Use of Phenytoin and Other Anticonvulsant Prophylaxis in Patients With Aneurysmal Subarachnoid Hemorrhage
To the Editor:
We read with great interest the article by Naidech et al.1 The authors started from the abstract statement that “Phenytoin is routinely used for seizure prophylaxis after subarachnoid hemorrhage … … ” and went on to investigate the possible harmful effects on cognitive and neurological outcome. After a study of 527 subarachnoid hemorrhage patients, the authors concluded that higher quartiles of phenytoin burden were associated with worse telephone interviews for cognitive status scores at hospital discharge (P<0.001) and at 3 months (P=0.003) as well as poor functional outcome at 14 days (P<0.001) but not at 3 months (P=0.09). The authors then suggested that exposure to phenytoin after subarachnoid hemorrhage should be minimized and argued for a prospective study of phenytoin in patients at high risk for seizures after subarachnoid hemorrhage.
We avoid using phenytoin as anticonvulsant prophylaxis in patients with aneurysmal subarachnoid hemorrhage in our center for another reason. Oral nimodipine is currently indicated in patients with aneurysmal subarachnoid hemorrhage to reduce the risk of poor outcome and secondary ischemia after aneurysmal subarachnoid hemorrhage.2 Nimodipine is metabolized via the cytochrome P450 3A4 system located in both the intestinal mucosa and in the liver. Drugs that are known to either inhibit or to induce this enzyme system may therefore alter the first pass metabolism or clearance of nimodipine. As recommended by the company information sheet (UK),3 Nimotop tablets should not be administered concomitantly with drugs which induce the CYP 3A4 system, such as the antiepileptics phenytoin, phenobarbitone, and carbamazepine, because this markedly reduces the bioavailability of nimodipine and hence its efficacy.
In our institute, we elected to use sodium valproate as anticonvulsant prophylaxis in patients with aneurysmal subarachnoid hemorrhage if indicated. The above problem in drug pharmacokinetic was avoided, but sodium valproate was suggested to be related to quantitative thrombocytopenia and functional defects in platelet aggregation.4 That might be a theoretical problem for patients selected for craniotomy and clipping of aneurysm and rebleeding before aneurysmal occlusion, though we did not find the above problem clinically. We agreed with the authors that, with the low incidence of seizures after subarachnoid hemorrhage (with most occurring soon after ictus), anticonvulsant prophylaxis perhaps should be reserved for the patients at high risk for seizures, and selection of appropriate agent remained a challenge.
Naidech AM, Kreiter KT, Janjua N, Ostapkovich N, Parra A, Commichau C, Connolly ES, Mayer SA, Fitzsimmons BF. Phenytoin exposure is associated with functional and cognitive disability after subarachnoid haemorrhage. Stroke. 2005; 36: 583–587.
Rinkel GJ, Feigin VL, Algra A, van den Bergh WM, Vermeulen M, van Gijn J. Calcium antagonists for aneurysmal subarachnoid haemorrhage. Cochrane Database Syst Rev. 2005; 25: CD000277.
Bayer Pharmaceuticals Corporation. Summary of characteristics: Nimotop 30mg tablets. Nimotop/Tablets (30 mg)/SMPC/Approved/UK/SmPC NimTab UK 005_3/DOC.
We thank Drs Wong and Poon for their thoughtful comments. We agree that increased metabolism of nimodipine might account for some, though probably not all, of the harmful effects of phenytoin after subarachnoid hemorrhage (SAH). They are not the only readers to suggest this thoughtful hypothesis.1
We attempted to repeat our analysis for valproate, but did not have enough data. Some clinicians believe that any other parenteral anticonvulsant must be better than phenytoin, but there are no data to support this. It is possible that other anticonvulsants might prevent seizures with fewer adverse events, but this remains to be seen.
Patients without risk factors for seizures after SAH2 (Table 2: previous seizure, subdural hematoma, cerebral infarction, NIH Stroke Scale at least 10, etc) probably do not benefit from any anticonvulsant after SAH. For the remaining patients, the tradeoffs for prophylactic anticonvulsant use in SAH, with any agent, remain to be prospectively defined.
- Received September 30, 2005.
- Accepted October 3, 2005.
Koch S, Gidal BE. Phenytoin and cognitive decline. Stroke. 2005; 36: 2070–2071.
Naidech AM, Kreiter KT, Janjua N, Ostapkovich N, Parra A, Commichau C, Connolly ES, Mayer SA, Fitzsimmons BF. Phenytoin exposure is associated with functional and cognitive disability after subarachnoid hemorrhage. Stroke. 2005; 36: 583–587.