Antiepileptic Drugs in Critically Ill Patients

Salia Farrokh; Pouya Tahsili-Fahadan; Eva K. Ritzl; John J. Lewin III; Marek A. Mirski


Crit Care. 2018;22(153) 

In This Article

Seizure Prevention in the ICU

Traumatic Brain Injury

The incidence of post-traumatic seizures accounts for 6% of overall symptomatic epilepsy[21–23] and is estimated to occur in up to 15% and 53% in civilian and military populations, respectively.[24,25] Clinical studies have divided post-traumatic seizures into either immediate (< 24 h), early (within 1 week, with a seizure incidence of 2.1–16.9%), or late (with an incidence of 1.9% to > 30.0%)[22,23,26]).

Early seizures occur in about 10–15% of patients not treated with anticonvulsants, and this incidence can be reduced to about 2–3% with the use of phenytoin.[27] There is, however, little evidence that such use reduces the occurrence of late seizures or the incidence of death and neurologic disability.[28] It thus appears that anticonvulsants are suppressive during the early period following traumatic brain injury (TBI), but are not prophylactic for the time period beyond the first week. The American Academy of Neurology (AAN)[29] and the Brain Trauma Foundation[30] advocate prophylactic use of AED only during the first 7 days after a head injury.[31,32] Phenytoin has been shown to decrease the incidence of early post-traumatic seizures[30] and to be more cost-effective than levetiracetam.[33] Although levetiracetam was shown in small early studies to be as effective as phenytoin,[33,34] there are recent data suggesting a lack of any prophylactic action in a comparative study of levetiracetam versus no prophylaxis.[35] A trial that incorporated a blinded design and the use of continuous electroencephalography (cEEG) monitoring demonstrated no difference in early or late seizure incidence between drugs, but did favor levetiracetam over phenytoin in the 6-month Glasgow Outcome score measure.[36]

The use of valproic acid, as compared with phenytoin, failed to demonstrate benefit and its use correlated with higher mortality.[37] However, a recent Cochrane analysis failed to discriminate between phenytoin and other anticonvulsants with regards to reduced incidence or mortality.[37]

Ischemic Stroke

Seizures following ischemic stroke occur within an incidence range of 4% to 14%.[38–40] According to a large recent registry from France, early seizures are not associated with higher mortality or unfavorable outcomes at 1 month or at 1 year.[41] Patients with late-onset seizures have a greater than twice the risk for subsequent stroke, although the causal relationship is unclear.[42]

Given the rather low incidence of seizures following most ischemic stroke syndromes, neither the American Heart Association (AHA) nor the American Stroke Association guidelines recommend prophylactic use of anticonvulsants following ischemic stroke.[43] However, some patients may be at greater risk for seizures. An increase in seizure risk has been reported following cardioembolism,[39] hyperglycemia,[41] intravenous thrombolysis with alteplase,[44] in patient with SE following poststroke seizures, and either large cortical or hemorrhagic infarction.[38,45–48]

If "prophylaxis" is considered, then the agent used should be selected for its adverse effect profile. In recent years there has been some interest in ascribing statins as a "first-line" anticonvulsant in stroke patients, although supportive data are by association only and this type of intervention is not readily practiced.[49,50]

Intracerebral Hemorrhage

In contrast to ischemic stroke, intracerebral hemorrhage (ICH) portends a somewhat higher risk of seizures, ranging from two- to seven-times that from ischemic stroke.[38,47,51,52] If cEEG is performed during the acute admission period, nonconvulsive epileptiform activity is commonly observed and may affect more than 20% of ICH patients.[53–56] As expected, lobar or supratentorial ICHs have the highest incidence of seizures; those in the posterior fossa have almost zero.[38,54] Surgical evacuation confers an increased incidence, and subarachnoid or subdural blood also increases the risk for seizures.[57]

Prophylactic anticonvulsant treatment in ICH patients is currently not strongly advocated. cEEG is suggested by some for ICH patients with a depressed mental status out of proportion to that expected for the severity of the stroke.[58] Levetiracetam has become the most widely prescribed agent despite a lack of evidence,[59] likely due to its ease of use. Uncontrolled study data have suggested that phenytoin confers worse outcomes than others (primarily against levetiracetam),[60–62] but these data are not supported by other recent studies.[63,64]

Subarachnoid Hemorrhage

Early and late-onset seizures are observed in patients with subarachnoid hemorrhage (SAH). Risk factors include the severity of SAH, concomitant intracerebral or intraventricular blood, and treatment with craniotomy.[65] A recent study noted a 10% incidence of seizures, with almost half (47%) occurring within the initial 24 h.[66] Interestingly, the use of prophylactic anticonvulsants did not reduce the overall risk. As seizures dramatically increase cerebral blood flow and blood pressure, rebleeding from a recently ruptured aneurysm during seizures may pose a serious risk.

Current guidelines from the AHA state that the use of anticonvulsants for a brief period is reasonable, without specific drug recommendation.[67] Beyond the immediate posthemorrhagic period, routine use of anticonvulsants is advocated by the AHA only in patients with a high risk for delayed seizures, such as prior seizure, intracerebral hematoma, intractable hypertension, infarction, or middle cerebral artery aneurysm. The Neurocritical Care Society (NCS) specifically recommended against the routine use of phenytoin for prophylaxis.[68]

Brain Tumors

The incidence of seizures in cerebral malignancy broadly ranges from about 10% to as high as 90%, and is correlated with tumor type (glioma and oligodendroglioma being amongst the highest risk) and also the rate of progression, with slow growing tumors tending towards higher seizure incidence.[69] Prophylactic use of AEDs in brain tumors remains controversial. There are strikingly little data in support of seizure prophylaxis for brain tumor patients,[70–72] and guidelines by the AAN and the European Federation of Neurosciences do not support this practice.[73,74] Since these guidelines were written prior to the widespread use of cEEG and prior to the introduction of newer, less toxic anticonvulsants (levetiracetam, lamotrigine, lacosamide, and so forth), some have suggested that such a recommendation should be reassessed.[75]

Whenever patients require adjuvant chemotherapy, it is prudent to avoid the use of potent CYP3A4 coenzyme inducers such as carbamazepine, phenytoin, and phenobarbital because of the risks of compromising concurrent chemotherapy.[74] Based on more recent evidence, more patients are being managed with levetiracetam than phenytoin or sodium valproate,[71] but evidence of superior efficacy remains absent.[72]

Cerebral Venous and Sinus Thrombosis

Seizures manifest as a common presentation, occurring in 29% to 50% of patients with cerebral venous sinus thrombosis.[76,77] Approximately a third to one half of seizures occur early—as the presenting symptom or within 2 weeks of diagnosis,.[77–79] Despite the lack of controlled studies, prophylaxis appears prudent where forthcoming seizures appear highly probable. There is some evidence that early seizures are predictive of a remote epilepsy condition[80] but, in and of themselves, seizures in the context of cerebral venous sinus thrombosis do not appear to be associated with death or 6-month worse outcomes.[81]