Seizure 49 (2017) 54–63

Contents lists available at ScienceDirect

Seizure
journal homepage: www.elsevier.com/locate/yseiz

Evaluation of the first seizure patient: Key points in the history and
physical examination
Tomasz A. Nowacki* , Jeffrey D. Jirsch
Division of Neurology, Department of Medicine, University of Alberta, 7th Floor Clinical Sciences Building, 11350 83 Avenue NW, Edmonton, Alberta T6G 2G3,
Canada

A R T I C L E I N F O A B S T R A C T

Article history: Purpose: This review will present the history and physical examination as the launching point of the first
Received 30 March 2016 seizure evaluation, from the initial characterization of the event, to the exclusion of alternative diagnoses,
Received in revised form 31 October 2016 and then to the determination of specific acute or remote causes. Clinical features that may distinguish
Accepted 1 December 2016
seizures from alternative diagnoses are discussed in detail, followed by a discussion of acute and remote
first seizure etiologies.
Keywords: Methods: This review article is based on a discretionary selection of English language articles retrieved by
Epilepsy/diagnosis
a literature search in the PubMed database, and the authors’ clinical experience.
Seizures/diagnosis
Syncope/diagnosis
Results: The first seizure is a dramatic event with often profound implications for patients and family
Diagnosis members. The initial clinical evaluation focuses on an accurate description of the spell to confirm the
Physical examination diagnosis, along with careful scrutiny for previously unrecognized seizures that would change the
Medical history taking diagnosis more definitively to one of epilepsy. The first seizure evaluation rests primarily on the clinical
history, and to a lesser extent, the physical examination.
Conclusions: Even in the era of digital EEG recording and neuroimaging, the initial clinical evaluation
remains essential for the diagnosis, treatment, and prognostication of the first seizure.
© 2016 Published by Elsevier Ltd on behalf of British Epilepsy Association.

1. Introduction
The first seizure is a memorable event for patients, family
members, and caregivers. For the patient who is young and
previously well, it may be the first important illness; for the older
patient, it may introduce an unexpected period of lost autonomy.
Patients recall first seizures as important life events that were
surprising and emotionally significant. Witnesses describe them as
“frightening, disturbing, and bizarre” [1]. The first seizure has far-
reaching implications for lifestyle, employment, driving, personal
relationships, insurance, and financial borrowing [2,3].
The history and clinical examination are the basis for evaluation
of the first seizure, even in the era of neuroimaging and digital EEG
recording. While there is ample evidence to inform the rational use
of EEG and neuroimaging in the evaluation of epilepsy [4], the
importance of the history and physical examination is supported
Abbreviations: GTCS, generalized tonic-clonic seizure; PNES, psychogenic non-
epileptic seizure; EEG, electroencephalogram; AEDs, anti-epileptic drugs; EMU,
epilepsy monitoring unit; CNS, central nervous system; CT, computed tomography;
MRI, magnetic resonance imaging.
* Corresponding author. Fax: +1 780 248 1807.
E-mail address: tnowacki@ualberta.ca (T.A. Nowacki).
mostly by expert opinion [5,6]. This review will present the history
and physical examination as the launching point of the first seizure
evaluation, from the initial characterization of the event, to the
exclusion of alternative diagnoses, and then to the determination
of specific acute or remote causes.
2. Diagnosis of the first seizure
2.1. Seizure history
While patients may present following an unequivocal seizure,
frequently the event could more accurately be described as a
“spell” of uncertain nature in which a seizure is one of many
possibilities. The differential diagnosis of spells is broad and
includes seizures, (pre-)syncope, transient ischemic attacks,
migraine auras, paroxysmal movement disorders, sleep disorders,
intracranial hypertension, and psychogenic non-epileptic seizures
(PNES) (see Section 3). A reliable witness account is essential in
order to define event semiology, since a patient suspected of
having suffered a seizure is most frequently an unreliable historian
due to altered consciousness at the occasion.
When questioning the patient or witness(es), imprecise terms
such as “grand mal” must be clarified, with attention paid to

http://dx.doi.org/10.1016/j.seizure.2016.12.002
1059-1311/© 2016 Published by Elsevier Ltd on behalf of British Epilepsy Association.
 T.A. Nowacki, J.D. Jirsch / Seizure 49 (2017) 54–63
specific features such as body stiffening, limb jerking, the order in
which they occurred, and their duration. Video analysis of
generalized tonic-clonic seizures (GTCS) has defined a consistent
pattern of five phases (onset, pre-tonic clonic, tonic, early clonic,
clonic) with a mean total duration of about one minute; often there
is an antecedent partial seizure [7]. Generalized tonic-clonic
seizures can occur abruptly from synchronous excitation of bi-
hemispheric thalamo-cortical pathways, or can occur secondarily
from the spread of abnormal electrical excitation of a more discrete
area of cerebral cortex. In the former situation GTCS can be
accompanied by other frequently brief seizures types such as
myoclonus (i.e. <1 s muscular jerk) or absence (typically <10 s of
staring and unresponsiveness with retained postural tone) events.
Seizures arising focally and that secondarily generalize are
important to define as they may direct further investigations
(e.g. neuroimaging, EEG).
Focal seizures are often heralded by a subjective sensory aura
that cannot be appreciated by an outside observer. The aura is
typically a minimally disabling phenomenon that results from a
discretely localized seizure, and is predicated by the functionality
of cortex involved. Auras preceding temporal lobe seizures often
involve an epigastric rising sensation, unpleasant olfactory
sensation, palpitations, or complex psychic manifestations such
as a déjà vu or jamais vu, fear, elation, or autoscopy (perception of
the self or environment from outside one's body) [8]. Occipital and
parietal lobe auras can be characterized by somatosensory
(paresthetic, painful, thermal, disturbances of body image) or
visual (amaurotic, elementary and complex hallucinations, illu-
sions) sensations. Insular seizures may be associated with altered
sensation in the face or throat, but can also be difficult to
differentiate from temporal lobe auras [8,9].
The objective manifestations of a focal seizure are more clearly
described by a witness than by patients themselves and again the
semiology is predicated by the region of cortex involved [10].
Focal clonic limb jerking arising from the primary motor cortex
may occur sequentially over one side of the body as the seizure
spreads along the motor homunculus (i.e. Jacksonian march).
Dystonic posturing wherein the patient adopts a “fencing”
position occurs from seizures located in the supplementary
sensorimotor area. Frontal lobe seizures are also often character-
ized by their short duration (e.g. 10–30 s), explosive onset with
hypermotor features, bilateral motor activity, and nocturnal
occurrence [11,12]. Focal seizures with dyscognitive features
frequently occur from seizures arising in the temporal lobe during
which the patient is found motionless and staring, unresponsive
to external cues. Contralateral to the temporal lobe focus, patients
frequently adopt a characteristic hand posture involving flexion at
the wrist, flexion at the metacarpal-phalangeal joints, and
extension at the interphalangeal joints [13]. Automatisms (i.e.
repetitive behaviours that do not meaningfully interact with the
environment) also strongly suggest localized-onset seizures very
often from the temporal lobe, and can range from simple oro-
alimentary movements such as swallowing, chewing, or lip-
smacking, to repetitive limb movements such as plucking at
clothing or objects, to complex behaviours such as walking,
running, or undressing [14]. It is important to ask about post-ictal
symptoms as they are nearly universal following seizures;
confusion and anterograde amnesia are hallmarks of generalized
tonic-clonic and temporal lobe seizures. Patients frequently are
transiently somnolent or fatigued and complain of sore limb
muscles following a generalized convulsion [15]. Post-ictal
hemiparesis may occur contralateral to the epileptogenic focus.
Post-ictal aphasia correlates strongly with an epileptogenic focus
in the language-dominant hemisphere, but it is difficult to
distinguish post-ictal confusion from aphasia without language
and speech testing during the event [16].
55
The evaluation of the event semiology rests primarily upon
witness accounts, but witnesses vary in their reliability. A
prospective study of epilepsy monitoring unit (EMU) patients
found that witness reports of ictal eye closure did not predict eye
closure occurring during video-recorded events [17]. When
university students were unexpectedly shown a video of either
seizure or syncope, many salient features were overlooked,
recalled inaccurately, or erroneous features were reported.
However, muscle tone during seizure or syncope was recalled
with high accuracy, as were drooling and gaze deviation during the
seizure [18]. When relatives and friends of EMU patients were
shown videos of the patient's events, the descriptions were often
inaccurate, especially for patients who had their diagnosis revised
from epilepsy to PNES during the admission [19]. Therefore,
witness descriptions of events must be interpreted carefully. With
the proliferation of digital cellphone cameras, patients are
increasingly arriving to clinic with videos of their events, which
can dramatically improve diagnostic certainty at the first visit [20].
Two case series have shown that the history and physical
examination yields a diagnosis in approximately 85% of cases of
suspected seizure or transient loss of consciousness, although
diagnosis was not validated using video/EEG telemetry (Day [127])
[21]. While video/EEG monitoring remains the gold standard for
the diagnosis of seizures [22], the history is the starting point and
often the key determinant of the diagnosis of an epileptic seizure
or spell, especially since it is not practical or cost-effective to admit
all suspected seizure patients to an EMU.
2.2. Signs of seizure
The physician seldom witnesses a seizure, and witness accounts
may not be sufficient to confidently state a diagnosis. However,
certain signs such as tongue biting, urinary incontinence, and
characteristic patterns of self-injury are associated with seizures,
and they should be sought on the history and physical examination
(Table 1) [5].
Several studies have examined the diagnostic value of oral
lacerations for seizures, finding them to be a specific sign for
epileptic seizures compared to PNES [23,24]. A meta-analysis
evaluating tongue biting in PNES and epileptic seizures found that
the presence of any tongue bite is poorly sensitive (38%) and
moderately specific (75%) to diagnose seizures, but when the
analysis was restricted to lateral tongue biting, presence of this
sign was insensitive but highly specific (100%) to diagnose seizures
[25]. A companion meta-analysis of seizures versus syncope also
confirmed the high diagnostic specificity but low sensitivity of
lateral tongue biting for seizures [26]. Urinary incontinence is
associated with GTCS, but also occurs during PNES and syncope,
with a meta-analysis comprising over 400 patients reporting that
urinary incontinence was neither sensitive nor specific to diagnose
epileptic seizures versus PNES or syncope [27]. Other sequelae of
seizures include contusions, wounds, fractures, abrasions, con-
cussions, and thermal injuries [28,29]. Injuries are also reported by
patients with PNES, although self-reported rates of injury are
higher than what is encountered in the EMU, which may reflect
embellishment of the history, or the relative safety of a hospital
environment [30]. Apart from their diagnostic value, careful
examination in the post-ictal period is essential to identify injuries
that require treatment.
Posterior shoulder dislocations rarely occur after a blow to the
anterior shoulder or a fall on an outstretched arm, but muscular
forces during a GTCS can produce unilateral or bilateral posterior
shoulder dislocations or fracture-dislocations. The presence of
such an injury without a history of direct trauma is highly
suggestive of an unwitnessed GTCS [31]. Still, the incidence of
posterior shoulder dislocations is low, with five instances of first-
56 T.A. Nowacki, J.D. Jirsch / Seizure 49 (2017) 54–63

Table 1
Physical examination findings and their potential significance in first seizure patients.

System Finding Potential significance

General Poor cooperation with examination; exaggeration or Psychiatric co-morbidities with PNES
appearance dramatization of features

Vitals Fever Acute symptomatic seizure from infection (e.g. encephalitis)

Hypertension PRES
Bradycardia or tachycardia Cardiogenic syncope

Head and neck Papilledema Syncope from intracranial hypertension (e.g. idiopathic intracranial hypertension); seizure
from cortical irritation (e.g. meningo-encephalitis, cerebral venous thrombosis)
Tongue or cheek bite Lateral tongue bite from seizure (bite to tongue tip or cheek occur in seizures or syncope)
Scalp or facial laceration Fall from loss of consciousness

Cardiovascular Drop in systolic BP of 20 mmHg or diastolic BP of Syncope from orthostatic hypotension
system 10 mmHg on standing
Irregular cardiac rhythm Cardiogenic syncope (e.g. sick sinus syndrome)
Heart murmur Cardiogenic syncope (e.g. aortic stenosis)
Drop in BP of 50 mmHg or asystole > 3 s with carotid Syncope from carotid hypersensitivity
massage

Respiratory Cough Syncope from increased intrathoracic pressure

Gastrointestinal Hepatomegaly, jaundice, scleral icterus, ascites, palmar Chronic alcoholism and risk of withdrawal seizures
system erythema, or gynecomastia

Musculoskeletal Unexplained long bone fracture Unwitnessed loss of consciousness and fall
system Posterior shoulder dislocation Generalized convulsion

Cutaneous Linear scars from “cutting” Psychiatric co-morbidities with PNES

Track marks Illicit drug injection and risk of acute symptomatic seizure
Café au lait spots, axillary or inguinal freckling, Neurofibromatosis
cutaneous neurofibromata
Hypomelanic macules (“ash leaf spots”), shagreen Tuberous sclerosis
patches, subungual fibromas, adenoma sebaceum
Facial capillary hemangiomata (“port-wine stain”) Sturge-Weber syndrome
Skin and mucosal telangiectasias Hereditary Hemorrhagic Telangiectasia
Macular hypopigmented whorls or patches Hypomelanosis of Ito

Nervous system Focal neurological deficits (motor, sensory, visual) Structural cerebral lesion as cause of seizure
Limb hemiatrophy In-utero or pediatric cerebral insult as cause of seizure

time shoulder dislocation occurring among a series of 806 EMU

patients [32]. Posterior shoulder dislocation-fractures have been
reported as the first presentation of epilepsy [33], and these
injuries can initially be overlooked (see Fig. 1).

2.3. First seizure, or newly-diagnosed epilepsy?

Following the diagnosis of a seizure, the next step is to

determine whether the event is truly the first seizure. Events may
be unwitnessed, be subtle and escape notice, or may have been
misdiagnosed. A large multi-centre prospective study of newly
diagnosed unprovoked seizures found that approximately half of
the patients met epidemiological criteria for epilepsy at time of
diagnosis. The delay in diagnosis was attributed to lack of access to
medical care, patients being unaware of the significance of earlier
events, or misdiagnosis [34].
The first seizure evaluation should include an inquiry into signs
suggestive of nocturnal seizures, such as waking in the morning to
find a bitten tongue, blood on the pillow, urinary incontinence, or
other unexplained injuries [35]. Evidence of non-convulsive
seizures should be sought by asking about spells of unresponsive-
Fig. 1. Multiple right-sided rib fractures with complicating hydropneumothorax in
ness, myoclonic jerks, or stereotyped sensory experiences sugges-
a 55 year old man seen by one of the authors (TN) who presented to hospital after
tive of auras. Among patients presenting with a presumed first two alcohol-withdrawal seizures. The injuries were not identified until the third
GTCS, approximately 40% of them have had a previous tonic-clonic post-admission day. Unable to recall any history of trauma, these injuries were
seizure, or another seizure type such as absence, myoclonus, or likely as a result of his seizures. He required open reduction and internal fixation of
temporal lobe auras [34,36]. the humerus, and placement of a chest tube.
 T.A. Nowacki, J.D. Jirsch / Seizure 49 (2017) 54–63
3. Differential diagnosis of the first seizure presentation
3.1. Syncope
3.1.1. Clinical features of syncope
Syncope is a transient loss of consciousness (T-LOC) due to
global cerebral hypoperfusion characterized by rapid onset, short
duration, and spontaneous complete recovery [37]. In the absence
of a witness, premonitory symptoms prior to the T-LOC may
suggest the diagnosis. Syncope is heralded by lightheadedness,
diaphoresis, nausea, or diminution of hearing and vision.
Palpitations occurring immediately prior to the T-LOC may further
suggest a cardiac cause of syncope. Witnesses may notice
diaphoresis or changes in skin colour such as pallor or flushing.
Situational factors preceding the T-LOC that suggest syncope
include rising quickly, prolonged standing, micturition, defecation,
pain, or venipuncture. There is little fatigue or confusion following
syncope, in contrast to the post-ictal state after a seizure. Features
that should be sought on physical examination include evidence of
a valvular or cardiac rhythm abnormality, and orthostatic vital
signs to look for postural hypotension [38,39] (see Table 1).
Intracranial hypertension may present with T-LOC episodes, and
the clinical evaluation should include inquiry for postural head-
aches and fundoscopic examination.
3.1.2. Convulsive syncope as a seizure mimic
The term “convulsive syncope” refers to motor activity
occurring during syncopal LOC, thought to be caused by hypoxic
disinhibition of reticulospinal pathways [38]. It has been reported
to occur in about 40% of cases of syncope among blood donors, if
they are carefully observed for subtle motor activity immediately
after LOC [40,41]. Video analysis has shown tonic and myoclonic
muscle activity, eye deviations, and vocalizations during syncope
[42]. Myoclonic activity, mostly multifocal arrhythmic jerking, is
particularly common, occurring among 90% of healthy subjects in a
study of induced syncope [43]. Even complex motor behaviours
such as oral and limb automatisms, which are typically associated
with seizures, occur during syncope [42], and their presence may
lead to the misdiagnosis of seizure [44]. Although motor activity
occurring during syncope may resemble a seizure, it is distin-
guished by its shorter duration, on average lasting less than thirty
seconds, and the relative lack of post-event confusion [42,45].
3.1.3. Distinguishing seizures from syncope
A study of 94 patients referred for evaluation of T-LOC identified
factors that favoured a diagnosis of seizure over syncope. Pre-ictal
factors were the absence of nausea, diaphoresis, spinning
sensation, and diminution of vision. Ictal factors that favoured
seizure were cyanosis, frothing at the mouth, and the absence of
pallor. Post-ictal factors were unconsciousness for greater than five
minutes, disorientation (self-reported or witnessed), sleepiness,
aching muscles, and tongue bite. Clinical features that did not
distinguish seizure from syncope were pre-ictal light-headedness
or paresthesias, injuries, urinary incontinence, and body position
at onset (e.g. sitting or standing) [46]. A study of 671 patients
previously diagnosed with either seizure or syncope created a
point score based on clinical features that distinguished syncope
from seizures. Features that supported a diagnosis of seizure
included waking with tongue bite, amnesia, witnessed unrespon-
siveness, unusual posturing or limb jerking, LOC with emotional
stress, head turning to one side during LOC, prodromal déjà vu or
jamais vu, and the absence of diaphoresis, light-headedness, or
onset during prolonged standing or sitting [47]. In summary, there
was good agreement between the two studies about features that
differentiate seizures from syncope, such as tongue bite, prolonged
unresponsiveness, and the absence of typical syncopal features at
57
onset; pre-ictal light-headedness was not consistently found to be
a reliable clinical feature, however.
3.2. Psychogenic non-epileptic seizures (PNES)
3.2.1. “Red flags” to suggest PNES
PNES are episodes of altered movement, emotion, sensation, or
experience, resembling epileptic seizures, but which arise from
emotional causes [48]. They often arise in a particular context in
response to external (place, time, witness) or internal triggers
(flashbacks, emotions) [49]. “Red flag” clinical features that should
raise a suspicion of PNES include resistance to anti-epileptic drugs
(AEDs), very high event frequency (e.g. multiple times daily),
atypical event triggers (stress, emotional upset, pain, certain
movements or sounds), tendency to occur around an audience
(such as in the clinic, during the examination), co-morbidities such
as fibromyalgia or chronic pain, and presenting to health care
providers with overly numerous symptoms, suggestive of somati-
zation [50]. Patient demeanour, effort, and co-operation with the
interview and physical examination should be observed. Over-
dramatization, histrionic features, give-way weakness or exagger-
ation of perceived deficits may raise suspicion of PNES [22]. There
is often a history of prior psychological trauma, physical abuse, or
sexual abuse, with three quarters of PNES patients reporting
traumatic antecedents in one case series [51]. It is important to be
vigilant for these “red flags” during the first seizure evaluation, as a
prior history of PNES may not have been recognized at the time of
referral.
3.2.2. PNES semiology
Unlike the typical progression and brief duration of a GTCS [7],
PNES are often longer-lasting, and variable in their presentation
and course [48]. Common features include a gradual onset or
termination, with discontinuous, irregular, or asynchronous limb
movements. Side to side head movements, pelvic thrusting,
opisthotonic posturing, stuttering, persistent eye closure, and
weeping are common. Oftentimes purposeful movements are
maintained during periods of unresponsiveness such as holding
onto hand rails, pushing away extraneous devices or persons, and
self-guarding against injury. Patients may lapse into quiet
unresponsiveness or “pseudosleep” or “pseudocoma” during a
PNES in which even deep painful stimuli cannot elicit a response
[22].
3.2.3. Distinguishing PNES from epileptic seizures
A number of studies of EMU patients have identified clinical
features which distinguish seizures from PNES. The characteristic
ictal cry during the tonic phase of a GTC seizure, caused by tonic
diaphragmatic contraction forcing air against tonic or clonic vocal
cords, is a sensitive and highly specific sign of a seizure, in contrast
to the variety of other sounds produced during PNES such as
moaning, crying, snorting, or heavy breathing [52]. Ictal stuttering,
in the absence of a previous speech disorder, appears infrequently
during PNES but is a highly specific finding that is not observed
during epileptic seizures [53]. Ictal eye closure, especially forceful
eye closure, can be a useful sign to distinguish PNES from seizures,
although its reported frequency during PNES ranges from 34% to
96% [54,55,56,17]. A meta-analysis found ictal eye closure to be
poorly sensitive (58%) and modestly specific (80%) for diagnosing
PNES, with the heterogeneity of results attributed to differences in
inclusion criteria for PNES, and differing definitions of eye closure
[57]. Lateral tongue bite is a highly specific feature of epileptic
seizures [26], as oral lacerations occur infrequently during PNES,
and are usually a bite to the cheek or tip of the tongue [55].
Urinary incontinence does not reliably distinguish seizures
from PNES [27]. Although pelvic thrusting often occurs during
58 T.A. Nowacki, J.D. Jirsch / Seizure 49 (2017) 54–63
PNES with hypermotor activity, it occurs in nearly a quarter of
frontal lobe seizures, and occasionally in temporal lobe seizures,
limiting its usefulness as a discriminatory feature [58].
PNES patients who present with unresponsiveness without
motor activity (“pseudocoma”) pose a diagnostic challenge and
may be misdiagnosed as nonconvulsive status epilepticus [59].
Testing responsiveness to non-noxious stimulation (tickling nostril
with a cotton swab, passive eye-opening), noxious stimulation
(corneal stimulation, sternal rub, nail-bed pressure), or avoidance
maneuvers (passively lifting patient's arm over the face and then
releasing it) can elicit volitional movements that distinguish the
spell from a seizure [59,8]. Non-responsiveness to painful
stimulation alone should not be used to exclude a diagnosis of
PNES, as these patients have been reported to remain quietly
motionless during remarkably painful stimulation [60]. Passive
head rotation may not yield a reliable oculocephalic response, but
caloric testing producing nystagmus beating away from ear
instilled with cold water confirms intact vestibulo-ocular reflex
function, and implies that the unresponsive state is not caused by a
structural brainstem lesion [61].
Suggestibility is a feature of PNES, but ethical concerns have
been raised regarding the use of provocative techniques that
involve deception, such as intravenous infusions or normal saline
[22]. In a small series of PNES patients, induction with
hyperventilation and intermittent photic stimulation, which were
truthfully described to the patients as routine EEG procedures,
caused the majority of patients to experience their habitual
episodes, without the need for deception [62].
3.3. Sleep disorders
When the first seizure arises from sleep, the main diagnostic
considerations are frontal lobe seizures or a parasomnia, usually an
arousal disorder. Arousal disorders include sleep terrors, sleep
walking, and confusional arousals. The clinical features of arousal
disorders are onset during early childhood, infrequent episodes
(rarely every night), duration lasting minutes, occurrence during
the first third of the night, and usually a spontaneous remission
after puberty. In contrast, frontal lobe seizures are shorter (often
less than 1 min), occur at any time of night, and may occur multiple
times per night [63]. The Frontal Lobe Epilepsy Parasomnia (FLEP)
scale was developed by an expert panel to aid in the differentiation
of nocturnal frontal lobe epilepsy (NFLE) from parasomnias. It is a
series of questions based on clinical features of parasomnias
(mostly arousal disorders) and nocturnal frontal lobe epilepsy; the
scale was validated in a population of patients with paroxysmal
nocturnal events with excellent sensitivity (100%) and good
specificity (90%) for the detection of NFLE [11].
4. First seizure caused by acute symptomatic etiology
4.1. Definitions
After a diagnosis of seizure is confirmed, the evaluation focuses
on potential causes. Acute symptomatic seizures (previously
termed “provoked seizures”) are seizures that occur in close
temporal relation to an acute central nervous system (CNS) insult.
The precipitant may be metabolic, toxic, structural, infectious, or
due to CNS inflammation [64]. Epidemiological operational
definitions state that cerebrovascular, traumatic, or infectious
causes are considered to be symptomatic causes if they precede the
seizure by less than 7 days (with some exceptions such as
continuing evidence of active CNS infection). For metabolic
disturbances, the seizure is required to occur within 24 h of the
demonstrated laboratory abnormality, and for seizures attributed
to alcohol withdrawal it must occur within 7–48 h of the last drink
[65]. These time limits are arbitrary and suspected seizure
precipitants should be considered in the context of each patient.
4.2. Causes of acute symptomatic seizures
A pair of seminal studies of incident seizures and newly-
diagnosed epilepsy found acute symptomatic seizures to be nearly
as common as epilepsy, with 696 cases identified versus 880 cases
of epilepsy and 328 cases of single unprovoked seizures [66,67]. In
that cohort, the most frequent causes of acute symptomatic
seizures were head trauma, cerebrovascular disease, CNS infec-
tions, and alcohol withdrawal, depending on age (more cases of
CNS infection among neonates and infants, more cases of stroke
among elderly patients). The frequency of structural CNS lesions as
a cause of acute symptomatic seizures underscores the importance
of the neurologic examination in the first seizure evaluation; focal
abnormalities on the neurologic examination are correlated with
an increased likelihood of detecting a lesion on neuroimaging
[68,69].
4.2.1. Traumatic brain injury (TBI)
Traumatic brain injury (TBI) is a risk factor for seizures,
depending on the severity of injury and the time elapsed since the
injury. So-called “concussive convulsions” consisting of brief tonic
stiffening or myoclonic jerks may occur immediately after TBI;
more rarely, an epileptic seizure may occur [70]. In the early period
after TBI, patients are at increased risk for seizures, even for mild
injuries. A population-based study identified 4541 cases of
traumatic brain injury (TBI) in which more patients had early
seizures (occurring less than 1 week from injury, or one month for
injuries with a protracted course) than late seizures, even for
follow-up periods exceeding a decade (117 early seizures vs 97 late
seizures). Nearly a third of the early seizures occurred among
patients with mild TBI, that is loss of consciousness or post-
traumatic amnesia for less than 30 min, with no skull fracture [71].
Since seizures can occur even after mild TBI, careful interrogation
of the event history and recent antecedent injuries, ideally with the
help of a collateral historian, may help identify an injury that was
at first unreported. Specific questioning for symptoms of concus-
sion such as headache, fatigue, short term memory difficulties, and
dizziness should be included.
4.2.2. Cerebrovascular disease
The overall risk of seizure after stroke ranges from 4 to 10% [72],
comprising both acute and remote symptomatic seizures, and
stroke is the most frequent cause of acute symptomatic seizures
among elderly patients [66]. A prospective multi-centre study
found that seizures occurred among 8.9% of stroke patients. When
seizures did occur, it was within 24 h post-stroke in 40% of
ischemic stroke and 57% of hemorrhagic stroke patients. The
authors concluded that post-stroke seizures parallel seizures after
TBI in that early seizures are attributed to direct neuronal injury,
while late seizures develop due to gliotic scarring [72].
4.2.3. CNS infection
CNS infection is a risk factor for acute symptomatic seizures. In
a population-based cohort of 714 survivors of encephalitis or
meningitis, seizures during the acute phase of infection occurred
among 136 (19%) of the patients [73]. Given the frequency of
seizures in patients with acute CNS infection, lumbar puncture is
recommend for febrile patients presenting with a first seizure [4].
The importance of checking for a fever in the acute period
following a first seizure is underscored by the findings of a
prospective study of 98 first seizure presentations to an emergency
department, in which five of nine febrile patients were found to
harbour a CNS infection [68]. First seizure patients who are human
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immunodeficiency virus (HIV) positive are more likely to harbour a
CNS infection, even if they have been treated with highly active
antiretroviral therapy [74,75,76].
4.2.4. Drugs of abuse
The clinical evaluation of a first seizure must inquire about drug
abuse, especially for certain groups such as juveniles, young adults,
or persons of low socio-economic status. Defining the epilepto-
genicity of such a drug exposure for a given patient is complicated
by a lack of knowledge about specific drugs, the frequent presence
of other potentially epileptogenic factors (alcohol use, head
trauma, etc.), inaccurate patient reporting, and the increased
prevalence of PNES among patients with a history of drug abuse
and co-morbid personality disorder [77]. Consumption of, or
withdrawal from, a variety of drugs can cause seizures.
4.2.4.1. Alcohol. Alcohol consumption increases the risk of first
seizure, with case-control studies showing a dose-dependent
correlation between alcohol and seizure risk [78], and even a
family history of alcoholism is a risk factor for the first seizure [79].
Alcohol withdrawal seizures present as a single seizure or cluster
of seizures over several hours, usually 6–48 h after cessation of
heavy drinking, although weekend binge alcohol consumption has
been demonstrated to provoke seizures [80]. Although alcohol
withdrawal seizures usually occur when blood alcohol levels reach
zero, a relative withdrawal state cause by a temporary drop in
levels may produce a seizure in an intoxicated alcohol-dependent
patient [81]. The alcohol history should include the quantity and
frequency of alcohol intake, changes in drinking pattern, and the
time of last intake. A collateral historian is helpful as patients may
underreport alcohol consumption [82]. Validated screening tools
such as the CAGE questionnaire [83], fast alcohol screening test
(FAST) [84], or AUDIT-C [85] are convenient methods to ascertain
alcohol consumption. A caveat of the CAGE questionnaire is that it
may be negative in patients who exclusively consume alcohol in
binges [82].
4.2.4.2. Psychostimulants. Cocaine is one of the most epileptogenic
psychostimulant drugs [77] and seizures have been associated
with cocaine use in 1–8% of cases, along with a range of other CNS
adverse effects including headache, altered mental status, and
stroke [86]. Seizures occur within hours of use, and may not be
associated with other signs of toxicity. Due to the risk of
intracerebral hemorrhage or cerebral vasospasm with cocaine
use, focal-onset seizures suggestive of an underlying lesion should
prompt further investigations with neurovascular imaging [87].
Seizures have been reported following use of amphetamines
and related substances such as MDMA (Ecstasy, 3,4-methylene-
dioxymethamphetamine). Seizures in the setting of amphetamine
abuse are usually accompanied by other signs of intoxication such
as fever, hypertension, cardiac arrhythmia, delirium, and coma
[77]. A series of 1019 first-seizure patients found that 4% of patients
reported use of amphetamines within 24 h of the seizure [88], but a
previous study found no difference in the frequency of amphet-
amine use among first-seizure cases and controls [89].
4.2.4.3. Marijuana and synthetic cannabinoids. Marijuana contains
a variety of cannabinoid compounds found to have pro-convulsant
or anti-convulsant properties in animal studies [90]. There are
conflicting case reports of seizures provoked by marijuana, or of
reduction in seizure frequency with marijuana use [91], with one
case-control study reporting no significant difference in the
frequency of marijuana use among first-seizure cases and
controls [89]. A Cochrane review of cannabidiol as a treatment
for epilepsy found insufficient evidence to draw any conclusions
regarding efficacy [92]. There are recent reports of seizures
59
following smoking and inhalation of herbal compounds mixed
with synthetic cannabinoid compounds [93,94,95], sold under
various brand names such as “spice”, “K2”, and “kronic”. A review
of known cases of “spice” toxicity reported 6 cases of seizures
among 39 patients, with other CNS adverse effects including
hallucinations, psychosis, agitation, and short-term memory
deficits [96].
4.2.4.4. Opioids. Heroin abuse is associated with seizures, with an
increased risk of both unprovoked and provoked first seizures
among patients with a history of heroin use. However, most cases
had a long duration of daily heroin use, and several had seizures
that could be attributed to complications of non-sterile IV injection
(i.e. CNS infection) rather than the drug itself [89]. Seizures are
infrequently reported in heroin overdose, and are not associated
with heroin withdrawal (except in neonates); their occurrence in
either state should prompt evaluation for another cause [91].
Therapeutic use of prescription opioids including pethidine,
diamorphine, methadone, propoxyphene, meperidine, morphine,
fentanyl, and tramadol has been reported to cause seizures
[86,77,97]. There is no clear evidence that one member of the
opioid class is more epileptogenic than the others, except for
meperidine which may cause seizures with chronic use due to the
accumulation of its epileptogenic metabolite, normeperidine [98].
There are many case reports implicating tramadol as a cause of
seizures, as well as seizures occurring in acute overdose [99], but a
retrospective study did not find an increased risk of seizures
among patients taking tramadol alone [100].
4.2.5. Other prescription medications
A multitude of prescription medications have been associated
with seizures [101,97]. Establishing causation is difficult since
seizures are common, especially in patients with medical illness
who are taking multiple medications [64]. Seizures associated with
prescription medications are likely an infrequent event: a drug
surveillance program for medical inpatients found that seizures
occur as an adverse drug reaction (ADR) among 0.08% of inpatients
[102].
4.2.5.1. Antibiotics. The epileptogenicity of antibiotics has been
recognized since the early use of penicillin. The antibiotics most
frequently associated with seizures are the penicillins, the
cephalosporins, and imipenem, a carbapenem [103].
Fluoroquinolones may be associated with seizures, and
metronidazole is a rare cause of seizures. The risk of seizure
likely increases with antibiotic concentration in the CNS, as risk
factors for antibiotic-induced seizures include impaired renal
function, intravenous high doses or direct CNS antibiotic
administration (intrathecal, intraventricular, or intracisternal
routes), co-administration with drugs that reduce antibiotic
clearance such as probenecid or cilastin, and conditions thought
to disrupt the blood-brain barrier such as meningitis, bacterial
endocarditis, sepsis, and cardio-pulmonary bypass [104].
4.2.5.2. Sedative-hypnotics. Abrupt discontinuation of
benzodiazepines, barbiturates, or other sedatives such as
meprobamate, chloral hydrate, and zolpidem can cause
withdrawal seizures [103]. The clinical features of withdrawal
from benzodiazepines and barbiturates mimic alcohol withdrawal,
including anxiety, irritability, tremor, seizures, and delirium
tremens in severe cases. The risk of withdrawal seizure is dose-
related and less likely to occur in patients taking therapeutic doses
of a sedative-hypnotic drug [87].
4.2.5.3. Antidepressants. The widespread use of antidepressants
means that many patients will be taking one at the time of their
60 T.A. Nowacki, J.D. Jirsch / Seizure 49 (2017) 54–63
first seizure. Tricyclic antidepressants (TCAs) are the most
important class to cause seizures, with estimated rates ranging
from 0.4% to 1–2%. Newer antidepressants including selective
serotonin reuptake inhibitors (SSRIs) and serotonin/
norepinephrine reuptake inhibitors (SNRIs) are less frequently
linked to seizures, with estimated incidence rates ranging from 0%
to 0.4%. Therapeutic use of monoamine oxidase inhibitors (MAOIs)
is not considered a significant risk factor for seizures [105].
Amoxapine, maprotilene, and bupropion have been associated
with a greater seizure risk than other antidepressants [106]. The
risk of seizures with bupropion is dose-dependent, exceeding 1%
for doses greater than 450 mg/d [107]. The overall rate of seizures
with therapeutic doses of anti-depressants is low, but the rate
increases in acute overdose with TCAs [105]. Seizures are
infrequently encountered in acute overdose with SSRIs [108],
and only rarely reported with MAOI overdose [105].
4.2.6. Medical co-morbidities
Evidence of other medical conditions that may cause acute
symptomatic seizures should be sought on history and physical
examination. Hepatic encephalopathy may be accompanied by
stigmata of chronic liver disease (see Table 1); as liver failure
progresses, neurologic signs appear including asterixis, tremor,
slurred speech, seizures, and coma [109]. Among intubated
patients with acute liver failure, the seizures may be subclinical.
Hyperbilirubinemia along with electrolyte abnormalities that
lower patients’ seizure threshold (e.g. hyponatremia, hypoglycae-
mia, hypocalcemia, hypomagnesemia) are seen in patients with
hepatic disease [110].
Patients with acute and chronic renal disease are at increased
risk of seizures related to metabolic alterations that reduce seizure
threshold. Acute symptomatic seizures may further occur as a
complication of acute fluid and electrolyte shifts associated with
dialysis (Boggs [101]). Dialysis disequilibrium syndrome is a
complication of hemodialysis that appears during or after a first
hemodialysis treatment. Symptoms include headache, muscle
cramps, confusion, seizures, and coma. Seizures appear in the late
stages of uremic encephalopathy [111], and also in dialysis
dementia, a neurodegenerative disorder which was caused by
aluminum in dialysis solutions [112].
Diabetes Mellitus is common in the general population, and
patients with diabetes are at risk for seizures not only from the
epileptic sequelae of later cerebrovascular disease, but also from
the acute metabolic disturbances [113]. A hypoglycemic seizure
may occur after administering too much insulin, not eating soon
after an insulin injection, or exercising vigorously without
adjusting the insulin dosage. Conversely, patients neglecting their
diabetes may develop a hyperosmolar hyperglycemic state and
diabetic ketoacidosis wherein seizures occur as patients progres-
sively become increasingly obtunded [113].
Seizures are the most common clinical feature of posterior
reversible encephalopathy syndrome (PRES), with headache and
encephalopathy also occurring in most cases [114]. Seizures occur
early in the course of PRES and may be the presenting symptom
[115]. Blood pressure should be measured in patients with
suspected PRES, and they should be carefully reviewed for
potential causes or contributing factors which are numerous
and include hypertension, renal disease, lupus, immunosuppres-
sive drugs, and interferon-a therapy [64,114].
5. First seizure caused by a remote symptomatic etiology
5.1. Definitions and epidemiology
Remote symptomatic seizures are seizures that occur in the
absence of an acute precipitating factor (i.e. they are unprovoked
seizures) but with evidence of a past static injury. The term
progressive symptomatic seizures indicates that the seizure
substrate is continuing to evolve [116]. In a large multi-centre of
newly-diagnosed unprovoked seizures, 18% of cases were remote
symptomatic seizures, with the most frequent causes being pre-
and perinatal insult, cerebrovascular disease, and head injury [34].
A retrospective study of newly-diagnosed epilepsy in Rochester,
MN, showed that etiologies varied with age, with congenital causes
(e.g. cerebral palsy) most frequent in children, brain tumours and
TBI most frequent among adults, and cerebrovascular disease most
frequent in the elderly. Among patients in this cohort with a first
unprovoked seizure, the majority were classified as “idiopathic”,
although many patients were diagnosed prior to the routine
clinical use of CT and MRI neuroimaging which may have identified
a remote symptomatic etiology [67].
5.2. Causes of remote symptomatic seizures
5.2.1. CNS infection
A history of meningitis or encephalitis greatly increases the risk
of subsequent seizures. A retrospective cohort study of CNS
infection survivors found a sevenfold increase in risk of unpro-
voked seizure over the course of an average 10 years of follow-up,
with the greatest risk among patients with a history of encephalitis
[73]. Remote CNS infections occurring during infancy or early
childhood may not be recalled by the patient, and so contacting
parents or other senior family members may yield vital informa-
tion regarding remote febrile infections and immunization status.
Early developmental issues or learning difficulties in school should
raise suspicion of a remote cerebral insult such as encephalitis or
meningitis.
5.2.2. Cerebrovascular disease
Remote cerebral infarctions are risk factors for subsequent
seizures; past strokes may be subclinical and not reported by first
seizure patients. The risk of seizure is greatest in the first year after
stroke, with a 23 to 35-fold increase in risk, with a subsequent
decline in risk [117,118]. Patients with remote symptomatic
seizures due to stroke (occurring more than 7 days after onset,
or without history of stroke but with CT signs of previous
hemispheric stroke) are more likely to have cerebral infarctions
with cortical involvement, larger lesion size, hemorrhagic lesions,
and multiple lesions [119]. Given the frequency of post-stroke
seizures, careful review of the past medical history for previous
stroke or TIA diagnoses, particularly in first seizure patients with
vascular risk factors, is essential to identify a possible substrate for
seizures.
5.2.3. Traumatic brain injury (TBI)
Late post-traumatic seizures occur more than one week after the
injury and are classified as remote symptomatic seizures [120].
Although TBI was identified as the cause of epilepsy in only 6% of a
large patient cohort with newly-diagnosed epilepsy, the proportion
rose to nearly 30% for the group of patients aged 15–34 years old [67].
The key determinant of development of post-traumatic seizures and
epilepsy is the severity of head injury. In the population-based study
of Olmsted County, MN, the cumulative probability of unprovoked
seizures 5 years after TBI was 0.7% in patients with mild TBI, 1.2% in
patients with moderate TBI, and 10.0% in patients with severe TBI
[71]. Additional clinical factors that predict late post-traumatic
seizures include the presence of skull fracture, intracranial hemato-
ma, and depressed level of consciousness at presentation [120]. The
possibility of seizures after even mild TBI highlights the necessity of
asking all first seizure patients about previous TBI or concussion, as
mild or remote injuries may have been forgotten, or dismissed as
unimportant.
 T.A. Nowacki, J.D. Jirsch / Seizure 49 (2017) 54–63
5.2.4. Pre-natal, developmental, and genetic causes
Since pre-natal and peri-natal insults are a significant cause of
remote symptomatic seizures [67], it is essential to review the
pregnancy and birth history during the first seizure evaluation. A
history of developmental delay or regression, due to a static or
progressive disorder, should be sought as well. Atypical handed-
ness may suggest a remote cerebral insult according to the
“pathological left-handedness hypothesis” although a recent study
of epilepsy patients found no association between their handed-
ness and seizure type or lateralization [121]. Additionally, the
physical examination may identify signs such as limb hemiatrophy,
spasticity, contractures, and hemiparesis that are suggestive of a
remote cerebral insult affecting corticospinal tract pathways [122].
The genetic contributions to epilepsy are complex, comprising
monogenic syndromes and disorders in which multiple genes and
likely environmental factors play a role in epileptogenesis [123].
Reviewing the family history during the first seizure evaluation
may identify a genetic epilepsy syndrome, and suggest seizure risk
for relatives. Among first-degree relatives of probands, the risk of
epilepsy is threefold greater compared to incidence rates in the
general population [124]. Additional informants, especially the
mother, add valuable information about the seizure history in
parents and siblings [125]. The physical examination may identify
signs of a genetic syndrome causing seizures, such as stigmata of a
neurocutaneous syndrome. These include café au lait spots and iris
hamartomas with neurofibromatosis; Ash leaf spots, shagreen
patches, subungual fibromas, and adenoma sebaceum with
tuberous sclerosis; capillary hemangiomata with Sturge-Weber
syndrome; skin and mucosal telangiectasias with Hereditary
Hemorrhagic Telangiectasia; and macular hypopigmented whorls
or patches with Hypomelanosis of Ito [122].
6. Conclusions
Although there is a paucity of direct evidence regarding its role,
expert opinion considers the history and clinical examination as
key information in the evaluation of a first seizure [5]. Historical
information from a reliable witness is necessary for accurate
diagnosis of seizures and exclusion of alternate diagnoses, and may
reduce or eliminate the need for further investigations. The clinical
examination adds evidence of recent seizures in some cases, as
well as clues to an underlying acute or remote symptomatic
etiology—information that is crucial in selecting further inves-
tigations (e.g. magnetic resonance imaging, electrophysiology,
echocardiography), predicting risk of future recurrence, and
directing therapeutics.
Conflict of interest statement
The authors declare no conflict of interest.
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