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Cranial MRI in Acute Hyperammonemic Encephalopathy
mal findings, or at best reveal diffuse atrophy. The diagnostic role of magnetic resonance imaging in acute hyperammonemic encephalopathy merits further consideration. Described here are the magnetic resonance imaging observations in three cases of hyperammonemic encephalopathy, each with a different cause. Case Reports
Parayil S. Bindu, DM*, Sanjib Sinha, DM*, Arun B. Taly, DM*, Rita Christopher, MD†, and Jerry M. E. Kovoor, MD‡ Cranial magnetic resonance imaging was performed in three cases of acute hyperammonemic encephalopathy with three diverse etiologies: infantile citrullinemia, acute hepatic encephalopathy, and proximal urea cycle disorder. All three patients exhibited diffuse extensive cortical signal changes and swelling. Neurologic outcome was poor in all three cases. Knowledge of the magnetic resonance imaging findings of hyperammonemic encephalopathy may help in early diagnosis and treatment and could influence the neurologic outcome. Ó 2009 by Elsevier Inc. All rights reserved. Bindu PS, Sinha S, Taly AB, Christopher R, Kovoor JME. Cranial MRI in acute hyperammonemic encephalopathy. Pediatr Neurol 2009;41:139-142.
Introduction Hyperammonemia in children may be detected in a variety of conditions, including urea cycle disorders, hepatic encephalopathy, Reye’s syndrome, and other metabolic or toxic encephalopathies. Prolonged hyperammonemic encephalopathy could lead to substantial parenchymal brain injury, and surviving patients develop impairment of intellectual function [1,2]. Few reports are available on magnetic resonance imaging in acute hyperammonemic encephalopathy, and different patterns of imaging findings have been described [3]. Moreover, it is often believed that magnetic resonance imaging might reveal only nor-
From the *Departments of Neurology, †Neurochemistry, and ‡ Neuroimaging and Interventional Radiology, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, India.
Ó 2009 by Elsevier Inc. All rights reserved. doi:10.1016/j.pediatrneurol.2009.02.012 0887-8994/09/$—see front matter
Patient 1 A 1-year-old boy presented with recurrent seizures, loss of acquired milestones, irritability, and frequent inconsolable crying spells of 20 days duration. There was a history of recurrent vomiting from early infancy. He had had left-side focal motor seizures with secondary generalization from the age of 3 months and was taking 30 mg daily of phenobarbital for control of seizures. He was born by cesarean section to healthy consanguineous parents. Birth and perinatal history were unremarkable. Initial developmental milestones were within normal limits. He could walk without support, identify family members, and use a few meaningful words. There was no particular dislike of proteinaceous food. There was no similar history in the family. He was alert and irritable, and had frontal bossing and hypopigmented scalp hair. He did not make eye-toeye contact, and exhibited motor stereotypies. He had brisk muscle stretch reflexes, with apparent normal muscle power and tone in the limbs. Plantar response was extensor bilaterally. There was tremulousness of the limbs as he reached for objects. No other findings from the examination were remarkable. Routine blood and urine findings were within normal limits. Biochemical parameters including liver function tests were normal. The serum ammonia level was high: 565 mmol/L (normal range, 11-35 mmol/L). High performance liquid chromatography of blood revealed high levels of glutamine (1078 mmol/L; normal, 690 73 mmol/L) and citrulline (974 mmol/L; normal, 45 12 mmol/L), indicating argininosuccinate synthase deficiency. Cranial magnetic resonance imaging demonstrated hypointensities involving the cerebral cortex in T1-weighted images; the T2-weighted and fluid attenuated inversion recovery images revealed symmetric hyperintensities of the temporal, insular, and parietal cortices and in the right frontal cortex (Fig 1a). These areas had a restricted diffusion on diffusion-weighted images (Fig 1b,c). Focal atrophy and ulegyric changes were noted in the left frontal lobe (Fig 1a). The occipital cortex, deep ganglionic structures, cerebellum, and brainstem were spared.
Patient 2 A 4-year-old boy was referred for evaluation of mental retardation, hyperactivity, and refractory myoclonic seizures. He was the first child born at term in normal delivery without any complications to healthy nonconsanguineous parents. His initial developmental milestones were normal. At 10 months of his age, he required prolonged hospitalization for unexplained fever and one episode of seizure. At that time, he was detected to have pallor, jaundice, hepatosplenomegaly, and altered liver function and was
Communications should be addressed to: Dr. Sinha; Department of Neurology; National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore 560 029, Karnataka, India. E-mail:
[email protected] Received October 20, 2008; accepted February 23, 2009.
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Figure 1. Cranial magnetic resonance imaging in acute hyperammonemic encephalopathy: patient 1, infantile citrullinemia. (a) T2-weighted axial image demonstrates hyperintensity and swelling diffusely involving the cerebral cortex and sparing the occipital cortex. Note atrophy and ulegyric changes in the left frontal lobe (TR/TE = 4200/120 ms). (b) Diffusion-weighted and (c) apparent diffusion coefficient (ADC) mapping axial images show restricted diffusion in the corresponding areas. Diffusion weighting b = 1000 s/mm2 by slice selection gradient. diagnosed to have hepatic encephalopathy. He was later evaluated for persistent hepatosplenomegaly. The serum ammonia level was high (248 mg/ dL; normal: 5-35 mg/mL). Liver biopsy revealed bridging fibrosis, moderate portal and lobular inflammation, and focal microvesicular steatosis. Bone marrow aspiration, however, did not reveal any storage cells. At the time of examination at 4 years, he was alert and hyperactive, and had repeated myoclonic seizures. Anthropometric measurements were below the third centile for age. Multiple injury marks were noted on the forehead, due to repeated falls. Neurologic examination revealed increased tone in the lower limbs, with brisk muscle stretch reflexes and extensor plantar response. Disorder of urea cycle was excluded by the normal serum amino acid profile obtained with high performance liquid chromatography. Cranial magnetic resonance imaging, done during hepatic encephalopathy, revealed extensive cortical signal changes and swelling in the frontal, temporal, insular, parietal, and occipital cortices bilaterally (Fig 2a,b). Followup magnetic resonance imaging after 3 months revealed profound cerebral atrophy and white matter signal changes (Fig 2c,d).
Patient 3 A girl aged 3 years and 8 months presented with episodic encephalopathy characterized by vomiting ataxia, altered sensorium, and seizures. Her physical examination was unremarkable. She had hyperammonemia, with serum ammonia at 387 mmol/L (normal range, 11-35 mmol/L). A proximal urea cycle disorder similar to ornithine transcarbamylase or carbamoyl phosphate synthase deficiency was diagnosed, based on the findings of elevated glutamine and low normal citrulline level on plasma aminoacidography. Magnetic resonance imaging during the third hyperammonemic episode revealed extensive and almost diffuse hyperintensity in T2-weighted images of cerebral cortex, along with swelling of the cortex (Fig 3a,b). The T1-weighted image demonstrated more hypointense signal of the insular cortex. Occipital cortex and cerebellum were spared.
Discussion Extensive cortical signal changes were observed in three patients with hyperammonemia due to different underlying etiology. Takanashi et al. [3] have classified magnetic resonance imaging findings in hyperammonemic encephalopathy into four important groups: (a) diffuse cerebral edema followed by diffuse cerebral atrophy, (b) extensive infarct-like abnormality often presenting as acute hemiplegia, (c) ischemic lesions in cerebral vascular territory, and (d) reversible symmetric cortical involvement of the
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cingulate gyri, temporal lobes, and insular cortex with sparing of the perirolandic cortex [3]. In the present patients, the changes on magnetic resonance imaging are close to those of the last group (d), but the changes were far more extensive and diffuse. Cortical signal changes limited to insular and cingulate cortex were reported in three patients with ornithine transcarbamylase deficiency [4]. Similar observations have been documented in some patients with hyperammonemia due to citrullinemia and valproic acid-induced hyperammonemia [5,6]. In a case of acute hepatic encephalopathy, Arnold et al. [7] reported that magnetic resonance imaging demonstrated widespread cortical signal intensity changes, with sparing of perirolandic and occipital cortices. In the child with citrullinemia (present patient 1), there was diffuse involvement except for the occipital cortex. An almost identical pattern of involvement was reported earlier in this patient with a proximal urea cycle disorder [8], the same etiology as present patient 3. The atrophy and ulegyric changes involving the left frontal lobe in the patient with citrullinemia is also noteworthy. This has been corroborated in earlier reports and is due to recurrent hyperammonemic episodes [9]. Atrophy and ulegyric changes are mentioned as the most important neuropathologic finding in patients with citrullinemia [10]. The reason for regional variation in signal changes in different reports is not clear. Involvement of insular and cingulate cortices has been noted in all the patients. The extent of damage might possibly be related to the extent and duration of hyperammonemia. Based on the present cases and previous studies, it might be reasonable to assume that variable degree and extent of swelling and signal changes in the cortex could be detected in acute hyperammonemic encephalopathy. More important, the timing of magnetic resonance imaging study might be crucial in detecting these lesions. As noted in the patient 2 (the child with a hepatic disease), a follow-up magnetic resonance imaging did not show the same features, although elevated ammonia levels persisted. Alternatively, the atrophy and signal changes might be secondary to the damage caused by the acute
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Figure 2. Cranial magnetic resonance imaging in acute hyperammonemic encephalopathy: patient 2, acute hepatic encephalopathy. (a) T2-weighted and (b) FLAIR axial images demonstrate diffuse cortical involvement including occipital cortex. (c) T2-weighted and (d) FLAIR axial images after 3 months demonstrate gross cerebral atrophy and white matter signal intensity changes. T2-weighted images: TR/TE = 4200/120 ms; FLAIR images: TR/TE = 9000/ 119 ms.
hyperammonemia, illustrating the devastating central nervous system consequences of hyperammonemia. The underlying mechanisms of central nervous system injury in hyperammonemic encephalopathy are variably described in literature. Most often intracerebral accumulation of glutamine is the major cause of the encephalopathy [11]. High levels of ammonia result in conversion of large amounts of glutamate to glutamine by glutamine synthetase, which occurs in astrocytes. This in turn causes changes in intracellular
osmolality and results in astrocyte swelling, brain edema, intracranial hypertension, and cerebral hypoperfusion. This hypothesis is further supported by the fact that impeding glutamine accumulation in the brain can prevent the cerebral edema associated with hyperammonemia. In addition, proton magnetic resonance spectroscopy has demonstrated high glutamine concentration in the affected areas in such patients [12,13]. (No magnetic resonance spectroscopy was performed with any of the present patients.)
Figure 3. Cranial magnetic resonance imaging in acute hyperammonemic encephalopathy: patient 3, proximal urea cycle disorder. T2-weighted coronal (a) and axial (b) images demonstrate swelling and hyperintensity involving the cerebral cortex (TR/TE = 4200/120 ms).
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In conclusion, imaging findings in three patients with hyperammonemic encephalopathy due to three different causes revealed the extensive nature of the cortical signal changes, in contrast to previous reports. The similar pattern of involvement in the three patients stresses the importance of pattern recognition for magnetic resonance imaging in children with neurometabolic disorders. In a patient with recurrent encephalopathy or suspected neurometabolic disorder, diffuse or selective involvement of the cortex during an ictus might suggest a diagnosis of hyperammonemia and might aid in choosing further investigations. Regardless of the etiology, hyperammonemic encephalopathy can lead to poor neurologic outcome, as was observed in these patients. Unless therapy is started during the earliest stages of hyperammonemic coma in infants, most are likely to be severely handicapped. Understanding of the magnetic resonance imaging findings of hyperammonemic encephalopathy can help in early diagnosis and treatment. References [1] Msall M, Batshaw ML, Suss R, Brusilow SW, Mellits ED. Neurologic outcome in children with inborn errors of urea synthesis: outcome of urea-cycle enzymopathies. N Engl J Med 1984;310: 1500-5. [2] Uchino T, Endo F, Matsuda I. Neurodevelopmental outcome of long-term therapy of urea cycle disorders in Japan. J Inherit Metab Dis 1998;21(Suppl. 1):151-9.
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[3] Takanashi J, Barkovich AJ, Cheng SF, et al. Brain MR imaging in neonatal hyperammonemic encephalopathy resulting from proximal urea cycle disorders. AJNR Am J Neuroradiol 2003;24:1184-7. [4] Takanashi J, Barkovich AJ, Cheng SF, Kostiner D, Baker JC, Packman S. Brain MR imaging in acute hyperammonemic encephalopathy arising from late-onset ornithine transcarbamylase deficiency. AJNR Am J Neuroradiol 2003;24:390-3. [5] Chen YF, Huang YC, Liu HM, Hwu WL. MRI in a case of adultonset citrullinemia. Neuroradiology 2001;43:845-7. [6] Baganz MD, Dross PE. Valproic acid-induced hyperammonemic encephalopathy: MR appearance. AJNR Am J Neuroradiol 1994;15: 1779-81. [7] Arnold SM, Els T, Spreer J, Schumacher M. Acute hepatic encephalopathy with diffuse cortical lesions. Neuroradiology 2001;43: 551-4. [8] Bindu PS, Sinha S, Taly AB, et al. Extensive cortical magnetic resonance signal change in proximal urea cycle disorder. J Child Neurol 2007; 22:238-9. [9] Albayram S, Murphy KJ, Gailloud P, Moghekar A, Brunberg JA. CT findings in the infantile form of citrullinemia. AJNR Am J Neuroradiol 2002;23:334-6. [10] Martin JJ, Farriaux JP, De Jonghe P. Neuropathology of citrullinemia. Acta Neuropathol 1982;56:303-6. [11] Brusilow SW, Horwich AL. Urea cycle enzymes. In: Scriver CR, Beaudet AL, Sly WS, Valle D, editors. The metabolic and molecular bases of inherited disease. 8th ed. New York: McGraw-Hill, 2001:1909-63. [12] Choi CG, Yoo HW. Localized proton MR spectroscopy in infants with urea cycle defect. AJNR Am J Neuroradiol 2001;22:834-7. [13] Takanashi J, Kurihara A, Tomita M, et al. Distinctly abnormal brain metabolism in late-onset ornithine transcarbamylase deficiency. Neurology 2002;59:210-4.
