Evaluation of First Seizure and Newly Diagnosed.4

REVIEW ARTICLE

Evaluation of First Seizure
CONTINUUM AUDIO
INTERVIEW AVAILABLE
ONLINE
and Newly Diagnosed
Epilepsy
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By Elaine Wirrell, MD, FRCP(C), FAAN
ABSTRACT
PURPOSE OF REVIEW: Thisarticle focuses on the evaluation of children and
adults who present with new-onset seizures, with an emphasis on
differential diagnosis, classification, evaluation, and management.
RECENT FINDINGS: New-onset seizures are a common presentation in neurologic

practice, affecting approximately 8% to 10% of the population. Accurate
diagnosis relies on a careful history to exclude nonepileptic paroxysmal
events. A new classification system was accepted in 2017 by the International
League Against Epilepsy, which evaluates seizure type(s), epilepsy type,
epilepsy syndrome, etiology, and comorbidities. Accurate classification
informs the choice of investigations, treatment, and prognosis. Guidelines for
neuroimaging and laboratory and genetic testing are summarized.
SUMMARY: Accurate diagnosis and classification of first seizures and

new-onset epilepsy are key to choosing optimal therapy to maximize
CITE AS: seizure control and minimize comorbidities.
CONTINUUM (MINNEAP MINN)
2022;28(2, EPILEPSY):230–260.
Address correspondence to INTRODUCTION
A
Dr Elaine Wirrell, Mayo Clinic, 200 pproximately 8% to 10% of the population will experience a seizure,
First St SW, Rochester MN 55905,
wirrell.elaine@mayo.edu. and approximately 1 in 26 people will develop epilepsy in their
lifetime, making seizures one of the most common neurologic
RELATIONSHIP DISCLOSURE:
Dr Wirrell has received personal
problems. The epilepsies are a diverse group of conditions that
compensation in the range of share a predisposition to recurrent, unprovoked seizures. In
$500 to $4999 for serving as a addition to seizures, the majority of patients have cognitive, psychiatric, or
Consultant for BioMarin and Eisai
Co, Ltd, and for serving on a
medical comorbidities, which must be appropriately diagnosed and treated.
scientific advisory or data safety Correctly identifying the epilepsy type and syndrome, as well as the underlying
monitoring board for Amicus etiology, is critical for choosing cost-effective, yet high-yield investigations,
Therapeutics, Inc, Encoded
Therapeutics, Inc, and optimizing therapy, and understanding long-term prognosis.
Neurocrine Biosciences, Inc, and
has received publishing royalties
What Is a Seizure?
from UpToDate, Inc.
An epileptic seizure was defined by the International League Against Epilepsy
UNLABELED USE OF (ILAE) as “a transient occurrence of signs and/or symptoms due to abnormal
P R O D U C T S/ I N V E S T I G A T I O N A L
USE DISCLOSURE:
excessive or synchronous neuronal activity in the brain.”1
Dr Wirrell reports no disclosure.
What Is Epilepsy?
© 2022 American Academy Epilepsy was defined in 2005 as “a disorder of the brain characterized by an
of Neurology. enduring predisposition to generate epileptic seizures and by the neurobiologic,
230 APRIL 2022
Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

cognitive, psychological, and social consequences of this condition.”1 In 2014, the KEY POINT
ILAE proposed a practical clinical definition for epilepsy that included any of the
● Epilepsy is defined as any
following: (1) at least two unprovoked (or reflex) seizures occurring more than of the following: (1) at least
24 hours apart, (2) one unprovoked (or reflex) seizure and a probability of two unprovoked (or reflex)
further seizures similar to the general recurrence risk (at least 60%) after two seizures occurring more
unprovoked seizures, occurring over the next 10 years, or (3) diagnosis of an than 24 hours apart, (2) one
unprovoked (or reflex)
epilepsy syndrome.2
seizure and a probability of
further seizures similar to
APPROACH TO DIAGNOSIS the general recurrence risk
A careful clinical history taken from both the patient as well as any witnesses to (at least 60%) after two
unprovoked seizures,
the clinical event(s) is the most critical aspect of making an accurate diagnosis.
occurring over the next
The questions that follow must be answered. 10 years, or (3) diagnosis of
an epilepsy syndrome.
Is This a Seizure or a Nonepileptic Event?
Multiple, nonepileptic paroxysmal events can mimic seizures, and thus, a careful
clinical assessment is required to reach an accurate diagnosis. Some of these
epilepsy mimics require prompt diagnosis to prevent adverse outcomes (ie,
prolonged QT syndrome). The patient should be asked to describe the event
from onset, including any auras or postictal symptoms. A history of
incontinence, tongue biting, or carpet burn is more suggestive of a seizure.
Terminology should be clarified; for example, the term dizziness may reflect
lightheadedness or vertigo, and an abnormal sensation in the abdomen could
reflect either nausea or an abnormal rising sensation. The physician should ask
about what the patient was doing at the onset, as well as possible triggers,
intercurrent illnesses, or medications. It is immensely helpful to speak directly to
the witness of the clinical event also, and this can be done by phone while the
patient is in the office. Observers should be asked about skin color change, motor
findings (ie, was the patient abnormally limp or stiff ), types of abnormal
movement (ie, rhythmic clonic versus irregular shaking), response to voice or
touch during the event, and any postictal confusion, sleepiness, focal weakness,
or language difficulties. If the diagnosis is suggestive of a generalized tonic-clonic
seizure, one should ask carefully about any focal features (ie, deviation of the
eyes or head) or confusion before onset. A thorough physical examination done
immediately after the seizure may show evidence of lateral tongue bites, bruises,
or other injury due to a fall or convulsive activity, and transient neurologic signs
or focal weakness suggestive of a Todd paralysis, which may provide important
information on the likely seizure localization.
Studies carried out in multiple settings have reported misdiagnosis rates
ranging from 4.6% to 30%.3 In adults, the misdiagnosis rate was higher for
patients diagnosed by nonspecialists than neurologists (19.3% versus 5.6%),4 and
the most common final diagnoses in misdiagnosed patients are cardiovascular
syncope and psychogenic nonepileptic events. Approximately 24% of children
referred with a first seizure were found to have had a nonepileptic event,5 and in
one study, 39% of children who were admitted to a tertiary epilepsy center were
found to not have epilepsy.6 Common final diagnoses in children included
nonepileptic staring spells (eg, daydreaming), psychogenic nonepileptic events,
syncope, parasomnias, and breath-holding spells. In many cases, incomplete
history taking and overinterpretation of the EEG contribute to misdiagnosis.
Common seizure mimics, typical ages at their presentation, and clinical
characteristics are listed in TABLE 1-1.
CONTINUUMJOURNAL.COM 231

EVALUATION OF FIRST SEIZURE AND NEWLY DIAGNOSED EPILEPSY
TABLE 1-1 Common Seizure Mimics
Epilepsy mimic Clinical clues
Neonates/early infancy
Benign sleep myoclonus Myoclonus of one or more limbs or face, occurring in brief clusters lasting <3-5 seconds with
pauses of variable duration
Occurs in sleep only and abolished on waking
Otherwise normal infant
Jitteriness Affects one or more limbs, often switching sides from event to event
Often spreads in nonanatomic pattern
Increased when the infant is stimulated, startled, or crying but is suppressed when the infant is
wrapped or the affected limb is gently restrained
Infants/early childhood
Benign myoclonus of Brief jerking of one or more limbs, lasting <5 seconds each, without altered awareness
infancy
Occurs in both wakefulness and sleep
Shuddering attacks Brief stiffening with shivering-like movement, without altered awareness
Often provoked by excitement or frustration
Breath-holding spells, Triggered by pain, crying, fright

cyanotic or pallid
Child usually cries (crying may be absent with pallid breath-holding), holds their breath at the
end of expiration, then becomes briefly tonic
Associated color change (cyanotic or pallid)
Sandifer syndrome Back-arching, dystonic posturing of the limbs, and turning/tilting of the head
May be provoked by feeding and lying flat and may be alleviated with sitting up
Often seen in neurologically abnormal children
Caused by gastroesophageal reflux
Spasmus nutans Rapid eye movements, with head-tilt and nodding, but with retained awareness
Hyperekplexia Infants are hypertonic but not spastic
Excessive startle is seen with noise or touch, with flexion of limbs and neck retraction; this at
times can be associated with apnea and cyanosis
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Childhood
Stereotypies Mannerisms that may be simple (such as body-rocking, head-banging) or complex (such as
finger movements or wrist flexion/extension); these are interrupted by tactile, and at times
verbal, stimulation
May occur in normal individuals but are seen more commonly in those with autism or
intellectual disability
Self-stimulatory behavior Rhythmic hip flexion and adduction with leg-crossing, often accompanied by a distant
expression
Can be interrupted, although child may be irritable if interrupted
Benign paroxysmal vertigo Abrupt onset of anxiety, feeling off balance; child often grasps onto parent
May have associated nystagmus
Cyclic vomiting Paroxysmal events of recurrent emesis that may last hours and be interspersed with symptom-
free periods of weeks to months
Daydreaming Staring off, more likely to occur when engaged in quiet activity such as schoolwork
Can be interrupted with tactile stimulation
Parasomnias Night terrors, sleepwalking, and confusional arousals are behaviors that arise out of deep
non–rapid eye movement (REM) sleep most commonly in the first few hours after falling
asleep; they typically last >3-5 minutes and occur intermittently
These must be distinguished from nocturnal frontal lobe seizures, which are brief (typically
<2 minutes), very frequent (multiple per night), and occur throughout the night
Sleep-related rhythmic Body-rocking, rolling, or head-banging during sleep that resolve when the child awakens
movement disorders
Childhood to adulthood
Tantrums/rage attacks Tantrums are primarily seen in young children and involve relatively brief periods of behavioral
dyscontrol in response to a stimulus; consciousness is not impaired
Rage reactions occur predominantly in older children and teens and, although triggered by
minor stimuli, are characteristically out of proportion; patients are often aggressive during
these periods, which can last for ≥30 minutes
Tics Involuntary, sudden, rapid, repetitive, nonrhythmic, simple, or complex movements or

vocalizations that often occur multiple times per day
These are interruptible and can be suppressed, albeit often for only a matter of seconds
Tics abate during sleep
REM sleep disorders Abnormal motor activity typically in the later third of sleep when the individual acts out
their dreams
The individual can recall the event
The events are not as stereotypic as seizures

Periodic leg movements Repetitive stereotyped flexion of toes, ankles, knees, and hips
in sleep
Resolve with waking
Postural orthostatic Episodic periods of lightheadedness, chest pain, blurred vision, abdominal pain
tachycardia syndrome
(POTS) or orthostatic Comes on with standing and resolves with sitting/lying down
intolerance
Panic attacks Brief episodes, lasting minutes only with sudden feeling of impending doom, accompanied by
shortness of breath, choking sensation, palpitations, chest pain, paresthesia, dizziness,
sweating, trembling, and feeling faint
Patient is very frightened but aware
No postictal sleepiness/confusion
Narcolepsy/cataplexy Excessive daytime sleepiness, cataplexy (loss of tone in response to strong emotion),
hypnagogic hallucinations, and sleep paralysis
Migraine with aura Most common aura is visual, typically in one visual field, and is characteristically a scintillating
scotoma, which is then followed by a migraine headache
Visual phenomena with occipital seizures are more commonly colored and of various shapes
Hemiplegic migraine Aura of focal weakness with or without speech disturbance; visual symptom and paresthesia
onset before typical migrainelike headache
Often family history is positive
Psychogenic Two main symptomatologies: (1) unresponsive periods without motor phenomena or (2) motor
nonepileptic spells phenomena with bizarre, irregular jerking and thrashing
Often prolonged >15-30 minutes
Often minimal postictal phase
Frequent and refractory from onset
Paroxysmal kinesiogenic Brief (<1 minute) attacks of abnormal movement, triggered by a sudden voluntary movement
dyskinesia
The movements are most commonly dystonic but may be choreiform
Affects limbs on one or both sides
No altered awareness
Family history may be present
Episodic ataxia Autosomal dominant
Brief episodes of cerebellar ataxia triggered by sudden movement, emotion, or illness
May have associated dysarthria, nystagmus, titubation, and nausea
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Adults
Transient ischemic Sudden onset of focal neurologic symptoms that typically reflect loss of function (ie, paresis,
attacks speech problems, etc), which then resolve completely within 24 hours, and usually within
30-60 minutes
Seizures more commonly present with positive symptoms due to an excess of neuronal
discharge (visual: flashing lights, zigzag shapes, lines, shapes, objects; somatosensory: pain,
paresthesia, or motor features, eg, clonic activity); transient ischemic attacks most commonly
involve loss or reduction of neuronal function (eg, loss of vision, hearing, sensation,
or limb power)
Any age
Vasovagal syncope Typically triggered by prolonged standing, dehydration, change in posture, warm environment,
or emotional upset (ie, blood draw)
Preceded by lightheadedness, blurred vision, ringing in the ears, pallor, diaphoresis, abdominal
discomfort
Loss of tone, which may be followed by brief myoclonic jerks or tonic posturing
Rapid return to awareness but lightheadedness may remain for a brief period thereafter
Cardiac syncope–long Sudden loss of consciousness with pallor, atonia, or tonic posturing
QT
Often triggered by fright, exercise, surprise, and immersion in water
Family history of syncope may be present
Neurogenic syncope Headache and sensory symptoms associated with collapse

(Chiari malformation,
colloid cyst of the third Exacerbated by straining
ventricle)

CASE 1-1 illustrates the importance of relying on a careful history and avoiding
overinterpretation of EEG.
In some cases, confident differentiation of a seizure from a nonepileptic event
may not be possible as specific historical details may be lacking. In the absence of
other compelling data, careful follow-up to clarify the diagnosis before initiation
of antiseizure medication is recommended.
If a Seizure, Is This Provoked or an Acute Symptomatic Seizure Versus an

Unprovoked Seizure?
Provoked seizures are due to identifiable causes such as toxins, drugs, or
metabolic factors. Most people with provoked seizures have a history of
confusion or behavior change that precedes the seizure and often persists beyond
the typical postictal phase. Additionally, provoked seizures are usually
generalized convulsive events, as opposed to focal seizures. Details of use or
abrupt cessation of any prescription medication or drug of abuse, including
alcohol, should be queried. Abrupt withdrawal of benzodiazepines, barbiturates,
or alcohol may lead to seizures. Young children may accidentally ingest
medications or toxins in the home, and thus, a careful inventory of all such
agents in the home is critical. Details of any chronic medical condition that could
lead to metabolic disturbances, such as diabetes or kidney disease, should be
sought. Careful assessment of vital signs and other clinical findings may point to
a specific toxidrome. Laboratory screening including serum glucose, electrolytes,
renal and liver function, and urine toxicology should be considered as patients
with provoked seizures may require urgent therapy to address the underlying
cause and prevent further brain injury (eg, hypoglycemia). In most cases of
provoked seizures, prophylactic antiseizure medication is not required. The basic
mechanisms by which toxins lead to provoked seizures are (1) increased
excitation, (2) decreased inhibition, or (3) withdrawal of central nervous system
depressants,7 and these categories are outlined in TABLE 1-2.
Acute symptomatic seizures result from an acute brain process such as
encephalitis, stroke, or traumatic brain injury. The history and physical
examination often provide important clues to the underlying diagnosis, and these
patients typically present with other neurologic findings consistent with their
brain injury, such as focal deficits and abnormal vital signs including fever.
Seizure symptomatology often reflects the location of the acute brain process,
and seizures usually are focal in onset. With acute symptomatic seizures, specific
treatment targeted to the underlying brain process may be required; however,
patients may additionally need short-term antiseizure medication
If This Is an Unprovoked Seizure, Does This Person Have Epilepsy?

Several studies have shown that a significant minority of patients presenting
with an alleged first, unprovoked seizure have actually experienced prior
seizures. It is typically the first convulsive seizure that brings the patient to
medical attention, whereas other seizures including absence, myoclonic, or
focal seizures without motor manifestations may have previously occurred but
have not been recognized. Correctly identifying these events is critical to making
a correct diagnosis of epilepsy. Thus, patients and their families should be
carefully questioned about any episodes of unresponsive staring, isolated quick
body jerks, and symptoms of nocturnal seizures such as unexplained tongue
biting or incontinence. Confirming a diagnosis of epilepsy as opposed to a single
236 APRIL 2022

seizure may have implications for the initiation of prophylactic KEY POINTS
antiseizure medication.
● A careful history taken
CASE 1-2 illustrates how the EEG can sometimes confirm a diagnosis of
from both the patient as
epilepsy, as opposed to a single unprovoked seizure, and thus alter well as any witnesses to the
recommendations for treatment. event(s) is the most critical
aspect in distinguishing a
seizure from a nonepileptic
If This Is Epilepsy, What Type Is This?
paroxysmal event.
The ILAE published a revised classification of seizure types (FIGURE 1-3) and
epilepsies (FIGURE 1-4) in 2017.8-10 These frameworks provide a mechanism to ● It is the first convulsive
understand the possible seizures patients have, what other seizure types they may seizure that typically brings
develop, potential triggers, underlying etiology, and prognosis. Furthermore, the patient to medical
attention. Many people
classification also informs the risk of important comorbidities, including learning presenting with a “first
disorders, intellectual disability, psychiatric disorders, and mortality. seizure” have a history of
prior seizures, which may
SEIZURE TYPE. The first level of classification is the seizure type, which is divided not have been recognized,
and thus have epilepsy.
into focal, generalized, and unknown onset. A generalized-onset seizure engages
bilateral brain networks from onset, whereas a focal seizure begins within one
region or hemisphere. Generalized-onset seizures are classified into motor or
nonmotor types, the latter comprising various subtypes of absence seizures.
Focal seizures are subdivided based on awareness (aware versus impaired
awareness) and motor symptoms (motor: tonic, clonic, atonic, or myoclonic
activity; nonmotor: behavior arrest, cognitive, emotional, sensory, or autonomic
features). Importantly, a focal seizure may evolve to bilateral convulsive activity,
and thus, one must carefully probe for auras or other focal features that preceded
a generalized tonic-clonic seizure.
Both focal impaired-awareness seizures, as well as absence seizures, may
present with staring spells. Important distinguishing features between these
seizure types are shown in TABLE 1-3.
EPILEPSY TYPE. The second level of classification focuses on epilepsy type, which is
based on the type(s) of seizures the patient is having. Epilepsy types are divided
into generalized, focal, combined generalized and focal, or unknown. A diagnosis of
generalized epilepsy would be made in a patient who has one or more types of
generalized seizures, which would include tonic, tonic-clonic, absence,
myoclonic, or atonic as well as generalized spike-and-wave discharge on EEG.
One needs to be cautious with a patient with a generalized tonic-clonic seizure
and normal EEG as it is unclear if that seizure was truly generalized in onset or
evolved to a bilateral tonic-clonic seizure.
Conversely, a diagnosis of focal epilepsy would be made if a patient has had one
or more types of focal-onset seizures, which could include focal to bilateral tonic-
clonic seizures. In most cases of focal epilepsy, the interictal EEG will show focal
epileptiform discharge; however, this EEG finding is not required to make a
diagnosis of focal epilepsy.
Less commonly but importantly, there are some patients who have both
generalized and focal seizures who have generalized and focal epilepsy. This
subgroup is most common in some of the early-onset, drug-resistant epilepsies
such as Lennox-Gastaut syndrome or Dravet syndrome. These patients have a
history of both generalized and focal seizure types, and their interictal EEG may
show both generalized and focal discharges; however, epileptiform activity is not
required for this diagnosis and is made on clinical grounds.

CASE 1-1 A 13-year-old girl presented with recurrent spells of lightheadedness

without vertigo. These occurred more commonly when she stood up too
quickly. She had two more severe events, one during a discussion on frog
dissection in biology class and another while she was getting her blood
drawn. Her examination was normal.
Her EEG was interpreted as showing independent bitemporal sharp
waves in drowsiness and sleep. She was diagnosed with focal epilepsy
and was started on oxcarbazepine. Her lightheadedness persisted, and
she had two more spells; one was just before a subsequent EEG when the
EEG technician was rubbing the girl’s head, and the other was after she
skinned her knee. During these spells, she was said to feel “woozy,” look
pale, and drop slowly to the ground. She lost consciousness and
remained limp for about 30 seconds, then gradually recovered over about
2 to 5 minutes.
She underwent video-EEG monitoring, during which time the EEG
technician rubbed the girl’s head to induce her spell. The EEG (FIGURE 1-1)
was found to be consistent with syncope, due to a cardiac cause, as
opposed to seizure. Careful review of her initial EEG showed 14 and 6
positive spikes as opposed to bitemporal sharp waves, which are a
normal variant and not epileptiform.
COMMENT This case exemplifies that a careful history taken from both the patient as
well as any witness to the event is the most critical aspect in distinguishing
a seizure from a nonepileptic paroxysmal event. A diagnosis of epilepsy
cannot be made solely by relying on EEG findings.
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FIGURE 1-1
Successive EEG tracings of the events of the patient in CASE 1-1. Note the ECG lead in red at
the bottom of the recording. There is artifact at P4. Initially, sinus bradycardia can be
seen (A), followed by asystole (B), and then resumption of heart rate (C). The initial EEG
change is diffuse delta slowing, which occurs after 8 seconds of asystole, and is caused by
a lack of brain perfusion. This is followed by overall suppression of activity, which reverts
to diffuse slowing once the heart rate is again restored.

The term unknown is used if information is inadequate to determine the

epilepsy type.
EPILEPSY SYNDROME. An epilepsy syndrome is a characteristic cluster of clinical

and EEG features that may be supported by specific etiologic findings.
Syndromes often have age-dependent presentations and specific comorbidities.
Many carry important implications for the choice of specific therapy and
prognosis, and we are seeing an increased focus on drug trials in
defined syndromes.
The ILAE has convened a task force to provide definitions for the various
syndromes, and their educational website provides an excellent resource for the
diagnosis of epilepsy syndromes.11 An epilepsy syndrome is identifiable in
approximately one-quarter of epilepsy cases beginning in infants and children
but is less frequent in adult-onset epilepsy. TABLE 1-4 provides an overview of
some of the more common epilepsy syndromes, along with their clinical and EEG
features and long-term prognosis.
The 2017 classification defined the term developmental and epileptic
encephalopathy to describe epilepsies that are associated with underlying
encephalopathy, where both the underlying etiology (developmental) and the
TABLE 1-2 Categories of Toxins Causing Provoked Seizures
Category Mechanism Other clinical findings Examples

Increased excitation
Stimulants Increased release of dopamine, Anxiety, delusions, delirium, Cocaine

serotonin, norepinephrine, and/or diaphoresis, hypertension,
epinephrine or blocking their tachycardia, hyperthermia, Amphetamines
reuptake hyperreflexia, mydriasis,
Phenethylamines
piloerection
Bath salts
ECG monitoring should be
considered for QRS and QTc Serotonergic agents
prolongation and arrhythmias
Bupropion
Venlafaxine
Synthetic cannabinoids
Phencyclidine
Cholinergic Binding of nicotinic or muscarinic DUMBBELS (defecation, Organophosphates

agents receptors or inhibiting urination, miosis, bradycardia,
acetylcholinesterase bronchospasm, emesis, Nicotine
lacrimation, and salivation)
Nerve gases (sarin and VX)
Glutamate Binding of N-methyl-D-aspartate Somnolence, hallucinations, Domoic acid (shellfish poisoning)

agonists (NMDA), α-amino-3-hydroxy-5- delirium, nausea and vomiting,
methyl-4-isoxazole propionic acid diarrhea, salivation Amanita muscaria mushroom
(AMPA), or kainate receptors ingestion
240 APRIL 2022

frequent seizures and epileptiform discharges (epileptic) are felt to contribute to
the encephalopathy.10 Although this term can be applied to people at any age, the
developmental and epileptic encephalopathies most commonly have an onset
early in life. Developmental and epileptic encephalopathies can be defined by
epilepsy syndrome (ie, infantile epileptic spasms syndrome, Dravet syndrome,
Lennox-Gastaut syndrome) or by etiology. In most cases, developmental and
epileptic encephalopathies are correlated with a high risk of lifelong, drug-
resistant seizures, variable degrees of intellectual disability (often severe), and
multiple other medical and behavioral comorbidities.
The idiopathic generalized epilepsies collectively account for approximately
15% to 20% of all epilepsies and are made up of four syndromes: childhood
absence epilepsy, juvenile absence epilepsy, juvenile myoclonic epilepsy, and
generalized tonic-clonic seizures alone, with juvenile myoclonic epilepsy being
the most prevalent among this group. These epilepsies typically affect
developmentally normal children and young adults and present with varied types
of generalized seizures. The main seizure type(s) and typical age at presentation
vary among the syndromes. In many cases, complete seizure control may be
achieved with medication, and in childhood absence epilepsy, remission often
occurs by adolescence.
Category Mechanism Other clinical findings Examples
Increased excitation or withdrawal of central nervous system (CNS) depressants
γ-Aminobutyric Blockage of GABA-ergic neurons or Tremor, tachycardia, Tramadol

acid (GABA) abrupt withdrawal of CNS hypertension, diaphoresis,
antagonists depressants nausea, anxiety, irritability, Antibiotics: isoniazid (depletes
insomnia, hallucinations pyridoxine, which inhibits GABA
synthesis from glutamate),
penicillin, cephalosporins,
carbapenems, fluoroquinolones
Abrupt withdrawal of GABA-

ergic agents such as alcohol,
benzodiazepines, baclofen,
barbiturates
Antidepressants and
antipsychotics including tricyclic
antidepressants, selective
serotonin reuptake inhibitors
(SSRIs), phenothiazines
Decreased CNS inhibition
Histamine Antagonism at histamine receptors Confusion, ataxia, Histamine antagonists including

antagonists hallucinations, delirium, dry diphenhydramine, doxylamine,
mucous membranes, mydriasis hydroxyzine, chlorpheniramine
Adenosine Antagonism of adenosine Cardiac dysrhythmias Theophylline, caffeine

antagonists
ECG = electrocardiogram.

CASE 1-2 A 19-year-old woman presented with her first generalized convulsive
seizure. She had been up late the night before and had a 3-minute
generalized tonic-clonic seizure, which was witnessed by her roommate,
approximately 10 minutes after getting up for work the next day. She
denied any aura. During the seizure, she lost bladder continence and bit
the side of her tongue. Her examination 2 hours after the seizure was
unremarkable, and her basic metabolic panel was normal.
Her paternal aunt had epilepsy as a young adult, which was well
controlled with medication.
On EEG (FIGURE 1-2), she was found to have generalized polyspike-and-
wave discharge and had several myoclonic jerks with clinical correlate
occurring spontaneously as well as with photic stimulation.
She admitted to episodes of hand-twitching in the morning that caused
her to spill her tea but had attributed that to nervousness. Based on the
history and EEG, she was diagnosed with juvenile myoclonic epilepsy, and
antiseizure medication was initiated.
FIGURE 1-2
Routine EEG (bipolar montage, 15 μV/mm) of the patient in CASE 1-2 shows a generalized
polyspike-and-wave discharge which correlates with a witnessed myoclonic jerk. This
example occurred spontaneously; however, these were also triggered with photic
stimulation.
COMMENT This case emphasizes that it is the first convulsive seizure that typically
brings the patient to medical attention. Many patients presenting with a
“first seizure” have a history of prior seizures that may not have been
recognized and, thus, have epilepsy. In this case, the patient described
hand-twitching in the morning, which was consistent with early-morning
myoclonus.
242 APRIL 2022

KEY POINT
● A diagnosis of an
epilepsy syndrome is
possible in approximately
one-quarter of epilepsy
cases beginning in infancy
and childhood but is less
frequently found in adults.
Diagnosis of a specific
syndrome provides key
information to assist with
choosing optimal
investigations and
treatment and for
providing accurate
prognosis.
FIGURE 1-3
Classification of seizure types by the International League Against Epilepsy (ILAE).
a
These could be focal or generalized, with or without alteration of awareness.
b
Because of inadequate information or inability to place in other categories.
Reprinted with permission from Fisher RS, et al, Epilepsia.8 © 2017 International League Against Epilepsy.
Another important syndrome group is the self-limited focal epilepsies of

childhood, which comprise self-limited neonatal epilepsy, self-limited infantile
epilepsy, self-limited epilepsy with autonomic seizures, and self-limited
epilepsy with centrotemporal spikes. Depending on the syndrome, seizures have
an onset anywhere from the neonatal period through late childhood but remit
with time.
CASE 1-3 illustrates how defining the epilepsy syndrome can help choose cost-
effective investigations and therapies and provide an accurate prognosis.
What Is the Etiology?

One of the main questions people with new-onset seizures have is “What has
caused this?” The range of possible etiologies for seizures is diverse, and a careful
investigation to determine the underlying cause is needed.
The causes of epilepsy are defined in the six following groups.
STRUCTURAL. Epilepsy is said to have a structural cause if a structural brain

change is present that results in epilepsy. Structural causes may be
developmental abnormalities, such as focal cortical dysplasia or polymicrogyria,
or acquired brain processes, such as infection, stroke, trauma, or tumor. In most
cases, structural abnormalities will be visible on MRI but may require specific
epilepsy protocols.

FIGURE 1-4
Classification of the epilepsies by the International League Against Epilepsy.
Reprinted with permission from Scheffer IE, et al, Epilepsia.10 © 2017 International League Against Epilepsy.
TABLE 1-3 Distinguishing Features Between Focal Impaired Awareness and Absence
Seizures
Focal impaired awareness Absence
Frequency (in Typically less than daily to monthly Often daily or more
untreated patients)
Duration Usually minutes Usually <10-30 seconds
Postictal state Usually present with confusion and possible Absent

language dysfunction if affects dominant
temporal lobe
Other possible Often contralateral head or eye deviation, May have bilateral oral or manual automatisms with
clinical features contralateral dystonic posturing with more prolonged absence seizures
ipsilateral automatisms
Interictal EEG in Normal, focal slowing, or focal discharges Usually see generalized spike-and-wave discharge on
untreated patients routine EEG, which may activate with hyperventilation
or photic stimulation
Other associated May evolve to bilateral tonic-clonic seizure May have associated myoclonic or generalized tonic-
seizure types clonic seizures
ECG = electrocardiogram.
244 APRIL 2022

GENETIC. Epilepsy is considered genetic if it is caused by a known or presumed KEY POINTS
genetic variant. In some cases of genetic epilepsy, a clear pathogenic variant
● Genetic causes of
in a single gene can be identified, such as KCNQ2, CDKL5, or STXBP1. These epilepsy are increasingly
single-gene disorders are often, but not always, associated with drug-resistant, recognized. In some cases,
early-onset developmental and epileptic encephalopathies. Some of these genes such as the idiopathic
may lead to structural brain changes (ie, ARX, TSC1, or TSC2) whereas others generalized epilepsies,
inheritance is polygenic, and
can result in metabolic alterations that contribute to seizures (ie, SLC2A1
pathogenic variants are
or ALDH7A1). typically not found on gene
Another large group of genetic epilepsies includes the idiopathic generalized panels. In other cases,
epilepsies. In these conditions, family studies have documented a strong particularly in early-onset
developmental epileptic
genetic predisposition, although a single causal gene is typically not found.
encephalopathies,
Rather, the underlying etiology is felt to be polygenic, with or without inheritance is monogenic,
environmental factors. and pathogenic variants are
identified on epilepsy gene
INFECTIOUS. Infectious etiologies are the most common worldwide cause of panels or whole-exome
sequencing.
epilepsy but are more prevalent in developing nations. An infectious etiology
implies that epilepsy and seizures are core symptoms of the disorder, and ● Increasingly, specific
examples include neurocysticercosis, human immunodeficiency virus (HIV), antibodies are being
cerebral malaria, or congenital infections such as Zika virus or cytomegalovirus. detected in people with
autoimmune encephalitis
Infectious etiology should not be used to describe acute symptomatic seizures that that result in acute
occur during brain infection, such as encephalitis or meningitis. symptomatic seizures.
These should be
METABOLIC. A metabolic etiology implies that epilepsy and seizures are the result distinguished from immune-
mediated epilepsies in
of biochemical changes that result from a known metabolic disorder. Some
which an enduring
metabolic disorders are critical to identify early because they have a specific predisposition to seizures is
therapy that will stop seizures and often prevent further developmental decline. present.
Examples are glucose transporter disorder, which is treatable with a ketogenic
diet, or a disorder of creatine metabolism, which is often treatable with high-dose ● Despite advances in
neuroimaging and genetics,
supplemental creatine. Many metabolic disorders also have an underlying approximately 40% of
genetic etiology. people with new-onset
epilepsy have no known
IMMUNE. An immune epilepsy implies that epilepsy directly results from the etiology found.
underlying immune disorder. A recent report by the ILAE Autoimmune and
Inflammation Task Force distinguishes immune-mediated epilepsy, where an
enduring predisposition to seizures is present, from acute symptomatic seizures
secondary to autoimmune encephalitis.12 Examples of immune epilepsy include
Rasmussen syndrome or glutamic acid decarboxylase 65 (GAD65)-associated
epilepsy.
UNKNOWN. The more extensive the investigations, the more likely a cause is to be
found. However, even after exhaustive investigations, no clear etiology can be
found in approximately one-third to one-half of patients with new-onset
unprovoked seizures.13,14
Some causes will fit into more than one etiologic category, and these should be
combined if needed. For example, tuberous sclerosis complex results in
structural brain changes leading to epilepsy but is caused by a pathogenic variant
in TSC1 or TSC2. Thus, it would be considered to have a structural-genetic
etiology. Glucose transporter deficiency results in hypoglycorrhachia but, in
most cases, is caused by a pathogenic variant of SLC2A1 and, thus, should be
considered to have genetic-metabolic etiology.

TABLE 1-4 Common Epilepsy Syndromes
Usual age Common

Syndrome at onset Seizure type(s) Interictal EEG comorbidities Prognosis
Focal epilepsy syndromes
Self-limited First month of Focal clonic or tonic Usually normal None Epilepsy remits by
neonatal epilepsy life, most in seizures which may 6 months with
first week evolve to bilateral normal
tonic-clonic development
Self-limited 3-20 months Focal impaired Usually normal Usually none; Most remit by
infantile epilepsy awareness or focal cases due to early preschool
clonic seizures, which PRRT2 variants years with normal
may evolve to may develop a development
bilateral tonic-clonic movement
disorder
Self-limited 2-9 years Focal autonomic High-amplitude None Remission by later

epilepsy with seizures (often focal or multifocal childhood
autonomic retching or vomiting) discharges that
seizures with or without increase in sleep
(Panayiotopoulos impaired awareness
syndrome)
Self-limited 3-12 years Focal seizures with High-amplitude None Remission by early
epilepsy with dysarthria, sialorrhea, centrotemporal adolescence
centrotemporal and unilateral tonic or discharges that
spikes clonic movement of increase in sleep;
the lower face; may normal background
evolve to bilateral
tonic-clonic seizures
in sleep
Sleep-related Childhood Focal motor seizures Often normal but Often none but Often drug-
hypermotor and with hyperkinetic or frontal discharges may have responsive;
epilepsy adolescence asymmetric tonic or may be seen mostly cognitive and surgery may be an
dystonic features, in sleep attentional option if drug-
occurring problems due to resistant
predominantly in disrupted sleep
sleep
Mesial temporal 2 years Focal aware or Often focal slowing Memory High incidence of
lobe epilepsy through impaired awareness or discharges in problems and drug resistance
with hippocampal adulthood seizures with features frontotemporal depression but may become
sclerosis referable to mesial leads seizure-free after
temporal lobe resective surgery
(autonomic: ie, rising or thermoablation
epigastric sensation;
cognitive: déjà vu or
jamais vu; emotional:
fear; or sensory
symptoms: olfactory
or gustatory)
246 APRIL 2022

Usual age Common

Generalized epilepsy syndromes
Childhood 3-10 years Typical absence Generalized 3-Hz Learning Two-thirds remit
absence seizures occurring spike-and-wave problems, typically by later
epilepsy multiple times per day discharge; most attention deficit childhood or
untreated patients hyperactivity adolescence; may
have a recorded disorder (ADHD) evolve to juvenile
seizure on EEG myoclonic
epilepsy if it does
not remit
Juvenile 8-19 years Typical absence Generalized 3-Hz Learning Often controlled
absence seizures; spike-and-wave problems, ADHD with antiseizure
epilepsy approximately 80% discharge; most medications, but
will also develop untreated patients remission is rare
generalized tonic- have a recorded
clonic seizures seizure on EEG
Juvenile Adolescence Myoclonic seizures; Generalized ADHD, Often controlled

myoclonic to young most also have polyspike-and-wave depression, with antiseizure
epilepsy adulthood generalized tonic- discharge, often anxiety medications, but
clonic seizures, and a activated with remission is rare
minority have brief photic stimulation
absence seizures
Epilepsy with Adolescence Generalized tonic- >3-Hz generalized ADHD, Often controlled
generalized to young clonic seizures only spike and wave or depression, with antiseizure
tonic-clonic adulthood polyspike and anxiety medications, but
seizures alone wave remission is rare
Epilepsy 2-14 years Eyelid myoclonia, 3- to 6-Hz Mild cognitive Eyelid myoclonia
with eyelid many patients also generalized delay, ADHD, is often drug-
myoclonia have typical absence polyspike or anxiety, resistant; remission
and generalized polyspike-and-slow- depression is possible but rare
tonic-clonic seizures wave, often
triggered by eye
closure or photic
stimulation
Myoclonic 2-12 years Myoclonic absence 3-Hz generalized Mild cognitive Remits in
absence seizures; generalized spike and wave delay, ADHD, approximately
epilepsy tonic-clonic seizures time-locked with anxiety, 40% of cases
may be seen in myoclonic jerks depression
some cases

Usual age Common

Focal and generalized epilepsy syndromes
Genetic epilepsy Childhood Autosomal dominant Usually normal but Usually none Usually remits
with febrile with incomplete may show with age
seizures plus penetrance; febrile generalized or focal
seizures, which may discharge
persist after 6 years,
other focal or
generalized seizures
Developmental and epileptic encephalopathies
Early infantile <3 months Tonic and/or Severely abnormal Moderate or Usually drug-
developmental myoclonic with diffuse slowing, greater resistant and
and epileptic multifocal intellectual lifelong
encephalopathy discharges, and/or disability,
burst suppression hypotonia
Gelastic seizures Usually in Gelastic seizures with Often normal Developmental Drug-resistant
with infancy or mirthless laughter delay and (unless treated
hypothalamic preschool behavior with surgery)
hamartoma years problems
common long-
term; may have
precocious
puberty
Infantile epileptic 1-24 months Clusters of epileptic Severely abnormal; High risk of High risk of
spasms spasms usually high- intellectual drug-resistant
syndrome amplitude disability epilepsy; may
background slowing evolve to focal/
with focal or multifocal epilepsy
multifocal discharge or Lennox-Gastaut
or hypsarhythmia syndrome
Dravet syndrome 1-20 months Often prolonged, Usually normal at Normal Drug-resistant
hemiconvulsive, or onset development at and lifelong
generalized tonic- onset, but with
clonic seizures with time all develop
fever intellectual
disability
248 APRIL 2022

Usual age Common

Epilepsy with Preschool Myoclonic-atonic Slow background Most are normal Two-thirds remit
myoclonic-atonic age seizures are with high-amplitude at onset, but but may have mild
seizures characteristic; other generalized spike cognitive and attention or
seizure types and wave attention cognitive
including generalized concerns can be concerns;
tonic-clonic, absence, seen and often 1/3 do not remit
myoclonic, atonic, and worsen during and often have
occasionally tonic periods of more more severe
seizures may also frequent learning and
occur seizures attention
problems
Lennox-Gastaut Mostly Tonic seizures;may Slow background Intellectual Drug-resistant and

syndrome preschool to also have other with high-amplitude, disability (often lifelong
school age; seizure types generalized slow moderate to
adolescent including generalized (<2.5 Hz) spike severe),
onset is rare tonic-clonic, and wave; behavior
myoclonic, atonic, generalized problems
atypical absence, or paroxysmal fast
focal seizures activity in sleep
Rasmussen Usually Focal/hemispheric Hemispheric Progressive Drug-resistant;

syndrome childhood seizures that increase background slowing hemispheric often seizures
in severity and and interictal dysfunction; resolve after
frequency with time discharge acquired hemispherotomy
and may culminate in hemiparesis,
epilepsia partialis visual field
continua deficit and
possible
language
deficits (if
dominant
hemisphere)
Developmental Late Usually focal motor, EEG shows Plateauing or Continuous spike
and/or epileptic preschool or which may evolve to significant activation regression in and wave in sleep
encephalopathy school age bilateral tonic-clonic of spike discharges cognition, typically resolves
with spike-and- seizures; some in sleep, with near behavior, or by adolescence;
wave activation patients may have continuous (usually motor function however,
in sleep other seizure types >50%) slow spike and with continuous depending on
and rarely, no seizures wave in slow sleep spike-and-wave etiology, seizures
may be seen pattern may persist
Progressive Any age Progressive Progressive Cognitive Progressive

myoclonus worsening of background slowing decline; decline with time;
epilepsies myoclonic seizures and/or increased progressive myoclonus is
with time; often epileptiform cerebellar signs drug-resistant
emergence of other discharges
seizure types
including generalized
tonic-clonic seizures

What Are the Associated Comorbidities?

The ILAE has recognized the importance of comorbidities in its core definition of
epilepsy as “a disorder of the brain characterized by an enduring predisposition to
generate epileptic seizures and by the neurobiologic, cognitive, psychological, and
social consequences of this condition.”1 Thus, management of people with epilepsy
must address cognitive and psychological comorbidities in addition to seizures. It is
increasingly recognized that such comorbidities are the rule, rather than the
exception, and they can have an even greater impact on quality of life than seizures.
Cognitive disorders are common and often precede seizure onset.15 Their
etiology is multifactorial and may include the underlying pathology that has led
to epilepsy, the impact of frequent seizures and epileptiform discharges, or
treatment-related effects (side effects of antiseizure medications or epilepsy
surgery). Furthermore, other neuropsychiatric disorders such as attention deficit
hyperactivity disorder and mood disorders are also more prevalent and often
precede seizure onset.16,17 These are critical to identify early, as they are treatable
and can significantly worsen cognitive function if left untreated.
FURTHER INVESTIGATIONS
The diagnosis of a first seizure and epilepsy is a clinical one in nearly all cases.
While the clinical history is the most critical piece of the puzzle, other
CASE 1-3 A 9-year-old boy, who was previously well, presented to the emergency
department with his first witnessed generalized tonic-clonic seizure that
occurred around 6:30 AM. His mother was getting ready for work and
heard a choking sound from her son’s room. She found him having a
generalized convulsive seizure that lasted approximately 3 minutes. He
had bitten his tongue. An ambulance was called, and he was taken to the
emergency department. His neurologic examination on arrival showed
paresis of the left arm and face, which rapidly resolved within 30 minutes.
Brain MRI was normal.
He had no significant medical history and was an excellent student. He
did admit to having two brief episodes over the past 6 months where he
woke up in the early morning and felt that he was drooling, his left mouth
was numb, and he could not speak clearly, although he was otherwise
alert. These resolved within 1 minute, and the family had attributed these
to a normal sleep variant.
His EEG in wakefulness showed occasional right centrotemporal
discharges; however, these became significantly more frequent in sleep
(FIGURE 1-5).
Based on the clinical history and EEG, he was diagnosed with self-
limited epilepsy with centrotemporal spikes. The family was reassured
that he would outgrow this seizure disorder, typically in the next 1 to
2 years. They were provided teaching on seizure safety and counseled on
the low risk of sudden unexpected death in epilepsy (SUDEP) and
associated cognitive concerns. They elected to withhold daily
medication. He had no further seizures over the subsequent 2 years and
continued to do well in school.
250 APRIL 2022

investigations may provide supportive data to confirm epilepsy or may yield
information on the underlying cause.
The American Academy of Neurology has developed an evidence-based
guideline for the management of a first seizure in adults18 and a practice
parameter for evaluating a first nonfebrile seizure in children.19
EEG
Studies have shown that between 18% and 56% of children and 12% and 50% of
adults presenting with new-onset seizures have an epileptiform abnormality
found on routine EEG.20 An EEG is recommended as part of the neurodiagnostic
evaluation in both children and adults with an apparent first unprovoked seizure
because it may impact management decisions.18,19
The diagnostic yield appears highest if the EEG can be done in the first
24 hours21; however, background findings such as focal slowing may be
seen transiently after a seizure as postictal phenomena and then resolve.
Thus, the presence of focal slowing in that time frame should not be assumed
to be due to an underlying structural change. Most studies have also shown
that the yield of EEG after a period of sleep deprivation is higher, particularly
for those with focal discharges. In patients presenting to the emergency
department with a first seizure who fully recover to neurologic baseline
FIGURE 1-5
Initial sleep EEG (30 μV/mm and 30 mm/s) from the patient in CASE 1-3 showing very frequent
right centrotemporal sharp waves, consistent with a diagnosis of self-limited epilepsy with
centrotemporal spikes.
This case illustrates how the accurate diagnosis of a specific syndrome COMMENT
provides key information to assist with choosing optimal investigations and
treatment and for providing accurate prognosis.

and are otherwise well, an EEG can typically be performed on an

outpatient basis.
Interpretation of EEG must be done in the context of the clinical history
because approximately 3% of people without epilepsy may show epileptiform
discharges, and thus, an abnormal EEG does not equate to epilepsy. Additionally,
caution must be taken to not overinterpret normal variants as pathogenic
(FIGURE 1-6).22 In young children, vertex sharp waves may appear spiky and lead
to misdiagnosis of central spikes, and hypnagogic hypersynchrony may be
misinterpreted as generalized spike and wave. In adolescents and adults, wicket
waves and rhythmic temporal theta of drowsiness are often miscalled as
FIGURE 1-6
Examples of normal EEG variants which are often misinterpreted as “epileptiform.” A, EEG
from a 4-year-old girl with a history of a single febrile seizure shows hypnagogic
hypersynchrony. B, EEG from an 11-year-old boy with a past history of childhood absence
epilepsy, now in remission, shows rhythmic temporal theta of drowsiness (also known as
rhythmic midtemporal theta of drowsiness) waveforms during light sleep, initially in the right
temporal (arrow) and later in the left temporal regions (arrowhead).
252 APRIL 2022

temporal epileptiform discharges. Thus, interpretation by a qualified KEY POINTS
electroencephalographer is key.
● Cognitive and psychiatric
Although it is relatively uncommon to detect clinical events during recording comorbidities are common
of routine EEG, both epileptic and nonepileptic events may be captured. In most in people with epilepsy and
laboratories, one channel is dedicated to ECG, which allows screening for often predate seizure onset.
potential cardiac arrhythmias. Psychogenic nonepileptic events may also be seen The causes are
multifactorial, but they are
on routine EEG; video recording during routine recordings can be helpful in
critical to diagnose and treat
appreciating their symptomatology. Activation parameters done during the as they often have an even
routine EEG typically involve both hyperventilation, which often triggers greater impact than seizures
absence seizures in those with untreated childhood or juvenile absence epilepsy, on quality of life.
and photic stimulation, which may trigger myoclonic seizures in someone with
● An EEG is indicated in all
juvenile myoclonic epilepsy. Detection of these more subtle seizure types often patients with new-onset,
points to a specific syndrome and typically would mandate initiation of unprovoked seizures. Care
prophylactic antiseizure medication. must be taken to avoid
The EEG may also help with determining the epilepsy type. Focal epilepsy is misinterpreting normal
variants as epileptogenic.
suggested if the EEG shows focal epileptiform discharges or focal slowing. In The EEG assists with
contrast, generalized spike-and-wave discharges would be consistent with a determination of seizure and
generalized epilepsy. Some epilepsy syndromes have a unique EEG signature. For epilepsy type, choice of
example, finding independent, high-amplitude centrotemporal spikes, which are further investigations, and
prognosis regarding the risk
activated in sleep, in a neurotypical, school-aged child with a history of early- for seizure recurrence.
morning convulsive seizures would support a diagnosis of self-limited epilepsy
with centrotemporal spikes. Conversely, an otherwise well 18-year-old woman
who presents with a single, early-morning generalized tonic-clonic seizure, and
who has generalized polyspike and wave triggered by photic stimulation, most
likely has juvenile myoclonic epilepsy.
The EEG may also help guide the need for other investigations. In most cases,
focal epileptiform discharges and/or focal slowing may suggest a diagnosis of an
underlying lesion.
Finally, the EEG provides information on the risk of seizure recurrence.
Approximately 40% to 50% of people who have a first unprovoked seizure will
experience a recurrence within the next 2 years.20 A systematic review in adults
with a first seizure reported that an EEG with epileptiform abnormalities was
associated with a relative rate increase for seizure recurrence at 1 to 5 years of 2.16
(95% confidence interval [CI], 1.07 to 4.38) compared with that in patients
without EEG abnormalities.18 Studies in children with a first seizure have shown
the risk of recurrence increases from 27% to 42% if the EEG is normal to 60% to
71% if the EEG shows epileptiform abnormalities.20
Prolonged video-EEG monitoring is rarely required after a first seizure.
However, such monitoring should be considered to exclude frequent subtle
seizures or status epilepticus in those who do not show recovery to baseline
neurologic function within 60 minutes, have fluctuating levels of consciousness,
or have unexplained focal neurologic findings.
Neuroimaging
The Commission on Neuroimaging of the ILAE has recommended that all
patients with epilepsy should undergo MRI, except those with a clearly defined,
drug-responsive idiopathic generalized epilepsy syndrome (childhood absence
epilepsy, juvenile absence epilepsy, or juvenile myoclonic epilepsy) or self-
limited focal epilepsy of childhood (self-limited epilepsy with centrotemporal
spikes or self-limited epilepsy with autonomic seizures).23,24

Patients with new-onset seizures with associated focal neurologic deficits,

fever, persistent headache, cognitive changes, or a recent history of head trauma
should be considered for urgent imaging, which is more commonly done by
CT given its ease of access. However, imaging with MRI is preferable to CT
because MRI avoids radiation exposure and enhances the detection of lesions. CT
has low sensitivity for detecting many small cortical epileptogenic lesions
including focal cortical dysplasia, mesial temporal sclerosis, low-grade gliomas,
or cavernous malformations, as well as lesions in the base of the skull such as the
orbitofrontal or mesial temporal regions. However, CT is more sensitive than MRI
for calcified lesions or bone lesions. Approximately 10% of adults with new-onset,
unprovoked seizures are found to have a clinically relevant structural lesion on
neuroimaging, and these individuals have a higher risk of seizure recurrence than
those without imaging abnormalities (relative risk, 2.44; 95% CI, 1.09 to 5.44).18
In patients who have returned to their neurologic baseline, who have no focal
neurologic deficits and for whom no other concern is present, MRI can be
obtained on an outpatient basis. An epilepsy protocol MRI with adequate spatial
resolution and multiplanar reformatting will enhance the yield of detection of
lesions.25 Other functional neuroimaging methods, such as positron emission
tomography (PET) or single-photon emission computed tomography (SPECT),
and magnetoencephalography (MEG) are often considered in cases of drug-
resistant, focal epilepsy and have little role in the evaluation of new-onset
seizures.
If a lesion is found on MRI, one must establish, using both clinical and
electrophysiologic data, whether it is indeed the underlying etiology for the
seizures. Small T2 hyperintensities, arachnoid cysts, or small meningiomas are
often coincidental as opposed to causal.
In children younger than 3 years of age, ongoing brain myelination often limits
the detection of lesions such as cortical dysplasia.26 In such cases, MRI studies
should be reviewed by a pediatric neuroradiologist, and consideration should be
given to repeating the MRI after the age of 3 years if seizures persist.
Laboratory Studies
Other laboratory studies may be indicated in a person with new-onset seizures.
ROUTINE BLOOD AND URINE STUDIES. Routine laboratory screening of patients with
new-onset seizures, with complete blood cell count, glucose, electrolytes including
calcium and magnesium, blood urea nitrogen, and creatinine, is commonly
done to exclude provoked seizures but has an overall low yield.19,27 Clinical
circumstances that may suggest a higher likelihood of underlying provoked
seizures include failure to return to baseline alertness, vomiting, diarrhea,
dehydration, failure to thrive, certain underlying medical conditions (eg,
diabetes), or medication exposures. More detailed screening for inborn errors
of metabolism should be considered in children who have concerning clinical
features, in addition to the seizures, including developmental plateauing or
regression, paroxysmal decompensation with altered consciousness, vomiting
or unusual odors with minor infectious illnesses, or unexplained organomegaly.
Such testing could include glucose, bicarbonate, alanine transaminase (ALT),
aspartate transaminase (AST), serum for amino acids, ammonia, lactate, pyruvate,
carbohydrate-deficient transferrin, very long chain fatty acids, and urine for
organic acids, mucopolysaccharides, oligosaccharides, and creatine metabolites.
254 APRIL 2022

TOXICOLOGY. Toxicology screening is not mandated in all cases but should be KEY POINTS
strongly considered if toxin exposure or substance abuse is a concern or if the
● Neuroimaging is
clinical findings are suggestive of a possible exposure (TABLE 1-2). recommended for all
patients with new-onset,
LUMBAR PUNCTURE. Lumbar puncture should be considered if the clinical picture unprovoked seizures,
is suggestive of possible meningitis, encephalitis, or subarachnoid hemorrhage except those with a well-
defined, drug-responsive
but is of limited value otherwise. A lumbar puncture should be considered in the
idiopathic generalized
presence of new, unexplained fever with seizures, encephalopathy, or meningeal epilepsy or self-limited
signs such as nuchal rigidity. Patients who are immunocompromised may also focal epilepsy of childhood.
have abnormal CSF results without overt clinical evidence of a brain infection. In patients who have
returned to their neurologic
Febrile seizures are relatively common, affecting 2% to 5% of children
baseline and for whom there
between the ages of 6 months and 5 years. Recommendations regarding the need are no concerns for an acute
for lumbar puncture have been published by the American Academy of neurologic process, urgent
Pediatrics.28 In children aged 6 months to 5 years presenting with a simple febrile CT is not needed. Rather,
seizure, defined as a duration of less than 15 minutes, without focal features and MRI can be obtained on an
outpatient basis.
without recurrence within a 24-hour period, a lumbar puncture should be
performed if meningeal signs are present or if the history or examination ● Routine blood and urine
suggests central nervous system infection. It should be considered an option for studies are commonly
infants aged 6 to 12 months who are deficient in either Haemophilus influenzae or obtained but of low yield in
patients with new-onset,
Streptococcus pneumonia immunization (or if immunization status cannot be unprovoked seizures.
determined) or in children who have received antibiotics, which may mask
clinical symptoms of intracranial infection. Although no guidelines have been ● A lumbar puncture should
determined for children with complex febrile seizures, in the absence of febrile be considered if the clinical
picture is suggestive of
status epilepticus, the risk of brain infection is low,29 and lumbar punctures
possible meningitis,
should be performed selectively. However, in children presenting with encephalitis, or
convulsive febrile status epilepticus, a lumbar puncture should be performed subarachnoid hemorrhage
because the risk of meningitis is approximately 17%.30 but is otherwise is of low
In the presence of possible increased intracranial pressure or new focal yield.
neurologic symptoms or signs, a brain imaging study should precede the

lumbar puncture.
AUTOIMMUNE TESTING. Neuronal antibodies may be associated with acute

symptomatic seizures because of an autoimmune encephalitis but are exceedingly
rare in new-onset epilepsy. A recent review of this topic noted several clinical
features that should suggest an autoimmune etiology, including a characteristic
onset (frequent, drug-resistant seizures), other associated features (cognitive
and/or behavioral dysfunction, dysautonomia, movement disorders such as
orofacial dyskinesias), and specific seizure types (faciobrachial dystonic
seizures).12 Serum and CSF autoimmune studies should be strongly considered in
the presence of suggestive clinical features but are of low yield in their absence.
GENETIC TESTING. Understanding of the genetic contributions to epilepsy has

markedly expanded over the past 20 years, with large-scale molecular genetic
studies leading to identification of an increasing number of novel epilepsy genes
(FIGURE 1-731). Although genetic testing should be selectively considered, it is not
recommended for most patients with new-onset epilepsy.
The report of the ILAE Genetics Commission suggests that the clinical utility
of testing should be evaluated before genetic testing. Testing should be
considered if the result will likely lead to a change in the procedures used for
evaluation or a change in the optimal treatment choice or prognosis and if it will

FIGURE 1-7
Significant growth in the past 20 years of the understanding of epilepsy genetics.
Reprinted with permission from Helbig I, et al, Epilepsia.31 © 2016 International League Against Epilepsy.
likely influence a decision about reproduction.32 Additionally, the social or

psychological impact on the patient must be considered.
Genetic testing is of the highest yield in infants and young children with
developmental and epileptic encephalopathies of unknown cause, with
approximately one-third to one-half of these patients having a pathogenic
variant found.33,34 Genetic testing should also be considered in patients whose
examination or other investigations point to a probable genetic cause. This
includes individuals with findings on neuroimaging suggestive of a genetic-
structural cause (ie, tuberous sclerosis complex or double cortex) or those with
imaging or laboratory findings suggestive of a genetic-metabolic etiology (eg,
mitochondrial disorders, Batten disease, or glucose transporter deficiency).35,36
The implications of genetic testing may be significant and should be discussed
with the family by a genetic counselor or other knowledgeable health care
provider before initiation of testing. These include the following:
u Medical implications: some genes may have implications for symptoms other than
epilepsy, and these implications may also extend to relatives of the person being tested
u Reproductive implications: the risk of passing on an abnormal variant
u Psychological implications: the impact of potentially carrying an abnormal variant that
could result in disease in oneself or increase risk of disease in one’s child
u Insurance and financial implications
Several possible genetic investigations, including karyotype, chromosomal

microarray, single-gene sequencing, epilepsy gene panel, and whole-exome or
256 APRIL 2022

whole-genome sequencing, and, in certain cases, specific clinical features, may KEY POINTS
drive the choice for a particular test. For example, in a 3-year-old child with
● All patients with new-
global developmental delay, absent speech, disrupted sleep, a happy demeanor, onset, unprovoked seizures
and new-onset epilepsy, whose EEG is found to have a notched delta appearance, must be counseled about
focused testing for Angelman syndrome will likely be pursued. However, in lifestyle issues, seizure
many cases, the phenotype does not suggest a specific gene. A recent meta- safety, and what to do if
further seizures occur.
analysis that assessed cost-effectiveness of various genetic tests commonly used
Water safety is of utmost
in patients with epilepsy suggested that either an epilepsy gene panel or whole- importance. Showers are
exome sequencing study should be the initial test ordered in such cases.37 safe; however, bathing or
swimming alone is not
recommended.
Management
In any individual presenting with a first unprovoked seizure or new-onset ● Although immediate
epilepsy, counseling on lifestyle issues, seizure safety, and what to do if further initiation of antiseizure
seizures occur must be provided. Although the risk of recurrence will depend on medication after a first
several factors, including underlying cause and EEG findings, in general, the unprovoked seizure does
reduce the risk of
highest risk of recurrence is in the first 1 to 2 years after the seizure. recurrence, it does not
The most important lifestyle modification that is indicated for all patients with impact long-term epilepsy
new-onset, unprovoked seizures pertains to safety around water. Although outcome or quality of life.
showers are generally safe, being in a bathtub or swimming alone is not
recommended. Patients should also be counseled about other safety issues such
as avoiding excessive heights. Other potential restrictions may be required based
on their occupation or participation in certain sports.38
For people who have had seizures that alter their awareness, guidance
regarding driving varies depending on the place of residence. The Epilepsy
Foundation website has a list of updated driving laws for each state.39
Patients should also understand the importance of managing seizure triggers.
Sleep deprivation is a common trigger for many epilepsy types, and thus,
regulating sleep hygiene is important. Overall, patients benefit from regular
mealtimes and a healthy diet, regular exercise, and management of emotional
stress and mood disorders. Other triggers can be specific for certain epilepsies,
such as flashing lights, or, in some cases, even eating or reading. Some women
have a catamenial pattern to seizures, and fever or intercurrent illness may also
trigger seizures in susceptible individuals.
Some patients may benefit from having a seizure rescue medication that could
be used if they have a prolonged seizure or cluster of seizures. This is particularly
important in those who live a considerable distance from emergency medical
services or those with a history of a previous seizure emergency. Patients and
their families should understand when and how to administer such therapy, as
well as other aspects of seizure first aid (rolling the patient on their side, avoiding
placing objects in the mouth, and when to call emergency medical services).
Finally, patients must be informed of the potential risks of recurrent seizures,
including status epilepticus, aspiration, and sudden unexpected death in
epilepsy (SUDEP).
In deciding whether to initiate a prophylactic antiseizure drug, one must
consider the recurrence risk for further seizures, the seizure severity, and the
potential impact of further seizures on the individual patient and balance this
against potential adverse effects of medication. Patient and family preferences
must be considered. Antiseizure medication is typically started in cases of new-
onset epilepsy but not in most cases of first unprovoked seizure with normal EEG
and imaging.

In adults presenting with a first unprovoked seizure, immediate antiseizure

medication treatment compared with treatment delayed until a second seizure
occurs was found to reduce the absolute risk of recurrence by about 35% for a
subsequent seizure within the next 2 years, but it did not alter quality of life or
improve the chance of obtaining sustained seizure remission over the longer
term.18 In children, a similar consensus was reached; however, few data are
available from studies limited to children.40
CONCLUSION
New-onset seizures are a common presentation to the neurologist. A careful
clinical history is key to excluding seizure mimics and provoked or acute
symptomatic seizures. Accurate classification of epilepsy assists with the choice
of cost-effective investigations, optimal treatment, and accurate prognosis.
Counseling regarding seizure safety and first aid should be addressed in all cases
of new-onset seizures.
USEFUL WEBSITES
EPILEPSY FOUNDATION STATE DRIVING LAWS DATABASE INTERNATIONAL LEAGUE AGAINST EPILEPSY
This is a database of state driving laws related to This website provides an online diagnostic manual
epilepsy. of the epilepsies.
epilepsy.com/driving-laws/2008806 epilepsydiagnosis.org
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Evaluation of First Seizure and Newly Diagnosed.4

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Evaluation of First Seizure and Newly Diagnosed.4

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By Elaine Wirrell, MD, FRCP(C), FAAN

RECENT FINDINGS: New-onset seizures are a common presentation in neurologic

SUMMARY: Accurate diagnosis and classification of first seizures and

Address correspondence to INTRODUCTION

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TABLE 1-1 Common Seizure Mimics

Epilepsy mimic Clinical clues

Occurs in sleep only and abolished on waking

Otherwise normal infant

Often spreads in nonanatomic pattern

Otherwise normal infant

Often provoked by excitement or frustration

Otherwise normal infant

Breath-holding spells, Triggered by pain, crying, fright

Associated color change (cyanotic or pallid)

Often seen in neurologically abnormal children

Caused by gastroesophageal reflux

Hyperekplexia Infants are hypertonic but not spastic

CONTINUED ON PAGE 233

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Epilepsy mimic Clinical clues

Can be interrupted, although child may be irritable if interrupted

May have associated nystagmus

Can be interrupted with tactile stimulation

Tics Involuntary, sudden, rapid, repetitive, nonrhythmic, simple, or complex movements or

Tics abate during sleep

The individual can recall the event

The events are not as stereotypic as seizures

CONTINUED ON PAGE 234

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CONTINUED FROM PAGE 233

Epilepsy mimic Clinical clues

Patient is very frightened but aware

Often family history is positive

Often prolonged >15-30 minutes

Often minimal postictal phase

Frequent and refractory from onset

Affects limbs on one or both sides

Family history may be present

Episodic ataxia Autosomal dominant

Brief episodes of cerebellar ataxia triggered by sudden movement, emotion, or illness

May have associated dysarthria, nystagmus, titubation, and nausea

CONTINUED ON PAGE 235

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Epilepsy mimic Clinical clues

Family history of syncope may be present

Neurogenic syncope Headache and sensory symptoms associated with collapse

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

If a Seizure, Is This Provoked or an Acute Symptomatic Seizure Versus an

If This Is an Unprovoked Seizure, Does This Person Have Epilepsy?

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CASE 1-1 A 13-year-old girl presented with recurrent spells of lightheadedness

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The term unknown is used if information is inadequate to determine the