Several pathophysiologic mechanisms appear to underlie the effects of FLF on the brain and may contribute to the development of seizures. The hallmark pathological feature of hepatic encephalopathy is astrocytic swelling. Astrocytes are rich in the enzyme glutamine synthetase, which catalyzes the conversion of ammonia to glutamine. When hepatic failure occurs, excessive ammonia is available for metabolism by glutamine synthetase. Intracellular glutamine accumulates, causing astrocytic swelling, breakdown of the blood-brain barrier (BBB), and cytotoxic edema [6].

Excessive glutamate, a major excitatory neurotransmitter, has been implicated in the development of seizures [7]. FLF models have demonstrated decreased GLT-1, a glutamate transport protein present on astrocytes [8] leading to reduced glutamate reuptake. Glycine, which activates excitatory n-methyl- d -aspartate (NMDA) receptors , has also been implicated. A similar animal model of FLF demonstrated decreased expression of Glyt-1, a glycine transport channel. Cerebral microdialysis in these animals revealed approximately three times the extracellular glycine concentration compared to controls [9].

Increased GABA-ergic tone may also play a role in both encephalopathy and, by inhibiting interneuron populations, the development of seizures. Flumazenil, a GABA antagonist, transiently improves neurological function in patients with hepatic encephalopathy, but randomized controlled trials have not demonstrated durable improvements in recovery or survival [10]. In astrocytic tissue samples, reuptake of GABA is inhibited by ammonia at concentrations associated with the development of hepatic encephalopathy [11]. Rabbit models of FLF have shown that the activity of the GABA-metabolizing enzyme GABA-transaminase is decreased, further supporting a role for excessive GABA activity [12].

Seizures in the critically ill, particularly those in the medical or surgical intensive care unit, are typically nonconvulsive [13–15] and require continuous EEG (cEEG) monitoring in order to achieve sufficient sensitivity [15, 16]. In the early stages of hepatic encephalopathy, movement disorders such as asterixis/myoclonus may be difficult to distinguish from ictal movements such as clonus. cEEG, which includes video recording, is crucial to elucidate shaking or jerking spells observed in the ICU environment. Further complicating the clinical observation of seizures in patients with hepatic failure, patients with more severe hepatic encephalopathy (Grades III/IV) often require mechanical ventilation, analgosedation, and/or paralysis. These mask clinical seizure activity, and therefore the threshold for considering cEEG monitoring in patients with organ failure, including those with FLF, must remain low [17].

The background EEG of patients with liver failure is traditionally characterized by three stages correlating to the depth of coma [18]. Grade I/II encephalopathy is associated with θ frequency background slowing. As encephalopathy progresses, δ frequency slowing becomes more pronounced. Generalized, symmetric, and periodic waves described as “triphasic” in morphology appear—classically with a positive-polarity dominant second or third phase, a frontal predominance, and an anterior-posterior lag (Fig. 14.1). These were originally described in close association with liver failure [5], but subsequently these generalized periodic discharges with triphasic morphology have been reported across a variety of conditions including other organ failure syndromes and as the ictal pattern in some patients with seizures [19, 20]. The presence of generalized periodic discharges of any kind, including those with triphasic morphology, is highly associated with nonconvulsive seizures [21, 22], and others have observed that indeed seizures are more common in liver failure with brain dysfunction during this second stage. A third stage, consisting of a diffuse, asynchronous polymorphic δ pattern, is observed in the most severe stage of hepatic coma.

The largest series to date retrospectively studied 118 of 526 patients admitted with a diagnosis of hepatic encephalopathy undergoing EEG. EEGs were typically “routine” and not continuous 24 h EEG. 18 patients (15%) were noted to have epileptiform abnormalities on EEG, and electrographic status epilepticus (SE) was observed in five patients (4%). Epileptiform activity was related to clinical deterioration or death, suggesting an association with poor prognosis [23]. More recently, medical and surgical ICU cohorts undergoing cEEG have not shown a relationship between acute hepatic failure and the presence of periodic discharges or seizures [13, 14].

After transplant, epileptiform abnormalities may increase in incidence during the first 7 days, with an incidence of seizures up to 42 % [24]. Mechanisms by which seizures occur posttransplant may be related to immunosuppressant medications or withdrawal from GABA-ergic metabolites, both pharmacologic and endogenous, that occur with a newly functioning liver [25].

As with any seizures in the critically ill, initial steps in management include an assessment for readily reversible causes. Particularly in organ failure and endocrine crises, biochemical derangements such as hypoglycemia or hyponatremia are seen frequently and may act as a precipitant for seizures to develop. If these have been addressed, the choice of antiepileptic drug (AED) itself may be complicated: with the exception of levetiracetam, vigabatrin, pregabalin, topiramate, and gabapentin, almost all AEDs undergo some degree of hepatic conversion (Table 14.2). Further, patients with liver dysfunction exhibit several relevant physiologic changes that may also impact the decision about which AED to choose (Table 14.3).

Acute seizures and particularly SE should be treated as medical emergencies [26]. Benzodiazepines form the first line of therapy based on two randomized controlled trials for SE in the prehospital setting [27, 28]. Although benzodiazepines are extensively metabolized by the liver (Table 14.2), they are not considered hepatotoxic as a class and therefore are considered safe to use as first line in those with acute liver failure. Benzodiazepines with shorter t _1/2 such as lorazepam might avoid prolonged sedation and therefore may be preferred as an initial benzodiazepine. Further, lorazepam is metabolized by glucuronidation (along with older benzodiazepines oxazepam and temazepam), and therefore although liver failure may affect its overall clearance, there are no active metabolites formed that may prolong effects of the medication, as is the case with diazepam.

Several AEDs are known to have to direct hepatotoxic effects on the liver, particularly phenytoin and phenobarbital, which may rarely cause toxic or hypersensitivity hepatitides. Valproic acid is a short-chain branched carboxylic acid with multiple active metabolites, including 4-ene-valproic acid, which may exhibit hepatotoxicity. Through metabolites formed via the carnitine shuttle, hypocarnitinemia and hyperammonemia may develop even in those with normal liver function [29]. Valproic acid should be avoided in patients with hepatic failure where possible, and supplementation with l-carnitine should be considered if hyperammonemia or other signs of hepatic failure occur in the setting of valproic acid use [30].

Despite the association between liver failure with brain dysfunction and the development of seizures or epileptiform abnormalities on EEG, routine prophylaxis with AEDs is not currently recommended. Two studies have investigated the role of phenytoin for prophylactic use in hepatic failure [4, 31]. One study of 42 patients with Grade III/IV encephalopathy used the cerebral function monitor, a limited montage EEG-based signal processing method used in the OR or ICU setting. Electrographic seizures were documented in 15% of those randomized to phenytoin prophylaxis compared to 32% without phenytoin. Of the 25 that died, 19 were autopsied; significantly fewer in the prophylaxis group had cerebral edema [4]. However, in another study of 42 patients, no difference in clinical seizures, clinical manifestations of cerebral edema, or survival was observed when phenytoin was used prophylactically [31]. When cerebral edema and intracranial hypertension are present, prophylactic AEDs in general may serve to optimize patients who might otherwise not be operative candidates for liver transplantation. Given the potential for toxicity, larger studies are warranted before phenytoin is used as a primary agent; the authors prefer levetiracetam in those with hepatic failure. The authors recommend AEDs only for those patients with confirmed clinical or electrographic seizure activity, for those with EEG patterns highly associated with seizures (e.g., periodic discharges), or as prophylaxis in those in coma with global cerebral edema or other signs of elevated intracranial pressure.