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Research Article | DOI: https://doi.org/10.31579/2642-973X/020
Division of Gastroenterology, Hepatology and Nutrition, College of Medicine, University of Florida, USA.
*Corresponding Author: Abeer Dagra, Division of Gastroenterology, Hepatology and Nutrition, College of Medicine, University of Florida, USA.
Citation: A Dagra, E Williams, Sina A Mehrizi, Michael A Goutnik, M Martinez, et al. (2022). Pediatric Subarachnoid Hemorrhage: Rare Events with Important Implications. J Brain and Neurological Disorders. 5(1); DOI:10.31579/2642-973X/020
Copyright: © 2022, Abeer Dagra, This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Received: 01 March 2022 | Accepted: 09 March 2022 | Published: 14 March 2022
Keywords: subarachnoid hemorrhage; aneurysm; SAH management; pediatric population.
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 Moya disease, pseudoxanthoma elasticum, type IV Ehlers-Danlos syndrome, fibromuscular dysplasia, von Hippel-Lindau syndrome, arterio-venous malformations secondary to Osler-Weber-RenduSyndrome, 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].
| Etiology | Description | Genetic mutation | References |
| Alagille syndrome | Chroniccholestasis due to a lack of intrahepatic bile ducts, congenital heart disease primarily affecting the pulmonary outflow tract and vasculature, butterfly vertebrae, a broad forehead, posterior embryotoxic and/or anterior segment abnormalities of the eyes, and pigmentary retinopathy are among the main clinical features and malformations of this autosomal dominant defect. Intracranial hemorrhage and renal dysplasia are two prominent characteristics. | JAG1 NOTCH2 mutation (rare cases) | [58,65, 76] |
| Sicklecell anemia | This autosomal recessive genetic disorder causes sickle-shaped red blood cells that are sticky and defective, resulting in ischemia. Despite the fact that cerebral infarctions are more common, aneurysm growthcontributes to SAH in thepopulation. | HBB gene on chromosome 11 | [59,61] |
| CarneyComplex | Myxomasthat begin in childhood and reoccur, causing disruptive cardiac outflow, embolic, and aneurysmal problems that contribute to stroke, are all symptoms of this autosomal dominant pattern disorder. | PRKAR1A/2p16 and 17q22– 24 (unknown gene) | [59,67] |
| Sturge-Weber Syndrome | Causes the growth of aberrant blood vessels in a child's face, brain, or both. Venous congestion is thought to be a key cause of SAH and ICH in this population. Majority of children are born with a mark on their face termed a capillary malformation or port wine stain. | GNAQgene on chromosome 9q21 | [40,45, 59] |
Tuberous Sclerosis | Mentalretardation, epilepsy, and adenoma sebaceum are the classic triad of this autosomal dominant defect.Multiple intracranial aneurysms and kidney cysts are associated with it. | TSC1 on chromosome 9 and TSC2 on chromosome 16 | [40,59] |
vascular anomalies | The inability to repair or maintain vascular integrity, as well as the presence of less stable versions of normal anatomy that are prone to aneurysm formation. | Secondary to various congenital diseases | [40,59] |
| Marfansyndrome | Aneurysms and hemorrhagic strokes are among the neurovascular consequences of this autosomal dominant musculoskeletal disorder. | Fibrillin-1 on chromosome 15 | [40,59] |
MoyaMoya Disease(MMD) | Autosomal dominant inheritance disease with thickened intima of major branches of the circle of Willis and Moya Moya arteries as a general finding. In individuals with MMD, intracerebral hemorrhage is a commoncause of mortality. | Mutations in chromosome 3p24.2–26, and 17q | [10, 23, 35, 59] |
Pseudoxanthoma elasticum | An autosomal dominant and recessive inheritance condition that generates cerebral and cardiovascular aneurysms. | ABCC6/16p13.1 | [59] |
Type IV Ehlers- Danlossyndrome | Ehlers-Danlos syndrome is characterized by hyperplastic skin and hyperextensible joints due to an autosomal dominant collagen synthesis deficiency. Furthermore, Ehlers-Danlos vascular type IV is associated with spontaneous rupture of arteries, including intracranial arteries. | typeIII procollagen (COL3A1) on chromosome 2q | [40,59] |
von Hippel- Lindau Syndrome (VHL) | Throughthe activities of transcription factors, growth factors, and matrix metalloproteinases, the VHL tumor suppressor gene may be causally linked to aneurysm formation, resulting to SAH in some cases. Although hemangioblastomas in VHL arenoninvasive, their increasing size can compress tissue and disrupt blood flow or they may hemorrhage, resulting in the observed clinical symptoms. | VHL gene on chromosome 3 | [8, 12, 59] |
Osler-Weber- Rendu Syndrome or Hereditary Hemorrhagic Telangiectasia (HHT) | Telangiectasias of the skinand mucosal membranes, as well as arteriovenous abnormalities in internal organs, contribute to hemorrhagic strokes. | Endoglin (ENG)/9q33–q34.1 and ALK1or ACVRL1/12q11– q14 | [59] |
Autosomal Dominant Polycystic Kidney Disease (ADPKD) | Intracerebral aneurysms caused by ADPKD are uncommon in children, but they are highly influenced by family history. Documented prevalence rates range from 0% to 41%. | PKD1 gene on chromosome 16 PKD2 gene on chromosome 4 | [19, 40, 48, 55, 59, 69] |
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.
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