What is the seizure threshold?

What is Seizure Threshold?

Seizure threshold is the minimum amount of electrical or chemical stimulation required to trigger abnormal, excessive, synchronous neuronal activity in the brain that manifests as a seizure. 1

Core Concept

Seizure threshold represents the brain's resistance to seizure activity—a higher threshold means greater resistance, while a lower threshold means increased vulnerability to seizures from various triggers. 1 This is fundamentally a measure of the balance between neuronal excitation and inhibition in the brain. 2

Clinical Measurement and Variability

In electroconvulsive therapy (ECT), seizure threshold is operationally defined as the minimal electrical dosage (measured in millicoulombs or charge) necessary to elicit an adequate generalized seizure. 3, 4

Seizure threshold varies dramatically between individuals—up to 6-fold variation exists across patients. 3 This wide variability is influenced by multiple factors:

Patient-Specific Factors That Increase Threshold:

• Age: Threshold increases with advancing age 3
• Male sex: Men have higher thresholds than women 3
• Bilateral electrode placement (in ECT context): Associated with higher thresholds compared to unilateral 3

Patient-Specific Factors That Decrease Threshold:

• Younger age: Adolescents characteristically have lower seizure thresholds than adults 5, 1
• Genetic conditions: Patients with 22q11.2 deletion syndrome have constitutionally lowered thresholds with 4-fold increased epilepsy risk 1
• Brain structural abnormalities: Stroke, cortical malformations, focal cortical compression, or blood-brain barrier dysfunction all lower threshold 1, 2
• Metabolic disturbances: Hypocalcemia, hypomagnesemia, and fever can provoke seizures by lowering threshold 1

Medications and Seizure Threshold

Many psychotropic medications lower seizure threshold in a dose-dependent manner. 6 The general population has a baseline first unprovoked seizure incidence of 0.07-0.09%, but this rises to 0.1-1.5% in patients on therapeutic doses of most antidepressants and antipsychotics. 6

High-Risk Medications (Lower Threshold Significantly):

• Antidepressants: Maprotiline and clomipramine 6
• Antipsychotics: Chlorpromazine and clozapine 6
• Tramadol: Explicitly lowers threshold through dual mechanism, with risk amplified when combined with SSRIs 1
• Theophylline: Prolongs seizure duration at both therapeutic and toxic levels 1
• Trazodone: Associated with prolonged seizures during ECT 1

Lower-Risk Medications:

• Antidepressants: Phenelzine, tranylcypromine, fluoxetine, paroxetine, sertraline, venlafaxine 6
• Antipsychotics: Fluphenazine, haloperidol, pimozide, risperidone 6

Neuroleptic medication use is associated with lower seizure thresholds. 3

Relationship to Seizure Duration

An inverse relationship exists between seizure threshold and seizure duration—patients with high thresholds have shorter seizure durations, while those with low thresholds have longer seizures. 3, 4 This indicates that seizure threshold measurement assesses functional neural activity. 4

For adequate therapeutic effect in ECT, an EEG seizure lasting 30-90 seconds is required. 5 The electrical dose should be moderately above threshold to minimize cognitive impact while maintaining efficacy. 5

Clinical Implications for Management

Risk Stratification:

Cumulative risk is often underestimated—a patient on an SSRI who is then prescribed tramadol faces compounded seizure risk from both medications. 1 This represents a critical pitfall in prescribing.

Dosing Strategies for At-Risk Patients:

• Use "start low, go slow" approach when prescribing threshold-lowering medications 1
• Consider prophylactic anticonvulsant medication when using high-risk drugs like clozapine in vulnerable patients 1
• Avoid tramadol completely in patients with seizure history 1
• Adjust for organ dysfunction (tramadol bioavailability increases 2-3 fold in liver disease, with maximum dose of 50mg per 12 hours in cirrhosis) 1

Monitoring and Correction:

• Monitor and correct metabolic triggers such as hypocalcemia and hypomagnesemia 1
• Counsel patients to avoid lifestyle factors that further reduce threshold, including caffeine excess and alcohol withdrawal 1

Threshold Changes Over Time

In ECT treatment, failure for seizure threshold to increase substantially over the course of treatment is associated with poor clinical outcome. 4 This suggests that threshold dynamics reflect therapeutic response and functional neural changes. 4

Sustained focal cortical compression significantly lowers seizure threshold, suggesting that localized injury can alter global brain excitability. 2