gelastic szs with hypothalamic hamartoma Hemiconvulsion-hemiplegia-epilepsy
I(c) Electroclinical syndromes of unknown cause
I(d) Conditions with epileptic szs that are traditionally not diagnosed as a form of epilepsy per se
	Benign neonatal szs (BNS) Febrile szs (FS)
II Nonsyndromic epilepsies with structural-metabolic cause
	Malformations of cortical development (hemimegalencephaly, heterotopias, etc.) Neurocutaneous syndromes (tuberous sclerosis complex, Sturge-Weber, etc.) Tumor, infection, trauma, vascular malformation, perinatal insults, stroke, inflammatory/autoimmune conditions
III Epilepsies of unknown cause
From Berg AT, Berkovic SF, Brodie MJ, et al. Revised terminology and concepts for organization of seizures and epilepsies: report of the ILAE Commission on Classification and Terminology, 2005—2009. Epilepsia. 2010; 51:676-685, with permission.⁷

SELECTED EPILEPSY SYNDROMES

Conditions with Epileptic Seizures that are Traditionally not Diagnosed as a form of Epilepsy

Febrile Seizures

DEFINITION: Sz in a neurologically healthy child between 6 mo and 5 y of age associated with fever (>38.4°C) without evidence of central nervous system (CNS) infection, electrolyte imbalance, or other defined cause and without history of a febrile seizure (FS).⁸^,⁹ Simple FS are brief generalized szs that do not recur within 24 hrs and without postictal neurologic abnormalities.⁸^,¹⁰ Complex FS are szs that occur for a duration of more than 15 min, recur multiple times within 24 hrs, or have focal features.

EPIDEMIOLOGY: Prevalence rates are 2% to 5% in children in the United States, and genetic predisposition often plays a role.⁹ Half the children present between 12 and 30 mo of age, and it is unusual to present for the first time at the upper end of the age range.¹⁰

TABLE 5.7 Neonatal Period: I(a) Electroclinical Syndromes with Age-Related Onset

Syndrome	Prev	Onset	Sz Type	EEG	Rx	Prognosis, Remarks
BNC (benign [idiopathic] neonatal convulsions, 5th-day fits)⁴²	Rare < 1% of pediatric epilepsy	Day 1-7 (most day 5)	Brief, 1-3 min. Clonic, partial tonic, or subtle (e.g., apnea). May start on one side, then affecting other side. Often repeated or clustering, leading to status epilepticus	Interictal normal or asynchronous rhythmic theta “theta pointu alternant,” ictal rhythmic usually focal sharp or slow waves, or spikes	PB, PHT, BDZ	Excellent prognosis. Remission after 24-48 h. Dx often after resolution and normal outcome. Some data suggest mild developmental deficits in 50% of cases, and ↑ risk epilepsy later. Hypotheses have included Zn²⁺ def., rotavirus (unconfirmed). Decreased frequency, no case series reported since 1990s
BNFC (benign neonatal familial convulsions)⁴³	Rare, unknown	Day 2-7, but can be up to 3 mo	Focal tonic and clonic, formally still categorized as generalized (new classification not adopted yet)	Normal interictal EEG. Ictal generalized flattening, next generalized spike-and-wave or focal discharges	PB	Spontaneous remission by 2-3 mo, normal neurological exam. Autosomal-dominant defect in voltage-gated potassium channel KCNQ2, 3 with incomplete penetrance. Later childhood epilepsy 11%-16%
EME (early myoclonic encephalopathy)⁴⁴	Rare, <1%	Neonatal period	Segmental & erratic myoclonic, generalized myoclonic, evolve into infantile spasms w/ atypical hypsarrhythmia, which may persist into late childhood	Suppression-burst: Bursts of spike and sharp waves alternate with periods of voltage attenuation, more pronounced in sleep	Steroids, BDZ, VPA, VGB, KGD	Malignant epilepsy syndrome: poor neurological outcome 100%, mortality 50% <1 y. Nonstructural, metabolic disorders common (e.g., NKH). Similar genetic associations as EIEE (below). MRI with atrophy and delayed myelination DDx: EIEE occurs in 1st mo, tonic szs main type, EEG has longer bursts and brain malformations are common, earlier transition to IS and LGS
EIEE (Ohtahara) (early infantile epileptic encephalopathy)⁴⁵	Rare, <1%	(Early) neonatal to 1st mo	Tonic szs main type, occur during wake, sleep, and typically not in clusters. Also partial motor, focal motor szs, hemicon-vulsions, GTCs	Suppression-burst (see above), but during wake and sleep, longer bursts	See above	Malignant epilepsy syndrome: Poor outcome in most. Structural brain abnormalities from encephaloclastic events, cerebral dysgenesis, even in cryptogenic cases, rarely metabolic. Genetic association with CDKL5, STXBP1 and ARX mutations (reviewed in⁴⁶ and see genetics table)

TABLE 5.8 Infantile Period: I(a) Electroclinical Syndromes with Age-Related Onset

Syndrome	Prev	Onset	Sz Type	EEG	Rx	Prognosis, Remarks
MMPEI (malignant migrating partial epilepsy of infancy)⁴⁷	Very rare, <<1%	<6 mo	At first occasional focal szs with rapid secondary generalization and autonomic symptoms, weeks to months followed by multiple clinical sz types in the second phase. Late 3rd phase w/ occasional breakthrough sz but prolonged sz-free intervals	1st phase: multifocal spikes, migrating patterns of focal slowing. 2nd & 3rd phase: migrating and expanding focal discharges, complicated multifocal EEG with near-merger of ictal and interictal patterns. Frequent status epilepticus and subclinical szs warrant prolonged inpatient video-EEGs	Any combination of multiple AEDs	Usually markedly drug-resistant to any combination of older and newer AEDs. KGD variable success. Outcome severe with progressive deterioration of psychomotor development, microcephaly, mental retardation, and death. MRI typically negative with later atrophy, some w/ mesial temporal sclerosis. Extensive genetic and neurometabolic workup typically negative.
IS (infantile spasms, West)⁴⁸	Uncommon, 1%-5%	3-14 mo (peak 4-9)	Brief tonic or clonic spasms, typically clustering, many times daily (on arousal). Flexor (arms, neck) and extensor (legs), or flexor (jackknife) or extensor. Can be subtle, e.g., head nods only. 50%-60% have szs in later life, frequently LGS	Disorganized high-voltage multifocal polymorphic slowing with interspersed epileptiform discharges. Initially may be during (light) sleep only. Ictal generalized high-voltage slow wave with electro-decrement or diffuse fast betarange activity	Steroids, VGB, TPM, Vit B6, LTG, RFA, KGD	West syndrome: Triad of clusters of IS, psychomotor deterioration, and hypsarrhythmia on EEG. >85%-95% symptomatic: prenatal, perinatal, and postnatal insults, e.g., hypoxic ischemic injury, perinatal infections, tuberous sclerosis, cerebral malformations and dysgenesis, chromosomal (trisomy 21, del1p36), gene mutations (ARX, CDKL5, STXBP1), metabolic (untreated PKU, tetrahydrobiopterine def, Menkes), and mitochondrial (NARP mutation). Poor prognosis, rarely good outcome with cryptogenic etiology ˜5%.
BMEI (benign myoclonic epilepsy of infancy)⁴⁹	Rare, <1%	3 mo-4y	Brief generalized myoclonic, mainly head and upper part of body, awake, upon falling asleep, or during slow sleep. Multiple daily, in isolation or nonrhythmic recurring, some subtle	Generalized (poly-) spike (and wave), with normal interictal EEG	VPA, BDZ, LTG	Normal neurological outcome (reportedly some with developmental delay). Reflex form is common variant with excessive sleep startle, photosensitivity, earlier onset, and usually good outcome. Other idiopathic generalized epilepsies may occur in adolescence.
Benign infantile (non)familial szs⁵⁰	Rare, <1%	<2 y	Behavioral arrest with staring, and then focal clonic, focal tonic, or secondarily GTC. May cluster	Interictal normal, ictal with focal discharges, may generalize	VPA, CBZ, PB	Sporadic, in some cases familial. Good response to Rx, good neurological outcome. Some are associated w/ familial paroxysmal choreoathetosis. Some associated with SCN2A mutations. PRRT2 is also identified in families with benign familial infantile convulsions and choreoathetosis (not yet clinically testable in the US).
SMEI (Dravet) (severe myoclonic epilepsy of infancy, some related syndromes with different phenotypes)⁵¹	Rare,<1%	1st y or life, peak 3-8 mo	Prolonged febrile sz (or status), next recurrent 1-2/mo, generalized and alternating unilateral clonic or tonic-clonic szs, often prolonged and w/ fever. Later myoclonic, atypical absence, complex, partial, atonic, and unilateral szs, nonconvulsive status epilepticus. Tonic szs are rare	Generalized spike and wave complexes, focal and multifocal spikes. Whole body myoclonic szs associated with generalized spikes and waves or occasionally without EEG Δ. Atypical absences: generalized 2-3.5-Hz irregular spike waves	Refractory to most AEDs. LTG and CBZ worsen	Malignant epilepsy syndrome. Recurrent febrile hemiclonic status epilepticus between 6 and 12 mo, w/developmental arrest after 1st y of life and regression with recurrent status. Early control may lead to better neurological outcome. Positive FHx for (febrile) szs in 25%. MRI normal at 1st, later hippocampal sclerosis. SCN1A (and GABRG2) mutations in >70%. MRI normal and later with nonspecific atrophy and gliosis, hippocampal atrophy.

TABLE 5.9 Childhood: I(a) Electroclinical Syndromes with Age-Related Onset

Syndrome	Prev	Onset	Sz Type	EEG	Rx	Prognosis, Remarks
GEFS+ (generalized epilepsy w/febrile szs plus)⁵²	Common, >5%	Febrile Szs < 5 y, others later childhood	Marked phenotypic diversity: typical febrile szs in early childhood. GTC, absence, myoclonic, (a)tonic, focal motor or continuing brief, generalized febrile szs follow	Normal or as in Idiopathic generalized epilepsies: generalized epileptiform discharges	Standard AEDs based on sz type	Autosomal dominant with incomplete penetrance 70%-80%. SCN1A, SCN2A, SCN1B, and GABRG2 gene mutations. Strong family history with variable phenotypes, including partial szs ˜15%. Variable outcome ranging from remission at 10-12 y to ongoing refractory epilepsy
Panayiotopoulos (early-onset benign childhood occipital epilepsy)⁵³	Common, 6%	1-13 (peak 3-6) y	Long (30+ min), mainly autonomic szs/status, often from sleep: (1) feeling sick, headache, pale, vomiting, pallor, flushing, cyanosis, eye deviation, mydriasis, cardio- & thermoregulatory sensations, incontinence, hypersalivation, ictal syncope (unresponsive, limp). Next may have (2) complex partial features and/or (hemi)clonic convulsions, brief	Multifocal spike and wave, Rolandic morphology, frequently with occipital predominance or with multifocal spikes	As in Rolandic Some: rectal DZP only	Better defined than Gastaut-tγpe (see below), reported to be common, but this depends on inclusion criteria. Despite autonomic status epilepticus usually benign prognosis, even if frequent szs: remission <2 y. Most have infrequent szs, 25% have only 1, 50% have total < 5. No increased risk later epilepsy in adulthood. Misdiagnosis is common, DDx with migraine, gastroenterologic (-itis, cyclic vomiting, abdominal migraine), syncope, sleep d/o. Cardiac arrest has been described, but is rare.
EMAS (Doose) (epilepsy with myoclonic astatic szs, myoclonic astatic epilepsy)⁵⁴	Uncommon, 1%-5%	7mo-6y	Generalized myoclonic, astatic, or myoclonic-astatic szs, leading to falls. Also short absences, generalized tonic-clonic szs and nonconvulsive status; no tonic szs or tonic drop attacks during daytime	Generalized EEG patterns ([poly-] spike and wave, photosensitivity, 2-3/s rhythms), no multifocal spikes	VPA, ESM, BDZ, LTG, TPM, LEV, RFA	Criteria: (1) Szs as outlined on left; (2) genetic predisposition (high incidence of szs and/or genetic EEG patterns in relatives 15%-40%); (3) normal development and neurologic exam prior to onset; (4) EEG as outlined on left; (5) exclusion SMEI, BMEI, and LGS. Differences with LGS: in Doose myoclonic predominant type, genetic basis, outcome usually better, but variable: at times fair with sz control and (near-) normal cognition.
BECTS (Rolandic) (benign childhood epilepsy with centrotemporal spikes, benign Rolandic epilepsy of childhood)⁵⁵	Most common epilepsy of childhood (10%-15%)	3-13 (peak 7-9) y	Nocturnal unilateral, tongue, lips, cheek, larynx, pharynx (anarthria), occasionally arm, preserved consciousness. May generalize during sleep. Sensory aura common but underreported by patient	Interictal unilateral or bilateral centrotemporal triphasic spikes with horizontal anterior-posterior dipole, prominent sleep activation, nl background	OXC, CBZ,LTG, TPM, GZP, LEV	Excellent outcome, szs almost always remit by puberty. May be frequent initially. Consider not treating if infrequent, nocturnal, or partial only. Learning and behavioral difficulties can be present, in part related to frequency of interictal discharges. Atypical BECTS associated with language and developmental delay. Genetic etiology suspected (ELP4). Agerelated penetrance suspected.
ADNFLE (auto-somal-dominant nocturnal frontal lobe epilepsy)⁵⁶	Rare	0-50 y (85% <25, mean 12, median 8)	Frequent (multiple per night), very stereotyped, brief, sudden onset and end, during non-REM sleep stage II: sudden arousal with complex, motor features, automatisms, (dys-)tonic posturing and hypermotor activity (e.g., leg pedaling), no postictal phase, may have daytime szs. Often preserved awareness	Routine EEG is normal, rarely frontal epileptiform or nonspecific abnormalities. Ictal EEG: frontal rhythmic beta frequency epileptiform abnormalities	CBZ, OXC, LTG, TPM	Challenging electroclinical diagnosis. Autosomal dominant with high degree of penetrance. Different mutations in several genes (20q13.2, 1p21) (nicotinic acetylcholine receptor, changes in presynaptic NT release), similar phenotype. Sleep deprivation and stress worsen or precipitate. Behavioral problems common until sz control. Previously was considered a paroxysmal nocturnal dystonia.
Gastaut (Late-onset) Idiopathic benign childhood occipital epilepsy⁵⁷	Rare, < 1%-2%	3-16 (peak 8) y	Brief, seconds to several min. Frequent, many times a day in awake patient. Visual aura (blindness, colored luminous discs, formed visual hallucinations). At times eye deviation, eyelid flutter, and postictal headache (50%) and vomiting (5%) can occur	High-amplitude spike-and-wave occipital discharges with eyes closed or during sleep. Ictal pattern consists of fast, occipital spikes	As in Rolandic	Overall, rare. “Idiopathic” is speculative as genetic etiology is not proven. Frequency, nature, and brevity of the visual symptoms should help distinguish from migraine with aura. Fair prognosis: 60% remit within few years. Migraines in 20%, family Hx(+) epilepsy in 50%.
Syndromes with absence szs and myoclonus or micturition⁵⁸			MAE (Tassinari) (myoclonic absence epilepsy): ictal 3-Hz myoclonus, arms “ratcheting” upward. Usually mental retardation, resistant to Rx EMA (Jeavons) (epilepsy with myoclonic absences): marked ictal eyelid, more subtle facial or upper arm jerking. AD inheritence, resistant to Rx MA (micturational absence epilepsy): ictal detrusor contraction with urination. May be resistant, prominent social implications
LGS (Lennox-Gastaut syndrome)⁵⁹	Uncommon, 1%-5%	<8 y, peak 3-6 y	Tonic szs (required for Dx, not at onset, more in sleep), variable severity and semiology. Atypical absences (2nd most common, gradual onset and ending), tonic and atonic szs (>50%) may be preceded by myclonus and lead to injury, (non)convulsive status (50%-70%), myoclonic, and others. ≥20% preceded by IS	Wake: bursts of diffuse slow 1-2.5-Hz spike and wave. Sleep: bursts of diffuse or bilateral fast rhythm patterns ≥10 Hz or “polyspikes,” aka generalized paroxysmal fast activity. Ictal: tonic diffuse fast bursts, atypical absence 1-1.5-Hz spike-and-slow waves, atonic or myoclonic diffuse spikes or polyspikes and slow waves	Refractory to most AEDs. VPA, BDZ, TPM, ZNS, LTG, LEV, FBM, RFA, steroids	Triad of multiple sz types, typical EEG, cognitive impairment. Tonic szs (hallmark) not present at onset, EEG not pathognomonic. Progressive developmental delay, regression, often psychosis. Causes (see IS) heterogeneous: cerebral malformation, tuberous sclerosis, in LGS less commonly acquired destructive lesions or metabolic diseases. Genetics less important. Rx: (1) AEDs; (2) nonpharmacological management: epilepsy surgery (callosotomy, VNS, others), KGD⁶⁰; (3) comorbid psychiatric, behavioral d/o: neuropsychiatric and psychiatric assessment; (4) monitor side effects (coordination, cognition, behavior, sz aggravation).
CSWS (continuous spike and wave during slowwave sleep)⁶¹	Rare, 0.2%-0.6% Male:female 3:2	Sz onset: 2-4 y. Onset of regression, ESES pattern, and worsened szs: 5-6 y	Before regression: infrequent and mostly nocturnal szs, predominantly unilateral motor szs After regression: much more frequent szs of different types: atypical absence of szs, motor szs, generalized tonic-clonic szs Tonic szs never present	ESES EEG pattern: near-continuous spike-waves during non-REM sleep More focal during wakefulness and REM sleep	DZP, VPA, LEV, steroids, IVIG, epilepsy surgery Avoid CBZ, PHT, PB	Severe epileptic encephalopathy with an age-related evolution. Global and profound developmental delay. Spontaneous improvement of szs and EEG abnormalities before puberty but severe residual neuropsychological deficits.
LKS (Landau-Kleffner syndrome)^61,62	Rare, 0.2% Male:female 2:1	Receptive aphasia around 3-5 y	Infrequent szs, mostly partial motor. One third never have szs	Bilateral centrotemporal, posterior temporal, and parieto-occipital spikes much more diffuse during non-REM sleep, leading to nearcontinuous spikes and waves	See above, ESM, CLB	Severe age-related language regression, frequent associated behavioral symptoms, improvement of EEG and szs before puberty, severe residual language deficits.
CAE (childhood absence epilepsy, formerly called petit mal)⁶³	Common, 5%-12%	School age (peak 6-7 y)	Several to innumerable absences per day, 5-15 s. May have motor manifestations (facial) myoclonic, tonic, and atonic components alone or in combination), automatisms and autonomic disturbances	Interictal 3-4-Hz generalized (poly-) spike and wave, normal background	ESM, VPA, LTG, LEV	Neurologically normal children, often with positive FHx of idiopathic generalized epilepsies. Not always “benign”: only 60% respond to 1st AED, in some patients lifelong (cognitive and) learning disabilities, 15% will develop JME later, may affect long-term psychosocial outcome. Hyperventilation frequently provokes absence in the office or during EEG.

TABLE 5.10 Adolescents and Adults: 1(a) Electro-clinical Syndromes with Age-Related Onset

Syndrome	Prev	Onset	Sz Type	EEG	Rx	Prognosis, Remarks
JAE (juvenile absence epilepsy)⁶³	Less common than CAE	7-16, peak 10-12 y	Absences, GTCs (awakening), and myoclonic jerks	Mildly faster than CAE: generalized 2.5-4.5-Hz (poly-) spike and wave, but EEG does not differentiate	See CAE	Overlap syndrome between CAE & JME. Prognosis not as favorable, lifelong disorder, although absences may become less severe. The EEG may show asymmetry, and the partially preserved awareness may lead to a false Dx of focal epilepsy and wrong Rx, e.g., CBZ will aggravate JAE.
JME (Janz) (juvenile myoclonic epilepsy)⁶⁴	Common, 5%-11%	8-26, peak 12-16 y	Bilateral, single or multiple myoclonic szs, predominantly in arms, more often on awakening. Also GTCs 90% and JAE-type absences in 10%-30%	Generalized (poly-) spike and wave, 3-6 Hz. Photosensitivity in 40%-70%	VPA, LTG, BDZ, TPM, LEV	Sz-precipitating factors (sleep deprivation, fatigue, alcohol, photosensitivity, stress). Genetics: see paragraph on genetics. Absences can appear during childhood, later followed by myoclonic jerks and GTCs in mid-teens. Lifelong condition, milder in 3rd or 4th decade, but withdrawal of AEDs may lead to recurrence. 70% control w/ VPA. Avoid PHT, CBZ: aggravation.
EGTCA (epilepsy with GTCs on awakening): GTCs soon after awakening or when relaxing. Aberrant wake-sleep cycle; unstable sleep.⁶⁵ This syndrome has recently been abandoned as an isolated syndrome, in favor of EGTCO (below). EGTCO (epilepsy with GTCs only): Less strictly defined—includes random and nocturnal GTCs. No absences or myoclonic szs.⁶⁶
Progressive myoclonic epilepsies (PME)		Group of rare myoclonic epilepsies with onset during childhood in which generalized or fragmentary myoclonic szs (and other types) are associated with neurological deterioration, including cerebellar impairment and cognitive dysfunction. Most are progressive, neurogenerative		Typically p/w PME: Lafora dz, Unverricht-Lundborg syndrome, sialidosis type 1 and 2, mucolipidosis type 1, juvenile neuropathic Gaucher’s dz (type 3), juvenile neuroaxonal dystrophy Occasionally p/w PME: neuronal ceroid lipofuscinosis (NCL), MERRF, Huntington’s dz, Wilson’s dz, Hallervorden-Spatz Atypically p/w PME: NKH, infantile hexosaminidase def (Tay-Sachs, Sandhoff’s), biopterin deficiency, sulphite oxidase deficiency
FMTLE (familial mesial temporal lobe epilepsy)^67,68	Rare	Mean onset at 10 y	Aura only: prominent psychic and autonomic features, only rare complex partial szs (CPS), and even more rare secondary GTC szs With MTS: CPS with oral or manual automatisms, rare secondary GTC szs	Interictal: normal or with focal slow waves or epileptiform abnormalities in the temporal regions	CBZ, OXC, LTG, TPM	Only positive FHx distinguishes from nonfamilial TLE (at least 2 family members with TLE in absence of being part of other epilepsy syndrome). Heterogeneous phenotype with mild to severe epilepsy and variable association with MTS and febrile szs. Genetics unclear.
ADTLE (autosomal-dominant lateral temporal lobe epilepsy)^67,68	Rare, < 1%	1-60 y, mean 18	Simple partial szs, often auditory auras (humming, buzzing, ringing), which may be triggered by external noises. Also aphasic, complex visual, psychic, autonomic, and other auras. High propensity to generalize	Interictal: normal or with focal slow waves or epileptiform abnormalities in the temporal regions	CBZ, OXC, LTG, TPM	Aka autosomal-dominant partial epilepsy with auditory features, penetrance 70%-80%. Normal conventional MRI Only gold members can continue reading. Log In or Register to continue Share this: Click to share on Twitter (Opens in new window) Click to share on Facebook (Opens in new window) Related Related posts: Neurodevelopment and Neurologic Examination Metabolic Disorders Mitochondrial Energy Metabolism Disorders Headache and Pain Syndromes Sleep Disorders in Child Neurology Neuro-ophthalmology Stay updated, free articles. Join our Telegram channel Tags: Handbook of Pediatric Neurology Jun 20, 2016 \| Posted by drzezo in NEUROLOGY \| Comments Off on Epilepsy and Paroxysmal Events Full access? Get Clinical Tree Get Clinical Tree app for offline access Get Clinical Tree app for offline access