Seizure (First Episode)

Overview

• Seizures occur from abnormal, excessive and synchronous neuronal activity in the brain 1, 2

• Depending on the area(s) of the brain involved, seizures may consist of loss of awareness with body shaking, confusion, difficulty responding, headache, tongue biting, visual or other sensory symptoms, posturing or jerking of a single limb, or brief loss of awareness, postictal confusion or psychosis 1, 3

• In a patient presenting with a first seizure, it is important to determine if the seizure was provoked (an acute symptomatic seizure) or unprovoked. This will aid further investigation and treatment decisions.

• Provoking factors include: 1, 4

• Unprovoked seizures are those of unknown aetiology (“idiopathic”) as well as those that occur in relation to a pre-existing brain lesion (e.g. malformations of cortical development and vascular malformations) or a progressive nervous system disorder (“remote symptomatic”) 5, 6

• A first unprovoked seizure may be the initial presentation of epilepsy. Epilepsy is defined as: 7

• Two or more unprovoked seizures occurring more than 24 hours apart; or

• One unprovoked seizure with a high recurrence risk (> 60% over the next 10 years); or

• A diagnosis of an epilepsy syndrome

• Examples of seizures that occur with no imaging findings include reflex seizures, seizures related to systemic metabolic or toxic disturbances, and genetic generalised epilepsy syndromes that exist without structural brain abnormalities 8

• Studies on first-seizure presentations have found that a significant number of patients have had similar events in the past that have either been unrecognised by the patient, not brought to medical attention, misdiagnosed or unrecognised by the patient 8-10

• Seizures are classified as focal onset, generalised, or unknown onset 11

• Focal arise from a single cerebral hemisphere and can remain localized or spread to a larger distribution. They can have motor and nonmotor onset symptoms and may be characterized by the patient being aware or by having impaired awareness

• Generalised seizures affect both hemispheres. They can be subdivided into tonic-clonic, other motor, or nonmotor (absence) 

• Trauma-related induced seizures can be subdivided into acute (within 24 hours), immediate (within a week) and late seizures (at least one week after insult) 11

• Immediate seizures are thought to be related to the force of injury while late seizures are thought to be due to permanent changes to the brain

• Psychogenic nonepileptic seizures (PNES) can appear as a seizure.

• 20% of patients referred to epilepsy clinics may have PNES

• At least 10% of patients with PNES also had epileptic seizures 12

• Signs and symptoms that can point towards PNES are resistance to antiepileptic drugs, multiple seizures per day on multiple days, and comorbid mental disorders including depression and anxiety.

• Signs that point towards epileptic seizures include evidence of oral lacerations (such as on the lateral sides of the tongue), incontinence during the event, and defined postictal period following the event. Long-term EEG monitoring may be useful to further distinguish a PNES event with epilepsy 13

Diagnostic Workup

• A thorough clinical history and examination, laboratory investigations and an ECG should be performed 7, 14

• Appropriate blood tests can include electrolyte panel (including sodium), blood glucose, complete blood count, and calcium to identify any significant co-morbidity. Urine and blood biochemistry and arterial blood gas (pH and lactate) including screening for illicit drug use may be taken at the discretion of the specialist 15, 13

• Serum prolactin measurements are not recommended for diagnosis of a seizure 15

• Lumbar puncture is indicated in all patients if there is a clinical suspicion of central nervous system infection as a cause of seizures. Such symptoms can include: fever, change in consciousness, and or neck stiffness 16

• EEG can support the diagnosis and provide information about whether focal or generalised and has predictive value regarding the risk of a second seizure. An EEG can further elucidate the cause and provide prognostic information, support the diagnosis, and provide info on treatment 17

• Neuroimaging is recommended in all patients after a first seizure to look for an underlying tissue abnormality or structural lesion. Abnormalities such as haemorrhage, tumours, oedema, cerebral venous thrombosis, encephalitis, or stroke can be identified 1, 4, 5, 18, 19

• Both CT and MRI are useful, however uncertainty remains regarding which modality should be used and when imaging should be performed 14, 20-22. Most guidelines recommend routine imaging in the emergency department (ED). There is, however, some evidence indicating that  select patients who make a full neurological recovery and have no seizure recurrence in the ED can be discharged if prompt neuroimaging and specialist follow-up can be organised 22

• CT of the brain is used in most acute settings and is usually the primary imaging modality after a first seizure because it is relatively accessible and can rapidly rule out an intracranial haemorrhage or mass requiring urgent neurosurgical attention 5, 17, 23

• MRI is the preferred imaging modality but because it is not as readily available as CT, it is usually used in non-emergency situations and when the CT is negative or inconclusive. MRI demonstrates superior depiction of brain anatomy and tissue composition 5, 20, 23

• Patients who present following a first seizure who do not return to baseline neurological function within 30-60 minutes, who have an altered level of consciousness or unexplained focal neurological deficit or recurrent episodes will generally require admission to hospital for further investigation and management 17

• Patients who have had a single unprovoked seizure, who return to baseline neurological function and have no significant findings on clinical assessment, blood investigations or neuroimaging can often be discharged with follow-up in a first seizure clinic 24

• NICE recommends all patients should be referred to an epilepsy specialist when available and as soon as possible. Referrals should be urgent meaning that the patient should be seen within 2 weeks 15

• Although MRI is the preferred imaging modality for patients following a first seizure, CT is more readily available in an ED setting and is helpful to identify lesions that have precipitated the seizure and require urgent intervention 4, 21, 25, 26, 27

• Role of imaging can help elucidate the etiology of first unprovoked seizure when not clinically obvious, provide prognostic information, and allow diagnosis of epilepsy

• Non-contrast CT is good at detecting epileptogenic foci of gliosis/encephalomalacia secondary to prior stroke, trauma, infection, and most tumours that account for a significant proportion of unprovoked seizures in adults 5, 23

• CT is sensitive in detecting calcified and bony lesions 11

• A review of seven studies with a total of 1092 patients found that CT was abnormal in an average of 15% (range 1-57%) of patients presenting with an apparent unprovoked first seizure. CT was reported as significantly abnormal in 10% (range 1-47%) of patients. 20 This is consistent with previous studies that have found that emergency CT changes management in 1.8-17% of cases. 21 Abnormalities that changed management were traumatic brain injury, subdural haematomas, non-traumatic bleeding, cerebrovascular accidents, tumours and brain abscesses 28

• However, a systematic review of nine studies by the American Academy of Neurology found that abnormal neurologic examination, a predisposing history, or a focal seizure are predictive of an abnormal CT scan. 28 When there are no focal neurological signs on examination, only 6-10% of CT scans are abnormal 22

• Some experts have suggested that in patients who have fully recovered from their seizure without any of the above factors, deferring imaging is safe if urgent outpatient imaging can be secured and reliable follow up is available. This could allow development of a clinical division rule for selecting patients for emergency imaging (usually CT) and guiding others straight to early outpatient MRI 21

• This study also found that the use of IV contrast picked up findings in an extra 1.8% of patients. Potentially missed findings on non-contrast CT were vascular anomalies, leptomeningeal processes and tumours. They concluded that, with the exception of meningeal infection, little benefit is added by using contrast 21

• Patients with an abnormal CT brain are more likely to have a second seizure and are more likely to be commenced on antiepileptic medications 19

• American College of Emergency Physicians (ACEP) clinical policy and guidelines state that CT should be used in ED with first-seizure if intracranial pathology, suspected/presents with partial focal seizure, persistent altered mental status, headache, focal neurologic deficit, fever, coagulation disorder. If these variables are absent it may be reasonable to postpone imaging to outpatient 29

• FDG-PET/CT, fMRI, MEG, SPECT/CT do not have relevant literature regarding their use as an initial imaging study in the context of new-onset seizures that are unrelated to trauma 11

• MRI is the imaging investigation of choice for patients presenting following a first seizure and for evaluation of epilepsy as it can provide additional diagnostic and prognostic information over CT 23, 27

• However, MRI is often unavailable or difficult to arrange in an emergency setting. Performing MRI in patients with a first unprovoked seizure has become practice in many first seizure clinics, however, because of time delays this is not usually feasible in the ED setting 26, 30

• MRI is more sensitive than CT for detecting hippocampal sclerosis, focal cortical dysplasia, vascular malformations and some tumours. MRI detects  potentially epileptogenic lesions in approximately one quarter of patients 1, 14, 22, 31

• Epileptogenic lesions are structural lesions that causally or potentially are related to epilepsy. Examples of categories that may fall into this designation are: vascular anomalies, developmental abnormalities, gliosis and encephalomalacia, brain tumours, and mesial temporal sclerosis 31

• Therefore, patients who have a normal or inconclusive CT (this includes CT that shows an obvious lesion but requires better anatomical data) will generally require a follow-up MRI unless an established provoking factor is identified

• Ho et al. found that MRI detected a lesion in 1 of 8 patients and a tumour in 1 of 67 patients when CT was normal 23

• MRI should be performed under an epilepsy-appropriate protocol and ideally be evaluated by a neuroimaging specialist 7,9

• MRI protocol should be driven by clinical features of the event. Studies have shown that 3T scanners have been more sensitive for detecting a focal lesion compared to the 1.5T 32

• Ponnatapura et al. during their prospective study of 129 patients with new-onset seizures found that standard MRI protocol missed 37% of epileptogenic lesions versus a dedicated seizure MRI protocol 33. Arabi et al. prospective study echoed the importance of a dedicated MRI protocol for people 60 and older by detecting 67% of epileptogenic lesions vs 40% yield from head CT/low tesla brain MRI 34

• Published MRI protocols often include volumetric T1-weighted sequences for cortical malformations, coronal T2-weighted and T2-weighted FLAIR sequences angled orthogonally to hippocampi for mesial temporal sclerosis and other temporal lobe abnormalities 8

• Suggested MRI protocol includes: volumetric T1-weighted imaging (1 mm) with multiplanar reformations for assessment of cortical malformations; coronal T2-weighted images orthogonal to the hippocampi (< 3 mm) for assessment of mesial temporal sclerosis and temporal cephalocele; axial and coronal T2-weighted FLAIR images (< 3 mm) orthogonal to the hippocampi, this allows for the detection of hippocampal signal abnormalities, as well as cortical and subcortical abnormalities in cortical malformations. Volumetric T2-weighted FLAIR images (1mm) with multiplanar reformations can be used as an alternative, T2*-weighted images can be used to assess for calcification and haemorrhage, and DW images for the assessment of infarction or infection 8

• MRI can provide prognostic information and guide treatment as it can provide support that a seizure is focal in onset and thus guides the choice of anti-seizure medication 8, 15. When a lesion is seen on MRI, risk of seizure recurrence and further seizures after commencing treatment are higher 7, 26

• In patients with uncontrolled epilepsy being considered for surgery, high-resolution (3T) MRI is an essential part of pre-surgical evaluation, even when a CT scan reveals an epileptogenic lesion 11

• MRI investigation should be completed as soon as possible with the goal of having it complete within 4 weeks of first-seizure episode 15

• MRI may not be useful when the aetiology of seizure is clearly genetic generalized epilepsy 17, 12, 15

• IV contrast is not routinely used however it can be useful when images without contrast are not sufficient or malignant processes are hypothesized to be at fault 11

• Outpatient MRI can be scheduled when patient returns to baseline neurological status if follow-up can be ensured 13

• Although an emergency CT brain is recommended in most guidelines, some recent evidence and guidelines suggest that early outpatient neuroimaging may be considered in selected patients who have fully recovered from their first single seizure 21

• However, this should only be considered in centres with rapid access to outpatient neuroimaging and specialist follow-up

• Emergency neuroimaging should be performed in all patients who have: 21, 22

• New focal neurological signs

• Altered mental status persisting until ED assessment

• Fever

• Headache

• Recent head trauma

• History of malignancy or immunocompromised state

• Focal or partial seizure

• Anticoagulation/bleeding diatheses

• Previous stroke or transient ischemic attack

• Patients whose follow-up cannot be ensured

• Provoked seizures are also referred to as acute symptomatic seizures. Provoked seizures are less likely to have a recurrence in the absence of said provoking factors, including those related to acute CNS insults13

• Acute symptomatic seizures can be provoked by a number of CNS or systemic insults including: 1, 4, 16

• Sleep deprivation is thought to contribute to seizures, but seizures associated with sleep deprivation are not considered to be provoked. Lawn et al. investigated the influence of sleep deprivation in patients with a first unprovoked seizure compared to patients with first a provoked seizure and found that sleep deprivation was not an independent predictor of seizure recurrence. They concluded that seizures occurring in the context of sleep deprivation should not be considered provoked 35

• When an acute insult has been identified, further investigations and treatment will be guided by the cause

• Alcohol consumption (29.8%) and cerebrovascular disease (16.4%) have been found to be frequent causes of provoked seizures. 13, 36

• Unprovoked seizures can be of unknown aetiology (“idiopathic”) or which occur in relation to a pre-existing or progressive nervous system disorder (“remote symptomatic”)

• Unprovoked seizures are those of unknown aetiology as well as those that occur in relation to a pre-existing brain lesion (e.g. malformations of cortical development and vascular malformations) or a progressive nervous system disorder 5

• A first unprovoked seizure may be the initial presentation of epilepsy. Epilepsy is defined as 7:

• Two or more unprovoked seizures occurring more than 24 hours apart; or

• One unprovoked seizure with a high recurrence risk (> 60% over the next 10 years); or

• A diagnosis of an epilepsy syndrome

• Patients who have had a single unprovoked seizure, who return to baseline neurological function and have no significant findings on clinical assessment, blood investigations or neuroimaging can often be discharged with follow-up in a first seizure clinic. They will generally undergo further investigation with MRI +/- EEG depending on available resources

• A routine EEG consists of a 20-30 minute recording of brain activity by scalp electrodes 1

• A safe, non-invasive, inexpensive, bedside test of neurological function 2

• An EEG should be considered in all patients following a first seizure. (37, 38) Inter-ictal epileptiform discharges can 6, 7, 18, 20, 26.

• Help predict risk of seizure recurrence – an abnormal EEG carries a hazard ratio of ~ 1.5, with an overall risk of seizure recurrence within the first 2 years of 21-50%

• Classify seizures as focal or generalized and indicate a specific epilepsy syndrome

• Help guide therapy, such as the decision of treating (presence of epileptiform abnormalities) and which anti-seizure medication to use

• However, an EEG cannot rule out a seizure disorder and a normal EEG may be seen in up to 50% of patients with established epilepsy 1

• A review of 11 studies (total of 1766 patients) assessing the yield of EEG in adults presenting with an apparent unprovoked first seizure found that EEGs were reported as abnormal in 12 to 73% (average 51%) of patients and significantly abnormal in 8 to 50% (average 29%) of patients. In this review the abnormality considered as significant by authors was the presence of epileptiform activity in the form of spikes or sharp waves as interpreted by the local or reading electroencephalographer 20, 37

• Performing an EEG soon after a seizure has a higher sensitivity than performing a delayed EEG and some clinicians therefore recommend performing an EEG at time of presentation. 26 Previous studies have found that when performed within 24-48 hours of a first seizure, EEG shows substantial abnormalities in up to 70% of cases 18

• If routine EEG has not contributed to diagnosis/classification, sleep deprived EEG may be performed at the discretion of the treating specialist 15

• Prolonged Video-EEG is often used to classify seizures, assess psychogenic nonepileptic seizures (PNES), and evaluate of epilepsy surgery candidacy 38, 13

• Indications for video-EEG: evaluation of spells, seizure classification, seizure quantification, assessment of precipitating factors of seizure, surgical localization in drug-resistant focal epilepsy 38

• EEG should not be performed when in the case of probable syncope 15