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Object: Intracranial arachnoid cysts are a relatively common benign intracranial pathology, accounting for as many as 0.75%-1% of nontraumatic CNS lesions. Although it has already been demonstrated that rupture of arachnoid cysts may lead to subdural hematomas/hygromas, no study to date has investigated benign extracerebral collection in infancy as a possible predisposing factor for further development of arachnoid cysts., Methods: The authors performed a retrospective imaging and chart review of macrocephalic infants 12 months old or younger who were referred to neurosurgical care at OSF St. Francis Medical Center from 2003 to 2010, and who were diagnosed with benign extracerebral fluid collection in infancy on thin-slice (1-mm) head CT scans. Special attention was given to the investigation of risk factors for further development of de novo arachnoid cysts. Several epidemiological factors in the infants and mothers were analyzed, including gestational age at delivery, mode of delivery, mother's age at delivery, delivery complications, birth weight, age of macrocephaly development, degree of macrocephaly, family history of macrocephaly, prenatal and postnatal history of infection, fontanel status, presence of papilledema, previous history of head trauma, and smoking status. Imaging characteristics of the initial scans, such as location of subdural collection (frontal vs frontoparietal and frontotemporal) and presence of ventriculomegaly, were also evaluated. For those patients in whom arachnoid cysts were identified on subsequent CT scans, the size and location of the cysts were also analyzed., Results: The authors identified 44 children with benign extracerebral fluid collection in infancy. From this group, over a mean follow-up of 13 months (range 6-13 months), 18 children developed intracranial arachnoid cysts (a 40.9% incidence of de novo development of arachnoid cysts), with 27.8% presenting with bilateral cysts. In the multiple logistic regression analysis, infants who presented with an extracerebral collection restricted to the bilateral frontal region were more likely to develop intracranial arachnoid cysts (p = 0.035) than those with collections involving the frontotemporal and frontoparietal regions (odds ratio [OR] = 5.73). Additionally, children with benign extracerebral fluid collections and plagiocephaly were more likely to develop intracranial arachnoid cysts (p = 0.043) than those without plagiocephaly (OR = 4.96)., Conclusions: This is the first report in the neurosurgical literature demonstrating that benign extracerebral fluid collections in infancy may constitute a significant risk factor for development of de novo arachnoid cysts. These findings support a 2-hit hypothesis for the development of arachnoid cysts, in which the combination of an embryological defect in arachnoid development followed by a second event leading to impairment of CSF fluid absorption in early childhood could lead to abnormal CSF dynamics and the consequent expansion of fluid collections in the intraarachnoid spaces.