Growing Brains

BSID-III: Bayley Scales of Infant Development CCHU: CURE Children's Hospital of Uganda CPC: choroid plexus cauterization CSF: cerebrospinal fluid ETV: endoscopic third ventriculostomy MM: myelomeningocele PHHP: posthemorrhagic hydrocephalus of prematurity PIH: postinfectious hydrocephalus VPS: ventriculo-peritoneal shunt THE GLOBAL PROBLEM OF INFANT HYDROCEPHALUS Infant hydrocephalus is an enormous and previously under recognized global health problem. Estimates have varied, but the global burden is likely around 400 000 new infant cases per year with at least 100 000 new cases per year in sub-Saharan Africa alone.1 In 2005, we first reported neonatal ventriculitis as the single most common cause of infant hydrocephalus in Uganda.2 We have subsequently shown that these infections have their peak incidence in times of moderate rainfall that occur biannually between the rainy and dry seasons.3 Although enteric organisms have been implicated, the main pathogens are still being sought. In addition to the hydrocephalus, children with postinfectious hydrocephalus (PIH) suffer from varying degrees of primary brain injury from the original infection. In a follow-up study of infants treated for PIH at CURE Children's Hospital of Uganda (CCHU), one-third of 5-yr survivors were significantly disabled.4 Thus, characterizing the pathogenesis in order to construct public health strategies for prevention is extremely important. TREATMENT BY COMBINED ENDOSCOPIC THIRD VENTRICULOSTOMY AND CHOROID PLEXUS CAUTERIZATION The long-time standard of treating infant hydrocephalus has been placement of a ven-triculo-peritoneal shunt (VPS). In low-income countries, the cost of a VPS can be prohibitive. We have previously shown that an inexpensive alternative to shunts typically used in North America and Europe has equivalent failure and infection rates.5,6 This ameliorates the up-front cost for the VPS device. But life-long shunt dependence is particularly problematic in the context of rural sub-Saharan Africa, given the near certainty of 1 or more shunt malfunctions over a lifetime. This was the impetus for developing the combined endoscopic third ventriculostomy (ETV) and bilateral choroid plexus cauterization (CPC) technique (ETV/CPC), which significantly increased the rate of success compared to ETV alone among infants younger than 1 yr of age.7 In this operation, we use a 3.7 mm flexible ventriculoscope inserted into the right frontal horn via the right lateral corner of the anterior fontanel. An ETV is created and the choroid plexus is then cauterized in both lateral ventricles from the foramina of Monro to the temporal horns. An endoscopic septostomy is created as needed to access the contralateral lateral ventricle. We have since demonstrated the efficacy of ETV/CPC as the primary treatment of infant hydrocephalus in a range of etiologies and have shown that the key factors predicting outcome are age, etiology, extent of CPC, and whether there is scarring of the prepontine cistern.8-14 One of the key rationales for using ETV/CPC as the primary treatment for infant hydrocephalus in this setting is that nearly all ETV/CPC failures occur within the first 6 mo.8,11,12,14 For infants, this means that failure occurs during a “safe zone” in which treatment failure is typically not an emergency and the diagnosis is visible to the mother, who has time to arrange for returning to the hospital. With a VPS, failure can occur at any time thereafter, and may well occur after the compliance of the brain and skull has decreased, such that treatment failure leads to an acute rise in intracranial pressure that becomes a life-threatening emergency. Exactly why the addition of CPC increases the success rate of ETV for infants is unclear. The bulk flow model of hydrocephalus would suggest that ETV bypasses an obstruction (eg, at the aqueduct or fourth ventricle outlets), infants have a reduced capacity for cerebrospinal fluid (CSF) absorption, and CPC counteracts this by reducing the rate of CSF production. More recent hydrodynamic models of hydrocephalus suggest that progressive ventriculomegaly is driven, at least in part, by increased intraventricular pulsation amplitudes. Thus, if ETV acts as a pulsation absorber and infants have more compliant ventricles that are more easily expanded, CPC could augment the ETV effect by suppressing the pulsation driver contribution of the plexus, which would further decrease intraventricular pulsation amplitudes.12,15,16 Regardless of the mechanism, we have consistently shown that ETV/CPC can avoid life-long shunt dependence in nearly two-thirds of all children less than 1 yr of age. ANSWERING SOME IMPORTANT QUESTIONS Because of the large number of hydrocephalus operations at CCHU (more than 800 per year), we have been able to answer a number of basic questions about the ETV/CPC procedure in addition to its efficacy. (1) ETV/CPC is a safe operation. Both the infection rate and the operative mortality (death from any cause within 30 d) are <1%.2,7 (2) An abandoned or failed ETV/CPC requiring ultimate VPS placement does not increase the risk of subsequent shunt infection or failure.17 (3) When ETV/CPC failure occurs as a result of ETV closure, reopening the ETV in lieu of placing a VPS is a very effective treatment strategy.18 The long-term success of reopening a closed ETV depends upon the length of time from initial ETV to treatment failure. Overall success was >50%, but those with failure at 3 to 6 mo following the initial ETV/CPC had 60% success with redo-ETV, and those presenting with treatment failure >6 mo after the initial procedure had >80% success with redo-ETV. Are Shunts Better at Facilitating Early Brain Growth? Until recently, a very important question remained unan-swered: Might the initial treatment of infant hydrocephalus by VPS be better than ETV/CPC in regard to brain growth and neurocognitive development? The observation that ETV (with or without CPC) does not lead to the same degree of reduction in ventricle size has begged this question. Despite the obvious advantages of shunt-independence, if early shunting produced better brain development, this would be an important dilemma affecting treatment selection. We first addressed this in a retrospective study of children with myelomeningocele (MM).19 The Bayley Scales of Infant Development (BSID-III) was used to evaluate the development of children with MM in 1 of 3 categories: those with no hydrocephalus, those with hydrocephalus treated by VPS, and those whose hydrocephalus had been treated by ETV/CPC. In this study, there was no significant difference in any of the BSID-III measures between those treated by VPS and those treated by ETV/CPC and developmental scores did not correlate with ventricular volume as determined by frontal-occipital horn ratio. In this same study cohort, we subsequently demonstrated that brain volume (as measured by CT-image-based volume metrics) but not CSF volume alone predicted developmental outcome.20 Given this, and our observation that long-term survival for infants with MM and PIH residing in districts near the hospital (CCHU) was unaffected by treatment type, there was equipoise for comparing VPS and ETV/CPC in a randomized prospective trial.4,21,22 With funding from the National Institutes of Health (project numbers R21TW009612 and R01HD085853), a randomized-controlled trial of VPS vs ETV/CPC for PIH in children <6 mo of age was registered at clinicaltrials.gov (NCT01936272) and begun in 2013 with my 2 coprincipal investigators, Dr. Abhaya Kulkarni at University of Toronto and Dr. Steven Schiff at Pennsylvania State University. The study is ongoing, but the preliminary data have been encouraging, with no significant difference observed between treatment modalities at 12 mo in regard to treatment failure, mortality, developmental outcomes, or brain volume (manuscript in preparation). These outcomes thus far suggest no advantage to shunt placement over endoscopic treatment in regard to early brain development. CONCLUSIONS AND RELEVANCE TO NORTH AMERICA In low-income countries where shunt dependence is more problematic, offering ETV/CPC as the primary treatment for infant hydrocephalus may be the better approach. Although the failure rate for ETV/CPC in the first few months is higher than for shunts, most ETV/CPC failures will have occurred by 6 mo (during the “safe zone”) and the shunt failure rate exceeds that for ETV/CPC over time, with failures often occurring beyond infancy when more urgent access to neurosurgical care is required. More than half of infants can be spared from life-long shunt dependence and its attendant risks, and there is no evidence that initial treatment by shunt placement carries any advantage in regard to neurodevelopment. Finally, the infection risk is lower than for shunt placement, and primary endoscopic treatment does not increase the subsequent risk of either shunt infection or failure in the event that shunt placement proves necessary. CURE Hydrocephalus (www.cure.org/hydrocephalus) is a program supported by CURE International that trains and equips neurosurgeons from developing countries in the ETV/CPC technique. Thus far, the program has trained 27 surgeons in 18 countries, treating 2975 children in the year 2015 alone, and more than 18 000 since 2001. Arguably, though, ETV/CPC may also prove to be the preferable treatment strategy in developed countries as well. Our experience at Boston Children's Hospital shows that we can prevent shunt dependence from the beginning in about 60% of all infants less than 1 yr of age presenting for treatment of hydrocephalus.23 The technique has been particularly beneficial for infants born with MM and for infants with posthemorrhagic hydrocephalus of prematurity (PHHP), which were 2 of the most common etiologies. In the latter group, we are selective as to which patients are offered this treatment option, using sagittal T2 FIESTA MRI to screen out those with substantial prepontine cistern scarring.24 For those with open prepontine cisterns, the success rate for ETV/CPC in PHHP was about 70%.23 Other centers in North America have begun to offer this treatment option, and it remains to be seen whether the overall results will support a general shift to this treatment paradigm. Adapting to the circumstances in Africa, in which shunt dependence is more dangerous than in developed countries and in which neonatal infection is a significant cause of infant hydrocephalus, has driven this work over the past decade and a half, but there are likely implications for children with hydrocephalus everywhere, including those in the developed world. Disclosure The author has no personal, financial, or institutional interest in any of the drugs, materials, or devices described in this article.

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