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Prophylactic antiepileptic drugs in Critical Care

"It ain't what people don't know, that hurt them,
It's what they know, that ain't so".
                                                   -Josh Billings

Evidence based medicine is quite frequently, not translated into, clinical practice. This may be due to the fact that, clinical practice is often guided by personal preference, and subjective sense of security, provided by conventional medical wisdom.

Use of prophylactic antiepileptic drugs (AED) in neurocritical care, is not an exception to this phenomenon.

Evidence suggests that, only in traumatic brain injury (TBI) and aneurysmal subarachnoid hemorrhage (aSAH), there may be some benefit of, short course prophylactic AED, by preventing early onset seizures.

●TRAUMATIC BRAIN INJURY (TBI):
Posttraumatic seizures (PTS) in TBI patients are classified as early posttraumatic seizure (occurring within first 7 days of injury) and late posttraumatic seizure (occurring after 7 days of injury). Incidence of early PTS is correlated with severity of injury, with higher incidence in penetrating injuries, skull fractures, sub dural hematoma, intracerebral hematoma, cortical contusions and low GCS. Prophylactic AED reduces incidence of early PTS, but has no effect on late PTS. However a cochrane systemic review showed that, seizure control in acute phase, does not reduces mortality or neurological disability.

•Recommendation: Brain Trauma Foundation (BTF):
○Prophylactic AED should be administered only for first 7 days after injury (II).

●ANEURYSMAL SUBARACHNOID HEMORRHAGE (aSAH):
Reported incidence of seizures is around 20%. Following aneurysm treatment and discharge, incidence of seizure appears low and is related to method of securing aneurysm, thickness of blood, aneurysm location, presence of subdural hematoma and secondary cerebral infarction. Long term follow up data from international subarachnoid aneurysm trial, showed a higher incidence of posttraumatic seizures, in patients treated with surgical clipping, compared to endovascular coiling. There is no RCT available to guide decision, on prophylaxis or treatment of seizure in aSAH. Available studies have demonstrated worse neurological outcome with prophylactic AED.

•Recommendation: ACC/ ASA 2012:
○Prophylactic AED may be considered in immediate post hemorrhagic period (class IIB).
○Routine long term use of AED is not recommended (class III), but may be considered in patients with prior seizure, intracerebral hematoma, intractable hypertension, infarction or aneurysm at MCA (class IIB).

●SPONTANEOUS INTRACEREBRAL HEMORRHAGE:
Incidence of early seizures has been reported as high as 16%. Continuous EEG has suggested subclinical seizures in 28-31% of patients, despite receiving AED. Reported incidence of late seizures is 2.6-10%.
Greatest risk of seizure is within the first few days, with over half occurring in the first 24 hour. Risk factors for seizures include severity of stroke, and cortical location of hematoma.
However, impact of clinical seizures in patients with ICH, has not been associated with worsened neurological outcome or mortality.
Most studies have shown that prophylactic AED is not associated with reduced risk of seizures. On the other hand it led to worse neurological outcome and increased mortality. However, in a recent large single centre study, prophylaxis AED significantly reduced incidence of clinical seizures after lobar ICH.

•Recommendation: AHA/ASA 2015:
○Prophylactic AED is not recommended (III B).
○Patients with a change in mental status, who are found to have electrographic seizures on EEG, should be treated with AED (I C).
○Continuous EEG is indicated in ICH patients with depressed mental status, that is out if proportion to the degree of brain injury (II A).

●ISCHEMIC STROKE:
Reported incidence of seizures range from 4-23%. There is no consensus on, how well the size of infarct, correlates with incidence of seizures. However there is general agreement that ischemic stroke is less epileptogenic than hemorrhagic stroke.

•Recommendation: ACC/ASA 2013:
○Prophylactic AED is not recommended  (III C).

●INTRACEREBRAL TUMOURS:
Seizures are presenting symptom in about 40% of patients with brain tumours. Seizures are more common in primary tumours than in metastatic lesions, low grade glioma than high grade glioma, and dysembryoblastic neuroepithelial tumours than with meningiomas.
However studies revealed that prophylactic AED is not effective in preventing seizures in patients, with a newly diagnosed brain tumour, and no prior history of seizures. In patients undergoing resection of intraparenchymal brain tumour, prophylactic AED does not reduce incidence of seizures, rather it is associated with higher adverse drug events.
AED are associated with significant drug interactions with commonly administered chemotherapeutic drugs, like erlotinib, gefitinib, temsirolimus and risk of serious cutaneous adverse events, such as stevens johnson syndrome and toxic epidermal necrolysis in patients undergoing radiation therapy.

•Recommendation: American Association of Neurology 2002:
○Prophylactic AED should not be routintly used in patients with primary brain tumour or metastatic lesion.

●Word of Caution:
All these recommendations are based on studies, that used either Phenytoin (ICH) or Phenytoin and other old AED, which are subject to significant adverse effect (fever, rashes), drug drug interaction, and require serum concentration monitoring, which may act as confounding factor.

Newer AED such as Leviteracetam and lacosamide have been shown to be safe.
Especially Leviteracetam which seems promising. It has been shown to be neuroprotective in animal studies. It also has advantage over other AED that, it does not require serum concentration monitoring, has favourable pharmacokinetic property, excellent bioavailability and no known drug interactions.

However, more studies are needed, of these newer AEDs, to support their use in seizure prophylaxis.




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