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Advancing the Care of Children with Cerebrovascular Disease

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Todd Abruzzo, MD, FAHA, FACR, FSNIS

Pediatric cerebrovascular disease is a significant cause of global morbidity and mortality among children. These diseases manifest a variety of complications that vary across the pediatric age spectrum ranging from high-output cardiac failure in newborn infants to ischemic stroke and hemorrhagic stroke in older children and adolescents.

Stroke can be broadly defined as any brain injury that results from a disruption of normal cerebrovascular function. Ischemic stroke involves damage to brain tissue that is the result of an interruption of normal cerebral blood flow, while hemorrhagic stroke involves a brain injury caused by non-traumatic intracranial bleeding from diseased blood vessels. Ischemic stroke and hemorrhagic stroke account for equal proportions (approximately 50% each) of stroke in the pediatric population.

New evidence from a controlled multicenter clinical study unveiled at the Congress of the International Pediatric Stroke Organization in March 2024, and published in the December 2024 issue of the Lancet shows that endovascular thrombectomy results in better neurological outcomes than the best medical care in children with acute intracranial large vessel occlusions. The benefit of thrombectomy was observed across all stroke subtypes, including those due to cardioembolic causes and those due to arteriopathy. Barrow Neurological Institute at Phoenix Children’s was one of the top three enrolling sites in this study, which is expected to shape the field of pediatric stroke care and positively impact stroke outcomes in children worldwide.

Figure 1: Frontal projection catheter-directed internal carotid artery digital subtraction angiograms in a 4-year-old Berlin Heart patient are shown in top panel, before (left) and after (right) endovascular thrombectomy with a stent-retriever device. The pre-treatment digital subtraction angiogram (left) shows complete occlusion of the intracranial left internal carotid artery without anterograde flow in the corresponding anterior cerebral artery or middle cerebral artery. The post-treatment digital subtraction angiogram (right) shows normal patency of the intracranial left internal carotid artery with restoration of normal flow in the left anterior cerebral artery and left middle cerebral artery. Bottom left panel shows pre-treatment perfusion CT image of the brain used for surgical decision making in the same patient with irreversibly damaged brain color coded red, and salvageable brain at risk for permanent injury color coded green. Bottom right panel shows stent-retriever device with extracted thrombus that was removed from index patient.

Causes of Pediatric Stroke

Outside the perinatal period, arteriopathy is the major cause of childhood ischemic stroke. Arteriopathy is any pathologic process that is centered in the arterial wall itself, and it may involve the extracranial or intracranial vessels that supply the brain. Focal cerebral arteriopathy (FCA) of childhood is a leading cause of childhood stroke. FCA may be the result of dissection or inflammation involving the intracranial internal carotid artery and its terminal first order branches. Barrow Neurological Institute at Phoenix Children’s is participating in the FOCAS trial, which is a large multicenter NIH-funded study investigating the efficacy of various therapies for FCA. Unfortunately, despite major advances in public health, community acquired bacterial meningitis (CABM) remains an important cause of childhood stroke worldwide. The incidence of CABM-related stroke across the globe ranges from 0.5/100,000/year in developed countries to 210/100,000/year in developing countries. These variations are primarily related to differences in vaccination status.  Approximately 25 to 30% of patients with CABM will experience ischemic stroke due to infectious arteritis of the central nervous system regardless of vaccination status. Neuroendovascular, Neurocritical care and Neurosurgical specialists at Phoenix Children’s have developed novel catheter-directed intra-arterial and intra-thecal treatments for infectious arteritis in children with CABM. The Phoenix Children’s experience was presented at the 2024 Aspen Conference on Pediatric Cerebrovascular Diseases and has led to new collaborative efforts which promise to further improve patient care through multicenter protocols currently under development.  

Cervical artery dissections are a less common but important cause of pediatric stroke. Cervical artery dissections in children may be the result of trauma or may occur spontaneously. Neurovascular specialists from Phoenix Children’s are participating a major study sponsored by the International Pediatric Stroke Organization investigating the causes of arterial dissection in the pediatric population, and the efficacy of existing therapies in affected children.

Figure 2: Frontal projection catheter-directed right common carotid artery digital subtraction angiograms in a 14-year-old patient with blunt neck trauma before (left) and after (right) intracranial endovascular thrombectomy with concurrent stent-assisted angioplasty of cervical right internal carotid artery. The pre-treatment digital subtraction angiogram (left) shows complete occlusion of the cervical and intracranial right internal carotid artery without flow in the corresponding anterior and middle cerebral arteries. The post-treatment digital subtraction angiogram (right) shows normal patency of right internal carotid artery (cervical and intracranial) with restoration of normal flow in the corresponding anterior and middle cerebral arteries. Far-right inset image is a magnified, un-subtracted fluoroscopic image of the stent implanted into the cervical right internal carotid artery (arrows indicate the location of the stent in companion post-treatment digital subtraction angiogram).       

Sickle cell disease (SCD) is one of the most important causes of childhood ischemic stroke around the globe. This is due in part to its substantial worldwide prevalence (1 in 500 African Americans, and 1 in 50 Sub-Saharan Africans) and the high burden of childhood stroke in affected patients. Notably, up to 50% of children with SCD will experience a complication of cerebrovascular disease by their 15th birthday, with the highest risk of stroke occurring between 2 and 5 years of age. Intracranial large vessel arteriopathy is the most important cause of childhood stroke in SCD.

Finding Hope for Children with Sickle Cell Disease

While transcranial Doppler screening programs and aggressive exchange transfusion have decreased stroke risk in children with SCD by 90%, the protective effects are lost when transfusion is discontinued. A recent case publication from Barrow Neurological Institute at Phoenix Children’s shows for the first time that hematopoietic stem-cell transplant not only cures the hematological problem in children with SCD but may help to restore severely diseased brain arteries to normal. This finding gives new hope to children suffering from advanced forms of SCD complicated by intracranial large vessel arteriopathy, a condition that has been notoriously difficult to treat.

Currently, children with the most severe forms of SCD-related intracranial large vessel arteriopathy (Moyamoya) are treated with cerebral revascularization surgery.  Stroke in Sickle Cell Revascularization Surgery Study, which includes Phoenix Children’s, is investigating the efficacy of cerebral revascularization surgery in this setting.

 

Figure 3: Left panel shows pre-transplant frontal projection catheter-directed right internal carotid artery digital subtraction angiogram in an 8-year-old patient with Sickle Cell Disease (SCD) . The patient presented with right hemisphere arterial ischemic stroke and was found to have a severe form of intracranial large vessel arteriopathy (moyamoya arteriopathy) manifesting severe narrowing of the intracranial right internal carotid artery, right middle cerebral artery and right anterior cerebral artery as depicted in the left panel. Right panel shows frontal projection catheter-directed right internal carotid artery digital subtraction angiogram obtained 3 years after hematopoietic stem cell transplant.  There is a striking interval resolution of intracranial stenoses (https://pubmed.ncbi.nlm.nih.gov/38263886/).

A New Surgical Treatment for Bowhunter’s Syndrome

Extracranial vertebral artery dissection is the most common cause of childhood posterior circulation ischemic stroke. Recent work led by our team at Phoenix Children’s has revealed the mechanisms of vertebral artery dissection and characterized two different patterns of Bowhunter’s syndrome as being responsible.

Bowhunter’s syndrome occurs when a dissection injury of the vertebral artery is caused by stretching forces generated by rotation, extension or lateral flexion of the head. This injury pattern most commonly occurs at the C1-C2 vertebral level. A different, previously unrecognized form occurs between the C1 vertebra and the skull base. The pioneering work of our team has shown how these different patterns are related to distinct anomalies of the cervical spine. Our team has further established the diagnostic standards for the two forms of Bowhunter’s syndrome and developed a novel approach to clinical angiographic assessment and classification.

Moreover, our team has established different forms of surgical treatment for each of the two different patterns to prevent recurrent stroke more effectively in affected children. Our team found that children with Bowhunter’s syndrome at the C1-C2 level respond well to bony decompression of the affected vertebral artery or C1-C2 spinal fusion, depending on the results of diagnostic testing. On the other hand, children with Bowhunter’s syndrome between C1 and the skull base do not respond well to C1-C2 fusion. In such cases, bony decompression of the affected vertebral artery is the favored treatment.

 

Figure 4: Right panel shows an un-subtracted, frontal projection, catheter-directed angiogram of the right vertebral artery in a 14-year-old child who previously suffered a stroke due to right vertebral artery dissection at the C1-C2 vertebral level (at the time of angiography, the right vertebral artery dissection is healed). During the angiogram shown in the figure, the patient’s head is passively rotated to the left by examiners revealing reversible occlusion of the previously dissected segment of right vertebral artery (white arrow) due to abnormal rotational forces exerted upon the affected segment of vertebral artery. Left panel shows a lateral radiograph of the cervical spine after the patient underwent surgical fusion of the C1 vertebra to the C2 vertebra to prevent recurrent injury of the right vertebral artery as a result of abnormal rotational forces.

Breakthrough Technique Offers Safer Surgery for VOGM

The vein of Galen malformation (VOGM) is a cerebrovascular malformation that is associated with severe morbidity and mortality, particularly in the neonatal population. In newborn infants, VOGM typically presents with high-output cardiac failure, pulmonary hypertension, renal insufficiency, liver failure, hydrocephalus and “melting brain” syndrome. Without treatment, the prognosis is poor. Treatment of VOGM in the newborn infant involves complex image-guided neuroendovascular surgery which has many risks.

Neuroendovascular surgery for VOGM is focused on occlusion of discrete arteriovenous fistulae (AVF) by deposition of embolic agents (acrylic glue, platinum coils or some combination) into the lumen of individual fistulae. The massive flow through the AVF prevents stable anchorage of embolic agent and promotes downstream embolization into the pulmonary arteries, resulting in a potentially fatal complication.

A new technique pioneered by the neuroendovascular surgery and cardiac electrophysiology teams at Phoenix Children’s uses a pacing catheter placed into the right ventricle to drop cardiac output and blood pressure during VOGM embolization, eliminating embolic agent instability due to torrential background flow. The new technique, which is now routinely used at Phoenix Children’s, has significantly improved the safety of neuroendovascular surgery for VOGM.

Figure 5: Right panel shows midline sagittal T2-weighted magnetic resonance (MR) image of the brain in a newborn infant presenting with high output cardiac failure on day-1 of life. The image shows a Vein of Galen malformation (VOGM) with massive aneurysmal dilatation of the vein of Galen. Left panel shows midline sagittal T2-weighted MR image of the brain obtained in the same patient 6-years after curative two-stage embolization with right ventricular overdrive pacing at Phoenix Children’s. The vein of Galen has remodeled and is no longer apparent in the image.

Novel Advancements for Treating Cerebral AVMs

Ruptured cerebral arteriovenous malformations (AVM) are the most common cause of hemorrhagic stroke in the pediatric population. Cerebral AVMs are among the most complex vascular lesions encountered in children. The management of cerebral AVMs in children requires a highly integrated, multidisciplinary approach that includes a wide range of neuroscience subspecialists.

The team at Barrow Neurological Institute at Phoenix Children’s involves neuropediatric intensivists, pediatric anesthesiologists, pediatric neuroradiologists, pediatric neurosurgeons, neurointerventionists, vascular microneurosurgical specialists and radiation oncologists, all of whom are leaders in their respective fields. The neuropediatric intensivists at Phoenix Children’s have specifically pioneered novel, advanced multimodal monitoring techniques for the early detection and treatment of complications in children with ruptured cerebral AVMs.

Our team has also led a multicenter effort to develop protocols aimed at the early detection and treatment of cerebral vasospasm as a complication of cerebral AVM hemorrhage in children. Currently, cerebral AVMs are treated by microneurosurgical resection, catheter-directed embolization, stereotactic radiosurgery or some combination of these modalities. Judicious patient-centered treatment selection is critical and is one of the most important determinants of neurological outcome. The other critical determinant of neurological outcome is the experience of the surgical and neurointerventional teams.

The surgical and neurointerventional team treating children with cerebral AVMs at Phoenix Children’s is among the most experienced in the world. The team at Barrow Neurological Institute at Phoenix Children’s is currently working on novel methods to treat cerebral AVMs with drug therapies that are guided by AVM genotype and monitored by flow sensitive MRI methods.



Figure 6: 4D flow magnetic resonance angiography (MRA) image of intracranial internal carotid artery obtained in a child with complex brain arteriovenous malformation (AVM) depicts flow vectors at each point in the internal carotid artery, with flow direction indicated by arrow orientation and flow magnitude in milliliters per minute depicted as arrow color.

 

References

  1. Sporns PB, Bhatia K, Abruzzo T, et al. Endovascular thrombectomy for childhood stroke (Save ChildS Pro): an international, multicentre, prospective registry study. Lancet Child Adolesc Health. 2024 Dec;8(12):882-890. doi: 10.1016/S2352-4642(24)00233-5. Epub 2024 Oct 11. PMID: 39401507.

  2. Baranoski JF, White AC, Chung CY, Catapano JS, De Oliveira Sillero R, Hui FK, Huisman TA, Lawton MT, Abruzzo T. Mechanical disorders of the cervicocerebral circulation in children and young adults. J Neurointerv Surg. 2023 Sep 11:jnis-2022-019577. doi: 10.1136/jnis-2022-019577. Epub ahead of print. PMID: 37696598.
  3. Booth N, Ngwube A, Appavu B, Shah S, Abruzzo T. Reversal of Cerebral Arteriopathy Post-Hematopoietic Stem Cell Transplant for Sickle Cell Disease. Pediatrics. 2024 Jan 1;153(2):e2023062643. doi: 10.1542/peds.2023-062643. PMID: 38263886.

  4. Choi JW, Qiao Y, Mehta TI, Wilson JN, Torigoe TH, Tsappidi S, Jonathan Zhang Y, Brown SC, Hui FK, Abruzzo T. Safety and efficacy of dynamic catheter-directed cerebral digital subtraction angiography for diagnosis of bowhunter syndrome spectrum disorders: A systematic review of the literature. Interv Neuroradiol. 2024 Mar 13:15910199241236820. doi: 10.1177/15910199241236820. Epub ahead of print. PMID: 38477583.

  5. Baranoski JF, Catapano JS, Albuquerque FC, Abruzzo TA. Rapid ventricular overdrive pacing and other advanced flow-control techniques for the endovascular embolization of vein of galen malformations. Front Pediatr. 2023 Mar 23;11:1082318. doi: 10.3389/fped.2023.1082318. PMID: 37056948; PMCID: PMC10089121.

  6. Appavu B, Foldes S, Burrows BT, Jacobson A, Abruzzo T, Boerwinkle V, Willyerd A, Mangum T, Gunnala V, Marku I, Adelson PD. Multimodal Assessment of Cerebral Autoregulation and Autonomic Function After Pediatric Cerebral Arteriovenous Malformation Rupture. Neurocrit Care. 2021 Apr;34(2):537-546. doi: 10.1007/s12028-020-01058-3. Epub 2020 Aug 4. PMID: 32748209.

  7. https://pediatricstrokejournal.com/bowhunter-syndrome-in-the-pediatric-population/

  8. https://pediatricstrokejournal.com/empiric-treatment-of-metameric-cerebrofacial-arteriovenous-malformation-syndrome-with-trametinib-mediated-mek-inhibition/