Pathology of Ischemic Cerebrovascular Disease in Children

Pathophysiology

Coagulopathies

• Excessive clotting: Mutations to certain components of the coagulation cascade may lead to hypercoagulable states, increasing the risk of ischemic stroke. See Molecular/Genetic Pathology for more details.

Sickle Cell Hemoglobinopathy

• Clinically significant and subclinical strokes: Up to 11% of patients with HbSS may experience clinically significant stroke (of any kind) by age 20 (112). Compared to the risk of clinically significant stroke, the risk of subclinical (silent) cerebral infarction is much higher in children with HbSS; up to 39.1% of these patients may develop silent infarcts by age 18 (149). The presence of silent infarcts is associated with increased stroke risk later in life (150).
• Multifactorial pathogenesis: The high risk of clinically significant stroke in HbSS, combined with an even greater risk of subclinical infarcts, is likely explained by multifactorial pathogenesis. Pathogenesis of cerebral infarction in children with HbSS likely involves vaso-occlusive events and the separate development of cerebral arteriopathy (151).
• Heightened coagulation in narrowed vessels: The interaction of cellular and vascular mechanisms increases the risk of ischemic stroke in HbSS. These mechanisms promote RBC aggregation, coagulation, and vessel stenosis and may cause progressive occlusion of cerebral arteries in patients with HbSS (152).
• Limited RBC migration, increased blood flow: Sickled RBCs are less able to travel the vasculature to deliver oxygen to target tissues; aggregation and decreased deformability slows RBC migration (152). Anemia caused by decreased oxygen perfusion may lead to a compensatory increase in blood flow, which can further contribute to RBC aggregation in patients with HbSS (152).
• Increased hemolysis, decreased nitric oxide: Sickled RBCs undergo hemolysis at a higher rate than RBCs with normal morphology (152). In HbSS patients who also have an alpha-thalassemia deficiency, the hemolytic rate is further increased (152). Hemolysis of either etiology decreases the bioavailability of nitric oxide, causing limited vasodilation and promoting coagulation (152).
• Limited vasodilation and hypoxemia, increased inflammation: Hypoxemia causes upregulation of the adhesion molecules on the endothelial vascular lining, white blood cells, and platelets, leading to further vessel stenosis (152). RBCs that adhere to the vessel walls promote inflammation, which can lead to intimal hyperplasia that further stenoses the vessel (152).
• Cerebral arteriopathy: Patients with HbSS may develop moyamoya arteriopathy, which is likely explained by progressive intimal hyperplasia (140,152). Moyamoya arteriopathy is associated with an increased risk of recurrent ischemic strokes in children with HbSS (83,140,141).

Congenital Heart Disease

• Anatomical abnormalities and thrombosis: CHD with anatomical variations such as transposition of the great vessels or septal defects can lead to turbulent flow and can create a nidus for thrombus formation (102,153-155).
• Stasis: Stasis in the cardiac chambers or appendages due to structural anomalies can precipitate clot formation (155).
• Paradoxical embolism: In conditions such as PFO or ASD, venous thrombi can bypass the lungs through a right-to-left shunt and directly enter the systemic circulation (156).
• Decreased cerebral perfusion: Cerebral hypoperfusion may result if cardiac output decreases due to CHD (157).
• Procedural causes: Cardioembolic strokes may be periprocedural (e.g., during cardiac surgery or catheterization to manage CHD) (158).

Metabolic Disorders

• Homocystinuria: Defective metabolism of the amino acid methionine leads to elevated levels of homocysteine, which induces endothelial dysfunction and thus contributes to vascular diseases and stroke risk (159).
• Fabry disease: Deficiency of the enzyme alpha-galactosidase A leads to accumulation of the globoside globotriaosylceramide in the vascular endothelium, contributing to stroke risk (160).
• MELAS: Mutations in mitochondrial DNA affect cellular energy production, impacting neural and vascular tissues and leading to stroke-like episodes (116).

Infections

• Focal cerebral arteriopathy: Infections (primarily viral infections) may induce an inflammatory response that induces focal cerebral arteriopathy, characterized by stenosis of the distal ICA and its proximal branches (37). This may be accompanied by injury to the arterial and/or cardiac endothelium.
• Bacterial infections: Bacterial infections, including bacterial meningitis, may increase stroke risk by activating the coagulation cascade, producing septic emboli and injuring vascular/endothelial tissue (107).

Craniocervical Arterial Dissection

• Arterial injury with intimal tear: Craniocervical arterial dissection begins with an arterial injury of traumatic or spontaneous origin, which leads to tearing of the tunica intima (108). Collagen, activated tissue factor, and von Willebrand factor are exposed, which predisposes to clot formation (89).
• Ischemic stroke due to vessel occlusion or embolus: Thrombus formation may cause vessel stenosis or occlusion at the site of dissection; the clot may also dislodge and occlude a distal vessel (107).

Noninfectious Vasculitides

• Several diseases implicated: Noninfectious vasculitides associated with pediatric ischemic stroke include childhood primary angiitis of the central nervous system, Takayasu’s arteritis, Kawasaki disease, childhood polyarteritis nodosa , small vessel vasculitis, Henoch-Schönlein purpura, and pediatric Behçet’s disease (132).
• Inflammation and stenosis: Vasculitides are characterized by inflammation of small, medium, or large vessels with associated stenosis; this can lead to multifocal strokes with diffuse neurological deficits (161).

Cerebral Venous Sinus Thrombosis

• Pathogenesis of CVST: Venous thrombosis in the dural venous sinuses may be due to venous stasis, vessel wall abnormalities, and/or prothrombotic states (162,163).
• Development of ischemic stroke: Thrombosis can lead to venous obstruction, which increases venous pressure, decreases capillary perfusion, and ultimately decreases cerebral perfusion pressure and cerebral blood flow; this leads to infarction (162).

Molecular/Genetic Pathology

Coagulopathies

• Excessive clotting: Disruptions to components of the coagulation cascade may increase the risk of clotting disorders that can lead to ischemic stroke. The most commonly implicated mutations associated with coagulopathies include factor V Leiden mutations, prothrombin G20210A mutations, methylenetetrahydrofolate reductase (MTHFR; C677T and A1298C) mutations, protein C deficiency, protein S deficiency, antithrombin deficiency, and lipoprotein(a) mutations (14).

Sickle Cell Hemoglobinopathy

• Genotypic variability leads to differences in risk: HbSS is caused by a single point mutation in the beta globin gene in which a valine from the beta globin chain is substituted for glutamic acid. Phenotypic variation of this disease is attributable to differences in inherited genotype. Homozygous HbSS (i.e., homozygous SS) and co-inherited HbS-B0 thalassemia are associated with more severe clinical presentations, including increased risk of ischemic stroke (62,164).

Congenital Heart Disease

• Specific gene mutations, single nucleotide polymorphisms, and genetic syndromes: Gene variants can alter normal cardiac development, which can, in turn, cause pediatric ischemic stroke (165).

Metabolic Disorders

• Homocystinuria: Mutations in the CBS gene, which produces the enzyme cystathionine β-synthase, are most commonly responsible (166).
• Fabry disease: This is caused by mutations in the GLA gene (160).
• MELAS: This is most commonly caused by a mutation in the MT-TL1 gene (167).

Craniocervical Arterial Dissection

• Coagulation pathway: Following an intimal tear, collagen, activated tissue factor, and von Willebrand factor are exposed, which predisposes to clot formation (89).
• Connective tissue disorders: Structural abnormalities of the vessel wall and defective connective tissue components are believed to contribute to arterial dissection (168). Accordingly, connective tissue disorders are believed to predispose patients to craniocervical arterial dissection. These disorders most notably include vascular Ehlers-Danlos syndrome (COL3A1 mutations), but Marfan syndrome (FBN1 mutations), osteogenesis imperfecta (COL1A1 and COL1A2 mutations), pseudoxanthoma elasticum (ABCC6 mutations), and fibromuscular dysplasia are also implicated (168).

Noninfectious Vasculitides

The pathophysiology of the noninfectious vasculitides associated with pediatric ischemic stroke is characterized by autoimmunity.

• Childhood primary angiitis of the central nervous system: Autoimmunity in childhood primary angiitis of the central nervous system is poorly understood but is likely T-cell-mediated (169).
• Takayasu’s arteritis: Autoimmunity in Takayasu’s arteritis is known to be associated with the HLA-B52 allele and may be triggered by pathogenic microbes that induce an autoimmune reaction via molecular mimicry (170).
• Kawasaki disease: Autoimmunity in Kawasaki disease is characterized by necrotizing arteritis and neutrophilic infiltration (171), with a Th17-mediated immune response due to noninfectious or infectious triggers (172).
• Childhood polyarteritis nodosa: Autoimmunity in childhood polyarteritis nodosa is poorly understood and may have a microbial trigger (173).
• Small vessel vasculitis with CNS involvement: Autoimmunity in these cases is often characterized by antineutrophil cytoplasmic antibodies (ANCA) autoantibodies (132).
• Henoch-Schönlein purpura (IgA vasculitis): Autoimmunity in Henoch-Schönlein purpura likely has a microbial trigger and is characterized by IgA1 immunocomplex deposition in vessel walls (174). Children with Henoch-Schönlein purpura who present with ischemic stroke may have circulating autoantibodies that predispose to thrombosis (175).
• Pediatric Behçet’s disease: Autoimmunity in pediatric Behçet’s disease is associated with the HLA-B51 allele and may have a microbial trigger (176).

Cerebral Venous Sinus Thrombosis

• Prothrombotic condition: CVST has been associated with a host of molecular and genetic risk factors that precipitate a prothrombotic condition; these include use of oral contraceptives (due to estrogenic impacts on the coagulation pathway), antiphospholipid syndrome, MTHFR mutations, factor V Leiden, the G20210A prothrombin gene mutation, antithrombin deficiency, protein C and S deficiency, and systemic conditions that predispose to thrombosis (162).

Histopathology

Sickle Cell Hemoglobinopathy

• Sickled RBCs under the microscope: Evidence of HbSS can be seen on peripheral blood smear, which will typically demonstrate elongated RBCs with pointed ends (also known as drepanocytes), RBCs with DNA remnants (Howell-Jolly bodies), target cells, polychromatic cells, and/or nucleated RBCs (177).

Congenital Heart Disease

• Endothelial damage: Histopathologic studies may show damage to endothelium in children with CHD, which can lead to platelet aggregation and subsequent thrombus formation, causing ischemic stroke (157).
• Cardiac tissue: In cases where CHD causes myocardial infarction, fibrous tissue may replace necrotic cardiac tissue (178). This can contribute to irregular blood flow and thrombus formation.

Metabolic Disorders

• Homocystinuria: Thrombotic occlusions in small- to medium-sized arteries and veins may be present; arterial dissections have also been reported (166,179).
• Fabry disease: “Zebra bodies” are characteristic findings in cells; vascular endothelial deposits are common (180).
• MELAS: Ragged-red fibers may be found on muscle biopsy, and spongiform changes in the brain are often noted (116,181).

Craniocervical Arterial Dissection

Craniocervical arterial dissection is characterized by an intimal tear with intramural hematoma, which compresses the lumen and increases the external diameter of the artery.

• Pseudoaneurysm: Hematoma expansion can lead to pseudoaneurysm formation (182).
• Other abnormalities are possible: When craniocervical arterial dissection occurs in association with a connective tissue disorder, disarray and other abnormalities of the connective tissue within the extracellular matrix may be observed (168).

Noninfectious Vasculitides

• Biopsy for diagnosis of cerebral vasculitis: Open-brain biopsy is pursued when the history, MRI, and cerebral angiogram are consistent with vasculitis (137).
• Childhood primary angiitis of the central nervous system: Lymphocytic vasculitis (mostly T cells) with intramural and perivascular inflammation and disruption of the endothelium may be observed (169).
• Takayasu’s arteritis: Inflammation of the adventitia and external media with inflammatory infiltrates of the vessel wall may be observed; vessel wall inflammation can lead to stenosis and thrombus formation (183).
• Kawasaki disease: Inflammatory infiltrate of the intima, media, and adventitia may be seen with inflammatory scar formation and stenosis (183,184).
• Childhood polyarteritis nodosa: Lymphohistiocytic infiltrate and fibrinoid necrosis, along with vessel stenosis and aneurysm formation, may be observed (186-188).
• Small vessel vasculitis: For small vessel vasculitis with positive ANCA, necrotizing vasculitis with granulomatosis and inflammatory infiltrate, occasionally with fibrinoid necrosis and edema, may be observed (189).
• Henoch-Schönlein purpura: Small vessels with vessel wall necrosis and inflammatory infiltrate, along with perivascular IgA deposition, may be observed (190).
• Behçet’s disease: Neutrophilic vasculitis of small and large vessels, with involvement of the veins, may be observed (191).

Cerebral Venous Sinus Thrombosis

• Diverse histological findings: CVST may be associated with a host of histological findings, including cerebral edema, fibrin-rich occlusive thrombi with extension into cortical veins, and ischemic and hemorrhagic lesions (192).