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COMMENTARY
Year : 2020  |  Volume : 68  |  Issue : 3  |  Page : 593--594

Use of Prophylactic Antiepileptics Following Aneurysmal Subarachnoid Hemorrhage: Time to Relook

R Girish Menon 
 Department of Neurosurgery, Kasturba Medical College, Manipal, Karnataka, India

Correspondence Address:
Dr. R Girish Menon
Department of Neurosurgery, Kasturba Medical College, Manipal - 576 104, Karnataka
India




How to cite this article:
Menon R G. Use of Prophylactic Antiepileptics Following Aneurysmal Subarachnoid Hemorrhage: Time to Relook.Neurol India 2020;68:593-594


How to cite this URL:
Menon R G. Use of Prophylactic Antiepileptics Following Aneurysmal Subarachnoid Hemorrhage: Time to Relook. Neurol India [serial online] 2020 [cited 2020 Sep 28 ];68:593-594
Available from: http://www.neurologyindia.com/text.asp?2020/68/3/593/289016


Full Text



Use of prophylactic antiepileptic drugs (AED) following aneurysmal subarachnoid hemorrhage (aSAH) is a matter of considerable debate. Cerebrovascular surgeons, generally prefer to err on the side of safety because of the lack of clear cut guidelines and phenytoin sodium (PHT) is the preferred antiepileptic by most. The use of PHT is controversial with doubts raised about its contribution to adverse outcome following aSAH. The authors of this interesting manuscript have conducted a hitherto unattempted technique and proven that PHT fails to cross the breached blood–brain barrier (BBB) of an aSAH brain to provide therapeutically adequate concentration levels.[1] Through this article, the authors question the evidence behind the long-standing clinical practices and attempt to raise several pertinent questions which can be summarized as follows.

A. Is the risk of seizures following aSAH significant enough to warrant AED usage?

Lanzino et al. reported that incidence of seizures following aSAH varies between 4% and 26%. It is believed that 15% of aSAH patients will have at least one seizure in the first week after the bleed with an accumulative 5-year epilepsy incidence of 12%.[2] Seizures can occur at the time of ictus (onset seizures) or during hospitalization. Most seizures occur within the first year after bleed and early seizures have been reported to be an independent risk factor for delayed ([3] Seizures following aSAH generally indicate a severe underlying pathology and usually correlate with poor neurological status, prolonged loss of consciousness, middle cerebral artery aneurysm location, higher cisternal clot burden, rebleeding, and the presence of intracerebral hematomas, hydrocephalus, and a higher risk of delayed cerebral ischemia.[4],[5] Thus, seizures can have a compounding effect on an already traumatized brain. It can thus be argued that the administration of prophylactic AEDs to prevent the risk of secondary injury especially in the predisposed subgroup is justified. The counter-argument would be that since seizure rates are comparatively low and the numbers needed to treat unknown, the possible side effects undetermined, AEDs usage should be limited. It cannot be denied that in the absence of good randomized controlled trials (RCT), there is little evidence that AED prophylaxis is effective and a number of retrospective series have demonstrated no significant difference between groups with or without prophylaxis in terms of seizure outcome. The current uncertainty is highlighted in the fact that while the current guidelines from the Neurocritical Care Society (NCS) specifically recommend against the routine use of phenytoin for prophylaxis, the American Heart Association guidelines state that the use of anticonvulsants is reasonable, without specifically recommending against or for any particular anticonvulsant.[3],[4]

B. What is the negative impact of AEDs on outcome following aSAH?

The safety and effectiveness of AEDs in aSAH has not been extensively analyzed but it is believed that the adverse effects of AEDs have likely been underestimated. It was Rosengarten, who first observed that patients who received AEDs had an odds ratio of 1.56 for worse outcome at 3 months, as well as increased risk for vasospasm, neurological deterioration, and delayed cerebral ischemia.[6] Later, Naidech et al. linked the prophylactic use of PHT with poor functional and cognitive outcome.[7] Phenytoin has also been linked to drug-induced fever and it is well known to reduce the bioavailability of nimodipine. While levetiracetam is a popular alternative to phenytoin, its superiority over PHT has not been scientifically proven. Levetiracetam, however, is definitely a better-tolerated drug than PHT in terms of common side effects like drug fever, etc.

C. What is the ideal duration of prophylactic AEDs treatment?

Since the maximum risk of seizure is in the initial phase following aSAH, it is reasonable to argue that a short course of therapy may suffice. While comparing a protocol for short duration versus prolonged AED, Lanzino et al. observed a significant reduction in phenytoin-associated complications without a difference in the rate of seizures using the shorter 1-week treatment regimen.[8] However, to date most studies have been unable to provide information on the regimen and intensity of treatment and when best to terminate prophylaxis.[5],[6] The ideal duration of treatment still remains unanswered.

D. How does one assess the efficacy of an AED—is it seizure freedom, is it the presence of therapeutic blood levels in the blood or brain?

aSAH does result in a breach of BBB which leads to changes in its permeability, affecting the penetration of drugs and other substances across this barrier. The choice of any AED during aSAH needs to be based on its efficacy to permeate through the disrupted BBB. The authors, through this pilot study have conclusively proven that the concentration of PHT penetrating the brain following aSAH significantly decreases in grade 3 and 4 aSAH. Their study is the first one to demonstrate the laboratory evidence of decreased penetration of PHT in aSAH brains. Since the therapeutic levels of PHT in brain tissue have not yet been established, the authors have not been able to quantify the deficit. The study is further limited by the lack of background knowledge on the importance of adequate brain tissue concentration of AEDs and pharmacodynamical endpoint in terms of seizure control. Nevertheless, the authors have been able to provide sufficient evidence to question the routine use of PHT prophylactically. They have also provided adequate ammunition for further researchers to follow their lead and arrive at much-needed conclusions on the use of prophylactic AEDs.

Use of prophylactic AEDs in aSAH is controversial. Incidence of seizures following aSAH is low and occurs early into the ictus. A seizure can have a negative impact on outcome, but so can AEDs. Multiple authors including the index article have raised concerns over the need and safety of PHT for seizure control after aSAH. The need of the hour is a scientifically conducted RCT to establish the need for AED, to select the best available AED and to confirm the ideal duration. Until then, it would be reasonable to continue preferably with an alternative like levetiracetam for a shorter period, especially in the vulnerable subgroup.

References

1Dhir N, Attri SV, Pattanaik S, Kumar MP, Gill NK, Patial A, et al. Aneurysmal Subarachnoid Hemorrhage: Impact on Phenytoin Permeability across the Blood– Brain Barrier. Neurol India 2020;68:588-592.
2Huttunen JM, Kurki MI, von und zu Fraunberg M, Koivisto T, Ronkainen A, Rinne J, et al. Epilepsy after aneurysmal subarachnoid hemorrhage: A population-based, long-term follow-up study. Neurology 2015;85:1997.
3Dmytriw A, Maragkos G, Zuccato J, Singh J, Wilcox M, Schweikert S. Use of antiepileptic drugs in aneurysmal subarachnoid hemorrhage. Can J Neurol Sci 2019;46:423-9.
4Connolly ES Jr, Rabinstein AA, Carhuapoma JR, Derdeyn CP, Dion J, Higashida RT, et al. Guidelines for the management of aneurysmal subarachnoid hemorrhage: A guideline for healthcare professionals from the American Heart Association/american Stroke Association. Stroke 2012;43:1711-37.
5Marigold R, Günther A, Tiwari D, Kwan J. Antiepileptic drugs for the primary and secondary prevention of seizures after subarachnoid haemorrhage. Cochrane Database Syst Rev 2013;2013:CD008710.
6Rosengart AJ, Huo JD, Tolentino J, Novakovic RL, Frank JI, Goldenberg FD, et al. Outcome in patients with subarachnoid hemorrhage treated with antiepileptic drugs. J Neurosurg 2007;107:253-60.
7Naidech AM, Kreiter KT, Janjua N, Ostapkovich N, Parra A, Commichau C, et al. Phenytoin exposure is associated with functional and cognitive disability after subarachnoid hemorrhage. Stroke 2005;36:583-7.
8Lanzino G, D'Urso PI, Suarez J, Seizures and anticonvulsants after aneurysmal subarachnoid hemorrhage. Neurocrit Care 2011;15:247-56.