Place in Therapy
A critical appraisal of the evidence base for levetiracetam — where it fits, where it does not, and the concept of Iatrogenic Refractory Epilepsy.
1. SANAD II Trial Findings
The SANAD II trial was a pragmatic, open-label, randomised controlled trial comparing lamotrigine, levetiracetam, and zonisamide as first-line monotherapy for newly diagnosed focal epilepsy. It is the most important head-to-head trial for levetiracetam in focal epilepsy.
Plain language: Patients prescribed levetiracetam were 32% more likely to fail to achieve 12-month seizure remission compared to those on lamotrigine. Levetiracetam also failed to meet the pre-specified non-inferiority criterion (HR limit: 1.329).
Clinical implication: For newly diagnosed focal epilepsy, lamotrigine should be the preferred first-line monotherapy over levetiracetam.
2. Generalised Epilepsy
For idiopathic generalised epilepsies, NICE guidelines list levetiracetam as one of three first-line options alongside lamotrigine and sodium valproate. However, the evidence base varies considerably by seizure type. Levetiracetam has the strongest evidence for juvenile myoclonic epilepsy (JME) and primary generalised tonic-clonic seizures, but is not recommended as first-line for absence epilepsy (where ethosuximide or valproate are preferred).
3. Reflex Prescribing
"Reflex prescribing refers to the practice of prescribing levetiracetam by habit or convenience — particularly in emergency settings — without adequately considering the patient's specific epilepsy type, comorbidities, psychiatric history, or drug interactions."
Levetiracetam's ease of use — no titration required, available intravenously, broad-spectrum activity, minimal drug interactions — has led to its widespread adoption as a default first choice. However, this convenience has come at a cost: the four critical questions that should precede any AED prescription are frequently not asked.
What is the epilepsy type?
Focal vs generalised vs unknown onset determines which drugs are appropriate. LEV is not superior for focal epilepsy (SANAD II).
Are there psychiatric comorbidities?
Pre-existing depression, anxiety, or personality disorder significantly increases the risk of neuropsychiatric adverse effects.
What is the patient's psychiatric history?
Prior psychosis, aggression, or suicidality are relative contraindications to levetiracetam.
Are there relevant drug interactions?
While LEV has few pharmacokinetic interactions, its pharmacodynamic interactions with other CNS-active drugs require consideration.
4. Iatrogenic Refractory Epilepsy (IRE)
Iatrogenic Refractory Epilepsy (IRE)
A condition in which apparent pharmacoresistance is caused by the prescription of an inappropriate first antiepileptic drug — not by intrinsic drug resistance of the epilepsy itself. IRE is preventable with correct initial drug selection.
The critical importance of first drug choice was established by Kwan and Brodie in their landmark 2000 NEJM study of 470 previously untreated patients. Of those who became seizure-free with the first drug, 47% achieved this outcome. After the first drug failed, only 11% achieved seizure freedom with a second drug. After two failures, the probability fell to just 4%.
False pharmacoresistance: Bašić et al. (2021) and Asadi-Pooya have documented that approximately 29% of patients referred to epilepsy centres with apparent drug-resistant epilepsy may have false pharmacoresistance — their epilepsy is not truly refractory, but appears so because they were placed on an inappropriate first drug. Correcting the drug choice can restore seizure control.
5. Status Epilepticus — ESETT Trial
The Established Status Epilepticus Treatment Trial (ESETT) was a double-blind, randomised trial comparing levetiracetam, valproate, and fosphenytoin in adults and children with benzodiazepine-refractory status epilepticus (Kapur et al., NEJM 2019; Chamberlain et al., The Lancet 2020).
No significant difference in seizure cessation between the three drugs (~50% response rate for each)
Despite this equivalence, levetiracetam has become the default choice in many emergency departments due to its ease of administration and perceived safety profile. The ESETT data do not support a preference for LEV over valproate or fosphenytoin in status epilepticus — yet reflex prescribing of LEV in this setting continues.
6. A Preventable Epidemic: 5 Clinician Action Points
Iatrogenic Refractory Epilepsy is preventable. These five evidence-based actions can reduce the risk of creating drug-resistant epilepsy through inappropriate prescribing.
- 1
Classify the epilepsy type before prescribing — focal, generalised, or unknown onset determines appropriate drug choice.
- 2
For focal epilepsy, prefer lamotrigine as first-line monotherapy (SANAD II, The Lancet 2021).
- 3
Screen for psychiatric comorbidities before prescribing levetiracetam — prior depression, anxiety, or psychosis are relative contraindications.
- 4
Counsel patients and families about the risk of neuropsychiatric adverse effects and establish a clear review plan.
- 5
If seizures fail to respond, consider whether the drug choice was appropriate before concluding the epilepsy is drug-resistant.