What treatment adjustments are recommended for a 31-year-old female patient with catamenial nocturnal epilepsy experiencing emotional instability while taking Keppra (levetiracetam)?

Management of Emotional Instability in a 31-Year-Old Female with Catamenial Nocturnal Epilepsy on Levetiracetam

If this patient is experiencing emotional instability on Keppra, you should strongly consider switching to an alternative antiepileptic drug, as behavioral and psychiatric side effects occur in up to 37.6% of patients and can include aggression, anxiety, depression, emotional lability, hostility, and irritability—effects that are well-documented and often require discontinuation. 1

Understanding Levetiracetam's Psychiatric Profile

Levetiracetam carries a significant burden of behavioral adverse effects that are particularly relevant in this clinical scenario:

• Behavioral symptoms occur in 13.3% of adult patients (compared to 6.2% on placebo), including aggression, agitation, anger, anxiety, apathy, depersonalization, depression, emotional lability, hostility, and irritability 1
• In pediatric patients, behavioral symptoms occur in 37.6% (compared to 18.6% on placebo), suggesting age-related vulnerability that may extend to young adult women 1
• Approximately 1.7% of patients discontinue treatment specifically due to behavioral events, and 0.8% require hospitalization for serious behavioral events 1
• Psychotic symptoms occur in 0.7% of patients, with cases developing within the first week of treatment 1
• Most behavioral problems occur within the first 4 weeks of treatment, though they can emerge later 1

Critical Context: Catamenial Epilepsy and Emotional Disorders

The intersection of catamenial epilepsy and emotional instability requires special consideration:

• Reproductive endocrine disorders in women with epilepsy are associated with higher rates of emotional disorders, independent of antiepileptic drug effects 2
• Regular monitoring of reproductive function is recommended, including assessment of menstrual disorders, weight changes, and mood symptoms 2
• If a reproductive endocrine disorder is found, antiepileptic drug treatment should be reviewed to ensure it is not contributing to the endocrine or emotional problem 2

Algorithmic Approach to Management

Step 1: Assess Severity and Timing

• Document the specific emotional symptoms (depression, anxiety, irritability, aggression, mood swings) and their severity
• Determine temporal relationship to levetiracetam initiation or dose changes (most occur within first 4 weeks) 1
• Screen for suicidal ideation or psychotic symptoms, which require immediate intervention 1

Step 2: Evaluate Contributing Factors

• Assess for reproductive endocrine disorders by obtaining menstrual history, checking for weight gain, hirsutism, or galactorrhea 2
• Consider hormonal evaluation if menstrual irregularities are present (cycle <23 days or >35 days, or amenorrhea >6 months) 2
• Rule out other causes of mood disturbance, including inadequate seizure control, sleep deprivation from nocturnal seizures, or concurrent stressors

Step 3: Treatment Decision Algorithm

If emotional instability is mild to moderate:

• Consider dose reduction if seizure control permits, as behavioral symptoms may be dose-related 1
• Add adjunctive psychiatric treatment (SSRI or anxiolytic) while monitoring for drug interactions, though levetiracetam has minimal cytochrome P450 interactions 1
• Reassess in 2-4 weeks; if symptoms persist or worsen, proceed to medication switch

If emotional instability is severe, includes psychotic symptoms, or involves suicidal ideation:

• Discontinue levetiracetam immediately and transition to alternative antiepileptic drug 1
• Psychiatric consultation is mandatory for acute stabilization
• Consider hospitalization if safety concerns exist (0.8% of patients require hospitalization for serious behavioral events) 1

Step 4: Alternative Antiepileptic Drug Selection for Catamenial Epilepsy

When switching from levetiracetam due to emotional instability, consider:

• Lamotrigine: Generally well-tolerated with favorable psychiatric profile, though requires slow titration and has no specific evidence for catamenial patterns 3, 4
• Clobazam: Cyclical use has been proposed for catamenial epilepsy, though evidence is limited to small series 4, 5
• Acetazolamide: Proposed for cyclical use in catamenial epilepsy, though evidence comes from small unblinded series 4, 5
• Avoid valproate in this reproductive-age woman due to teratogenicity, weight gain, and association with polycystic ovary syndrome 2

Specific Considerations for Catamenial Nocturnal Epilepsy

• Current evidence for hormonal treatments is limited: Progesterone trials show conflicting results, with one study showing no benefit and another showing decreased seizure frequency, but overall evidence is low to moderate certainty 3
• Norethisterone shows no treatment difference compared to placebo based on very low-certainty evidence 3
• No RCTs exist for non-hormonal treatments specifically targeting catamenial epilepsy 3
• The diagnosis of catamenial epilepsy requires careful assessment of menstrual and seizure diaries to characterize cycle type (perimenstrual C1, periovulatory C2, or luteal C3 pattern) 4, 5

Common Pitfalls to Avoid

• Do not dismiss emotional symptoms as "adjustment issues"—levetiracetam has a well-documented psychiatric adverse effect profile that may necessitate discontinuation 1, 6
• Do not continue levetiracetam indefinitely hoping symptoms will resolve if they persist beyond 4-8 weeks or are severe 1
• Do not overlook reproductive endocrine evaluation in women with epilepsy experiencing mood symptoms, as these disorders are common and treatable 2
• Do not assume catamenial patterns will respond to hormonal therapy—evidence is insufficient, and optimizing conventional antiepileptic therapy remains the priority 3
• Do not forget to counsel about pregnancy risk and encourage enrollment in the North American Antiepileptic Drug pregnancy registry (1-888-233-2334) if pregnancy occurs 1

Monitoring During Transition

• Taper levetiracetam gradually while introducing alternative agent to minimize seizure risk during transition
• Monitor for seizure frequency changes and document any catamenial pattern with new medication
• Reassess emotional symptoms at 2-week intervals during transition and for 8 weeks after stabilization on new regimen
• Follow up on reproductive health including menstrual regularity, weight, and fertility concerns 2