Hydrocephalic holoprosencephaly: An oxymoron? Insights into etiology and management.

Holoprosencephaly is usually associated with microcephaly, although macrocephaly is not uncommonly seen. However, the cause of hydrocephalus in holoprosencephaly remains ill-defined. Here, the authors report a case of CSF ascites following ventriculoperitoneal shunt placement in a five month-old child with alobar holoprosencephaly, and hypothesize that the excessive CSF production which occurs in this condition may be responsible for the formation of CSF ascites. Further research is required to assess whether the gene responsible for holoprosencephaly is also responsible for upregulating CSF production in patients with concomitant hydrocephalus.

Introduction

Holoprosencephaly is a complex brain malformation resulting from incomplete cleavage of the prosencephalon, occurring between the 18th and the 28th day of gestation, with an estimated incidence of 1/16,000 live births and 1/250 conceptuses. Three ranges of increasing severity are described: lobar, semi-lobar, and alobar holoprosencephaly. Although hydrocephalus can occur during pre- or postnatal development, the cause of hydrocephalus remains to be elucidated. We report here a case of hydrocephalic holoprosencephaly who developed CSF ascites following a ventriculoperitoneal shunt (VP shunt) and discuss the possible factors involved in this development.

Case Report

A five month-old male child presented with complaints of enlarging head size and poor feeding. The child was not fixing his gaze and had upward gaze palsy. The head circumference was 48 cm and the anterior fontanelle was open and bulging. A diagnosis of holoprosencephaly was established on performing a CT scan of the head [Figure 1]. Following this, a low-pressure VP shunt was inserted through the left occipital burr hole. The patient became symptomatically better after the shunt and a repeat CT scan of the head showed the shunt tip [Figure 2]. One month after the shunt, the child presented with progressive distension of the abdomen and decreased feeding. There was no history of fever or vomiting and he was passing stools normally. On examination, he was found to have a grossly distended abdomen, fluid thrill and sluggish bowel sounds. The anterior and posterior fontanelles were open and full. The head circumference was 47 cm. A CT scan of the head revealed enlarged the shunt to still be . A shunt tap was done and the ventricular end was freely aspirable. CSF analysis results were nonmeningitic and the culture was sterile. Ultrasound of the abdomen was done and revealed gross ascites. CT of the abdomen also showed gross ascites without any evidence of loculated fluid collection or lymphadenopathy [Figure 3]. Under ultrasound guidance, ascitic fluid was aspirated which was clear and transudative. Ascitic fluid culture was also sterile. The shunt was exteriorized from the abdominal end, following which abdominal distension decreased and there was improvement in feeding. A new VP shunt was done with the shunt valve upgraded to a medium pressure valve. Following this procedure, the child became asymptomatic and is presently on follow-up.

Figure 1

Plain CT scan of the head showing agenesis of bilateral cortical structures seen in alobar holoprosencephaly, along with associated hydrocephalus

Figure 2

Plain CT scan of the head showing the shunt tip in situ with good visualization of sulcul space, suggestive of a well-functioning shunt

Figure 3

Contrast CT of the abdomen showing the marked ascites in the abdominal cavity

Discussion

CSF ascites has been defined as the ‘accumulation of excess CSF within the peritoneal cavity.’ It is a rare complication of the ventriculoperitoneal (VP) shunt. The exact cause of CSF ascites is still not clear. On review of literature, various possible mechanisms have been described: i) excessive CSF production in a cases of choroid plexus papilloma may cause CSF ascites after VP shunt due to imbalance between CSF production and peritoneum absorption.[12] ii) Infection has been proposed as a causative factor by some authors.[34] iii) Chronic inflammatory conditions like tuberculosis,[5] peritoneal inflammation by multiple shunt revisions,[6] or allergy to shunt material[7] decrease the absorptive capacity of peritoneum, leading to CSF ascites. iv) CSF ascites has also been reported in optic nerve gliomas and in craniopharyngioma. [8-12] v) In brain tumors, especially in astrocytoma, increased vascular permeability can cause microvascular extravasation of plasma into the peritoneal cavity and cause ascites.[1314] Despite all these postulated mechanisms, no satisfactory explanation has been given to date, and most of the reported cases have unknown etiology.[1516]

Holoprosencephaly is a birth defect that occurs during the first few weeks of intrauterine life. There is incomplete or absent division of the embryonic forebrain (prosencephalon) into distinct lateral cerebral hemispheres. Variable degrees of facial deformities, mental retardation, epilepsy, or abnormalities of other organ systems such as the cardiac, skeletal, genitourinary, and gastrointestinal may be present. Microcephaly is the rule, and macrocephaly is suggestive of hydrocephalus. The reason for hydrocephalus remains unclear in alobar hloprosencephaly, and the formation of CSF ascites in our case offers an insight into the possible mechanisms involved in the formation of hydrocephalus in these patients. We hypothesize that that the primary problem lies in excessive CSF production, which may be actually excacerbating the holoprosencephaly by preventing the growth of the cortical mantle, besides leading to CSF ascites, as seen in our case. The cause of excessive CSF production may also have a molecular basis and it may be possible that the genes responsible for causing holoprosencephaly may also be responsible for upregulating the CSF production. The management of a patient with holoprosencephaly presenting with hydrocephalus remains complex. Although we achieved a satisfactory short-term outcome in our patient by upgrading the opening pressure of the shunt valve, this may not be desirable as it may lead to chronic hydrocephalus in these patients.

Patients with holoprosencephaly can develop hydrocephalus, the etiology of which remains to be elucidated. These patients are a management dilemma and shunt placement may lead to CSF ascites. Research into the molecular change which occurs at genetic level may shed light on the etiopathogenesis of hydrocephalus in these patients.