Histopathological examination of characteristic brain MRI findings in acute hyperammonemic encephalopathy: A case report and review of the literature

Abstract

Introduction

Acute hyperammonemic encephalopathy is associated with distinct brain MRI findings, namely, hyperintensity in T2-weighted sequences as well as restricted diffusion in diffusion-weighted imaging with accentuation in the insular cortex and cingulate gyrus. The pathophysiology and the histopathological correlates of these characteristic MRI findings are largely unknown.

Case report

We present a 57-year-old male with a history of chronic alcohol abuse, liver cirrhosis and portal hypertension, and a clinical syndrome (variceal bleeding, depression of consciousness, seizures), elevated plasma ammonia levels, and characteristic brain MRI abnormalities suggestive of acute hyperammonemic encephalopathy. A postmortem histopathological examination revealed extensive hypoxic ischemic encephalopathy without evidence for metabolic encephalopathy. No episodes of prolonged cerebral hypoxemia were documented throughout the course of the disease. We conducted a review of the literature, which exhibited no reports of hyperammonemic encephalopathy in association with characteristic brain MRI findings and a consecutive histopathological examination.

Conclusion

This is the first report of a patient with acute hyperammonemic encephalopathy together with characteristic brain MRI findings and a histopathological correlation. Although characteristic MRI findings of acute hyperammonemic encephalopathy were present, a histopathological examination revealed only hypoxic pathology without signs of metabolic encephalopathy.

Introduction

Hyperammonemic encephalopathy characterizes a potentially reversible acute or chronic toxic metabolic impairment of brain function, leading to a variety of neurological and psychiatric manifestations and a high mortality rate. ¹ Symptoms range from mild changes in mental status through to coma. ¹ Acute hyperammonemic encephalopathy most often occurs alongside an underlying liver disease (the so-called hepatic encephalopathy), such as liver cirrhosis, alcohol-mediated liver disease, non-alcoholic fatty liver disease, viral hepatitis, urea cycle disorders, or primary biliary cholangitis. ¹ Elevated blood ammonia levels due to decreased elimination seem to be the primary factor responsible for brain toxicity. ¹ Further pathophysiologic aspects include neuroinflammation, oxidative stress, derangements in cerebral energy metabolisms as well as cerebrospinal fluid composition, and changes in blood–brain barrier permeability. ¹ Depending on the metabolic nature of the underlying cause of acute hyperammonemic encephalopathy, reversibility has been reported, especially after liver transplantation. ¹ However, more recent studies have indicated a certain irreversibility caused by neuronal cell death and neuroinflammation.^2,3

The exact mechanism for acute hyperammonemic encephalopathy is not yet known, since not every patient with an elevated ammonia level develops hyperammonemic encephalopathy. ⁴ An increased ammonia-to-glutamine conversion in cerebral ammonia detoxification seems to play a key role, especially in terms of the inadequate activation of protective compensatory cellular mechanisms in astrocytes (called Alzheimer type II astrocytes).^5,6 This is supported by MRI spectroscopy studies showing an increase in glutamine/glutamate and a decrease in myo-inositol and choline resonances.^5,7

Hyperammonemic encephalopathy leads to a variety of neuropsychiatric symptoms. In accordance with the West Haven classification, which describes neurological symptoms in hepatic encephalopathy, there are four grades of symptomatic manifestations. ⁸ Early symptoms are only identifiable with neurocognitive testing with a distinct focus on attention, working memory, psychomotor speed, and visuospatial ability. With disease progression, cognitive function decreases with obvious alterations in consciousness and motor function, increased daytime sleepiness, and the occurrence of personality changes. End-stage disease is characterized by coma. Motor system impairment includes muscle hypertonia, hyperreflexia, and positive pyramidal signs, as well as extrapyramidal manifestations such as hypomimia, muscular rigidity, brady-/hypokinesia, dyskinesia, slowness of speech, and Parkinsonian-like tremor. Comatose patients may have diminished deep tendon reflexes. Involuntary movements and seizures are rare findings. Asterixis, which is a negative myoclonus with the loss of postural tone, is a frequent observation in the early and middle stages of hyperammonemic encephalopathy. ⁸

Individual treatment depends on the severity of the disease. The superior goal is to maximize ammonia clearance and minimize ammonia production, since there are no current treatment options for other contributing factors. Furthermore, management of the precipitating factors is of great importance in hyperammonemic encephalopathy.^4,8 Lactulose is the first choice of treatment and is widely used for this disease. It has several mechanisms of action, including a laxative effect and a growth effect on beneficial microorganisms in the intestines. ⁸ As a non-absorbable antibiotic, rifaximin leads to decreased ammonia levels via alterations in the gut microbiota, especially in combination with lactulose. Rifaximin is effective as an add-on therapy to lactulose. Furthermore, it has anti-inflammatory effects.^4,8 Oral BCAAs, L-ornithine L-aspartate, neomycin, and metronidazole can be used as alternative or additional agents. In severe cases, extracorporeal albumin dialysis is a considerable treatment option. ¹ Liver transplant is considered as ultima ratio. ⁸ Nutritional management should also be taken into account. ⁹

Regarding the characteristic brain MRI findings of acute hyperammonemic encephalopathy of various etiologies in children and adults, specific regions of brain MRI abnormalities have been reported in the literature. T₂ and FLAIR hyperintensity as well as restricted diffusion in DWI with a corresponding decrease in the ADC signal predominantly involves the insular cortex and the cingulate gyrus in a mostly bilateral, symmetrical manner with frequent sparing of the perirolandic and occipital cortex. Abnormalities in other brain regions are more diffuse and variable in extent.^10–33 Leptomeningeal contrast enhancement in T₁-weighted contrast-enhanced MRI was reported in one study. ¹²

The purpose of this case report and literature review is to highlight and discuss the characteristic MRI features of acute hyperammonemic encephalopathy and to correlate them with postmortem neuropathological findings.

Case report

A 57-year-old male was admitted to the emergency department with acute gastrointestinal bleeding and somnolence. After a suspected seizure, melena, and deterioration in mental status, the airways were secured via endotracheal intubation and the patient was admitted to the intensive care unit. An upper endoscopy of the gastrointestinal tract presented a variceal hemorrhage as the most likely source of bleeding with gastroesophageal varices type II. Hemostasis was achieved with local cyanoacrylate. Furthermore, red blood cell transfusions and factors X, IX, VII, and II were administered.

The patient had a history of chronic alcohol abuse, liver cirrhosis and portal hypertension, and a withdrawal in a hospital setting 3 months prior. Plasma ammonia levels were within the normal range during the hospital stay for alcohol withdrawal. Plasma ammonia levels measured 1 day after admission showed significant elevation, to 104 µmol/L (reference 16–60 µmol/L), with a subsequent increase to 139 µmol/L 2 days later. Transaminases at admission showed slightly elevated AST (58 U/L, reference 10–50 U/L) and normal ALT. Gamma-GT was elevated to 217 U/L (reference <60 U/L). Following installation of dietary protein restriction and lactulose therapy, the plasma ammonia levels decreased to a normal range within 5 days. Due to recurring seizures during weaning, anticonvulsive therapy was initiated with levetiracetam and subsequently increased to a total daily dosage of 3 g. Acute seizures were treated with benzodiazepines and propofol. The seizure frequency decreased, and there were no further seizures after 13 days. Electroencephalograms were abnormal with amplitude depression and pseudoperiodic discharges in the central region, albeit without epileptiform discharges. The patient did not regain consciousness following the withdrawal of the pharmacologic sedatives. Cranial computed tomography scans showed diffuse edematous swelling with sparing of the central and occipital region. A subsequent brain MRI displayed cortical T₂ hyperintensity and restricted diffusion in DWI with accentuation in the insular cortex and the cingulate gyrus and sparing of the perirolandic and occipital region (Figure 1). The imaging findings were interpreted as cerebral edema in the context of acute hepatic encephalopathy. A follow-up brain MRI 17 days later showed the decreasing extent of swelling and restriction in the DWI, as displayed in Figure 1. The patient was transferred to a general ward after 22 days in the intensive care unit, with little improvement in mental status. A neurological examination at this time showed intermittent gaze fixation, mutism, spastic tetraparesis with only minimal spontaneous movement of the extremities, and positive left-sided Babinski reflex. Four days later, the patient died due to cardiovascular complications of pneumonia.

Figure 1.

Brain MRI of our patient on days 8 (a)–(d) and 25 (e)–(h) after admission. (a) DWI B1000 sequence on day 8 showing bilateral cortical restricted diffusion including the insular cortex and anterior cingulate gyrus and relative sparing of the medial occipital cortex and (b) the corresponding FLAIR sequence. (c) DWI B1000 sequence on day 8 displaying bilateral sparing of the central region and (d) the corresponding FLAIR sequence. (e) DWI B1000 sequence on day 25 showing a decreased extent of restricted diffusion and (f) the corresponding FLAIR sequence. (g) DWI B1000 sequence on day 25 with almost full regression of restricted diffusion in the frontal and parietal lobe and (h) the corresponding FLAIR sequence.

A postmortem histopathological examination of the brain, as displayed in Figure 2, showed extensive hypoxic ischemic encephalopathy without signs of acute metabolic encephalopathy. No prolonged episodes of hypoxemia had been documented during the course of the disease.

Figure 2.

Neuropathological findings: Severe hypoxic-ischemic damage in all neocortical regions and the cerebellum. (a) Coronal section, inset marks the right insular cortex (b) and the cingulate gyrus (c) stained with Luxol fast blue, revealing (d) marked cortical laminar damage with spongiosis of upper and middle cortical layers and severe neuronal depletion, most prominent in the upper cortical layers II and III (asterisk, hematoxylin and eosin [H&E]), (e), (f) associated reactive astrogliosis (white arrowheads in F, H&E) and infiltration by macrophages (black arrowhead in E, H&E), (g) staining for acid fuchsine shows prominent nuclear red staining in affected cortical neurons (arrows) indicating acute hypoxic-ischemic neuronal damage, and (h) severe Purkinje cell loss in the cerebellar cortex associated with proliferation of Bergmann glia (asterisk), with the remaining hypoxic neurons showing pronounced cytoplasmic eosinophilia and fading pyknotic nuclei. Immunohistochemical staining for (i) p62, a helpful marker for identifying Alzheimer type II astrocytes commonly found in metabolic encephalopathies, is ubiquitously negative, whilst staining for (j) glial fibrillary acidic protein (GFAP) and (k) HLA-DR demonstrate severe astrogliosis with laminar accentuation of the cortical lamina II and III as well as in the lower cortical layer V and VI, and prominent microglial activation, respectively, (l) with less involvement of the central regions (betz cells shown in inset, HLA-DR). Scale bars: (c), (l): 1 mm; (b) 500 μm; (d) 250 μm; (i)–(k) 100 μm, (e)–(h), (k) inset: 50 μm; (j) inset, (l) inset: 25 μm.

On 10 February, 2023, we conducted a literature search on PubMed that included the terms “acute hyperammonemic encephalopathy,” “acute hyperammonemic encephalopathy AND MRI,” and “acute hepatic encephalopathy AND MRI” to identify any English-language reports published since 1 January, 2000, of acute hyperammonemic encephalopathy with T₂ hyperintensity and restriction in DWI in the insular cortex and cingulate gyrus.

We identified 21 reports that included 56 patients. Characteristic bilateral abnormalities in T₂ sequences and DWI were seen in 51 patients (91%). Sparing of the occipital and/or perirolandic cortex was reported in 13 patients (23%). If this issue was not pointed out by the authors, the patients were labeled “0” in Table 1 (see Online Supplemental Data). Abnormalities in other cortical areas were found in 49 patients (88%). Ages ranged from 1 to 84 years, with a median age of 48 years. Twenty-five patients were female and 31 were male (f:m ratio of 1:1.2). The most common etiologies were liver cirrhosis and urea cycle disorder, with nine patients each (Table 1 in Online Supplemental Data).

Discussion

Besides characteristic neurological signs and symptoms, acute hyperammonemic encephalopathy can also show characteristic brain MRI abnormalities. This case report adds new histopathological information to the known clinical and imaging findings in acute hyperammonemic encephalopathy.

In 2001, Arnold et al. were among the first to report diffuse cortical swelling in the brain MRI of a patient suffering from acute hyperammonemic encephalopathy. Although the authors did not point out the location of the MRI abnormalities, predominant bilateral involvement of the insular cortex and cingulate gyrus in T₂-weighted sequences and DWI could be seen on the reported images. Sparing of the perirolandic and occipital cortex was also mentioned. ¹⁰

The largest cohort on this subject was published by Guo et al. in 2018. ¹² They retrospectively reviewed 25 liver transplant patients with acute hepatic encephalopathy as well as 40 liver transplant patients without neurological symptoms and with an underlying liver disease such as cirrhosis and carcinomas. All patients received brain MRI on admission and after symptom onset or 3 days after liver transplant. No cerebral lesions were found in patients without neurological symptoms. Of the 25 patients with acute hepatic encephalopathy, 21 (84%) presented with new-onset bilateral symmetric involvement of the insular cortex and cingulate gyrus, namely with hyperintensity in T₂-weighted sequences as well as restricted diffusion in DWI and diffuse variable and asymmetric swelling of other cortical areas. ¹² This is in line with previous reports, since almost all of the mentioned studies of this issue went on to describe diffuse cortical swelling in a variety of cortical areas without a striking resemblance to each other.^{10,11,14–23,25–32}

In our literature review, we found reports of 51 patients (91%) presenting with predominant bilateral T₂ hyperintensity and restricted diffusion in DWI in the insular cortex and cingulate gyrus in acute hyperammonemic encephalopathy of various etiologies and age, including acute hepatic encephalopathy due to an underlying chronic liver disease (which may be suspected by T₁ hyperintensity in the deep gray matter, such as the globus pallidus, putamen, subthalamic regions and substantia nigra due to accumulation of paramagnetic manganese),^5,34 medication-induced hyperammonemic encephalopathy, and urea cycle disorders.^{10–23,25–30,32} We also identified three cases (5%) with unilateral abnormalities,^11,24,31 as well as 13 cases (23%) where the unique sparing of the perirolandic and occipital cortex was emphasized.^{10,11,14,20–22,25,26,28,30,32} This number would probably have been higher, but many authors did not specify this issue in their reports, although images were frequently provided in the articles to suggest sparing of those areas. The brain MRI findings of our patient were consistent with the characteristic abnormalities of acute hyperammonemic encephalopathy reported in our literature review, including bilateral abnormalities in the insular cortex and cingulate gyrus with additional diffuse swelling in various other cortical areas and sparing of the perirolandic and occipital cortex. We found no report with a subsequent histopathological workup on this topic.

In our patient, postmortem histopathologic examination of the brain showed signs of an extended hypoxic ischemic encephalopathy with punctum maximum in the frontal regions (Figure 2). There was no histomorphological or immunohistochemical evidence of an acute metabolic encephalopathy, such as the identification of Alzheimer type II astrocytes. In hepatic encephalopathy, Butterworth described pseudolaminar cortical necrosis and neuronal cell loss from basal ganglia, thalamus, and cerebellum in a 47-year-old male, who died following acute hepatic encephalopathy after liver transplantation. As expected in hyperammonemic encephalopathy, these findings were accompanied by Alzeimer type II astrocytosis. ³⁵ The autopsy of our patient displayed edematous alterations with neuronal cell depletion in laminae 2–3 and 5–6 in the insular region without any demonstration of Alzheimer type II astrocytes, which would be typical for a hyperammonemic encephalopathy. In contrast to the frontal, temporal, and parietal lobes, the occipital lobes showed less pronounced edema and neuronal cell depletion, which is in line with the reported sparing of the occipital region in the brain MRI. The cingulate gyrus only displayed mild gliosis. Alongside neuronal cell depletion, there were also areas of diffuse and subpial gliosis in both insular cortices. Gliosis in the cingulate gyrus and insular cortices, as seen in our patient, has previously been reported in the literature during the disease course of acute hyperammonemic encephalopathy. Ito et al. and other authors reported a reduction in the extent of the T₂ hyperintense signal with residual gliosis and atrophy on follow-up MRI in patients without death due to complications, suggesting a certain reversibility of the MRI abnormalities.^{15,16,19,22,25,26,28,30} This is in accordance with the published data, which also display the possibility of clinical improvement in successfully treated patients.^{12,13,15,16,18,19,23–27,29,31,32}

The gliosis in the insular cortex and the cingulate gyrus in our patient may represent residual pathology after hyperammonemic encephalopathy, although no Alzheimer type II astrocytes were found in those regions, and neuronal cell depletion, a characteristic for hypoxic ischemic encephalopathy, was also present in the insular cortex.

In contrast to acute hyperammonemic encephalopathy, hypoxic ischemic encephalopathy most prominently includes diffuse swelling of the cerebral cortex with restricted diffusion in DWI in the basal ganglia and the hippocampus. ³⁶ No abnormalities were found in either MRI in those regions in our patient. However, the hippocampus and thalamus displayed signs of hypoxic ischemic encephalopathy in the pathology report. Muttikkal et al. reported seven MRI imaging patterns in 64 patients with hypoxic ischemic injury. The most observed pattern was diffuse cortical with deep gray matter and perirolandic involvement in 38 patients. Cortical and basal ganglia involvement with perirolandic sparing was reported in seven patients and would not fit the MRI imaging pattern of our patient, since deep gray matter was not affected. ³⁷ Lastly, the distribution pattern in hypoxic ischemic encephalopathy is not usually associated with the predominant involvement of the insular cortex and cingulate gyrus. Clinically, plasma ammonia levels can help distinguish between these two entities. ³⁶

The brain MRI abnormalities in our patient were not typical for hypoxic ischemic encephalopathy but compatible with acute hyperammonemic encephalopathy, whereas the histopathological report identified characteristics of hypoxic ischemic encephalopathy without signs of metabolic encephalopathy. Clinically, there was no documented prolonged episode of hypoxemia in our patient. As far as retrospectively accessible, the patient presented with a short episode of oxygen desaturation while staying in the emergency department during a seizure and subsequent melena, which led to endotracheal intubation. Maybe, this episode can explain the hypoxic ischemic encephalopathy seen in the pathology report and the acute findings of hyperammonemic encephalopathy have partially regressed, as MRI demonstrated.

Conclusion

We presented the first report correlating clinical findings, brain MRI abnormalities, and a postmortem histopathological workup for an adult patient with acute hyperammonemic encephalopathy. The histopathological correlates of the typical MRI findings of hyperammonemic encephalopathy in our patient suggest hypoxic ischemic encephalopathy rather than metabolic encephalopathy. Whether the brain MRI abnormalities resembled acute hyperammonemic encephalopathy and our patient developed hypoxic ischemic encephalopathy during the disease cannot be finally clarified. However, the histopathological signs of metabolic encephalopathy were absent. Further studies with postmortem histopathological examinations in acute hyperammonemic encephalopathy are warranted.

ORCID iD

Denk CH https://orcid.org/0009-0001-8308-8495