Should I Give Antiepileptics to a Patient with Non-traumatic Subarachnoid Hemorrhage?
Author: Dr. Kim Papa
36yo F PMH sickle cell disease presents to ED via EMS for altered mental status. History is limited due to patient condition. On exam, patient is minimally responsive with a GCS=7 (E1V2M4) and pupils unequal, minimally reactive. Left pupil=2mm, right pupil=4mm. Gaze deviation to right is noted. No signs of trauma are present and they are moving all extremities spontaneously. Upon completion of the primary survey, the patient is immediately sent to the CT scanner and found to have a subarachnoid hemorrhage (SAH) concerning for aneurysmal rupture. The patient is intubated for expected course and low GCS. Neurosurgery is consulted and recommends keppra, mannitol, elevated HOB, hyperventilate to pCO2=35 and transfer for neuroendovascular intervention.
Clinical Question: Should I give antiepileptic drugs (AEDs) to a patient with non-traumatic subarachnoid hemorrhage?
PubMed was searched using MESH terms: Seizures AND subarachnoid hemorrhage; Subheading: prevention and control
I identified 49 articles for our question and reviewed them. After initial inspection, the three articles determined to be most relevant were reviewed in detail.
Summary of Findings
The development of seizures after a non-traumatic SAH is a well-documented adverse event. Also, seizure activity has been associated with secondary neurologic injury including reduced cerebral blood flow and increased intracranial pressure.1 Finally, the development of seizures post-SAH leads to increased bleeding, lower GCS, rebleeding, as well as delayed ischemic events 2/2 vasospasm.2 However, since seizures originate in the cortex, and most spontaneous SAH occur deeper in the midbrain and do not cause seizures, it is up for debate as to whether or not we need seizure prophylaxis on every patient. The incidence of seizures was initially thought to be as high as 27% in this population, however recent studies have shown the incidence to be significantly lower than previously described (1–10%).2,3 Additionally, up to 21% of those receiving AED prophylaxis suffered adverse medication side effects, including impaired liver function, thrombocytopenia, rash, and Stevens-Johnson syndrome.4 So, does the benefits outweigh the risks of giving patients with SAH antiepileptic drugs?
Rosengart et. al performed a retrospective analysis of four trials which included 3,552 patients with SAH.3 This study showed a higher in-hospital complication rate for patients who were treated with AEDs compared with patients not treated with AEDs. Furthermore, after adjusting for study center, grade, age, and systolic BP on admission, AED use was associated with increased odds of clinical vasospasm, neurological worsening, increased odds of cerebral infarction, and elevated temperature. An argument can be made that the patients being treated with AEDs were sicker at baseline, however with these controls, it would be difficult to make that argument. This study concludes that there was no beneficial effect of prophylactic AEDs and an increased association with multiple adverse events.
Raper, et. al. performed a systematic review of the MEDLINE database between 1985-2010, which included 25 studies for analysis.5 Their objective was to study the incidence of postoperative seizures with patients after coiling or clipping of their aneurysm. They concluded that the incidence of early and late postoperative seizures is 2.3% and 5.5% respectively. Unfortunately, after reviewing all of the data, there seems to be no benefit to the administration of prophylactic AEDs among aneursymal SAH patients.
Finally, a systematic review was performed and published in the Cochrane library to determine if there was high level evidence to establish whether or not the use of AEDs in the primary and secondary prevention of seizures after SAH.6 Their review considered all RCTs and quasi-RCTs where there was comparison to a placebo-control group. The result: there are no studies! No studies provided a randomized controlled trial of an AED versus placebo. The Cochrane Review established that an RCT, placebo-controlled study is of great need and should be studied to finally answer this important clinical question.
I was not expecting to come to a complete dead end regarding my clinical question. There seems to be evidence that states there is no difference between the prevention of seizures post-SAH with AEDs, and there even seems to be studies that say they may cause more harm than good. The conclusion to my search is that this is something that needs to be studied now to establish practice guidelines, as there is no consensus within the specialty. So the next time you have a non-traumatic SAH patient in the ED, should we be giving AEDs for seizure prophylaxis? The answer to this question remains uncertain, however given that there is such insufficient evidence, I may not initiate treatment until I have consulted my neurosurgery colleagues and have shared decision-making. What I would also like to see in further studies is more of an emergency medicine application. Does the time to initiating treatment affect outcomes?
What is your practice? Do you think we should we be giving AEDs in the ED immediately or waiting until after surgical interventions such as coiling or clipping? Leave your comments below!
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EM Cases: Intracerebral Hemorrhage
- 1.Rhoney D, Tipps L, Murry K, Basham M, Michael D, Coplin W. Anticonvulsant prophylaxis and timing of seizures after aneurysmal subarachnoid hemorrhage. Neurology. 2000;55(2):258-265. https://www.ncbi.nlm.nih.gov/pubmed/10908901.
- 2.Talley B. Outcome in Patients With Subarachnoid Hemorrhage Treated With Antiepileptic Drugs. The Journal of Emergency Medicine. January 2008:111-112. doi:10.1016/j.jemermed.2007.10.007
- 3.Rosengart A, Huo J, Tolentino J, et al. Outcome in patients with subarachnoid hemorrhage treated with antiepileptic drugs. J Neurosurg. 2007;107(2):253-260. https://www.ncbi.nlm.nih.gov/pubmed/17695377.
- 4.Lin Y, Chang W, Chang H, et al. Risk factors and outcome of seizures after spontaneous aneurysmal subarachnoid hemorrhage. Eur J Neurol. 2008;15(5):451-457. https://www.ncbi.nlm.nih.gov/pubmed/18325027.
- 5.Raper DMS, Starke RM, Komotar RJ, Allan R, Connolly ES Jr. Seizures After Aneurysmal Subarachnoid Hemorrhage: A Systematic Review of Outcomes. World Neurosurgery. May 2013:682-690. doi:10.1016/j.wneu.2012.08.006
- 6.Marigold R, Günther A, Tiwari D, Kwan J. Antiepileptic drugs for the primary and secondary prevention of seizures after subarachnoid haemorrhage. Cochrane Database of Systematic Reviews. June 2013. doi:10.1002/14651858.cd008710.pub2
2 thoughts on “Should I Give Antiepileptics to a Patient with Non-traumatic Subarachnoid Hemorrhage?”
Really nice review of this topic! I think you came to a very similar conclusion as me which is that the data is pretty poor quality but there is no evidence to support the routine seizure prophylaxis for patients with spontaneous SAH; and there is a suggestion of possible harm. When expanding my search to look at spontaneous ICH, I found similar conclusions to SAH: https://www.ncbi.nlm.nih.gov/pubmed/30935318
With the increasing availability of continuous EEG, we are probably better able to identify patients with depressed mental status who are having subclinical seizures and would benefit from antiepileptic drugs.
Thanks Papa, great review. Must admit that I was not that familiar with the literature on this topic. I will definitely consider seriously now my decision to administer AEDs to this population. After all what seems “sensible” in clinical practice is not always right and can be harmful as you’ve nicely demonstrated.
One question I did have with regards to article 4 that you reference, is whether these adverse events were seen with Keppra or other AEDs. In general I have thought of Keppra as being relatively safe, but perhaps I am wrong.
Also, are you ready to do a clinical trial now to answer that question!?