Acute hydrocephalus in nonketotic hyperglycinemia

Case reports.

Case 1.

In the first 3 days of life, this baby girl became hypotonic and lethargic, had clonic movements, and was intubated for apnea. Electroencephalogram showed a burst suppression pattern. The plasma glycine level was 830 μM, the CSF glycine level was 218 μM, with a CSF to plasma glycine ratio of 0.26. Urine organic acids were normal. A diagnosis of NKH was made, and she was treated with 500 mg/kg of sodium benzoate per day, 7.5 mg/kg of dextromethorphan per day, ranitidine, phenobarbital, and d-serine. A CT scan on day three of life showed mild dilatation of the lateral ventricles posteriorly greater than anteriorly, as would be seen in partial absence of the corpus callosum (figure, A). The ventricular dilatation was slightly increased at the end of the first week. There was no evidence of brain atrophy. Infantile spasms appeared at age 31/2 months and were treated with vigabatrin. At age 41/2 months, an acute increase in head circumference to above the 95th percentile was associated with vomiting, a bulging fontanel, and increased flexor spasms. Computed tomography scan showed pronounced enlargement of all ventricles with effacement of sulci, and decreased attenuation around the frontal horns suggestive of transependymal egress of fluid (figure, B). Dilatation of the optochiasmatic cistern suggested that hydrocephalus had been present for some time before the scan. A ventriculoperitoneal shunt was placed, and MRI showed a decreased ventricular size (figure, C). On sagittal images (figure, D), the corpus callosum was markedly thinned. There was a posterior fossa cyst that caused anterior and superior displacement of the cerebellar vermis. This was not noticeable on the images in the first week of life. There was no evidence of gyral malformations. Myelination was absent in the internal capsule and in the dorsal brainstem. Follow-up MRI 10 months later showed persistent ventriculomegaly. At age 1 year and 5 months, the patient had severe axial hypotonia, hyperreflexia, and dystonic posturing. She had no grasp reflex. She reacted to sound and touch, but not to visual stimuli. Gastrostomy tube feeding was required. Her head circumference had decreased to the 95th percentile. Medications included sodium benzoate, dextromethorphan, and vigabatrin.

• Download figure
• Open in new tab
• Download powerpoint

Figure. CT scan of Patient 1 taken in the first week of life (A), CT scan taken at age 41/2 months at the time of the hydrocephalus (B), and MRI imaging after shunting at age 5 months in the axial (C) and sagittal plane (D).

Discussion.

In all four patients, acute hydrocephalus occurred between ages of 2 to 6 months, requiring urgent ventriculoperitoneal shunting. Hydrocephalus had not been reported previously in NKH. Hydrocephalus presented with increasing irritability, increased seizures, papilledema, and increasing head size to greater than the 95th percentile. It involved the supratentorial ventricles in two patients, and all four ventricles in two patients. There was no increase in extra axial spaces to suggest impaired resorption of CSF by the arachnoid granulations. All four patients had a large retrocerebellar cyst that had not been noted before the acute hydrocephalus. The association of the large posterior fossa cystic malformation with obstructive hydrocephalus suggests a decompensation of a preexisting developmental malformation. The temporal relationship of the development of hydrocephalus and enlargement of the posterior fossa cyst suggests a possibly causal relationship.

Thin or absent corpus callosum has been reported in NKH as early as the first week of life.3,4 Pathology has shown cystic myelinopathy and gliosis,6,7 a usual preservation of gray matter,7 and a loss of Purkinje cells and granular neurons in the cerebellum.8,9 Magnetic resonance studies have shown absent or delayed myelination, its degree unrelated to CSF glycine levels.3 In a few patients, gyral malformations or cerebellar hypoplasia were reported.4 In our patients, we did not see gyral malformations, but the corpus callosum was very thin to nearly absent, and myelination was strikingly delayed to absent in all. The mild ventricular dilatation on the third day of life in Patient 1 suggests abnormalities occur very early.

All four patients were severely affected with NKH, presenting neonatally and having a high CSF to plasma glycine ratio (>0.2). There were no other known predisposing factors for the development of hydrocephalus. The plasma level of glycine varied from very low (Patient 1) to elevated (Patients 2 and 3) without correlation with the development of hydrocephalus. Medications shared by our patients included sodium benzoate and dextromethorphan, in widely varying doses. None of these medications has been previously reported to be associated with hydrocephalus in human patients. Recently, a fetal neurotoxic effect of dextromethorphan was reported in avian embryos.10 It is possible, though unlikely, that an agent with potential fetal neurotoxicity such as dextromethorphan, may enhance the already present cerebellar atrophy8,9 and contribute to the development of the posterior fossa abnormalities.

Outcome was very poor in all patients. There was profound mental retardation at the most severe end of the spectrum seen in NKH. Even after shunting, the ventricles remained significantly enlarged despite there being no evidence of increased pressure. Myelination was nearly absent in these regions. Marked brain atrophy was previously only reported in patients more than 1 year of age, and never in such young infants.3 Our three older patients had severe visual impairment consistent with absent myelination of the optic radiation. In conclusion, these findings suggest that the development of acute hydrocephalus in patients with NKH is associated with a dismal prognosis.