Hepatic encephalopathy (HE) is a brain dysfunction that frequently presents as a complication of acute liver failure, advanced liver disease, or portosystemic shunting manifesting with neuropsychiatric signs and symptoms that may be subtle such as impaired attention and sleep disturbances or altered mental status with personality changes, confusion, asterixis, and then coma [7]. The pathophysiology of seizures in HE is not well defined and likely multifactorial. Hyperammonemia and possibly presence of short-chain fatty acids, mercaptans, and phenols may be contributing factors [8, 9].

The EEG in HE has been associated with nonspecific findings such as a slow background, an initial increase then decrease in amplitude, and triphasic waves [10]; however epileptiform abnormalities and electrographic seizures are infrequent [11, 12]. In a retrospective investigation of 81 encephalopathic patients with prior orthotropic liver transplantation, 29 % of the 47 patients who died had epileptiform abnormalities and clinical or subclinical seizures on EEG vs. 6 % of the 34 patients who survived. Of the 11 patients who underwent autopsy, 10 were found to have serious cerebral structural changes, suggesting that encephalopathy with EEG epileptiform abnormalities after liver transplant may be associated with poor prognosis [13]. Animal studies of HE have demonstrated that several neuronal cell death mechanisms may be activated [14]. A prospective study in liver transplant patients demonstrated improved cognitive function but persistent brain atrophy following transplantation. Those with pre-transplant HE, diabetes, or alcoholic cirrhosis had lower posttransplant global cognitive scores, and pre-transplant HE was associated with smaller brain volumes [15]. These findings suggest that HE may be associated with neuronal loss [14, 15]. NCS/NCSE or HE should be considered in the differential diagnosis of altered mental status in patients with severe liver dysfunction. Although the incidence of seizures or NCSE in patients with HE is unknown [7, 8], case reports and retrospective studies suggest that seizures/NCSE may be rare and associated with a poor prognosis [9, 11, 16].

Chronic renal failure has been associated with NCS in critically ill patients. In a retrospective study of medical intensive care unit (MICU) patients undergoing continuous EEG without primary neurologic diagnosis, those with sepsis, chronic renal failure, and circulatory shock were significantly associated with NCS or periodic epileptiform discharges. Patients with NCS or periodic epileptiform discharges were associated with worse outcomes [4]. As in patients with HE, those with uremic encephalopathy may demonstrate similar nonspecific EEG findings of slow background and triphasic waves [12, 17].

Patients with renal failure and reduced creatinine clearance may be at increased risk of NCSE when exposed to medications or toxins, including use of beta-lactam antibiotics [17]. There are few published case reports/series of NCS/NCSE in chronic renal failure patients undergoing peritoneal dialysis [18] and hemodialysis [19]. A majority of those patients presented with acute confusion and were undergoing treatment with antibiotics for concomitant infections. (See Chap. 23 for Medication Induced NCS/NCSE.)

Hyponatremia has been documented in ~2.5 % of hospitalized patients and may present with nausea, confusion, and agitation; however, severe decreases may be associated with seizures, coma, and death [20]. Symptoms as well as EEG changes are strongly associated with the rapidity of the change rather than the actual sodium level [20]. The EEG pattern manifests with generalized slowing and in more extreme cases, posteriorly dominant background slowing that persists after sodium has normalized. Less common patterns include paroxysmal high-amplitude rhythmic delta activity, triphasic waves, central high-amplitude theta frequencies, stimulus-induced delta activity, and rarely lateralized periodic discharges [10, 12, 20, 21]. The EEG in NCSE due to hyponatremia without a history of epilepsy demonstrates generalized seizure patterns on a slow background; however generalized patterns that subsequently lateralized, thus suggestive of a focal onset, have also been reported [20].

Like hyponatremia, acute hypocalcemia manifestations are more strongly associated with the rate of change rather than absolute number. They range from tetany to agitation, confusion, psychosis, and in up to 70 % of patients, seizures [20, 21]. Infrequently, atypical absence and atonic seizures can be seen in hypocalcemia [21]. The EEG in hypocalcemic patients demonstrates generalized background slowing with paroxysmal theta/delta activity and hyperventilation-enhanced focal or generalized spike and spike-and-wave discharges. Hypocalcemic seizures in neonates have been associated with focal, rhythmic, high-voltage, and frontocentral epileptiform discharges that typically rapidly generalize. There are several case reports of NCSE solely or in part due to hypocalcemia, most of which were attributed to idiopathic or iatrogenic hypoparathyroidism, with associated EEG often demonstrating focal rhythmic epileptiform activity [21].

Hypercalcemia manifests with lethargy, confusion, and infrequently with coma. Because hypercalcemia results in reduced membrane excitability, seizures are rare and, if seen, may be due to calcitonin treatment, PRES, and vasoconstriction with epileptiform activity in the parieto-occipital regions [20]. Other EEG findings in hypercalcemic patients include generalized slowing with paroxysms of bifrontal theta/delta activity, prominent lambda waves and possible triphasic waves, and lateralized periodic discharges [20, 21].

Hyperglycemia may present with altered mental status, focal deficits, confusion, and seizures. Seizures, usually focal with or without altered consciousness, and NCSE are more common in nonketotic (vs. ketotic) hyperglycemia likely due in part to increased metabolism of gamma-aminobutyric acid, accumulation of lactate and adenosine, or concomitant electrolyte derangement. Hyperglycemic seizures may remain intractable to antiepileptic drugs until metabolic and glycemic abnormalities are corrected. Continuous EEG is indicated to distinguish between hyperglycemic encephalopathy and NCSE due to similarities in clinical presentation [20]. EEG changes are usually seen above 400 mg/dL with mixed slow and fast background, lateralized periodic discharges progressing to generalized medium-high-voltage delta/theta activity as serum concentrations increase. In patients with hyperglycemia-associated seizures, the EEG may demonstrate paroxysmal focal spike-and-wave discharges and focal medium- to high-voltage theta/delta transients, often in the parieto-occipital region suggestive of focal cortical irritability/cerebral dysfunction [20].