Epileptic seizures are one of the most frequent causes of so-called “transient neurological events” (TNEs). About up to 10% of people will experience a seizure during their lifetime but only 2% to 3% will develop epilepsy 1. A first unprovoked epileptic seizure (FUES) is a troublesome event for people who experience it and close relatives. Therefore, there is a need for the diagnosis to be as fast and accurate as possible. A lot of questions will probably arise in relation to the event, such as: “are you sure that it was really a seizure?”, “will it recur?”, “is it epilepsy?, “do I need to take drugs?”, “for how long?”, and “what is going to happen in the future?”. Furthermore, the word “epilepsy” is usually linked to significant social, personal and professional stigmatization. ILAE Curriculum

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In this article, the authors aim to guide the reader through this topic in a practical way. The authors will offer some suggestions, stemming from our current practice, of how to act in this situation. However, each case is unique and, as such, there will be room for subjective decisions, either by the neurologist, the patient or relatives.

Was “this” TNE an epileptic seizure?

There is a broad differential diagnosis to consider when facing a TNE, including the following: transient ischemic attacks, migraine auras, paroxysmal movement disorders, (pre-)syncope, sleep disorders, intracranial hypertension and psychogenic non-epileptic seizures (PNES). By definition, an epileptic seizure is a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain 2. And yet, precise diagnosis is frequently not an easy task (table 1). Indeed, like most TNEs, an epileptic seizure is very rarely seen by the physician and the patient is frequently an unreliable source of information, especially if consciousness is altered. Neurological examination and ancillary examinations may not always be of great help in this setting. However, two case series have shown that history and physical examination yield a diagnosis in approximately 85% of cases 3. A witness to the event can provide valuable information on history and semiology, but description should be interpreted carefully. While features such as muscle tone during seizure, drooling and gaze deviation are more frequently correctly reported 4, others such as eye closure are more unreliably reported 5. A video is rarely available for a first seizure, but should be sought because it increases diagnostic accuracy 6. A more rudimentary but practical and often effective solution, especially when the witness cannot accurately describe the event, is to ask the person to mimic what has been observed. The presence of previous neurological phenomena may be useful for the differential diagnosis, especially if additional information on semiology can be obtained. While some patients may present an unequivocal seizure, many patients describe more of a “spell”, with a seizure as only one of the possible TNEs. There is a lack of validated diagnostic criteria to help the physician in diagnosing a TNE 7. The Sheldon questionnaire 8 may be useful for the differential diagnosis of syncope. As for PNES, a review-of-system questionnaire 9 may aid in the different diagnosis, although it should not be used as the sole clinical tool. The Frontal Lobe Epilepsy and Parasomnias (FLEP) scale can be useful in differentiating nocturnal frontal lobe epilepsy from parasomnias 10. It is certainly not practical to have the questionnaires at hand, but if the clinician is familiar with the questions, they can help to direct the clinical history and examination. Lateral tongue biting may be indicative of epileptic seizures with low sensitivity but high specificity 11. Posterior shoulder dislocation in the absence of direct trauma favours an unwitnessed GTCS 12. Some findings in the physical examination may aid in the differential diagnosis of an epileptic seizure. However, they should not be used as the only tool (table 2).

Table 1. Difficulties in diagnosing a first epileptic seizure.

I. Reliability of testimony

1. The physician rarely witnesses a seizure 2. The patient is not the best person to describe the event because most seizures are accompanied by a disturbance of consciousness 3. A witness may be present during the event (for instance, for a seizure in a street)

4. A witness of the seizure may have difficulty in describing it due to:

 (a) significant nervousness and anxiety with respect to the unexpected event  (b) not seeing the very beginning of the seizure (for instance, the aura)  (e) considering the seizure too complex to be properly described  (d) seizures occurring at night

II. Biomarkers for seizure detection in the emergency setting for generalized-onset or focal-to-bilateral tonic-clonic seizures (usually with low specificity and sensitivity)

1. Prolactin secretion 2. Changes in serum adrenocorticotropic hormone and cortisol levels 3. Increased levels of ammonia 4. Troponin I elevation 5. Creatine kinase elevation 6. Anion gap > 10 mEq/L within the first 2 hours

III. Ancillary examinations (either in the emergency setting or outpatient clinic)

1. EEG is seldom performed in the emergency setting. 2. Neurophysiological markers (e.g. interictal EEG) show high specificity but low sensitivity. 3. The interictal, or even prolonged EEG or video-EEG may be normal. 4. Imaging, mainly MRI, may be normal or show abnormalities that are not seizure-related. Table 2. Physical examination findings that can aid in the differential diagnosis of a TNE (adapted from ). System Finding Potential significance General appearance Poor cooperation with examination Psychiatric co-morbidities with PNES exaggeration/dramatization of features Vitals Bradycardia or tachycardia Cardiogenic syncope Head and neck Scalp or facial laceration Fall from loss of consciousness Cardiovascular system Drop in systolic BP of ≥ 20 mmHg or diastolic BP of ≥ 10 mmHg on standing Syncope from orthostatic hypotension 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 >3s with carotid massage Syncope from carotid hypersensitivity Respiratory Cough Syncope from increased intrathoracic pressure Cutaneous Linear scars from “cutting” Psychiatric co-morbidities with PNES

Laboratory markers can help to determine whether an unwitnessed event was more likely to be epileptic or non-epileptic. Prolactin testing helps differentiate epileptic seizures from PNES in adults and adolescents, and is associated with high specificity and moderate sensitivity 13, but not recommended as a diagnostic test for epileptic seizures 14, 15. Elevation in creatine kinase (CK) level is common after generalized tonic-clonic seizures (GTCS) with high specificity and moderate sensitivity. Metabolic markers such as ammonia, lactate and increased anion gap (typically driven by increase in serum lactate) may have diagnostic potential for postictal blood tests 16, 17. However, no laboratory test can reliably diagnose or exclude an epileptic seizure 18.

Electrocardiogram should be performed in all adults with loss of consciousness, to identify features suggesting cardiac arrhythmia and syncope, which may mimic epilepsy 15, 19.

If the TNE was an epileptic seizure, was it an acute symptomatic seizure (ASS) or an unprovoked epileptic seizure?

Unprovoked epileptic seizures are defined as seizures occurring in the absence of a potentially causal clinical condition or beyond the interval estimated for the occurrence of ASS. Unprovoked seizures differ from ASS in terms of risk of seizure recurrence and mortality, related to several aetiologies 20. For these reasons, the therapeutic approach is also different.

ASS often occur when systemic (metabolic, toxic or other systemic illness) or brain (traumatic brain injury, cerebrovascular, infectious, tumour or inflammatory/demyelination disease) insults are documented 20. In general, the gap between the insult and the seizure occurrence may be as long as seven days. Suggestions have been made to define ASS as events that occur within one week of a stroke, traumatic brain injury, anoxic encephalopathy, intracranial surgery, or at first identification of subdural hematoma, in the presence of an active central nervous system (CNS) infection, or during an active phase of multiple sclerosis or other autoimmune diseases. In addition, a diagnosis of ASS should be made in cases of severe metabolic derangements (documented within 24 hours based on specific biochemical or haematological abnormalities), drug or alcohol intoxication and withdrawal, or exposure to well-defined epileptogenic drugs 20. The incidence of ASS is about 29 to 39 per 100,000 per year and predominates in the youngest ages 21. Clinically, ASS may be focal or bilateral tonic-clonic. Electrolyte disturbances may themselves cause focal seizures 22. Physical examination may provide some clues as to the aetiology of the ASS, such as fever (infection, e.g. encephalitis), hypertension (e.g. posterior reversible encephalopathy syndrome), papilledema (intracranial hypertension), hepatomegaly, jaundice, scleral icterus, ascites, palmar erythema or gynecomastia (chronic alcoholism) or track marks (illicit drug use).

New-onset seizures are frequently encountered in community and hospital settings, with different aetiologies and prognoses, requiring different approaches for investigation and treatment 23.

Most laboratory abnormalities are predicted based on history and physical examination, and the yield resulting from laboratory evaluations in patients which have returned to baseline is low 24. Laboratory evaluations which should be considered in the evaluation of a first seizure include electrolytes, glucose, calcium, magnesium, complete blood count, renal function tests and liver function tests 15. Laboratory tests, which are recommended even in healthy adults who have returned to baseline, include serum glucose and sodium, based on literature reports of unsuspected hypoglycaemia and hyponatremia 24. The International League Against Epilepsy has proposed cut-off values for ASS in cases of common metabolic disorders (table 3), however, these are only partially evidence-based 20. Other non-specific laboratory abnormalities may be present after a generalized tonic-clonic seizure, including elevated leukocyte count, creatine phosphokinase, cortisol, lactate dehydrogenase, and neuron-specific enolase. Screening for drug abuse should be considered, although there is no compelling evidence for routine screening of drugs 24. The probability of seizure occurrence varies between specific drugs –high (cocaine, crack, normeperidine, meperidine, methaqualone, glutarimide; stimulants), fair (hallucinogens; angel dust [PCP, phencyclidine], quatadine) and low (heroin, marijuana).

Table 3. Proposed cut-off values for acute symptomatic seizures in common metabolic disorders (adapted from ). Biochemical parameter Value Serum glucose <36 mg/dL (2.0 mM) or >450 mg/dL (25 mM) associated with ketoacidosis (whether or not there is long-standing diabetes) Serum sodium <115 mmol/L (<5 mM) Serum calcium <5.0 mg/dL (<1.2 mM) Serum magnesium <0.8 mg/dL (<0.3 mM) Urea nitrogen >100 mg/dL (>35.7 mM) Creatinine >10.0 mg/dL (>884 lM)

In the emergency department (ED), the main role of brain imaging is to exclude immediately treatable intracranial pathology. Not surprisingly, the neuroimaging yield is higher in the presence of a focal neurological deficit on physical examination 25-27. However, significant intracranial abnormalities are found in 10-22% of patients with a first seizure and normal neurological examination 27. Recommendations vary on whether neuroimaging should be performed in the ED. In the acute setting, unenhanced head CT is an appropriate initial neuroimaging study 15, 25, 28. Some guidelines recommend immediate head CT in all adult patients presenting with a first seizure 27, based on data suggesting that emergency head CT leads to an acute change in management in 9-17% of patients 25, 26. Other recommendations allow deferred neuroimaging 26, particularly in patients who have returned to normal baseline when reliable follow-up is available 24. In the experience of the authors, all adult patients presenting with a first seizure undergo unenhanced head CT in the ED. Depending on its availability in the ED, some clinical situations may merit urgent brain MRI, such as cerebral venous thrombosis 29 and viral encephalitis 30, as the diagnosis may have direct and urgent impact in the patient's management.

Lumbar puncture (LP) is not routinely recommended as part of the diagnostic evaluation of the patient presenting with a first epileptic seizure 15, 24, 31. However, it should be performed if there is clinical suspicion of an acute infectious process involving the central nervous system. There is some evidence supporting LP in otherwise asymptomatic immunocompromised patients 24, 32. In this context, LP should only be performed after a neuroimaging study has excluded mass lesions or other causes of increased intracranial pressure.

It has been clearly shown that ASS are associated with higher early mortality but a lower risk of subsequent unprovoked epileptic seizures, i.e. epilepsy 33. Control of ASS requires treatment of the underlying aetiology although, when prolonged, as in status epilepticus 34, or recurrent, further efforts to control ASS with antiepileptic drugs (AED) should be put in place 35, 36. Indeed, although different in aetiology, it is well known that ASS increase the risk of posterior development of remote symptomatic seizures or epilepsy 37.

An unprovoked epileptic seizure has been accepted as the most likely diagnosis

An initial assumption that the epileptic seizure is a FUES is most frequently based on the work-up performed in the ED which should include the clinical history, general and neurological examination, blood tests and imaging, most frequently brain CT. An acute EEG is seldom performed in this setting if the patient has fully recovered. Comprehensive further work-up should be performed in the setting of an outpatient epilepsy clinic, to be performed within two weeks 38 However, patients with abnormal imaging, prolonged or recurrent seizures or incomplete recovery may benefit from a brief admission for more urgent medical and neurological assessment 39.

Which elements of the clinical history and physical examination can aid in the diagnosis? Clinical history

Regarding generalized tonic-clonic seizures (GTCS) or the generalized phase of focal to bilateral tonic-clonic seizures, video analysis has identified a consistent pattern of five phases (onset, pre-tonic clonic, tonic, early clonic, clonic) with a mean duration of one minute 40. GTCS can be accompanied by other brief seizure types such as myoclonus (i.e. <one-second muscular jerk) or absence (typically <10 seconds of staring and unresponsiveness with retained postural tone) events 41. Focal-onset seizures are accompanied by retained or altered consciousness. The so called “auras” are focal seizures with retained consciousness of subjective sensations that cannot be seen by the outside observer. The patient experiences a sensation related to the area of cortex involved. Some patients may even have had these events before but not given them a second thought. Temporal lobe auras may include an epigastric rising sensation, unpleasant olfactory sensation, palpitations or complex psychic manifestations such as déja-vu or jamais vu, fear, elation or autoscopy. Occipital and parietal lobe auras can be characterized by somatosensory (paresthetic, painful, thermal, disturbances of body image) or visual (amaroutic, elementary and complex hallucinations, illusions) 42 characteristics. Objective seizure manifestations can also occur, depending on the location of the cortex involved, and are usually the reason why patients seek help. These symptoms are part of the symptomatogenic zone 43 and do not necessarily indicate that the seizure arises from that region. These objective manifestations may include: focal clonic limb jerking, dystonic posturing, an explosive onset of hypermotor features, bilateral motor activity and likely nocturnal occurrence, sudden onset of lack of movement and unresponsiveness, and automatisms (i.e. repetitive behaviours that do not meaningful interact with the environment) such as swallowing, chewing, lip-smacking, and repetitive movements such as picking at clothing or objects, or more complex behaviours such as waking up, running and undressing. Symptoms that follow a seizure can be equally important, namely disorientation, anterograde amnesia, transient somnolence or fatigue and sore limb muscles. Post-ictal aphasia or hemiparesis should also be sought during history taking, since these are helpful towards the diagnosis of a (focal) seizure and may not be present during the physical examination. These and other objective manifestations can have some lateralizing and localizing value but such a detailed discussion is beyond the scope of this paper 44, 45.

Physical examination

Physical examination is unremarkable in most patients with FUES. However, some findings may provide clues as to the aetiology of the epileptic seizure (table 4).

Table 4. Physical examination findings and their potential significance in first-seizure patients (adapted from ). System Finding Potential significance Cutaneous Café au lait spots, axillary or inguinal freckling, cutaneous neurofibroma Neurofibromatosis Hypomelanotic macules, shagreen patches, subungueal fibromas, adenoma sebaceum Tuberous sclerosis Facial capillary haemangiomata (“port wine stain”) Sturge-Weber syndrome Skin and mucosal telangiectasias Hereditary haemorrhagic Telangiectasia Macular hypopigmented whorls or patches Hypomelanosis of Ito Nervous system Focal neurological deficits (motor, sensory, visual) Structural cerebral lesions as cause of seizure Limb hemiatrophy In utero or paediatric cerebral insult as cause of seizure Epilepsy is currently defined as a brain disturbance including any of the following:

(1) at least two unprovoked, or reflex seizures occurring more than 24 hours apart;

(2) one unprovoked, or reflex seizure with a risk of further seizures similar to that of recurrence typically after two unprovoked seizures (at least 60%), occurring over the next 10 years;

(3) and diagnosis of an epilepsy syndrome 46. For the second point, for a lesion that is believed to generate an enduring predisposition for unprovoked seizures, the patient is considered to have epilepsy.

In this setting, aetiology of the epilepsy and seizure type(s) should be determined as accurately as possible. The decision to treat or not to treat, the choice of the most appropriate AED for a given patient, treatment duration, and prognosis are all important topics that must be considered and discussed with the patient/relatives (table 5).

Table 5. What must be discussed with the patient/relatives at the time of diagnosis of a FUES. The decision to treat/or not to treat with AEDs, taking the wishes of the patient/relatives into account Medication (including decision to treat, role of medication, side effects, expected treatment duration, relapse rate) Seizure first-aid Purpose of tests and procedures (including blood tests, EEG, brain imaging studies) Lifestyle considerations (including sleep deprivation, alcohol, bathing, work-related activities) Driving constraints Counselling about sudden unexplained death in epilepsy (SUDEP) Psychological issues (including stigma, psychiatric comorbidity) The role of EEG in the management of a FUES

EEG is the gold standard for identifying different biomarkers of epileptogenesis and ictogenesis. In fact, EEG is an essential neurophysiological examination in the evaluation of patients with epileptic seizures, status epilepticus and/or epilepsy, both for diagnosis and classification, as well as for prognostication and establishment of an appropriate management plan 38.

Why request an EEG after a FUES? To aid diagnosis

Although EEG is frequently used as a tool to help clinical diagnosis, the sensitivity reported for EEG as a diagnostic test for epilepsy ranges from only 26% to 56% 38. Different clinical recommendations state that an EEG should be performed only to support a diagnosis of epilepsy when the clinical history suggests that the neurological event is likely to be epileptic. It should not be used to exclude the diagnosis of an epileptic seizure when the clinical presentation supports a non-epileptic event 19, 38. Therefore, whenever in doubt about the epileptic nature of a transitory neurological event, referral to a specialized epilepsy centre is of paramount importance 38. A normal EEG does not exclude the diagnosis of epilepsy.

Although the general predictive value of EEG for diagnosis is low, EEG should be requested after an epileptic seizure, especially in young people, to aid syndromic classification 19. The presence of a specific type and the location of epileptiform activity will enable the diagnosis of an epileptic syndrome, and thus a diagnosis of epilepsy (even after only one epileptic seizure) 47. Additionally, the presence of a photoparoxysmal response on EEG implies important daily-life recommendations 19.

To evaluate the risk of recurrence

The EEG demonstrates predictive value in determining the risk of seizure recurrence with Class 1 evidence 48. Unequivocal epileptiform activity shown on EEG can be used to assess the risk of a FUES 38, estimated on average in 51% cases 49. In fact, seizure aetiology and EEG are the strongest recurrence predictors and can be used to distinguish patient subgroups with risks as low as 24% and as high as 65% 49 or more. The finding of epileptic discharges has been associated with a risk of recurrence of 83% (95% confidence interval [CI]: 69-97%) vs 41% (95% CI: 29-53%) in patients with non-epileptic abnormalities 50. Antiepileptic drug treatment after a first seizure should therefore be recommended in cases with unequivocal epileptic discharges on EEG 19.

To ascertain the self-limited nature of a seizure

Another indication for EEG after an epileptic seizure is to ensure that it was in fact a self-limited event. This is of utmost importance in patients with previous neurological structural lesions, and consequently neurological deficits, for whom neurological examination cannot confidently assure that the patient will return to his previous neurological status. Furthermore, in patients with an apparently increased post-seizure deficit (such as aphasia or hemiparesis), EEG will help to distinguish between the presence of persistent epileptic activity and a post-ictal deficit.

When should EEG be performed?

Although EEG is available in most hospitals, it is not available in the majority of EDs (not even in some epilepsy outpatient clinics). As such, a broad spectrum of possible critical decisions regarding EEG request and patient management must be taken by the clinician facing a first-seizure patient.

After a few days or weeks

In the case of a self-limited FUES, there are recommendations for performing an EEG soon after the event 38. According to NICE Guidelines, ‘soon’ means within four weeks. In fact, the likelihood of finding epileptiform activity on EEG seems to decrease over time after a paroxysmal event 51, but can be increased by recordings during sleep or following sleep deprivation 52-54. Therefore, when a standard EEG has not contributed to diagnosis or classification after a FUES, a sleep EEG should be performed 38. Repeat EEG can also be useful when the diagnosis of epilepsy is not clear 38, 55, 56. Furthermore, as discussed, an EEG carried out within the first few weeks after a first epileptic seizure carries prognostic value, as patients with epileptiform abnormalities are more likely to have a second epileptic seizure 50.

After a few days or weeks under antiepileptic medication

As mentioned above, in certain cases, epilepsy diagnosis can be made after a FUES, including a reflex epileptic seizure (or reflex) 47. Although the chance of recurrence is unknown for the majority of seizure aetiologies, evidence suggests an elevated risk in the case of post-stroke unprovoked seizures occurring at least one month after a stroke 33. Therefore, after an unprovoked post-stroke epileptic seizure, AEDs should be prescribed immediately in the ED along with postponement of EEG based on the risk of recurrence.

Immediately in the ED

Prompt recognition of specific EEG patterns can justify immediate and appropriate therapeutic decisions, leading to rapid resolution of the clinical picture 57.

When a patient has not returned to his/her previous neurological state, due to either the persistence of altered mental status (including confusion, lethargy, memory disturbances and even coma), subtle involuntary movements (myoclonus and unusual behaviour, anxiety, agitation, delirium and hallucination) or apparent persistent neurological deficits (e.g. speech disturbance, paresis), non-convulsive status epilepticus (NCSE) 58 should be suspected. Patients who present with “de novo” status epilepticus present unique challenges in therapeutic management 61, and in these cases, EEG is mandatory 59, 60 for diagnosis. The discussion on NCSE is, however, beyond the scope of this paper.

Which investigations should be performed in a patient with a FUES? Laboratory testing

Laboratory testing is indicated to identify not only causes of ASS, but also systemic comorbidities affecting both diagnostic testing and the choice and dosing of antiepileptic drug therapy. In women of childbearing age, a pregnancy test is recommended, since pregnancy may affect testing and initiation of antiepileptic drug therapy 24.

Neuroimaging

At this point, head CT performed in the ED might have already identified a remote symptomatic cause, such as stroke, trauma or infection, associated with a 10-year recurrence risk of over 60% 28, meeting the criteria for epilepsy 47. If the topography of the lesion is congruent with seizure semiology, it is our opinion that further neuroimaging is not essential in the setting of a first epileptic seizure.

When head CT is non-contributory, MRI is indicated. The sensitivity of MRI is much higher than that of CT for a variety of pathologies causing epilepsy, including infarcts, tumours, mesial temporal sclerosis, and cortical malformations, and is the modality of choice in the outpatient setting, where it is fundamental for the diagnostic assessment of a patient with a first epileptic seizure 15, 27, 31. In one study, 23% of patients who underwent MRI at the time or soon after a first epileptic seizure had a potentially epileptogenic lesion 62. The American Academy of Neurology recommends neuroimaging, preferably MRI, as one of the eight epilepsy measures for all patients with epilepsy, with the exception of confident diagnoses of idiopathic generalized epilepsy syndromes that are known to lack neuroimaging abnormalities 63. In the latter case, neuroimaging should not be routinely requested 15, 19, 31. The ILAE Neuroimaging Task Force also recommends MRI soon after the first seizure, with the same exception for genetic generalized syndromes 64. An epilepsy protocol should be used based on the ILAE recommendations for the use of the Harmonized Neuroimaging of Epilepsy Structural Sequences (HARNESS-MRI) protocol in order to standardize neuroimaging of epilepsy 64.

Additional testing in select cases

Though most metabolic diseases begin in childhood, some, including porphyria and urea cycle disorders, can appear in adulthood. In the appropriate clinical setting, urine porphobilinogen and porphyrins may be assessed for porphyria, or serum ammonia and urine organic acids for urea cycle defects. If there is clinical suspicion of an autoimmune encephalitis, such as cognitive and psychiatric deterioration that develops contemporaneou