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

a Knowledge Summary by

Connor Hawes BVetmed (Hons) MRCVS ^1*

Kali Lazzerini DVM DrMedVet MSc DipECVN MRCVS ¹

¹Bristol Veterinary School, University of Bristol, Langford House, Langford, Bristol, BS40 5DU
^*Corresponding Author (chawes2@rvc.ac.uk)

Clinical scenario

A 6 month old Yorkshire Terrier diagnosed with a single congenital portosystemic shunt has surgical attenuation with an ameroid constrictor following medical management with lactulose, amoxicillin and a hydrolysed diet. The dog develops post-attenuation seizures 24 hours after surgery, despite no prior history of seizures. Would the administration of levetiracetam, an anti-epileptic drug, prior to attenuation reduce the risk of post-attenuation seizures?

The evidence

Four retrospective cohort studies were found relevant to the PICO (Fryer et al., 2011; Mullins et al., 2018; Otomo et al., 2020; and Strickland et al., 2018). All studies compared the frequency of post-attenuation seizures in patients treated with or without prophylactic levetiracetam. Prior medical treatment, surgical technique, anaesthetic, frequency of preoperative neurological signs and levetiracetam protocols varied between and within studies, which all may have influenced seizure frequency. 

Fryer et al. (2011) was the only study to find a clinical benefit to prophylactic levetiracetam, the other three studies found no benefit (Mullins et al., 2018; Otomo et al., 2020; and Strickland et al., 2018). The frequency of post-attenuation seizures were low in all studies.

Currently the evidence does not support the use of levetiracetam, although a prospective controlled study with standardised treatment protocol would be required.

Summary of the evidence

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.

Methodology Section

Search Strategy
Databases searched and dates covered:	CAB Abstracts on the OVID interface, 1973–2022 Week 01 PubMed on the NCBI interface. 1920–January 2022
Search strategy:	CAB Abstracts: (dog or dogs or canine or canines).mp. or exp dogs/  (congenital or primary).mp.  (portosystemic or portasystemic or porto-systemic or porta- systemic or shunt* or PSS or cPSS or cEHPSS or extrahepatic or extra-hepatic).mp.  (levetiracetam or antiseizure or antiepileptic or anticonvulsant or anti-seizure or anti-epileptic or anti-convulsant).mp.  1 and 2 and 3 and 4 PubMed: #1 dog or canine  #2 congenital or primary  #3 portosystemic or portasystemic or porto-systemic or porta-systemic or shunt or PSS or cPSS or cEHPSS or extrahepatic or extra-hepatic  #4 levetiracetam or antiseizure or antiepileptic or anticonvulsant or anti-seizure or anti-epileptic or anti-convulsant  #5 #1 and #2 and #3 and #4
Dates searches performed:	12 Jan 2022

Exclusion / Inclusion Criteria
Exclusion:	Not related to PICO. Review paper. Book chapter. Foreign language.
Inclusion:	Research papers including the use of levetiracetam in the prevention of post-attenuation seizures even if not the primary aim.

Search Outcome
Database	Number of results	Excluded – Not related to PICO	Total relevant papers
CAB Abstracts	7	3	4
PubMed	10	6	4
Total relevant papers when duplicates removed			4

The authors declare no conflicts of interest.

1. Fryer, K.J., Levine, J.M., Peycke, L.E., Thompson, J.A. & Cohen, N.D. (2011). Incidence of Postoperative Seizures with and without Levetiracetam Pretreatment in Dogs Undergoing Portosystemic Shunt Attenuation. Journal of Veterinary Internal Medicine. 25(6), 1379–1384. DOI: https://doi.org/10.1111/j.1939-1676.2011.00819.x
2. Gommeren, K., Claeys, S., De Rooster, H., Hamaide, A. & Daminet, S. (2010). Outcome from status epilepticus after portosystemic shunt attenuation in 3 dogs treated with propofol and phenobarbital. Journal of Veterinary Emergency and Critical Care. 20(3), 346–351. DOI: https://doi.org/10.1111/j.1476-4431.2010.00537.x
3. Hardie, E.M., Kornegay, J.N. & Cullen, J.M. (1990). Status Epilepticus after Ligation of Portosystemic Shunts. Veterinary Surgery. 19(6), 412–417. DOI: https://doi.org/10.1111/j.1532-950X.1990.tb01224.x
4. Matushek, K.J., Bjorling, D. & Mathews, K. (1990). Generalized motor seizures after portosystemic shunt ligation in dogs: five cases (1981–1988). Journal of the American Veterinary Medical Association. 196(12), 2014–2017.
5. Mullins, R.A., Sanchez Villamil, C., de Rooster, H., Kummeling, A., White, R.N., Thieman Mankin, K.M., Tivers, M.S., Yool, D.A., Anderson, D.M., Pratschke, K.M., Gordo, I., Brissot, H., Singh, A., Olive, M., Billet, J.P., Selmic, L.E. & Kirby, B.M. (2018). Effect of prophylactic treatment with levetiracetam on the incidence of postattenuation seizures in dogs undergoing surgical management of single congenital extrahepatic portosystemic shunts. Veterinary Surgery. 48(2), 164–172. DOI: https://doi.org/10.1111/vsu.13141
6. Otomo, A., Singh, A., Jeong, J., Dobberstein, R., Lundhild, A., Peter, E., Brisson, B., Oblak, M. & Milovancev, M. (2020). Long‐term clinical outcomes of dogs with single congenital extrahepatic portosystemic shunts attenuated with thin film banding or ameroid ring constrictors. Veterinary Surgery. 49(3) 436–444. DOI: https://doi.org/10.1111/vsu.13384
7. Packer, R., Nye, G., Porter, S.E. & Volk, H.A. (2015). Assessment into the usage of levetiracetam in a canine epilepsy clinic. BMC Veterinary Research. 11(1), 25. DOI: https://doi.org/10.1186/s12917-015-0340-x
8. Strickland, R., Tivers, M.S., Adamantos, S.E., Harcourt-Brown, T.R., Fowkes, R.C. & Lipscomb, V.J. (2018). Incidence and risk factors for neurological signs after attenuation of single congenital portosystemic shunts in 253 dogs. Veterinary Surgery. 47(6), 745–755. DOI: https://doi.org/10.1111/vsu.12925
9. Tisdall, P.L.C., Hunt, G.B., Youmans, K.R. & Malik, R. (2000). Neurological dysfunction in dogs following attenuation of congenital extrahepatic portosystemic shunts. Journal of Small Animal Practice. 41(12), 539–546. DOI: https://doi.org/10.1111/j.1748-5827.2000.tb03150.x