Tuesday, July 18, 2023

Neonatal hyperammonemia and cerebellar hemorrhages

This 36-week gestation baby was transferred from another hospital because of metabolic acidosis, respiratory distress, and abnormal movements. His mother’s pregnancy was complicated by maternal diabetes, premature rupture of membranes, and a three-day history of vaginal bleeding. He was born limp, lethargic, and cyanotic, with Apgar scores of 3 and 7 at one and five minutes. On day two of life, he developed metabolic acidosis and required intubation because of apnea. He exhibited abnormal facial movements and posturing that were suspected to represent seizures.

Phenobarbital and levetiracetam were halted after continuous electroencephalography showed no epileptiform discharges during the abnormal movements. Blood cultures and cerebrospinal fluid analysis were unremarkable aside from the spinal fluid protein of 240 mg/dL. An inborn error of metabolism was initially suspected because his serum ammonia was dramatically elevated at 1284 μg/dL. Urine organic acids, plasma amino acids, serum pyruvate, and carnitine were normal. However, next-generation DNA sequencing of serum confirmed evidence of Ureaplasma urealyticum, and he began azithromycin.

His hospital course was complicated and prolonged. His ammonia level increased to 1374 μg/dL despite infusion of sodium benzoate and sodium phenylacetate, and he began continuous kidney replacement therapy. At one week of age, he was documented to have multifocal cerebellar hemorrhages on ultrasound and computed tomography. He developed a thrombosis of the right external iliac and right common femoral veins and was anticoagulated with careful monitoring of the cerebellar hemorrhages. By three weeks of age, his condition had improved and his ammonia level had fallen to 63 μg/dL.

What caused this child’s hyperammonemia? Why did he develop cerebellar hemorrhages?

This child was first suspected to have seizures, but continuous electroencephalography showed no epileptiform discharges even during the movements. His serum ammonia level was dramatically elevated, but subsequent testing failed to identify an inborn error of metabolism. The cause of his hyperammonemia was quickly clarified by the presence of Ureaplasma urealyticum. These organisms release substantial amounts of ammonia during urea hydrolysis, sometimes leading to clinical hyperammonemia.1,2

The reason for the multifocal cerebellar hemorrhages is less certain. Cerebellar hemorrhages have been documented in children with organic acidemias.3-5 Propionic, methylmalonic, and isovaleric acidemia typically present in babies as acute metabolic decompensation and encephalopathy, often associated with hyperammonemia. We suspect that severe hyperammonemia, whatever its origin, may promote cerebellar hemorrhage in neonates. However, most of these children are seriously ill, so it is possible that other factors could be responsible.

When seen at 13 months of age, the child was thriving. He had experienced no seizures or periods of lethargy. He was starting to walk, playfully interacting, and saying several typical words.

Final Diagnosis

(1) Severe hyperammonemia due to Ureaplasma urealyticum sepsis and (2) bilateral cerebellar hemorrhages, possibly related to hyperammonemia.

References

Cheema F, Kutzler HL, Olowofela AS, et al. Successful management of noncirrhotic hyperammonemia syndrome after kidney transplantation from putative Ureaplasma infection. Transpl Infect Dis 2020;22:e13332.

Higgins AB, Farmakiotis D, Rogers R, et al. Hyperammonemia syndrome due to Ureaplasma urealyticum in a kidney transplant recipient: a case of disseminated disease from a fluoroquinolone-resistant isolate. Transpl Infect Dis 2020;22:e13328.

Dave P, Curless RG, Steinman L. Cerebellar hemorrhage complicating methylmalonic and propionic acidemia. Arch Neurol 1984;41:1293-1296.

Velasco-Sanchez D, Gomez-Lopez L, Vilaseca MA, et al. Cerebellar hemorrhage in a patient with propionic acidemia. Cerebellum 2009;8:352-354.

Fischer AQ, Challa VR, Burton BK, McLean WT. Cerebellar hemorrhage complicating isovaleric acidemia: a case report. Neurology 1981;31:746-748.

https://app.econnect.utexas.edu/e/es.aspx?s=1740541080&e=613405&elqTrackId=f0d6624887924d1e9a4f4b03108dd7d5&elq=05c82f186e854103a68695de2b387ea3&elqaid=32011&elqat=1

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