In dogs undergoing extrahepatic portosystemic shunt attenuation, does pretreatment with levetiracetam reduce postoperative seizure incidence?

[...]

Appraisal, application and reflection

Following attenuation of a portosystemic shunt approximately 5–18% will experience post-attenuation seizures as a complication (Gommeren et al., 2010; Hardie et al., 1990; and Tisdall et al., 2000). These seizures typically occur within 72 hours of attenuation, are refractory to treatment and are associated with a high mortality (Gommeren et al., 2010). The pathophysiology of this condition is poorly understood and may be associated with a reduction in endogenous benzodiazepines, alongside postoperative metabolic events (Hardie et al., 1990; and Matushek et al., 1990), and may represent a number of aetiologies. Reported risk factors for post-attenuation seizures include: increased age (Hardie et al., 1990; Matushek et al., 1990; Strickland et al., 2018; and Tisdall et al., 2000), porto-azygos shunts (Tisdall et al., 2000), pre-existing signs of hepatic encephalopathy (Strickland et al., 2018), and increase serum osmolality (Strickland et al., 2018). Because of the lack of predictive factors or effective treatment there is a growing interest in developing preventative measures for post-attenuation seizures. One such treatment is the anti-epileptic drug levetiracetam, used for the treatment of status epilepticus, focal and generalised seizures, as well as not being contraindicated in hepatic dysfunction (Packer et al., 2015).

Fryer et al. (2011) was the first paper to explore the use of prophylactic levetiracetam, and the only study suggesting a benefit. No patients treated with levetiracetam had post-attenuation seizures, whereas 4/84 4.8% of patients not treated did. Despite the promising results the further three papers reviewed showed no benefit to levetiracetam (Mullins et al., 2018; Otomo et al., 2020; and Strickland et al., 2018). Mullins et al. (2018) and Strickland et al. (2018) also had substantially larger samples sizes and seizure frequencies compared to Fryer et al. (2011). Based on this it can be concluded that prophylactic levetiracetam does not reduce the risk of post- attenuation seizures. Strickland et al. (2018) did suggest that the use of prophylactic levetiracetam did reduce the mortality associated with post-attenuation seizures, although frequency of seizures and number of patients on levetiracetam were low.

The major limitation in all studies were other factors potentially contributing to post-attenuation seizures, and being able to determine if the seizures were secondary to other factors. No study was consistent in the use of anaesthetic protocol, surgical technique, and use of preoperative medication, all of which may contribute to seizure frequency. The use of levetiracetam was also not consistent, with varied protocols, which may alter its efficacy. Lastly the presence of preoperative neurological signs and seizures varied largely between studies ranging from 64/123 (52%) (Otomo et al., 2020), 85/125 (68%) (Fryer et al., 2011), 61/75 (81%) (Mullins et al., 2018), and 253/253 (100%) (Strickland et al., 2018). Strickland et al. (2018) was the only study to try and grade preoperative neurological signs, although did not appear to consider grade in their analysis. The presence of preoperative hepatic encephalopathy is considered a risk factor for post-attenuation seizures (Strickland et al., 2018), and severity of preoperative neurological signs may be an important source of bias not considered in all of these studies.

In conclusion the evidence does not support the use of prophylactic levetiracetam in reducing post- attenuation seizures, levetiracetam may be useful in reducing mortality associated with this condition although further studies would be required to conclude this.

[…]