This retrospective case series study included 5 patients >18 years of age, treated between January 2016 and December 2021 at King Fahad Specialist Hospital-Dammam (KFSH-D) (Dammam, Saudi Arabia). The patients were all identified to have documented hyperammonemic HE. The study was approved by the Ethics Committee of King Fahad Specialist Hospital Dammam (IRB-Pub-024-01). Written informed consent for publication was obtained from all subjects. Clinical and laboratory data were collected using electronic medical records for each patient. All 5 patients were critically ill in the intensive care unit (ICU) due to a decline in their level of consciousness. The patients underwent an MRI of the brain 3-10 days after the onset of symptoms. A neuroradiologist analyzed all the images. The common clinical features of the patients were that they presented with decreased levels of consciousness secondary to acute hepatic failure with hyperammonemia. The brain MRI of each patient was performed using a 3-T MRI scanner (Magnetom Skyra; Siemens Healthineers) with a 20-channel phased array head coil. The imaging protocol included axial and sagittal T1-weighted images, axial and coronal T2-weighted images, axial fluid-attenuated inversion recovery (FLAIR), axial susceptibility weighted imaging, axial echo-planar diffusion-weighted imaging and apparent diffusion coefficient map. Additional axial and sagittal T1-weighted images were recorded for 2 patients after administering the intravenous contrast agent.

A total of 5 patients (2 men and 3 women) were included in this study (Table I). The causes of hepatic failure were metastatic colon cancer, chronic inflammatory hepatitis in the background of sickle cell anemia, primary sclerosing cholangitis associated with ulcerative colitis, autoimmune hepatitis, and post-bypass surgery steatohepatitis, respectively. Plasma ammonia levels ranged from 165 to 512 µmol/l (normal range, 11-32 µmol/l). Diffuse cortical swelling was observed in the MRI brain scans of all patients, involving the frontal, temporal, and parietal lobes, as well as the insula. The underlying white matter, peri-rolandic area, and posterior occipital lobe were spared. These cortical MRI abnormalities have been shown to worsen with increased ammonia levels (Table I). In 4 of the 5 patients, the bilateral thalami were affected, and another patient showed a few focal ischemic lesions in the caudothalamic groove and splenium of the corpus callosum. Of the 5 patients, 2 survived, while 3 died due to septic shock and multiorgan failure.

A 37-year-old man with a known case of colon adenocarcinoma with liver metastasis was admitted electively in November 2017 under the care of the hepatobiliary team at KFSH-D for a hepatectomy. However, the procedure was complicated by portal vein air thrombosis and hypotension, necessitating an ICU admission. The serum ammonia level was significantly elevated at 165 µmol/l. Additionally, liver enzymes were increased, with an aspartate transferase (AST) level of 105 U/l (normal range, 8-38 U/l), an alanine aminotransferase (ALT) level of 228 U/l (normal range, 17-45 U/l), a total bilirubin level of 211 µmol/l (normal range, 4-21 µmol/l) and an international normalized ratio (INR) of 2.4 (normal range, 0.80-1.20). The patient's level of consciousness remained low even after sedation was stopped. Initially, the patient [Glasgow Coma Scale (GCS) score of 6/15] could open their eyes in response to painful stimulation, but had no verbal or motor responses, although the brainstem reflexes were intact.

Routine electroencephalography (EEG) showed generalized slowing within the delta range and no epileptiform discharges or electrographic seizures. The brain MRI on the seventh day post-surgery demonstrated bilateral symmetrical cortical edema with marked diffusion restriction involving the insula, temporal lobe, cingulate gyrus, and thalami (Fig. 1). After 10 days, the patient's condition deteriorated even more. The liver enzymes increased (AST, 84 U/l; ALT, 139 U/l; and total bilirubin, 245 µmol/l), and the serum ammonia level reached 188 µml/l due to acute liver failure. A subsequent follow-up MRI revealed an increase in bilateral symmetrical, predominantly cortical edema, with intermediate signal intensity on T2/FLAIR, but a decrease in diffusion restriction (Fig. 2). The patient exhibited marked improvement gradually throughout the month following the liver transplant. A follow-up was conducted in the clinic 2 months after discharge, and the patient was doing well. Furthermore, the follow-up lab results indicated a significant recovery of liver enzymes, with AST at 23 U/l, ALT at 24 U/l, and serum ammonia at 19 µml/l. However, the patient declined further brain imaging due to the resolution of the symptoms.

A 27-year-old man with a known history of sickle cell disease and chronic inflammatory hepatitis was admitted to the ICU of the Procare Hospital (Khobar, Saudi Arabia) with low consciousness and severe jaundice. In December 2018, the patient was transferred to KFSH-D, where a diagnosis of decompensated liver failure complicated by disseminated intravascular coagulation and multiorgan failure was formed based on clinical and laboratory findings. During the physical examination, it was observed that the patient was in a deep coma, with a GCS score of 3 out of 15 and intact brainstem reflexes. The patient exhibited generalized hypotonia and did not respond to painful stimuli. The deep tendon reflexes were decreased, and there was no bilateral reaction in the plantar reflexes.

Laboratory tests showed leukocytosis, with a white blood cell count of 28.3x10⁹/l (normal range, 3.4-9.6x10⁹/l), a low hemoglobin level of 5.8 g/dl (normal range, 13.6-16.9 g/dl), thrombocytopenia, with a platelet count of 58x10³/l (normal range, 152-324x10³/l), and a high ammonia level of 193 µmol/l. Liver function tests indicated a total bilirubin level of 886 µmol/l, a conjugated bilirubin level of 809 µmol/l (normal range, 0.8-3.0 µmol/l), an alkaline phosphatase (ALP) level of 405 U/l (normal range, 54-144 U/l), an ALT level of 137 U/l (normal range, 17-45 U/l) and an AST level of 263 U/l (normal range, 8-38 U/l). Renal function was also elevated, with a blood urea nitrogen (BUN) level of 50 mmol/l (normal range, 2.1-8.5 mmol/l) and a creatinine level of 256 µmol/l (normal range, 61.9-114.9 µmol/l). The brain MRI, taken 8 days post-admission (Fig. S1), showed bilateral, nearly symmetric cortical swelling, with FLAIR/T2 high signal intensity and diffusion restriction affecting the frontal, parietal, and temporal regions while sparing the peri-rolandic and occipital areas. The patient's clinical condition deteriorated steadily, and they succumbed to septic shock and multiorgan failure 2 weeks later.

A 36-year-old woman with ulcerative colitis (UC) underwent a deceased donor liver transplant (split liver) smooth surgery hepaticojejunostomy for primary sclerosing cholangitis in Feb 2021 at KFSH-D, and recovered without any complications. However, on the fifth day after surgery the patient's level of consciousness began to deteriorate. During a physical examination, while not sedated, it was noted that the patient had an elevated temperature of 38.1˚C, generalized jaundice, and a GCS score of 4 out of 15. The patient later experienced multiple generalized tonic-clonic convulsions, and the EEG showed generalized background slowing with epileptiform discharges. At that time, laboratory tests revealed high level of ammonia (512.75 µmol/l), liver enzymes (total bilirubin, 344.6 µmol/l; conjugated bilirubin, 259 µmol/l; ALP, 118 U/l; ALT, 1,325 U/l; and AST, 1,856 U/l) and renal function (BUN, 10.5 mmol/l; and creatinine, 179 µmol/l). The seizures were controlled using a midazolam infusion at 2 mg/h for 3 days. An MRI of the brain 3 days later showed diffuse symmetrical cerebral edema with high signal intensity and diffusion restriction, sparing the bilateral occipital lobes and peri-rolandic region (Fig. S2). The patient passed away on the next day.

An 18-year-old woman with autoimmune hepatitis was transferred from Aramco Hospital (Dhahran, Saudi Arabia) to the ICU at KFSH-D in February 2020. The patient had acute liver failure, decreased consciousness, and a new left-sided focal unaware seizure. The seizure was aborted after receiving levetiracetam loading of 3,000 mg over 10 min and a midazolam infusion of 2 mg/h over 24 h. The initial computed tomography brain scan (CT) showed cerebral edema, diffuse sulcal effacement, and crowding of the foramen magnum. The patient underwent a liver transplant procedure. Brain MRI 3 days later showed diffuse symmetrical cerebral cortical abnormalities with high signal intensity on T2-weighted imaging and FLAIR, affecting the splenium of the corpus callosum, the left Globus pallidus, bilateral thalamic regions, the posterior limb of the internal capsule, and the hippocampi. This was associated with diffusion restriction, but the occipital lobes and peri-rolandic region were spared (Fig. S3). After withdrawing the midazolam infusion, the physical examination showed a GCS score of 4 out of 15, with all brainstem reflexes intact, generalized hypotonia and hyperreflexia, and unresponsive plantar reflexes. Laboratory tests revealed an ammonia level of 310 µmol/l and elevated liver enzymes, with an ALT level of 5,075 U/l, an AST level of 1,914 U/l, and a total bilirubin level of 334 µmol/l.

A follow-up EEG showed a generalized slowing in the delta range, and no epileptiform discharges were present. Additionally, a follow-up MRI, conducted 10 days after the initial scan, showed interval evolution of the intraparenchymal changes (Fig. S4). The patient passed away due to septic shock and multiorgan failure after 39 days in the ICU.

A 51-year-old woman with a known case of hypothyroidism and a history of gastric bypass surgery complicated by steatohepatitis presented with impaired consciousness and jaundice. The patient was admitted to KFSH-D in December 2018 through the Emergency Department with acute-on-chronic liver failure and pulmonary edema that required intubation. The patient's level of consciousness deteriorated within 3 days. Upon examination, the patient was unresponsive, with a GCS of 5 out of 15, and preserved brainstem reflexes. Laboratory investigations revealed a high serum ammonia level of 174 µmol/l, mildly elevated liver enzymes (AST, 93 U/l; and ALT, 63 U/l), and a total bilirubin level of 158 µmol/l. The EEG results showed generalized slowing of the background without epileptiform discharges. A brain MRI scan performed 10 days after the onset of symptoms showed bilateral asymmetric cortical swelling and diffusion restriction in the insula, cingulate gyri, and bilateral hippocampi, with corresponding T2/FLAIR hyperintensity and T1 hyperintensity sparing the occipital lobes and peri-rolandic region (Fig. S5). The patient experienced a prolonged generalized convulsion for 30 min, which was controlled with levetiracetam in a 3,000-mg intravenous infusion over 15 min, followed by 750 mg orally twice and lamotrigine at 50 mg twice. The patient's condition improved as the seizure subsided and the ammonia level normalized, but residual memory impairment was still present. A follow-up brain MRI revealed complete resolution of the cortical and subcortical T2 and FLAIR high signal intensities, along with marked bilateral symmetrical brain atrophy (Fig. S6). The patient was regularly followed up by the neurology team and remained seizure-free after adding phenytoin at 100 mg every 12 h to the treatment, but still complains of memory impairment.