Acute Hyperammonemic Encephalopathy in Adults: Imaging Findings

Discussion

All our 4 patients were very ill and were being treated in the ICU. In all cases, extensive cortical signal-intensity changes, with associated restricted diffusion, were seen; these features are in keeping with early changes seen in hyperammonemic encephalopathy. These early imaging findings are not well-recognized in the adult literature; for example, in their comprehensive review of MR imaging findings in hepatic encephalopathy published in the American Journal of Neuroradiology in 2008, Rovira et al¹⁰ only discussed MR spectroscopic findings and late changes such as cerebral edema and brain herniation in the setting of fulminant hepatic failure and hyperammonemia.

Bilateral involvement of the insular cortex and cingulate gyrus was a strikingly common feature, seen in all our 4 patients, and these findings have also been described in several other cases, mainly in the pediatric literature.^4,11

Bindu et al⁴ reported 3 cases of hyperammonemic encephalopathy in children due to various causes including infantile citrullinemia, acute hepatic encephalopathy, and proximal urea cycle disorder, with similar cortical abnormalities and involvement of the insular and cingulate cortices. Takanashi et al¹¹ described 3 cases of acute hyperammonemic encephalopathy arising from late-onset ornithine transcarbylamase deficiency, all with evidence of injury to the cingulate and insular cortices, and they described sparing of perirolandic and occipital cortices.

Involvement of brain regions other than the insular or cingulate gyrus was clearly more variable. Unlike the cases described by Takanashi et al,¹¹ involvement of the occipital or perirolandic cortex was seen in 2 of our cases (patients 1 and 3, respectively). Additional sites of involvement, such as the basal ganglia, brain stem, and thalami, were seen in 1 patient only (patient 2). Brain stem involvement was also reported by Arnold et al,¹² who described extensive cortical changes in an adult patient with hepatic encephalopathy, which were initially reported as diffuse ischemic injury. Although the involvement of insular and cingulate cortices was not emphasized, this can clearly be seen on the MR images provided in their article.

Other causes of hyperammonemic encephalopathy with similar imaging findings include valproic acid−induced hyperammonemia and adult-onset citrullinemia.^7,13,14

Patient 1 also had signal-intensity change involving the subcortical white matter in addition to the cortical abnormalities; this pattern is recognized in the pediatric literature in patients with inborn errors of metabolism, in which subcortical white matter involvement may often predominate over cortical signal-intensity changes.³ Thus, it is plausible that both the cortical and subcortical changes are due to the same underlying etiology. Subcortical white matter involvement was not seen in 2 of the other patients in our series, though subtle subinsular changes were seen in patient 3. It is possible that this pattern is only seen at higher plasma ammonium levels, as in the case of patient 1, who had the highest plasma ammonium level at 168 μmol/L.

Three of our cases were related to hepatic failure (1 acute fulminant hepatic failure and 2 others with sepsis and a background of chronic hepatic failure), and 1 case was seen post–heart-lung transplantation. Hyperammonemic encephalopathy post–orthotopic lung transplantation without evidence of hepatic dysfunction has been well-described; in the series by Lichtenstein et al,² 4 of 6 cases resulted in fulminant and fatal cerebral edema. The authors postulate a multifactorial etiology including immunosuppressive drugs, TPN, and medical stressors such as major gastrointestinal complications.

Most of the patients in our series had a number of systemic problems, and we are unable to completely exclude the fact that the MR imaging changes could potentially be partly due to other factors such as hypoxic injury or seizure activity. However, the changes in the cingulate and insular gyri were very symmetric, more in favor of a toxic encephalopathy. Moreover, it is very plausible from the striking similarity among our cases and others reported in the literature, that the imaging pattern described is directly related to hyperammonemia rather than to seizure or hypoxic injury or to the various causative underlying conditions, whether hepatic failure, post-lung transplantation, or inborn errors of metabolism.¹⁵

Ammonia is produced mainly in the gastrointestinal tract as a by-product of protein digestion and bacterial metabolism.¹⁶ It is metabolized primarily in the liver as urea through the urea cycle, where several key enzymes include carbamyl phosphate synthetase and ornithine transcarbamylase.^1,16 When the metabolic capacity of the liver is overwhelmed, elimination becomes dependent on the kidneys, brain, and skeletal muscle. In the brain, astrocytes rapidly metabolize ammonia and glutamate to glutamine via the glutamine synthetase pathways; however, this is physiologically costly and the subsequent rapid increase in cellular osmolarity causes astrocyte swelling and loss.¹⁷ Inflammatory cascades, apoptosis, and various metabolic pathways are triggered, resulting in elevation in lactate, loss of cerebral autoregulation, and cerebral edema.¹⁶ This mechanism is supported by MR spectroscopy, which has shown high glutamine concentration in affected areas in patients with urea cycle disorders.¹⁸ It is not known why the insular and cingulate cortices seem particularly susceptible to the toxic effects of hyperammonemia. Most interesting, Takanashi et al¹⁹ described 3 cases of neonatal hyperammonemic encephalopathy from proximal urea cycle disorders with a slightly different pattern, with involvement of the lentiform nuclei, insular sulci, and perirolandic regions. They postulated that these may be more metabolically active brain areas in the neonatal period and suggested that hypoperfusion and ischemia may be playing a part in the mechanism of injury in the setting of raised intracranial pressure.

Cortical changes in hyperammonemic encephalopathy have been shown to be potentially reversible¹⁴ or to result in variable amounts of atrophy in the cingulate and insular cortex after treatment (seen in patient 3).^4,11,13 Our findings support the general view that these cortical changes appear to be early imaging findings and potentially reversible if aggressive treatment is instituted.^4,11 The extent of injury may be dependent on the severity and duration of the hyperammonemia and predisposing susceptibility to the metabolic insult.^2,11 Our data also suggest that the plasma ammonium levels may reflect the extent of injury. While coma, cerebral edema, and brain herniation are usually seen at higher levels of plasma ammonia (at least 4 times the normal range), early clinical manifestations of hyperammonemia (eg, anorexia, irritability, lethargy, vomiting, somnolence, disorientation) can be seen with lower plasma ammonia levels of ≥60 μmol/L, and our findings suggest that early MR imaging changes can be seen at such levels.²⁰ Patient 4, with the lowest plasma ammonium level (55 μmol/L), had the least extensive MR imaging changes and made an excellent recovery without significant neurologic deficit. Patient 3, with plasma ammonium levels of 82 μmol/L, survived with severe intellectual impairment. Both patients with plasma ammonium levels of 102 μmol/L (patient 2) and 186 μmol/L (patient 1) did not survive, and patient 1, with the highest plasma ammonium levels, proceeded to fulminant cerebral edema and brain herniation as demonstrated on CT.