History of Management of Ischemic Cerebrovascular Disease in Children

Understanding of Disease

History of Pediatric Stroke

• 1667 — First described: The first description of stroke in a child is attributed to Thomas Willis, an English physician who in 1667 described the case of a neonate who died from stroke (1).
• Late 19th century — Large case series: Sigmund Freud and Oskar Rie, William Osler, and Bernard Sachs and Frederick Peterson each published extensive case series describing children with “cerebral palsy” and hemiplegia; many of these children were noted to have cerebrovascular lesions associated with hemorrhagic and ischemic stroke (2,3,4).
• Early 20th century — Systematic study of pediatric stroke: In 1927, Ford and Schaffer published the first systematic study of the etiology and outcome of “acquired hemiplegia” in children (5). The authors astutely noted that pediatric and adult stroke have distinct etiologies. A decade later, Ford published a textbook that comprehensively reviewed the etiologies of pediatric stroke (6).
• 1960s — Expanded understanding: Improvements in imaging technologies and diagnostic techniques in the 1960s allowed for an expanded understanding of the etiologies of pediatric stroke, including CHD, sickle cell hemoglobinopathy, arterial dissections, intracranial arterial and venous thromboses, and infections (7,8,9).
• Late 20th and early 21st centuries — Modern understanding of pediatric stroke: Efforts in the late 20th and early 21st centuries yielded databases, retrospective case series, registries, clinical trials, and consensus guidelines that have shaped the modern understanding of pediatric stroke and its treatment (10,11,12,13).

Coagulopathies

• 1990s — Identifying prothrombotic predictors: Between 20% and 50% of children presenting with arterial ischemic stroke have prothrombotic abnormalities; associated genetic factors include mutations in factor V Leiden, prothrombin G20210A, and methylenetetrahydrofolate reductase (MTHFR; C677T and A1298C) (14). These mutations were identified in the period between 1993 and 1998 (15,16,17,18,19).
• 21st century — Increased appreciation of the role of additional risk factors: While coagulopathies secondary to genetic mutations may increase the risk of arterial ischemic stroke, most pediatric stroke experts now believe that other risk factors play a role in coagulopathy-associated arterial ischemic stroke (14,20,21).

Sickle Cell Hemoglobinopathy

• 1923 — First associated with pediatric stroke: Homozygous sickle cell (HbSS) disease was first associated with stroke in children in 1923, just 13 years after HbSS was first described in the literature (22).
• 1972 — First description of moyamoya arteriopathy in HbSS: Moyamoya arteriopathy, characterized by progressive stenosis of the intracranial internal carotid arteries and their proximal branches, is associated with elevated ischemic stroke risk in children with HbSS (23). Moyamoya arteriopathy associated with HbSS was first described in 1972 (24).

Congenital Heart Disease

• Mid-20th century — Growing evidence of association with pediatric stroke: Case reports presenting clinical and pathologic evidence of cerebral thrombosis associated with CHD were published as early as 1942 (25). Larger case series and pathologic studies were published shortly thereafter: in 1951, Berthrong and Sabiston examined 135 patients with CHD and found pathologic evidence of cerebral infarction in 25 patients (26).

Metabolic Disorders

• 1960s — Homocystinuria associated with pediatric stroke: Two independent groups discovered homocystinuria in 1962 during the evaluation of children with a history of intellectual disability (27,28). Three years later, in 1965, researchers reported pathologic evidence of ischemic stroke in children with homocystinuria (29,30).
• 1984 — MELAS characterized: MELAS was characterized in 1984 in a report describing two children with neurological deficits (31).
• Early 21st century — Fabry disease associated with stroke in young people: Fabry disease was discovered by two independent researchers in 1898 (32,33). However, the association between this metabolic disorder and stroke in young people (including adolescents) was not firmly established until the early 21st century (34,35,36).

Infections

• Late 19th century — Acute infection associated with pediatric stroke: In children, ischemic strokes are often triggered by bacterial and viral infections, such as bacterial meningitis and varicella zoster virus infection (37). An association between acute infections and pediatric stroke was first reported in the late 19th century (38).
• 21st century — Elucidating the underlying mechanisms of stroke due to infections: An understanding of these infections and their potential to cause focal cerebral arteriopathy is essential in both preventing strokes and delivering targeted treatments in affected children. Researchers are currently investigating the link between human antimicrobial effector molecules and moyamoya arteriopathy (39).

Craniocervical Arterial Dissection

• Mid-20th century — First descriptions: The first report of traumatic ICA dissection was made in 1947 (40). Later, in 1959, the first case of spontaneous ICA dissection leading to fatal stroke was reported (41).
• 1980s — Association with hereditary disorders: Case reports and observational studies published since the early 1980s have improved our understanding of the association between hereditary connective tissue disorders and spontaneous craniocervical arterial dissections (42).

Noninfectious Vasculitides

• 19th and 20th centuries — Evolving understanding of complex etiology of pediatric stroke: Systemic vasculitis was first described in the 19th century, although our understanding of certain vasculitides remains limited (43). Associations between pediatric stroke and various vasculitides were made throughout the 20th century (44). Vasculitis may account for 4% of ischemic strokes in children (45).

Cerebral Venous Sinus Thrombosis

• 1825 — First described: Ribes was the first to describe a case of CVST, in 1825 (46).
• 1940s — Descriptive reports increased diagnosis: In the 1940s, case reports improved the clinical diagnosis of CVST, but this was limited to vague symptoms, signs, and lumbar puncture findings (47,48).
• 1942 — First use of heparin in CVST: Heparin was first used in the treatment of CVST in 1942 (48).
• 1950s — Venography improves diagnosis: The development of venography in 1950 facilitated the diagnosis of CVST and helped differentiate CVST from idiopathic intracranial hypertension (49,50).
• 21st century — Clinical trials and large observational studies: More recently, clinical trials and large observational studies have guided treatment and risk stratification for CVST (51,52).

Technological Development

Imaging Modalities

• 1927-1950 — Cerebral angiography: Egas Moniz introduced the technique of cerebral angiography in 1927 (53). Two decades later, in 1948, he reported the first case of pediatric stroke confirmed by cerebral angiography (54). Subsequently, venography was developed and used in the diagnosis of CVST in 1950 (49).
• 1970s — CT: In the early 1970s, work by Godfrey Hounsfield led to the introduction of CT scans in clinical practice (55). Shortly thereafter, use of CT imaging in the evaluation and diagnosis of pediatric stroke became common practice (56,57).
• 1970s — MRI: The development of MRI for clinical use is often attributed to Raymond Damadian, whose work in the 1970s enabled the use of clinical MRI in the following decade (13,58). Analogous to CT, MRI was quickly employed in the evaluation of pediatric stroke and continues to be crucial in clinical practice (13).

Advances in Acute Stroke Management

• 1995 — NINDS tPA trial results published: Results of the National Institute of Neurological Disorders and Stroke IV tPA trial were published in 1995 (59).
• 1996 — IV tPA approved by FDA for in adults with ischemic stroke: One year later, IV tPA was approved by the FDA for use in adults with ischemic stroke during the acute phase (60).
• 2013 — Thrombolysis study of children closed by the NIH: NINDS later funded the Thrombolysis in Pediatric Stroke study, although low patient enrollment prompted the National Institutes of Health to close the study (61,62). Although not approved for use in pediatric stroke, tPA is occasionally used in this context (61).
• 2019 — Tenecteplase efficacy: Recently, tenecteplase has been demonstrated to be as effective as tPA in dissolving blood clots in adults (63).

Endovascular Technologies

• 21st century — Advancements in endovascular technologies and devices: Selective angiography and various endovascular technologies have improved stroke care for both adults and children. Recent advances, such as mechanical thrombectomy devices for thrombus removal and stenting for craniocervical arterial dissection, may play a role in the treatment of pediatric stroke, although it is not expected that this will be studied in prospective randomized trials in children (64,65,66).

Coagulopathies

• 2010s — Increasing options for anticoagulation: Direct oral anticoagulants — the first of which became available in 2010 — provide more options for the treatment of coagulopathy. Each has its own risk-benefit and patient tolerance profile (67). However, these drugs are not well-studied in children outside of the cardiac literature (68).

Sickle Cell Hemoglobinopathy

• 1990s — TCD ultrasonography: In the 1990s, TCD ultrasonography was applied to screening for stroke risk in children with sickle cell hemoglobinopathy (69). Preventive chronic red blood cell transfusion in HbSS patients with elevated TCD velocity has been shown to decrease the occurrence of stroke in HbSS patients younger than age 20 up to 10-fold, reducing the prevalence of stroke in this population from 11% to approximately 1% (69,70,71,72,73).

Congenital Heart Disease

• 1953 — Echocardiography invented: Edler and Hertz captured the first echocardiographic images in 1953 and published their findings the following year (74). This imaging modality facilitated the diagnosis and evaluation of children with congenital heart disease.
• 1950s to 1970s — Advancements in surgical technology: Major advancements in cardiac surgery technology were achieved during this period, including the heart-lung (cardiopulmonary bypass) machine and devices that enabled the percutaneous closure of an ASD, which were first used in 1953 and 1975, respectively (75,76).

Metabolic Disorders

• 1960s to 1980s — Biochemical genetics: Various techniques used in biochemical research, including chromatography, electrophoresis, and enzyme assays, were developed and/or adapted for the characterization and diagnosis of metabolic disorders during this period (77). These techniques also enabled researchers to study the genetic basis of metabolic disorders associated with pediatric stroke.
• 21st century — Genetic testing: Advancements in genetic testing, including the construction of gene panels, have provided a pathway for early detection of metabolic conditions that may predispose patients to stroke (78).

Surgical Technique

Open Surgical Technique

• 1901 — Decompressive craniectomy: Open surgery is rarely indicated in the treatment of pediatric stroke. However, decompressive craniectomy may be indicated in severe pediatric stroke with refractory intracranial hypertension (79). The first modern report of decompressive craniectomy is often attributed to Kocher, who published his report in 1901 but did not perform this procedure in the context of pediatric stroke (80).
• 1972 — Revascularization surgery for proximal arteriopathies: Moyamoya, both idiopathic and associated with a comorbid syndrome such as HbSS, can have a high recurrent stroke risk that can be mitigated by revascularization surgery (81,82). Various techniques, most of which were developed in the 1970s and 1980s, exist; Yaşargil is reported to have been the first to perform a revascularization procedure in 1972 (83).
• 1990s — Carotid ligation and bypass: Carotid ligation and bypass surgery were occasionally performed in the treatment of craniocervical arterial dissection in the 1990s (84,85).

Endovascular Technique

• 1990s — Endovascular treatment of craniocervical arterial dissection: Stent placement for craniocervical arterial dissection was first described in 1994 (86). Stent placement in combination with intra-arterial thrombolysis was described in 1998 (87). These techniques, however, are not found to be effective in focal cerebral arteriopathies, vasculitis, or moyamoya arteriopathy. In the 21st century, endovascular techniques are occasionally used in the treatment of craniocervical arterial dissection refractory to medical therapy (88,89,90).
• 1990s — Endovascular treatment of CVST: Mechanical thrombectomy (including aspiration), local thrombolysis, mechanical thrombus disruption, and balloon angioplasty have been used in the endovascular treatment of CVST since 1992 (91). However, endovascular treatment of CVST is inadequately studied in children and is currently being investigated by multicenter consortia such as the IPSS.
• Early 21st century — Mechanical thrombectomy: Mechanical thrombectomy devices were introduced in the early 21st century and have been used for endovascular recanalization in children with large vessel embolic arterial ischemic stroke (92,93). Mechanical thrombectomy may be appropriate for treatment of stroke associated with coagulopathy and CHD with LVOs but not for cases of intracranial arteriopathy or vasculitis.