Introduction

Early seizures occur in up to one in five patients with moderate-severe traumatic brain injury (TBI). To reduce this risk, most centres prescribe a short course of antiseizure medication (ASM). Levetiracetam (Keppra) has become the agent of choice, owing to its ease of use, lack of drug-drug interactions, and availability in both IV and oral forms.

Guidelines from the Brain Trauma Foundation, Neurocritical Care Society and others are broadly aligned: prophylaxis may reduce seizures in the first seven days but does not prevent late post-traumatic epilepsy. In practice, however, levetiracetam is often continued well beyond this window. UK data is limited, but international cohorts suggest that 38-39% of TBI inpatients are prescribed ASMs (most commonly levetiracetam), frequently carried forward through rehabilitation. In one series, only 13.9% of mild TBI cases adhered to the ≤7-day recommendation, meaning more than four out of five were treated longer. This points to a clear pattern: prolonged levetiracetam use is common and rarely aligned with guideline standards.

Why is it continued?

Partly inertia, partly caution. Commonly, clinicians will continue “just in case.” Yet the evidence for benefit falls away after the first week, as the patient begins their rehabilitation journey.

Neuropsychiatric profile in context

Irritability, aggression, depression, anxiety, and even psychosis are well-documented adverse effects of levetiracetam. Behavioural complaints occur in approximately 13% of adults. In children, aggression and agitation are reported in 1-2% of cases. Across all groups, behavioural adverse events may affect up to one in five patients, with discontinuation rates of around 18%. These effects are prominent enough to have earned their own label: “Keppra rage.”

The difficulty in TBI is that these same problems – anger, impulsivity, affective lability, fatigue, depression – are already part of the natural history of recovery. A patient who becomes irritable or withdrawn on levetiracetam may be assumed to be “just behaving like a TBI patient.” Conversely, clinicians may blame the drug for what is in fact the underlying injury. Attribution becomes extremely difficult, complicated because the drug is commonly introduced during the time of sedation or anaesthesia, so the temporal relationship to neuropsychiatric effects is masked.

Case series highlight fatigue and somnolence as particularly common on levetiracetam in TBI populations, around 15% in mixed-age cohorts, and up to 85% in a paediatric group. A minority of adults discontinued the drug due to sedation. In rehabilitation settings, fatigue, irritability, or disturbed sleep can reduce therapy engagement.

Where levetiracetam is continued, clinicians should recognise that its side-effect profile and TBI symptomatology are not merely overlapping but potentially additive. Fatigue may become disabling, irritability may escalate into aggression, and depressive symptoms may deepen. Even if each effect is modest in isolation, together they can tip patients into clinically significant dysfunction. This “double burden” underscores the need for regular review of whether levetiracetam is helping or hindering recovery.

Alternatives and comparisons

Other ASMs offer limited alternatives. Phenytoin and carbamazepine are cognitively dulling; valproate has mood-stabilising benefits but serious metabolic and teratogenic risks; lamotrigine is mood-friendly but too slow to titrate for acute prophylaxis. Lacosamide may be emerging as a gentler option, though comparative data in TBI remain sparse.

Clinical and medico-legal considerations

The medico-legal dimension is straightforward: extending levetiracetam beyond guideline-backed windows requires a defensible rationale, recorded clearly in the notes. If mood or behavioural changes emerge, documentation should show whether these were considered drug-related, injury-related, or both, and what steps were taken in response.

Looking forward

There is an urgent need for trials comparing longer-term levetiracetam with other ASMs (or placebo) in patients at high risk of late epilepsy. Until such evidence emerges, the most prudent course is to follow existing guidance: limit prophylaxis to seven days.

Ultimately, the challenge lies in balancing seizure prevention with the risk of compounding neuropsychiatric symptoms. A careful, time-limited approach, combined with regular review, remains the most evidence-based and patient-centred course for now.

In managing any patient in their rehab journey, if they remain on levetiracetam, obtain a clinical review as to its clinical indication and whether it can be withdrawn.

References

1. Brain Trauma Foundation (BTF)
2. Brain Trauma Foundation, American Association of Neurological Surgeons, Congress of Neurological Surgeons. Guidelines for the management of severe traumatic brain injury, 3rd edition. J Neurotrauma. 2007;24 Suppl 1:S1-106.
3. American Academy of Neurology (AAN) Practice Parameter

Chang BS, Lowenstein DH. Practice parameter: antiepileptic drug prophylaxis in severe traumatic brain injury. Neurology. 2003;60(1):10-6.

1. Neurocritical Care Society (NCS) 2024 Clinical Practice Guideline

Frontera JA, Gilmore EJ, Johnson EL, et al. Guidelines for seizure prophylaxis in adults hospitalised with moderate–severe traumatic brain injury: a clinical practice guideline from the Neurocritical Care Society. Neurocrit Care. 2024;40:819-44.

1. NICE (UK) – Head Injury

National Institute for Health and Care Excellence (NICE). Head injury: assessment and early management. NICE guideline [NG232]. 2023.Lee HT, Liao FF, Kung SS, Hwang SJ, Hsieh KP. Trends of anti-seizure medication prescribing pattern in traumatic brain injury patients for the prevention of post-traumatic seizure in Taiwan. Epilepsy Behav Rep. 2024;26:100662.

1. Zhang JF, Piryani R, Swayampakula AK, Farooq O. Levetiracetam-induced aggression and acute behavioural changes: a case report and literature review. Clin Case Rep. 2022;10(3):e05586.

Benge JF, Phenis RA, Bernett A, Cruz-Laureano D, Kirmani BF. Neurobehavioral effects of levetiracetam in patients with traumatic brain injury. Front Neurol. 2013;4:195.