Delayed Cerebral Abnormalities in Acute Hyperammonemic Encephalopathy

Patients with acute hyperammonemic encephalopathy (AHE) present with impaired consciousness, seizures, and death due to the toxic effect of ammonia on the brain [1]. AHE can be caused by hepatic disorders, urea cycle disorders, and drugs, including antiepileptics [2].

The typical radiologic findings of AHE have been known as four different types: diffuse cerebral edema, extensive infarct-like abnormalities, ischemic lesions, and symmetric cortical involvement [3]. However, little is known about the time course of changes in imaging findings of AHE.

Here we describe a patient with cirrhotic AHE who presented with persistent disorientation. Her magnetic resonance (MR) images of the brain were normal on admission, which later showed bilateral cortical abnormalities.

An 81-year-old Japanese woman with hepatitis B virus-related cirrhosis admitted to our hospital because of impaired consciousness. Her heart rate was 103 beats per minute, blood pressure 154/72 mmHg, temperature 98℉, and respiratory rate 16 per minute. Neurological examination did not reveal neck rigidity and abnormal deep tendon reflexes. She was suspected of having hepatic encephalopathy because of asterixis and received branched-chain amino acids and lactulose. The plasma ammonia level was 322 μg/dL as seen in Table 1, and cerebrospinal fluid polymerase chain reaction for herpes simplex virus was negative.

Initial MR images of the brain showed no remarkable changes (Figure 1A). Electroencephalogram revealed triphasic waves.

She developed status epilepticus and was intubated on the third hospital day. MR images on day 11 showed symmetric abnormal signal intensity in the insular and cingulate cortices bilaterally, which suggested the toxic effect of accumulated ammonia (Figure 1B).

Her consciousness improved slightly after extubation on day 13, when the plasma ammonia level was 32 μg/dL. The abnormal signal intensity on the brain MR images partially improved on day 24, but her disorientation remained (Figure 1C). She was transferred to a long-stay hospital to continue rehabilitation on day 52.

Figure 1: MR images of the brain

(A) Initial MR images of the brain showing no remarkable changes. (B) MR images on day 11 showing symmetric abnormal signal intensity in the insular (arrows) and cingulate cortices (arrowheads) on diffusion-weighted imaging (DWI) and fluid-attenuated inversion recovery (FLAIR) imaging sequences. (C) MR images on day 24 showing improvement of the abnormal signal intensity.

We found out two important clinical issues. AHE can present as delayed cerebral abnormalities. Follow-up MR imaging is useful for the diagnosis of this condition.

First, AHE can present as late-onset abnormalities of the brain. Previous reports have described various radiographic findings of AHE (Table 2).

The mechanism of these findings has not been fully elucidated, but a major hypothesis is that glutamine produced from ammonia causes swelling of astrocytes, resulting in brain edema. Other hypotheses include the production of the neurotoxin alpha-ketoglutaramate [14]. However, several reports have described AHE patients whose radiographic findings of the brain were within normal limits. These patients might have presented with delayed cerebral edema if they had undergone follow-up imaging tests.

Second, follow-up MR imaging is useful in detecting late-onset cerebral abnormalities. Our patient showed prolonged MR imaging abnormalities, which seemed correlated with her persistent disorientation. Treusch and colleagues described a woman with HAE who became asymptomatic two weeks after onset when her MR images also became normal [8]. Although the relationship between abnormalities on MR images and neurological prognosis has not been investigated, follow-up MR imaging may be useful in predicting neurological recovery of HAE patients. The differential diagnosis of symmetric abnormal signal intensity in MR images includes posterior reversible encephalopathy syndrome, seizure activity, and diffuse hypoxic-ischemic injury [6].

The delayed imaging findings of diseases have well been described in other fields, which can be detected by follow-up imaging tests. For example, it has been known that patients with early pneumonia may not present with significant findings on chest radiographs [15]. Follow-up chest radiography is useful in diagnosing pneumonia in some of these patients [16]. Imaging tests should, if possible, be evaluated more than once to assess the state of diseases over time.

AHE can present as delayed cerebral abnormalities, and follow-up MR imaging is useful for the diagnosis of this condition. These abnormalities can be revealed in MR images several days after the serum ammonia level reaches its peak, and can be missed without follow-up imaging tests. Further reports should be accumulated to determine whether “hidden” AHE may be much more frequently present and whether follow-up imaging tests may contribute to picking up AHE patients with poor clinical outcomes.