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Evaluation of the first seizure patient: Key points in the history and physical examination

Open ArchivePublished:December 08, 2016DOI:https://doi.org/10.1016/j.seizure.2016.12.002

      Highlights

      • The first seizure evaluation rests primarily on the clinical history.
      • An accurate description of the spell is necessary to confirm the diagnosis.
      • Identifying prior unrecognized seizures may change the diagnosis to epilepsy.
      • The interview aims to find specific acute or remote symptomatic seizure etiologies.
      • The clinical findings influence further investigations, prognostication, and therapy.

      Abstract

      Purpose

      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. Clinical features that may distinguish seizures from alternative diagnoses are discussed in detail, followed by a discussion of acute and remote first seizure etiologies.

      Methods

      This review article is based on a discretionary selection of English language articles retrieved by a literature search in the PubMed database, and the authors’ clinical experience.

      Results

      The first seizure is a dramatic event with often profound implications for patients and family members. The initial clinical evaluation focuses on an accurate description of the spell to confirm the diagnosis, along with careful scrutiny for previously unrecognized seizures that would change the 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.

      Keywords

      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)

      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” [
      • Aydemir N.
      • Tekcan A.İ.
      • Özkara Ç.
      Epilepsy & behavior.
      ]. The first seizure has far-reaching implications for lifestyle, employment, driving, personal relationships, insurance, and financial borrowing [
      • Bonnett L.J.
      • Tudur-Smith C.
      • Williamson P.R.
      • Marson A.G.
      Risk of recurrence after a first seizure and implications for driving: further analysis of the multicentre study of early epilepsy and single seizures.
      ,
      • Heaney D.C.
      • Bell G.S.
      • Sander J.W.
      The socioeconomic, cultural, and emotional implications of starting or withholding treatment in a patient with a first seizure.
      ].
      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 [
      • Krumholz A.
      • Wiebe S.
      • Gronseth G.
      • Shinnar S.
      • Levisohn P.
      • Ting T.
      • et al.
      Practice parameter: evaluating an apparent unprovoked first seizure in adults (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology and the American Epilepsy Society.
      ], the importance of the history and physical examination is supported mostly by expert opinion [
      • Beghi E.
      Management of a first seizure. General conclusions and recommendations.
      ,
      • Berg A.T.
      • Berkovic S.F.
      • Brodie M.J.
      • Buchhalter J.
      • Cross J.H.
      • van Emde Boas W.
      • et al.
      Revised terminology and concepts for organization of seizures and epilepsies: report of the ILAE Commission on Classification and Terminology, 2005–2009.
      ]. 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 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 [
      • Theodore W.H.
      • Porter R.J.
      • Albert P.
      • Kelley K.
      • Bromfield E.
      • Devinsky O.
      • et al.
      The secondarily generalized tonic-clonic seizure: a videotape analysis.
      ]. 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) [
      • Rossetti A.O.
      • Kaplan P.W.
      Seizure semiology: an overview of the ‘inverse problem’.
      ]. Occipital and parietal lobe auras can be characterized by somatosensory (paresthetic, painful, thermal, disturbances of body image) or visual (amaurotic, elementary and complex hallucinations, illusions) 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 [
      • Rossetti A.O.
      • Kaplan P.W.
      Seizure semiology: an overview of the ‘inverse problem’.
      ,
      • Tufenkjian K.
      • Lüders H.O.
      Seizure semiology: its value and limitations in localizing the epileptogenic zone.
      ].
      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 [
      • Lüders H.
      • Noachtar S.
      Epileptic seizures: pathophysiology and clinical semiology.
      ]. 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 characterized by their short duration (e.g. 10–30 s), explosive onset with hypermotor features, bilateral motor activity, and nocturnal occurrence [
      • Derry C.P.
      • Davey M.
      • Johns M.
      • Kron K.
      • Glencross D.
      • Marini C.
      • et al.
      Distinguishing sleep disorders from seizures: diagnosing bumps in the night.
      ,
      • So E.L.
      Value and limitations of seizure semiology in localizing seizure onset.
      ]. 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 [
      • Kotagal P.
      • Lüders H.
      • Morris H.H.
      • Dinner D.S.
      • Wyllie E.
      • Godoy J.
      • Rothner A.D.
      Dystonic posturing in complex partial seizures of temporal lobe onset: a new lateralizing sign.
      ]. 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 [
      • Saint-Hilaire J.M.
      • Lee M.A.
      Localizing and lateralizing value of epileptic symptoms in temporal lobe epilepsy.
      ]. 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 [
      • Ettinger A.B.
      • Weisbrot D.M.
      • Nolan E.
      • Devinsky O.
      Postictal symptoms help distinguish patients with epileptic seizures from those with non-epileptic seizures.
      ]. 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 [
      • Loddenkemper T.
      • Kotagal P.
      Lateralizing signs during seizures in focal epilepsy.
      ].
      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 [
      • Syed T.U.
      • Arozullah A.M.
      • Suciu G.P.
      • Toub J.
      • Kim H.
      • Dougherty M.L.
      • et al.
      Do observer and self-reports of ictal eye closure predict psychogenic nonepileptic seizures?.
      ]. 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 [
      • Thijs R.D.
      • Wagenaar W.A.
      • Middelkoop H.A.M.
      • Wieling W.
      • Van Dijk J.G.
      Transient loss of consciousness through the eyes of a witness.
      ]. 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 [
      • Rugg-Gunn F.J.
      • Harrison N.A.
      • Duncan J.S.
      Evaluation of the accuracy of seizure descriptions by the relatives of patients with epilepsy.
      ]. 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 [
      • Zeiler S.R.
      • Kaplan P.W.
      Our digital world: camera phones and the diagnosis of a seizure.
      ].
      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 [
      • Day S.C.
      • Cook E.F.
      • Funkenstein H.
      • Goldman L.
      Evaluation and outcome of emergency room patients with transient loss of consciousness.
      ]) [
      • Angus-Leppan H.
      Diagnosing epilepsy in neurology clinics: a prospective study.
      ]. While video/EEG monitoring remains the gold standard for the diagnosis of seizures [
      • Benbadis S.
      The differential diagnosis of epilepsy: a critical review.
      ], 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) [
      • Beghi E.
      Management of a first seizure. General conclusions and recommendations.
      ].
      Table 1Physical examination findings and their potential significance in first seizure patients.
      SystemFindingPotential significance
      General appearancePoor cooperation with examination; exaggeration or dramatization of featuresPsychiatric co-morbidities with PNES
      VitalsFeverAcute symptomatic seizure from infection (e.g. encephalitis)
      HypertensionPRES
      Bradycardia or tachycardiaCardiogenic syncope
      Head and neckPapilledemaSyncope from intracranial hypertension (e.g. idiopathic intracranial hypertension); seizure from cortical irritation (e.g. meningo-encephalitis, cerebral venous thrombosis)
      Tongue or cheek biteLateral tongue bite from seizure (bite to tongue tip or cheek occur in seizures or syncope)
      Scalp or facial lacerationFall from loss of consciousness
      Cardiovascular systemDrop in systolic BP of ≥20 mmHg or diastolic BP of ≥10 mmHg on standingSyncope from orthostatic hypotension
      Irregular cardiac rhythmCardiogenic syncope (e.g. sick sinus syndrome)
      Heart murmurCardiogenic syncope (e.g. aortic stenosis)
      Drop in BP of ≥50 mmHg or asystole > 3 s with carotid massageSyncope from carotid hypersensitivity
      RespiratoryCoughSyncope from increased intrathoracic pressure
      Gastrointestinal systemHepatomegaly, jaundice, scleral icterus, ascites, palmar erythema, or gynecomastiaChronic alcoholism and risk of withdrawal seizures
      Musculoskeletal systemUnexplained long bone fractureUnwitnessed loss of consciousness and fall
      Posterior shoulder dislocationGeneralized convulsion
      CutaneousLinear scars from “cutting”Psychiatric co-morbidities with PNES
      Track marksIllicit drug injection and risk of acute symptomatic seizure
      Café au lait spots, axillary or inguinal freckling, cutaneous neurofibromataNeurofibromatosis
      Hypomelanic macules (“ash leaf spots”), shagreen patches, subungual fibromas, adenoma sebaceumTuberous sclerosis
      Facial capillary hemangiomata (“port-wine stain”)Sturge-Weber syndrome
      Skin and mucosal telangiectasiasHereditary Hemorrhagic Telangiectasia
      Macular hypopigmented whorls or patchesHypomelanosis of Ito
      Nervous systemFocal neurological deficits (motor, sensory, visual)Structural cerebral lesion as cause of seizure
      Limb hemiatrophyIn-utero or pediatric cerebral insult as cause of seizure
      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 [
      • Benbadis S.R.
      • Wolgamuth B.R.
      • Goren H.
      • Brener S.
      • Fouad-Tarazi F.
      Value of tongue biting in the diagnosis of seizures.
      ,
      • Oliva M.
      • Pattison C.
      • Carino J.
      • Roten A.
      • Matkovic Z.
      • O’Brien T.J.
      The diagnostic value of oral lacerations and incontinence during convulsive seizures.
      ]. 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 [
      • Brigo F.
      • Nardone R.
      • Bongiovanni L.G.
      Value of tongue biting in the differential diagnosis between epileptic seizures and syncope.
      ]. A companion meta-analysis of seizures versus syncope also confirmed the high diagnostic specificity but low sensitivity of lateral tongue biting for seizures [
      • Brigo F.
      • Storti M.
      • Lochner P.
      • Tezzon F.
      • Fiaschi A.
      • Bongiovanni L.G.
      • et al.
      Tongue biting in epileptic seizures and psychogenic events: an evidence-based perspective.
      ]. 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 [
      • Brigo F.
      • Nardone R.
      • Ausserer H.
      • Storti M.
      • Tezzon F.
      • Manganotti P.
      • et al.
      The diagnostic value of urinary incontinence in the differential diagnosis of seizures.
      ]. Other sequelae of seizures include contusions, wounds, fractures, abrasions, concussions, and thermal injuries [
      • Kerr M.P.
      The impact of epilepsy on patients’ lives.
      ,
      • Long L.
      • Reeves A.L.
      The practical aspects of epilepsy: critical components of comprehensive patient care.
      ]. 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 [
      • Peguero E.
      • Abou-Khalil B.
      • Fakhoury T.
      • Mathews G.
      Self-injury and incontinence in psychogenic seizures.
      ]. 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 [
      • Gosens T.
      • Poels P.J.
      Posterior dislocation fractures of the shoulder in seizure disorders-two case reports and a review of literature.
      ]. Still, the incidence of posterior shoulder dislocations is low, with five instances of first-time shoulder dislocation occurring among a series of 806 EMU patients [
      • DeToledo J.C.
      • Lowe M.R.
      Seizures, lateral decubitus, aspiration, and shoulder dislocation: time to change the guidelines?.
      ]. Posterior shoulder dislocation-fractures have been reported as the first presentation of epilepsy [
      • White J.R.
      • Palejwala A.
      Bilateral shoulder fracture, dislocation and replacement: a first presentation of epilepsy.
      ], and these injuries can initially be overlooked (see Fig. 1).
      Fig. 1
      Fig. 1Multiple right-sided rib fractures with complicating hydropneumothorax in a 55 year old man seen by one of the authors (TN) who presented to hospital after two alcohol-withdrawal seizures. The injuries were not identified until the third post-admission day. Unable to recall any history of trauma, these injuries were likely as a result of his seizures. He required open reduction and internal fixation of the humerus, and placement of a chest tube.

      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 [
      • Jallon P.
      • Loiseau P.
      • Loiseau J.
      Newly diagnosed unprovoked epileptic seizures: presentation at diagnosis in CAROLE study. Coordination Active du Réseau Observatoire Longitudinal de l’Epilepsie.
      ].
      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 [
      • Angus-Leppan H.
      First seizures in adults.
      ]. Evidence of non-convulsive seizures should be sought by asking about spells of unresponsiveness, myoclonic jerks, or stereotyped sensory experiences suggestive of auras. Among patients presenting with a presumed first GTCS, approximately 40% of them have had a previous tonic-clonic seizure, or another seizure type such as absence, myoclonus, or temporal lobe auras [
      • Jallon P.
      • Loiseau P.
      • Loiseau J.
      Newly diagnosed unprovoked epileptic seizures: presentation at diagnosis in CAROLE study. Coordination Active du Réseau Observatoire Longitudinal de l’Epilepsie.
      ,
      • King M.A.
      • Newton M.R.
      • Jackson G.D.
      • Fitt G.J.
      • Mitchell L.A.
      • Silvapulle M.J.
      • et al.
      Epileptology of the first-seizure presentation: a clinical, electroencephalographic, and magnetic resonance imaging study of 300 consecutive patients.
      ].

      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 [
      • Moya A.
      • Sutton R.
      • Ammirati F.
      • Blanc J.-J.
      • Brignole M.
      • Dahm J.B.
      • et al.
      Guidelines for the diagnosis and management of syncope (version 2009): The Task Force for the Diagnosis and Management of Syncope of the European Society of Cardiology (ESC).
      ]. 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 [
      • Karceski S.
      Seizures versus syncope.
      ,
      • McKeon A.
      • Vaughan C.
      • Delanty N.
      Seizure versus syncope.
      ] (see Table 1). Intracranial hypertension may present with T-LOC episodes, and the clinical evaluation should include inquiry for postural headaches 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 [
      • Karceski S.
      Seizures versus syncope.
      ]. 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 [
      • Lin J.T.
      • Ziegler D.K.
      • Lai C.W.
      • Bayer W.
      Convulsive syncope in blood donors.
      ,
      • Newman B.H.
      • Graves S.
      A study of 178 consecutive vasovagal syncopal reactions from the perspective of safety.
      ]. Video analysis has shown tonic and myoclonic muscle activity, eye deviations, and vocalizations during syncope [
      • van Dijk J.G.
      • Thijs R.D.
      • van Zwet E.
      • Tannemaat M.R.
      • van Niekerk J.
      • Benditt D.G.
      • et al.
      The semiology of tilt-induced reflex syncope in relation to electroencephalographic changes.
      ]. Myoclonic activity, mostly multifocal arrhythmic jerking, is particularly common, occurring among 90% of healthy subjects in a study of induced syncope [
      • Lempert T.
      • Bauer M.
      • Schmidt D.
      Syncope: a videometric analysis of 56 episodes of transient cerebral hypoxia.
      ]. Even complex motor behaviours such as oral and limb automatisms, which are typically associated with seizures, occur during syncope [
      • van Dijk J.G.
      • Thijs R.D.
      • van Zwet E.
      • Tannemaat M.R.
      • van Niekerk J.
      • Benditt D.G.
      • et al.
      The semiology of tilt-induced reflex syncope in relation to electroencephalographic changes.
      ], and their presence may lead to the misdiagnosis of seizure [
      • Zaidi A.
      • Clough P.
      • Cooper P.
      • Scheepers B.
      • Fitzpatrick A.P.
      Misdiagnosis of epilepsy: many seizure-like attacks have a cardiovascular cause.
      ]. Although motor activity occurring during syncope may resemble a seizure, it is distinguished by its shorter duration, on average lasting less than thirty seconds, and the relative lack of post-event confusion [
      • van Dijk J.G.
      • Thijs R.D.
      • van Zwet E.
      • Tannemaat M.R.
      • van Niekerk J.
      • Benditt D.G.
      • et al.
      The semiology of tilt-induced reflex syncope in relation to electroencephalographic changes.
      ,
      • Lempert T.
      Recognizing syncope: pitfalls and surprises.
      ].

      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) [
      • Hoefnagels W.A.
      • Padberg G.W.
      • Overweg J.
      • van der Velde E.A.
      • Roos R.A.
      Transient loss of consciousness: the value of the history for distinguishing seizure from syncope.
      ]. 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 unresponsiveness, 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 [
      • Sheldon R.
      • Rose S.
      • Ritchie D.
      • Connolly S.J.
      • Koshman M.-L.
      • Lee M.A.
      • et al.
      Historical criteria that distinguish syncope from seizures.
      ]. 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 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 [
      • Lesser R.P.
      Psychogenic seizures.
      ]. They often arise in a particular context in response to external (place, time, witness) or internal triggers (flashbacks, emotions) [
      • Perrig S.
      • Jallon P.
      Is the first seizure truly epileptic?.
      ]. “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 somatization [
      • Benbadis S.R.
      A spell in the epilepsy clinic and a history of chronic pain or ‘fibromyalgia’ independently predict a diagnosis of psychogenic seizures.
      ]. Patient demeanour, effort, and co-operation with the interview and physical examination should be observed. Over-dramatization, histrionic features, give-way weakness or exaggeration of perceived deficits may raise suspicion of PNES [
      • Benbadis S.
      The differential diagnosis of epilepsy: a critical review.
      ]. 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 [
      • Duncan R.
      • Oto M.
      Predictors of antecedent factors in psychogenic nonepileptic attacks: multivariate analysis.
      ]. 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 [
      • Theodore W.H.
      • Porter R.J.
      • Albert P.
      • Kelley K.
      • Bromfield E.
      • Devinsky O.
      • et al.
      The secondarily generalized tonic-clonic seizure: a videotape analysis.
      ], PNES are often longer-lasting, and variable in their presentation and course [
      • Lesser R.P.
      Psychogenic seizures.
      ]. 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 [
      • Benbadis S.
      The differential diagnosis of epilepsy: a critical review.
      ].

      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 [
      • Elzawahry H.
      • Do C.S.
      • Lin K.
      • Benbadis S.R.
      The diagnostic utility of the ictal cry.
      ]. 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 [
      • Vossler D.G.
      • Haltiner A.M.
      • Schepp S.K.
      • Friel P.A.
      • Caylor L.M.
      • Morgan J.D.
      • et al.
      Ictal stuttering: a sign suggestive of psychogenic nonepileptic seizures.
      ]. 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% [
      • Chung S.S.
      • Gerber P.
      • Kirlin K.A.
      Ictal eye closure is a reliable indicator for psychogenic nonepileptic seizures.
      ,
      • DeToledo J.C.
      • Ramsay R.E.
      Patterns of involvement of facial muscles during epileptic and nonepileptic events: review of 654 events.
      ,
      • Flügel D.
      • Bauer J.
      • Käseborn U.
      • Burr W.
      • Elger C.E.
      Closed eyes during a seizure indicate psychogenic etiology: a study with suggestive seizure provocation.
      ,
      • Syed T.U.
      • Arozullah A.M.
      • Suciu G.P.
      • Toub J.
      • Kim H.
      • Dougherty M.L.
      • et al.
      Do observer and self-reports of ictal eye closure predict psychogenic nonepileptic seizures?.
      ]. 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 [
      • Brigo F.
      • Ausserer H.
      • Nardone R.
      • Tezzon F.
      • Manganotti P.
      • Bongiovanni L.G.
      Clinical utility of ictal eyes closure in the differential diagnosis between epileptic seizures and psychogenic events.
      ]. Lateral tongue bite is a highly specific feature of epileptic seizures [
      • Brigo F.
      • Storti M.
      • Lochner P.
      • Tezzon F.
      • Fiaschi A.
      • Bongiovanni L.G.
      • et al.
      Tongue biting in epileptic seizures and psychogenic events: an evidence-based perspective.
      ], as oral lacerations occur infrequently during PNES, and are usually a bite to the cheek or tip of the tongue [
      • DeToledo J.C.
      • Ramsay R.E.
      Patterns of involvement of facial muscles during epileptic and nonepileptic events: review of 654 events.
      ].
      Urinary incontinence does not reliably distinguish seizures from PNES [
      • Brigo F.
      • Nardone R.
      • Ausserer H.
      • Storti M.
      • Tezzon F.
      • Manganotti P.
      • et al.
      The diagnostic value of urinary incontinence in the differential diagnosis of seizures.
      ]. Although pelvic thrusting often occurs during 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 [
      • Geyer J.D.
      • Payne T.A.
      • Drury I.
      The value of pelvic thrusting in the diagnosis of seizures and pseudoseizures.
      ].
      PNES patients who present with unresponsiveness without motor activity (“pseudocoma”) pose a diagnostic challenge and may be misdiagnosed as nonconvulsive status epilepticus [
      • Leis A.A.
      • Ross M.A.
      • Summers A.K.
      Psychogenic seizures: ictal characteristics and diagnostic pitfalls.
      ]. 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 [
      • Leis A.A.
      • Ross M.A.
      • Summers A.K.
      Psychogenic seizures: ictal characteristics and diagnostic pitfalls.
      ,
      • Rossetti A.O.
      • Kaplan P.W.
      Seizure semiology: an overview of the ‘inverse problem’.
      ]. 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 [
      • Maddock H.
      • Carley S.
      • McCluskey A.
      An unusual case of hysterical postoperative coma.
      ]. 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 [
      • Posner J.B.
      • Saper C.B.
      • Schiff N.D.
      • Plum F.
      Plum and Posner’s Diagnosis of Stupor and Coma.
      ].
      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 [
      • Benbadis S.
      The differential diagnosis of epilepsy: a critical review.
      ]. 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 [
      • Benbadis S.R.
      • Johnson K.
      • Anthony K.
      • Caines G.
      • Hess G.
      • Jackson C.
      • et al.
      Induction of psychogenic nonepileptic seizures without placebo.
      ].

      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 [
      • Zucconi M.
      • Ferini-Strambi L.
      NREM parasomnias: arousal disorders and differentiation from nocturnal frontal lobe epilepsy.
      ]. 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 [
      • Derry C.P.
      • Davey M.
      • Johns M.
      • Kron K.
      • Glencross D.
      • Marini C.
      • et al.
      Distinguishing sleep disorders from seizures: diagnosing bumps in the night.
      ].

      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 [
      • Karceski S.
      Acute symptomatic seizures and systemic illness.
      ]. 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 [
      • Beghi E.
      • Carpio A.
      • Forsgren L.
      • Hesdorffer D.C.
      • Malmgren K.
      • Sander J.W.
      • et al.
      Recommendation for a definition of acute symptomatic seizure.
      ]. 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 [
      • Annegers J.F.
      • Hauser W.A.
      • Lee J.R.
      • Rocca W.A.
      Incidence of acute symptomatic seizures in Rochester, Minnesota, 1935–1984.
      ,
      • Hauser W.A.
      • Annegers J.F.
      • Kurland L.T.
      Incidence of epilepsy and unprovoked seizures in Rochester, Minnesota: 1935–1984.
      ]. In that cohort, the most frequent causes of acute symptomatic seizures were head trauma, cerebrovascular disease, CNS infections, 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 [
      • Sempere A.P.
      • Villaverde F.J.
      • Martinez-Menéndez B.
      • Cabeza C.
      • Peña P.
      • Tejerina J.A.
      First seizure in adults: a prospective study from the emergency department.
      ,
      • Tardy B.
      • Lafond P.
      • Convers P.
      • Page Y.
      • Zeni F.
      • Viallon A.
      • et al.
      Adult first generalized seizure: etiology, biological tests, EEG, CT scan, in an ED.
      ].

      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 [
      • Clear D.
      • Chadwick D.W.
      Seizures provoked by blows to the head.
      ]. 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 [
      • Annegers J.F.
      • Hauser W.A.
      • Coan S.P.
      • Rocca W.A.
      A population-based study of seizures after traumatic brain injuries.
      ]. 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 concussion 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% [
      • Bladin C.F.
      • Alexandrov A.V.
      • Bellavance A.
      • Bornstein N.
      • Chambers B.
      • Coté R.
      • et al.
      Seizures after stroke: a prospective multicenter study.
      ], comprising both acute and remote symptomatic seizures, and stroke is the most frequent cause of acute symptomatic seizures among elderly patients [
      • Annegers J.F.
      • Hauser W.A.
      • Lee J.R.
      • Rocca W.A.
      Incidence of acute symptomatic seizures in Rochester, Minnesota, 1935–1984.
      ]. 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 [
      • Bladin C.F.
      • Alexandrov A.V.
      • Bellavance A.
      • Bornstein N.
      • Chambers B.
      • Coté R.
      • et al.
      Seizures after stroke: a prospective multicenter study.
      ].

      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 [
      • Annegers J.F.
      • Hauser W.A.
      • Beghi E.
      • Nicolosi A.
      • Kurland L.T.
      The risk of unprovoked seizures after encephalitis and meningitis.
      ]. Given the frequency of seizures in patients with acute CNS infection, lumbar puncture is recommend for febrile patients presenting with a first seizure [
      • Krumholz A.
      • Wiebe S.
      • Gronseth G.
      • Shinnar S.
      • Levisohn P.
      • Ting T.
      • et al.
      Practice parameter: evaluating an apparent unprovoked first seizure in adults (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology and the American Epilepsy Society.
      ]. 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 [
      • Sempere A.P.
      • Villaverde F.J.
      • Martinez-Menéndez B.
      • Cabeza C.
      • Peña P.
      • Tejerina J.A.
      First seizure in adults: a prospective study from the emergency department.
      ]. First seizure patients who are human immunodeficiency virus (HIV) positive are more likely to harbour a CNS infection, even if they have been treated with highly active antiretroviral therapy [
      • Holtzman D.M.
      • Kaku D.A.
      • So Y.T.
      New-onset seizures associated with human immunodeficiency virus infection: causation and clinical features in 100 cases.
      ,
      • Kellinghaus C.
      • Engbring C.
      • Kovac S.
      • Möddel G.
      • Boesebeck F.
      • Fischera M.
      • et al.
      Frequency of seizures and epilepsy in neurological HIV-infected patients.
      ,
      • Modi M.
      • Mochan A.
      • Modi G.
      New onset seizures in HIV-Seizure semiology, CD4 counts, and viral loads.
      ].

      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 epileptogenicity 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 [
      • Smith P.E.
      • McBride A.
      Illicit drugs and seizures.
      ]. 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 [
      • Ng S.K.
      • Hauser W.A.
      • Brust J.C.
      • Susser M.
      Alcohol consumption and withdrawal in new-onset seizures.
      ], and even a family history of alcoholism is a risk factor for the first seizure [
      • Leone M.
      • Bottacchi E.
      • Beghi E.
      • Morgando E.
      • Mutani R.
      • Amedeo G.
      • et al.
      Alcohol use is a risk factor for a first generalized tonic-clonic seizure. The ALC.E. (Alcohol and Epilepsy) Study Group.
      ]. 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 [
      • Hillbom M.E.
      Occurrence of cerebral seizures provoked by alcohol abuse.
      ]. 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 [
      • Hillbom M.
      • Pieninkeroinen I.
      • Leone M.
      Seizures in alcohol-dependent patients: epidemiology, pathophysiology and management.
      ]. 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 [
      • Bråthen G.
      • Ben-Menachem E.
      • Brodtkorb E.
      • Galvin R.
      • Garcia-Monco J.C.
      • Halasz P.
      • et al.
      EFNS guideline on the diagnosis and management of alcohol-related seizures: report of an EFNS task force.
      ]. Validated screening tools such as the CAGE questionnaire [
      • Mayfield D.
      • McLeod G.
      • Hall P.
      The CAGE questionnaire: validation of a new alcoholism screening instrument.
      ], fast alcohol screening test (FAST) [
      • Hodgson R.J.
      • John B.
      • Abbasi T.
      • Hodgson R.C.
      • Waller S.
      • Thom B.
      • et al.
      Fast screening for alcohol misuse.
      ], or AUDIT-C [
      • Bush K.
      • Kivlahan D.R.
      • McDonell M.B.
      • Fihn S.D.
      • Bradley K.A.
      The AUDIT alcohol consumption questions (AUDIT-C): an effective brief screening test for problem drinking. Ambulatory Care Quality Improvement Project (ACQUIP). Alcohol Use Disorders Identification Test.
      ] 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 [
      • Bråthen G.
      • Ben-Menachem E.
      • Brodtkorb E.
      • Galvin R.
      • Garcia-Monco J.C.
      • Halasz P.
      • et al.
      EFNS guideline on the diagnosis and management of alcohol-related seizures: report of an EFNS task force.
      ].

      4.2.4.2 Psychostimulants

      Cocaine is one of the most epileptogenic psychostimulant drugs [
      • Smith P.E.
      • McBride A.
      Illicit drugs and seizures.
      ] 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 [
      • Leach J.P.
      • Mohanraj R.
      • Borland W.
      Alcohol and drugs in epilepsy: pathophysiology, presentation, possibilities, and prevention.
      ]. 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 [
      • Brust J.C.M.
      Seizures, illicit drugs, and ethanol.
      ].
      Seizures have been reported following use of amphetamines and related substances such as MDMA (Ecstasy, 3,4-methylenedioxymethamphetamine). Seizures in the setting of amphetamine abuse are usually accompanied by other signs of intoxication such as fever, hypertension, cardiac arrhythmia, delirium, and coma [
      • Smith P.E.
      • McBride A.
      Illicit drugs and seizures.
      ]. A series of 1019 first-seizure patients found that 4% of patients reported use of amphetamines within 24 h of the seizure [
      • Brown J.W.L.
      • Dunne J.W.
      • Fatovich D.M.
      • Fatovic D.M.
      • Lee J.
      • Lawn N.D.
      Amphetamine-associated seizures: clinical features and prognosis.
      ], but a previous study found no difference in the frequency of amphetamine use among first-seizure cases and controls [
      • Ng S.K.
      • Brust J.C.
      • Hauser W.A.
      • Susser M.
      Illicit drug use and the risk of new-onset seizures.
      ].

      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 [
      • Brust J.C.
      • Ng S.K.
      • Hauser A.W.
      • Susser M.
      Marijuana use and the risk of new onset seizures.
      ]. There are conflicting case reports of seizures provoked by marijuana, or of reduction in seizure frequency with marijuana use [
      • Brust J.C.M.
      Seizures and substance abuse: treatment considerations.
      ], with one case-control study reporting no significant difference in the frequency of marijuana use among first-seizure cases and controls [
      • Ng S.K.
      • Brust J.C.
      • Hauser W.A.
      • Susser M.
      Illicit drug use and the risk of new-onset seizures.
      ]. A Cochrane review of cannabidiol as a treatment for epilepsy found insufficient evidence to draw any conclusions regarding efficacy [
      • Gloss D.
      • Vickrey B.
      Cannabinoids for epilepsy.
      ]. There are recent reports of seizures following smoking and inhalation of herbal compounds mixed with synthetic cannabinoid compounds [
      • de Havenon A.
      • Chin B.
      • Thomas K.C.
      • Afra P.
      The secret spice: an undetectable toxic cause of seizure.
      ,
      • Schneir A.B.
      • Baumbacher T.
      Convulsions associated with the use of a synthetic cannabinoid product.
      ,
      • Tofighi B.
      • Lee J.D.
      Internet highs—seizures after consumption of synthetic cannabinoids purchased online.
      ], 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 [
      • Zawilska J.B.
      • Wojcieszak J.
      Spice/K2 drugs—more than innocent substitutes for marijuana.
      ].

      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 [
      • Ng S.K.
      • Brust J.C.
      • Hauser W.A.
      • Susser M.
      Illicit drug use and the risk of new-onset seizures.
      ]. 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 [
      • Brust J.C.M.
      Seizures and substance abuse: treatment considerations.
      ].
      Therapeutic use of prescription opioids including pethidine, diamorphine, methadone, propoxyphene, meperidine, morphine, fentanyl, and tramadol has been reported to cause seizures [
      • Leach J.P.
      • Mohanraj R.
      • Borland W.
      Alcohol and drugs in epilepsy: pathophysiology, presentation, possibilities, and prevention.
      ,
      • Smith P.E.
      • McBride A.
      Illicit drugs and seizures.
      ,
      • Wills B.
      • Erickson T.
      Chemically induced seizures.
      ]. 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 [
      • Kaiko R.F.
      • Foley K.M.
      • Grabinski P.Y.
      • Heidrich G.
      • Rogers A.G.
      • Inturrisi C.E.
      • et al.
      Central nervous system excitatory effects of meperidine in cancer patients.
      ]. There are many case reports implicating tramadol as a cause of seizures, as well as seizures occurring in acute overdose [
      • Shadnia S.
      • Soltaninejad K.
      • Heydari K.
      • Sasanian G.
      • Abdollahi M.
      Tramadol intoxication: a review of 114 cases.
      ], but a retrospective study did not find an increased risk of seizures among patients taking tramadol alone [
      • Gasse C.
      • Derby L.
      • Vasilakis-Scaramozza C.
      • Jick H.
      Incidence of first-time idiopathic seizures in users of tramadol.
      ].

      4.2.5 Other prescription medications

      A multitude of prescription medications have been associated with seizures [
      • Boggs J.G.
      Seizures in medically complex patients.
      ,
      • Wills B.
      • Erickson T.
      Chemically induced seizures.
      ]. Establishing causation is difficult since seizures are common, especially in patients with medical illness who are taking multiple medications [
      • Karceski S.
      Acute symptomatic seizures and systemic illness.
      ]. 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 [
      • Porter J.
      • Jick H.
      Drug-induced anaphylaxis, convulsions, deafness, and extrapyramidal symptoms.
      ].

      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 [
      • Beleza P.
      Acute symptomatic seizures.
      ]. 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 [
      • Wallace K.L.
      Antibiotic-induced convulsions.
      ].

      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 [
      • Beleza P.
      Acute symptomatic seizures.
      ]. 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 [
      • Brust J.C.M.
      Seizures, illicit drugs, and ethanol.
      ].

      4.2.5.3 Antidepressants

      The widespread use of antidepressants means that many patients will be taking one at the time of their 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 [
      • Montgomery S.A.
      Antidepressants and seizures: emphasis on newer agents and clinical implications.
      ]. Amoxapine, maprotilene, and bupropion have been associated with a greater seizure risk than other antidepressants [
      • Kumlien E.
      • Lundberg P.O.
      Seizure risk associated with neuroactive drugs: data from the WHO adverse drug reactions database.
      ]. The risk of seizures with bupropion is dose-dependent, exceeding 1% for doses greater than 450 mg/d [
      • Mago R.
      • Mahajan R.
      • Thase M.E.
      Medically serious adverse effects of newer antidepressants.
      ]. The overall rate of seizures with therapeutic doses of anti-depressants is low, but the rate increases in acute overdose with TCAs [
      • Montgomery S.A.
      Antidepressants and seizures: emphasis on newer agents and clinical implications.
      ]. Seizures are infrequently encountered in acute overdose with SSRIs [
      • Isbister G.K.
      • Bowe S.J.
      • Dawson A.
      • Whyte I.M.
      Relative toxicity of selective serotonin reuptake inhibitors (SSRIs) in overdose.
      ], and only rarely reported with MAOI overdose [
      • Montgomery S.A.
      Antidepressants and seizures: emphasis on newer agents and clinical implications.
      ].

      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 [
      • White H.
      Neurologic manifestations of acute and chronic liver disease.
      ]. 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, hypoglycaemia, hypocalcemia, hypomagnesemia) are seen in patients with hepatic disease [
      • Ellis A.J.
      • Wendon J.A.
      • Williams R.
      Subclinical seizure activity and prophylactic phenytoin infusion in acute liver failure: a controlled clinical trial.
      ].
      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 [
      • Boggs J.G.
      Seizures in medically complex patients.
      ]). 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 [
      • Baumgaertel M.W.
      • Kraemer M.
      • Berlit P.
      ], and also in dialysis dementia, a neurodegenerative disorder which was caused by aluminum in dialysis solutions [
      • Bansal V.K.
      • Bansal S.
      ].
      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 [
      • Chen Y.
      • Xuefeng W.
      Association between seizures and diabetes mellitus: a comprehensive review of literature.
      ]. 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 progressively become increasingly obtunded [
      • Chen Y.
      • Xuefeng W.
      Association between seizures and diabetes mellitus: a comprehensive review of literature.
      ].
      Seizures are the most common clinical feature of posterior reversible encephalopathy syndrome (PRES), with headache and encephalopathy also occurring in most cases [
      • Lamy C.
      • Oppenheim C.
      • Mas J.L.
      Posterior reversible encephalopathy syndrome.
      ]. Seizures occur early in the course of PRES and may be the presenting symptom [
      • Kastrup O.
      • Gerwig M.
      • Frings M.
      • Diener H.-C.
      Posterior reversible encephalopathy syndrome (PRES): electroencephalographic findings and seizure patterns.
      ]. 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, immunosuppressive drugs, and interferon-α therapy [
      • Karceski S.
      Acute symptomatic seizures and systemic illness.
      ,
      • Lamy C.
      • Oppenheim C.
      • Mas J.L.
      Posterior reversible encephalopathy syndrome.
      ].

      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 [
      • Hauser W.A.
      • Beghi E.
      First seizure definitions and worldwide incidence and mortality.
      ]. 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 [
      • Jallon P.
      • Loiseau P.
      • Loiseau J.
      Newly diagnosed unprovoked epileptic seizures: presentation at diagnosis in CAROLE study. Coordination Active du Réseau Observatoire Longitudinal de l’Epilepsie.
      ]. 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 [
      • Hauser W.A.
      • Annegers J.F.
      • Kurland L.T.
      Incidence of epilepsy and unprovoked seizures in Rochester, Minnesota: 1935–1984.
      ].

      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 unprovoked seizure over the course of an average 10 years of follow-up, with the greatest risk among patients with a history of encephalitis [
      • Annegers J.F.
      • Hauser W.A.
      • Beghi E.
      • Nicolosi A.
      • Kurland L.T.
      The risk of unprovoked seizures after encephalitis and meningitis.
      ]. 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 information 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 [
      • Burn J.
      • Dennis M.
      • Bamford J.
      • Sandercock P.
      • Wade D.
      • Warlow C.
      Epileptic seizures after a first stroke: the Oxfordshire Community Stroke Project.
      ,
      • So E.L.
      • Annegers J.F.
      • Hauser W.A.
      • O’Brien P.C.
      • Whisnant J.P.
      Population-based study of seizure disorders after cerebral infarction.
      ]. 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 [
      • Leone M.A.
      • Tonini M.C.
      • Bogliun G.
      • Gionco M.
      • Tassinari T.
      • Bottacchi E.
      • et al.
      Risk factors for a first epileptic seizure after stroke.
      ]. 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 [
      • Lowenstein D.H.
      Epilepsy after head injury: an overview.
      ]. 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 [
      • Hauser W.A.
      • Annegers J.F.
      • Kurland L.T.
      Incidence of epilepsy and unprovoked seizures in Rochester, Minnesota: 1935–1984.
      ]. 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 [
      • Annegers J.F.
      • Hauser W.A.
      • Coan S.P.
      • Rocca W.A.
      A population-based study of seizures after traumatic brain injuries.
      ]. Additional clinical factors that predict late post-traumatic seizures include the presence of skull fracture, intracranial hematoma, and depressed level of consciousness at presentation [
      • Lowenstein D.H.
      Epilepsy after head injury: an overview.
      ]. 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.

      5.2.4 Pre-natal, developmental, and genetic causes

      Since pre-natal and peri-natal insults are a significant cause of remote symptomatic seizures [
      • Hauser W.A.
      • Annegers J.F.
      • Kurland L.T.
      Incidence of epilepsy and unprovoked seizures in Rochester, Minnesota: 1935–1984.
      ], 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 handedness 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 handedness and seizure type or lateralization [
      • Slezicki K.I.
      • Cho Y.W.
      • Yi S.D.
      • Brock M.S.
      • Pfeiffer M.H.
      • McVearry K.M.
      • et al.
      Incidence of atypical handedness in epilepsy and its association with clinical factors.
      ]. 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 [
      • Ahmed S.N.
      • Spencer S.S.
      An approach to the evaluation of a patient for seizures and epilepsy.
      ].
      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 [
      • Scheffer I.E.
      • Zhang Y.-H.
      • Gecz J.
      • Dibbens L.
      Genetics of the epilepsies: genetic twists in the channels and other tales.
      ]. 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 [
      • Peljto A.L.
      • Barker-Cummings C.
      • Vasoli V.M.
      • Leibson C.L.
      • Hauser W.A.
      • Buchhalter J.R.
      • et al.
      Familial risk of epilepsy: a population-based study.
      ]. Additional informants, especially the mother, add valuable information about the seizure history in parents and siblings [
      • Ottman R.
      • Hauser W.A.
      • Susser M.
      Validity of family history data on seizure disorders.
      ]. 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 [
      • Ahmed S.N.
      • Spencer S.S.
      An approach to the evaluation of a patient for seizures and epilepsy.
      ].

      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 [
      • Beghi E.
      Management of a first seizure. General conclusions and recommendations.
      ]. 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 investigations (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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