Serious and reversible levetiracetam-induced psychiatric symptoms after resection of frontal low-grade glioma: two case histories

Abstract

Levetiracetam may induce serious behavioral disturbances, especially after surgical resection of frontal lobe low-grade glioma. Two patients, treated with levetiracetam, developed serious psychiatric complications postoperatively which completely resolved after switching to valproate. We aim to create awareness for this serious but reversible adverse effect of levetiracetam in this specific patient category.

Keywords:

• Low-grade glioma
• frontal lobe resection
• levetiracetam
• valproate
• psychiatric symptoms
• behavioral changes

Clinical details

The first patient is a 31-year-old male, without a relevant medical history, known with apathetic behavior but without a previous psychiatric history. He was admitted after having two secondarily generalized seizures. After admission, the seizures were treated successfully with levetiracetam, 750 mg twice daily, for 6 months. Magnetic resonance imaging (MRI) showed a space-occupying lesion in the right frontal lobe, suspect for a low-grade glioma (Figure 1(A)). As the patient was left-handed and had mild dysphasia, a functional MRI was performed. This demonstrated a bilateral language representation and a close relationship between Broca’s area and the tumor. No neuropsychological assessment was performed preoperatively. Resection of the tumor was performed by an awake craniotomy (Penfield procedure) (Figure 1(B)). Histological analysis demonstrated a WHO Grade 2 oligodendroglioma.

Figure 1. Case 1: preoperative MR T2 image (A) and postoperative MR T2 image (B).

Postoperatively prednisone, 4 mg four times daily, was tapered rapidly within 4 days. Initially the patient demonstrated apathetic behavior that was not different from his pre-operative behavior. On the sixth postoperative day, the patient showed motor restlessness and made an attempt to leave the ward. The treating physician interpreted this as a complex-partial-seizure, though without an EEG examination, and increased the levetiracetam dosage toward 1000 mg twice daily. Thereafter, the patient developed progressive apathy and distrust. As this behavior stabilized to an acceptable level, the patient was discharged 9 days postoperative after intensive consultation with his family, the rehabilitation specialist, the neurologist and the psychiatrist. However, instead of leaving the hospital, he returned to the ward, anxious and confused. He displayed paranoid delusions and bizarre behavior. An EEG demonstrated diffuse slowing asymmetric activity in the right hemisphere, with a focal abnormality in the right frontal lobe, not suspect for focal or generalized epileptiform activity. It was decided to reduce and stop the levetiracetam and switch to valproate, in an increasing dose up to 1000 mg three times daily. The patient’s behavior returned to normal within a few days, and he was discharged 7 days after the medication switch. At follow-up, 6 weeks later, he was completely seizure free and his behavior was not different from his preoperative behavior.

The second patient is a 53-year-old male, without a relevant medical or psychiatric history, who was admitted with a sudden collapse and loss of consciousness. Diagnostic workup excluded cardiac pathology and a secondarily generalized seizure was suspected. The patient received levetiracetam 750 mg twice daily for the prevention of further seizures. An MRI scan demonstrated a space-occupying lesion in the left frontal lobe, suspect for a low-grade glioma (Figure 2(A)). No neuropsychological assessment was performed preoperative. During the 6 weeks from admission until surgery he was seizure free. As the patient was right-handed and the tumor was anatomically located in the vicinity of Broca’s speech area, an awake craniotomy (Penfield procedure) was performed to resect the tumor (Figure 2(B)). Histological analysis demonstrated a WHO Grade 2 oligodendroglioma. Postoperative administered prednisone 4 mg four times daily were tapered rapidly within 4 days and stopped. On the fifth postoperative day, the patient was discharged in a good clinical condition.

Figure 2. Case 2: preoperative MR T2 image (A) and postoperative MR T2 image (B).

In the week after hospital discharge, the patient’s behavior gradually changed. He demonstrated bizarre behavior, as he demanded strict obedience from his wife and children in their daily routines, in for example their food and drink habits and the regulation of the temperature in their house. He demonstrated an intimidating and verbally aggressive behavior, and threatened with violence. No other psychiatric symptoms, such as depressive or delusional symptoms, were present. His family did not recognize this behavior. He was admitted to the psychiatric ward of our hospital. The psychiatrist believed an organic factor induced his aggressive behavioral changes and interpreted them as likely due to adverse effects of levetiracetam in combination with his frontal tumor location and resection. Levetiracetam was reduced and stopped and valproate was started. Again, after this medication switch, his behavior returned to normal and the patient could be discharged 5 days after admission. At the 6-month outpatient follow-up, behavior was still normal according to the patient and his family and no seizures were reported.

Discussion

We report two patients with serious psychiatric complications deteriorating over 1 week after resection of a frontal lobe LGG and while using levetiracetam for seizure control and prevention. The psychiatric symptoms in both patients disappeared completely within a few days after switching from levetiracetam to valproate. We consider the adjunctive therapy with levetiracetam as well as the frontal lobe tumor resection as attributive causal factors for this psychiatric derangement. In the first case, it was not excluded that the patient went through a postictal psychosis at the sixth postoperative day. However, an EEG did not show focal or generalized epileptiform activity when psychiatric symptoms deteriorated. In the second case, no EEG examination was performed because there was no clinical suspicion for apparent seizures, although we may have missed a subclinical status. The clinical effect of switching from levetiracetam toward valproate was obvious and would probably not have been so clear when the patient would have had a subclinical status.

The exact association between levetiracetam and behavioral adverse effects remains unclear.^1,2 A recent systematic review and meta-analysis reported levetiracetam to be well tolerated in general and to be better tolerated than valproate, mainly on long term. Behavioral or psychiatric adverse effect were not well documented.³ A recent hypothesis states that the several synonyms that are used to describe behavioral adverse effects may cause underestimation of behavioral and psychiatric adverse effects of levetiracetam.^1,2 When several synonyms for behavioral adverse effects were clustered, levetiracetam was associated with behavioral adverse effects. The described dosages were comparable with the dosages in our cases. Previous studies only described this association in patients with pre-existing mood disorders.¹ Earlier literature also reported an increased risk on psychiatric adverse effects, mainly depression, for levetiracetam compared to valproate, resp. 4% versus 1%. Also, valproate was associated with positive effects on behavioral problems like aggression and impulsivity.⁴ These findings confirm our hypothesis that levetiracetam can induce severe psychiatric derangement in patients with increased risk of psychiatric or behavioral adverse effects. These individual risk factors are poorly reported in the current literature.

Frontal lobe tumors can induce serious behavioral changes as well, which may potentially be reinforced by frontal lobe surgery. Patients with surgery for tumors located in the frontal lobe develop significantly more impairment in recognizing their own or other’s emotional states, have more impairment in recognizing other cognitive stimuli and exhibit less self-maturity compared with patients who undergo temporal or parietal lobe tumor resections. Decreased activity of the anterior cingulate cortex may be involved in this location related difference.⁵

Although no literature on the risk on psychiatric symptoms after frontal lobe tumor resections combined with levetiracetam usage is available, we argue that frontal lobe lesions, for which frontal lobe surgery is indicated, increase the risk of behavioral adverse effects of levetiracetam.

The two cases presented here developed behavioral changes after frontal low-grade-glioma resection, while treated with levetiracetam. Switching to valproate induced rapid and complete remission of the psychiatric symptoms. The frontal lobe location of the tumor may increase the adverse behavioral changes of levetiracetam. Therefore, we recommend caution in the use of levetiracetam for seizure control in patients with frontal lobe tumor. If levetiracetam is used, potential behavioral changes need to be closely monitored, and if observed, an immediate switch to another AED is recommended.

Informed consent

Informed consent was obtained from all individual participants for whom identifying information is included in this article.

Disclosure statement

The authors report no declarations of interest.