What are acute symptomatic seizures?

Acute symptomatic seizures occur at the time of a systemic insult or in close temporal association with a brain insult (such as trauma, infection, or stroke)

GENERAL NEUROLOGY

Acute symptomatic seizures

David Goldemund M.D.
Updated on 25/06/2024, published on 20/05/2024

a seizure is defined as a transient occurrence of signs and/or symptoms resulting from abnormal synchronous (epileptic) neuronal activity in the brain
- seizures can affect behavior, movement, sensation, and levels of consciousness
acute symptomatic seizures (ASS) occur in close temporal association with an acute cerebral insult or disturbance and account for about 40% of first seizure episodes
- the time frame for ASS is typically within 7-10 (14) days of the event (such as stroke, traumatic brain injury, metabolic disorder, or infection)
- unlike epilepsy, which involves recurrent seizures with no apparent immediate cause, ASSs are directly related to the transient disturbance caused by the acute condition

the risk of ASS is influenced by the nature and location of the cerebral disorder, as well as other factors (genetics, age, comorbidities)
continuous EEG (cEEG) can be used to predict the occurrence of symptomatic seizures (2HELPS2B)
ASSs do not include:
- seizures triggered by specific stimuli (e.g., visual), which are common in patients with epilepsy
- seizures triggered by sleep deprivation (sleep deprivation is not an independent trigger for the development of ASSs)

What is the difference between acute symptomatic seizure and epilepsy?

Acute symptomatic seizures are directly related to an acute insult or condition, while epilepsy is a chronic disorder characterized by recurrent unprovoked seizures

Etiology

Structural brain lesions
stroke (25-30%) ischemic stroke, ICH, venous sinus thrombosis, SAH head trauma (15%) neurosurgical operations tumors
Toxic-metabolic disorders
hypo- Ca, Mg, Na alkalosis hypoglycemia, hyperglycemia (nonketotic and with ketoacidosis) hyperammonemia uremia, hemodialysis alcohol abuse drugs (cocaine, amphetamines, cannabinoids) medications related to use (see below) related to withdrawal (barbiturates, benzodiazepines)

Inflammation
brain abscess herpetic encephalitis meningitis HIV-related encephalopathy
Others
CO intoxication hypoxic encephalopathy hypertensive encephalopathy, eclampsia pyridoxine deficiency hypo- and hyperthyroidism

Ischemic stroke

according to various sources, 25-60% of all ASSs
- 50-70% of ASSs occur in the first 48 hours after the onset of stroke
more common in patients with bleeding and dural sinus thrombosis
especially in hemorrhage, continuous EEG monitoring is recommended in the acute stage → significantly higher detection rate of clinically unrecognized seizures and NCSE
ASS risk increases with more extensive lesions and cortical involvement; in SAH, a relationship with the amount of blood in the basal cisterns has been described
prophylactic administration of anti-seizure medication (ASM) is not recommended (AHA/ASA 2019 III/C-LD)

Traumatic brain injury (TBI)

continuous EEG monitoring shows a higher incidence of ASS (mainly non-convulsive) in moderate to severe TBI
most seizures occur within 24 hours after injury
the risk of ASS or epilepsy depends on the severity of the injury and is higher in hemorrhage (SDH, EDH, or parenchymal – 7-10%), as well as in impressive calvary fractures and contusion injuries

Metabolic disorders

laboratory abnormalities occur in temporal relationship with seizures; both the absolute value and the speed at which the disorder develops play important roles
uremia or electrolyte imbalance may play a role in renal failure; seizures occur in hemodialysis patients due to:
- uremic encephalopathy
- dysequilibration syndrome
- hypocalcemia
- hypoglycemia
- hyponatremia
ASSs are uncommon in hepatic failure and are related to hyperammonemia
ASSs occur in patients with hyponatremia, hypomagnesemia, and hypocalcemia

hypoglycemia	glucose < 2,0 mmol/l
hyperglycemia with ketoacidosis	glucose > 25 mmol/l
hypomagnesemia	Mg < 0,3 mmol/l
hypocalcemia	Ca²⁺ < 1,2 mmol/l
hyponatremia	Na < 115 mmol/l
renal failure	urea > 35.7 mmol/l creatinine > 884 umol/l

Neuroinfection

high risk of ASS and epilepsy is associated with brain abscess and herpetic encephalitis

Toxic substances

alcohol
- ASSs are most commonly associated with withdrawal syndrome (in regular consumption > 5 g/day) (⇒ Alcohol Withdrawal Seizure – AWS)
- seizures occur between 7-48 hours, often in combination with delirium
- clustered seizures or even ASSE may occur
- in chronic alcoholics, it is necessary to rule out concurrent metabolic disorders (hypoglycemia, hyponatremia, etc.) and consider structural brain lesions (hemorrhage, trauma, etc.)
medications
- dose-dependent effect, often due to intoxication (intentional or unintentional)
- higher risk associated with polypharmacy and more common in older patients
- ASS and SE can also occur during drug withdrawal (barbiturates, benzodiazepines, opioids, baclofen, vigabatrin)
drugs (cocaine, amphetamines, cannabinoids)

Drugs with the risk of developing ASS when used in therapeutic dose
neuroleptics	phenothiazines (chlorpromazine), haloperidol, clozapine
antidepressants	tricyclics, maprotiline, clomipramine, SNRIs (venlafaxine), SSRIs (fluoxetine, sertraline)
antibiotics	beta-lactams (penicillins), fluoroquinolones, metronidazole
analgesics	meperidine and normeperidine, tramadol, fentanyl and sufentanil, morphine intrathecally
anesthetics	sevoflurane, propofol
cytostatics	5-fluorouracil, busulfan, chlorambucil, methotrexate
antiasthmatics	theophylline
immunosuppressants	cyclosporine
antihistamines	diphenhydramine
muscle relaxants	baclofen
antiulcer drugs	cimetidine

Clinical presentation

semiology of seizure (see ILAE classification for more information)
- focal seizures with/without impaired consciousness (motor or non-motor onset)
  - focal impaired awareness seizures – FIAS (previously complex partial seizures)
  - focal aware seizures – FAS (previously called simplex partial seizures)
- focal to bilateral tonic-clonic seizures (FBTCS) (previously secondary generalized seizure)
- generalized seizures (motor x non-motor)
- unknown onset (motor x non-motor)
number of seizures:
- isolated seizure
- cluster of seizures
- acute symptomatic status epilepticus (ASSE)

ILAE classification of seizures

Abbreviations for the most important seizure types

Management

Detection and elimination of provoking causes

causal treatment of seizures – correction of metabolic disorders, management of intoxication, withdrawal of inappropriate medication, etc.

Antiseizure medication (ASM)

there are no clear recommendations based on trials for choosing ASMs for short-term treatment of ASSs
the most commonly used drugs are diazepam or clonazepam, levetiracetam, valproate, phenytoin, lacosamide
- clonazepam is preferred for focal seizures
for treatment of status epilepticus, follow local protocols
short-term preventive treatment may be considered in selected patients

Management of seizure clusters

administer intravenous anticonvulsants
- Establish intravenous (IV) access via cubital or jugular vein
rectal or intramuscular diazepam can be used as initial therapy

1^st line therapy: diazepam, midazolam
2^nd line therapy:
- focal seizures: clonazepam, lacosamide
- generalized seizures: levetiracetam, valproate, lacosamide, phenytoin

Levetiracetam

Parameter	Details
Initial dosing (PO)	start with 500 mg twice daily can be rapidly titrated up; typical increments are 500 mg every 1-2 days, depending on seizure control and tolerability
Initial dosing (IV)	20-30 mg/kg + 100 mL of NS infused over 15 minutes (< 150 mg/minute) SE: 30-60 mg/kg + 100 mL of NS infused over 10 minutes
Maintenance dose	500-1500 mg twice daily, adjusted based on response, tolerance, and renal function
Notes	adjust dose for renal impairment monitor for psychiatric symptoms such as depression or agitation
Main contraindications	hypersensitivity to levetiracetam or any component of the formulation

Phenytoin

Parameter	Details
Initial dosing (PO)	slow titration of 100 mg per week
Initial dosing (IV)	250 mg over 5 minutes, which can be repeated to a total dose of 750-1000 mg (especially in repeated seizures) SE: 15 mg/kg, administered at a rate < 50 mg/min, followed by 100mg every 6 hours
Maintenance dose	typically 300 mg/day (max dose 500mg/d) in adults divided into 2-3 doses
Notes	monitor for hypotension and arrhythmias during IV administration
Contraindications	sinus bradycardia, sinoatrial block, second-and third-degree AV block hypersensitivity to phenytoin

Valproate

Parameter	Details
Initial dosing (PO)	start with 400-600 mg, divided into 2 doses
Initial dosing (IV)	repeated seizures: bolus 10-15 mg/kg, administered over 5 minutes, followed by infusion SE: bolus 30 mg/kg, administered over 10 minutes (3-6 mg/kg/min), followed by infusion follow-up infusion: 1-2 mg/kg /h 1200 mg+50 ml NS (1mL=24mg) IV 0.042-0.083 mL/kg/h (1-2 mg/kg/h)
Maintenance dose	usual daily dose: 1000-2000 mg, divided into 2-3 doses, adjusted based on clinical response and tolerance target VPA levels: 300-700 µmol/L / 50-100 µg/mL
Notes	monitor liver function, blood counts, and serum ammonia levels be cautious of potential teratogenic effects
Contraindications	significant hepatic dysfunction urea cycle disorders porphyria hypersensitivity to valproate

Lacosamide

Parameter	Details
Initial Dosing (PO)	start with 50 mg twice daily
Initial Dosing (IV)	200 mg +100 mL NS infused over 20-40 minutes SE: 200-400 mg loading dose over 3-5 minutes, followed by a maintenance dose of 100 mg every 12 hours (then switch to PO)
Maintenance dose	100-200 mg twice daily, adjusted based on response and tolerance
Notes	monitor for PR interval prolongation; use caution in patients with cardiac conduction abnormalities adjust dose for renal and hepatic impairment (half dose for ClCr≤30 mL/min) monitor for dizziness, ataxia
Contraindications	hypersensitivity to lacosamide or any component of the formulation second- or third-degree AV block without an artificial pacemaker

Carbamazepine

Parameter	Details
Initial Dosing (PO)	start with 100-200 mg twice daily
Maintenance dose	800-1200 mg/day divided into 2 doses; adjust dose based on response and tolerance
Notes	monitor for blood dyscrasias, liver function, and dermatological reactions (such as signs of Stevens-Johnson syndrome) may cause dizziness and nausea
Contraindications	hypersensitivity to carbamazepine history of bone marrow depression use of MAO inhibitors within the last 14 days

Clonazepam

Parameter	Details
Initial Dosing (PO)	start with 0.5 mg twice daily
Dosing (IV)	1mg + 5 mL NS bolus injection over 5 minutes (max speed 0.25-0.5 mg/min) 1mg + 100 mL NS infusion over 5-10 minutes continuous infusion – 5mg/20mL NS (1ml=0.25 mg) 0-2 mL/h (0.25-0.5 mg/h) maximum daily dose is 10mg
Maintenance dose	1-4 mg/day in divided doses
Notes	titrate dose slowly to minimize sedation and dizziness; monitor for signs of dependency and withdrawal
Contraindications	significant liver disease, acute narrow-angle glaucoma, and hypersensitivity to clonazepam or benzodiazepines

Therapeutic levels of ASMs

*ASMs therapeutic levels* (values may differ in various labs)
carbamazepine (CBZ)	17-51 µmol/L (4-12 µg/mL) toxic level: >85 µmol/L (>20 µg/mL)
valproate (VPA)	350-700 µmol/L (50-100 µg/mL) toxic level: >1040 µmol/L (>150 µg/mL)
phenytoin (PHE)	40-80 µmol/L (10-20 µg/mL) toxic levels: >120 µmol/L (>30 µg/mL)
lamotrigine (LTG)	10-60 µmol/L (3-14 µg/mL) toxic levels: >70 µmol/L (>18 µg/mL)
levetiracetam (LEV)	35-217 µmol/L (5-25 µg/mL)
topiramate (TPM)	10-50 µmol/L (2-10 µg/mL)
lacosamide (LCM)	10-60 µmol/L (2.5-15 µg/mL)

Indications for a long-term prophylactic anticonvulsant therapy

An isolated seizures, the cause has resolved (e.g., hyper/hypoglycemia, hyponatremia)

low risk of recurrence (<3%), ASM is not indicated

An isolated seizure or multiple seizures, the cause persists (severe stroke, TBI)

increased risk of recurrent seizures that could endanger the patient in the acute stage (progression of intracranial hypertension, risk of rebleeding in SAH, etc.)
short-term antiepileptic treatment is indicated (weeks to months); duration is influenced by imaging findings and EEG
If high-risk cause persists (e.g., uremia in CKD), long-term ASM can be given

An initial cluster of ASS or ASSE

with complete resolution of the cause, short-term ASM can be advised (<7 days)
with persistent cause (severe stroke, TBI), long-term ASM is recommended (months)

Two or more seizures with at least one seizure occurring > 14 days post-insult ⇒ epilepsy

long-term ASM medication is indicated

Prognosis

the risk of transition from symptomatic seizures to unprovoked seizures (epilepsy) depends on the following:
- the cause, extent, and location of lesions
  - increased risk is associated with, e.g., parenchymal hemorrhage, presence of malformations, cortical, larger ischaemic lesions, etc.
- comorbidities (e.g., previous insults, chronic metabolic conditions)
  - premorbid and postmorbid conditions may play a role in the pathogenesis of stroke-related epilepsy (STRE)
  - the term primary STRE can be used only if no such significant condition is detected
prognostic tools to detect an increased risk of STRE:
- SeLECT score – its usefulness is debated [Finsterer, 2018]
focal seizures (especially with Todd’s hemiparesis) may pose a diagnostic challenge (Is it a new stroke or seizure? Should we initiate thrombolysis?)
in the case of recurrent, uniform attacks that occur despite effective secondary prevention, a therapeutic trial with ASMs is appropriate

→ Stroke-related epilepsy (STRE)