Rupture of an aneurysm is the leading cause of subarachnoid hemorrhage (SAH) which results in accumulation of blood between the arachnoid and pia mater, consequently increasing intracranial pressure. This often results in life threatening conditions like herniation or clinical presentations including focal neurological deficits. In children, these events, although rare, have significant implications. Pediatric SAH is associated with better outcomes in the hospital setting and may even be prevented proactively by the recognition of potential risk factors. Specifically, better recognition of genetic predispositions, metastatic lesions, and infectious causes of aneurysms is important to understand their growth and prevent hemorrhagic events. This review highlights the causes of pediatric SAH, reviews the models of current understanding of this etiology, and discusses the current treatment schema to provide a succinct summary and highlight gaps in current knowledge. This may lead to future investigations aimed at further improving prevention strategies, patient care, and patient outcomes.

Pediatric subarachnoid hemorrhage (pSAH) is a relatively rare clinical event with life-threatening implications that affect 0.5 percent to 4.6 percent of children [[1, 28, 31, 43, 44, 49]]. Aneurysms, arteriovenous malformations, and pediatric tumors are the most common causes of pSAH. Increased predilection is based on genetics or underlying infection. Common symptoms of pSAH include lethargy, irritableness, seizures, increased or decreased muscular tone, altered consciousness, vomiting, poor eating, breathing problems, and apnea [[18]]. Common causes of pSAH include genetic and infectious etiologies that predispose children to develop aneurysms. One of the probable complications of pSAH is brain swelling, or hydrocephalus; this buildup of cerebrospinal fluid (CSF) and blood between the brain and the skull raises the intracranial pressure [29, 58, 62, 63, 75]. In an event of SAH, blood vessels in the brain can become irritated and damaged by the breakdown of blood products (including oxyhemoglobin) leading them to constrict which limits intracerebral blood flow [15, 58, 62]. This could lead to stroke and further exacerbation of the existing injury. Potential consequences of the bleeding include lifelong brain damage, paralysis, or coma in severe circumstances. Given these implications of pSAH, the need for understanding the causation and to plan the management of these events is vital for improved patient outcomes.

Genetics:

Aneurysms in children are thought to be characterized by changes in arterial flow, extracellular matrix, and arterial wall deterioration or repair, all of which may trigger molecular alterations that lead to formation of aneurysms [33, 76]. Genetic and infectious predispositions include: Alagille syndrome, sickle cell anemia, irradiation, cardiac myxoma (Carney complex), HIV/AIDS, tuberous sclerosis, vascular anomalies, Marfan syndrome, syphilis, Moya disease, pseudoxanthoma elasticum, type IV Ehlers-Danlos syndrome, fibromuscular dysplasia, von Hippel-Lindau syndrome, arterio-venous malformations secondary to Osler-Weber-Rend Syndrome, hypertension, coarctation of the aorta and polycystic kidney disease. [13, 31, 76] (summarized in Table 1). In addition, compared to the adult population, mycotic aneurysms make up a greater fraction of aneurysms (4%) in the pediatric population [5, 28]. In immunocompetent individuals, Staphylococcus aureus and Streptococcus are the causal organisms, while in immunocompromised patients, Aspergillus, Candida, and Phycomycetes are the causative organisms [3, 31,76].

Although uncommon, pSAH secondary to neoplasms has been recorded in 3-10% of cases, with medulloblastoma (malignant), primitive neuroectodermal tumors, malignant astrocytomas, and ependymomas being the most prevalent [24, 72]. Possible disruption of tumor vasculature due to the increasing tumor size, direct tumor infiltration of vessels, and/or aberrant tumor vascularity are some of the theorizedmechanisms for aneurysm development and rupture [72].

                                                                                              Table 1: Genetic Predispositions of Pediatric Subarachnoid hemorrhage

Vascular abnormalities:

Pediatric aneurysms differ from classical adult aneurysms; they are rarer, tend to be larger, have an overall male predominance, are commonly caused by infection or trauma, and have increased predilection for the posterior circulation [28, 31, 44, 50, 52, 70]. Additionally, aneurysmsin children tend to be associated with congenital disorders [3, 5, 13, 31, 40, 44, 47, 50, 66] (table 1).

Intracranial aneurysms may present in children commonly 2-4 weeks (but up to 10 years) following trauma, usually a closed head injury (72% of cases) and may present with massive epistaxis [26, 57]. Traumatic brain injury may damage the distal anterior carotid artery (ACA) in40% of cases, the major vessels along the skull base in 35% of cases, and the distal cortical vessels in 25% of cases [37]. The patient presents with hemorrhage in about 50

Pediatric SAH may be treated effectively by either microsurgery or endovascular techniques such as coil embolization whereby an aneurysm is stabilized to prevent rupture by placing a coil that prevents enlarging of false lumen [30, 42, 50, 54, 56, 59, 60, 71]. Choice of procedure may be decided based on location, Hunt and Hess grade, complex shape, amenability to coiling, vessel occlusion probability, and parental choice [50, 56, 60, 71]. The decision should not be influenced by aneurysm size [60].Depending on the preferences of the institution, endovascular approaches may be employed for specific anatomic locations, such as the basilar trunk and posterior cerebral artery (PCA) [56]. Surgical excision remains the treatment of choice for parenchymal AVMs in children [36, 53, 74], with complete removal achieved in most patients (up to 90%). Complete AVM resectionusually results in normalneurological outcome [36].

Treatment options also include endovascular embolization and stereotactic radiosurgery alone or in combination. The Spetzler-Martin (SM) grading scale, which estimates the risk for patient with undergoing neurosurgery by evaluating the AVM size, location, and pattern of venous flow, is often used to determine the treatment modality, with low grade, accessible SM grade 1-3 AVMs being best managed with surgery, while low grade inaccessible AVMs are best treated with stereotactic radiosurgery. High grade (SM grade 4-5) AVMs in pediatric patients are often deep or inaccessible making surgical excision less possible. The best treatment modality for these AVMs is unclear [53]. Conservative management for children with AVMs is generally not recommended, with anannual risk of rupture increasing by 2-4% per year [14, 36, 37,53, 74].

Aggressive management is likely to result in superior clinical outcomes in pediatric patients [36, 37, 53, 74]. Moreover, Stiefel et al. suggested that surgical intervention may be first line, but coil embolization is preferred when surgery is not viable, or the aneurysm is located at the basilar apex [50]. Long-term follow up studiesare needed to compare the durability of coiling comparedto standard microsurgical clipping because of better outcomes in children contributing to longer survival. Thus, comparing the modalities in preventing future hemorrhage is a uniquely important consideration in the pediatric population [50, 71].

Pediatric patients are more likely to have favorable post-surgical outcomes, compared to adults [68]. Favorable outcomes range from approximately 63.6% to 90

SAH is associated with trauma, infection, and vascular abnormalities in the pediatric population, and it requires high levels of care during management and after discharge. However, whenidentified in a timely manner, the outcomes for patients with pSAH are more favorable in this population. Specifically, preventing rebleeding and vasospasms, using pharmacotherapy to improve blood flow, and closely monitoring symptoms and vitals help prevent neurologic and hemodynamic complications. Patients who may develop such complications may require extended hospital stay, additional surgeries, and therapies like Triple-H. Many SAH survivors may develop chronically disabling medical disorders, including issues with mood, neurophysiological function, and memory. For populations with predisposing genetic conditions that affect vasculature (e.g. AVM formations), early monitoring may be an effective preventative measure for these acute events. Moreover, closing the knowledge gap on epidemiological and biochemical predisposition to aneurysmal growth and rupture will inspire better preventive, management, and treatment protocols for pSAH.