Pediatric Stroke: Evaluation and Differential Diagnosis

Overview of Pediatric Stroke

Pediatric stroke is an uncommon but serious cause of neurological problems and death in children. It is generally divided into arterial ischemic stroke (AIS), hemorrhagic stroke (HS), and cerebral sinovenous (venous) thrombosis (CSVT). The rate of childhood AIS is about 2–3 per 100,000 in early childhood, increasing to 8–13 per 100,000 in later childhood. Neonatal strokes, which happen within the first 28 days of life, are even more common—about 1 in 4,000 live births. Stroke ranks among the top 10 causes of death in children, with the highest rates during the first year of life. Outcomes are often severe, with mortality around 5–10%, and more than half of survivors experience long-term neurological issues. The recurrence rate is approximately 10–20%. These figures highlight that, although pediatric stroke is rare, it requires quick recognition and proper evaluation.

Ischemic strokes occur due to arterial blockages (AIS) or venous thrombosis (CSVT), which lead to brain infarction. Hemorrhagic strokes happen from bleeding into or around the brain (intracerebral or subarachnoid hemorrhage). In children, AIS makes up just over half of all strokes. Notably, the common adult risk factors, such as atherosclerosis and hypertension, are usually absent in children. Instead, pediatric strokes generally result from a mix of unique causes, with over three-quarters of children having at least one identifiable risk factor, often multiple. Neonatal strokes are frequently linked to perinatal and maternal factors—such as placental thrombi, birth trauma, or maternal hypercoagulability—as well as conditions like dehydration, sepsis, or congenital heart disease. In contrast, strokes in older infants and children are often associated with cerebral arteriopathies and cardiac embolic sources, each accounting for about 20–50% of childhood AIS in developed countries. Other significant risk categories include hematologic disorders, infections, and systemic conditions, as discussed below.

Clinical Presentation and Age-Related Variations

The clinical signs of stroke in children can be subtle and differ with age. Focal neurologic deficits, such as hemiparesis or facial droop, are classic signs, but they are most reliably observed in older children and teenagers. In younger patients, symptoms are often nonspecific. Seizures at stroke onset are common in pediatrics, occurring in up to approximately 50% of childhood strokes (both ischemic and hemorrhagic) – a much higher rate than in adults. Neonatal strokes typically present with seizures (focal or generalized) and signs of encephalopathy, such as lethargy, irritability, poor feeding, or apnea, whereas focal weakness is seen in less than 25% of neonates. Infants and toddlers may similarly show nonspecific signs like excessive sleepiness, irritability, vomiting, or even a sepsis-like picture. An early hand preference or developmental delay might be the first clue to a perinatal stroke later diagnosed. Conversely, older children are more likely to present with an abrupt, adult-like presentation, including sudden hemiparesis, facial droop, speech or visual disturbances, ataxia, or other focal deficits. Headache, especially in cases of hemorrhagic stroke or cerebral sinus venous thrombosis (CSVT), and altered mental status can occur at any age, often alongside focal signs. Importantly, children—particularly those with arteriopathies—may experience fluctuating or transient deficits, similar to transient ischemic attack (TIA) episodes that resolve within hours, which should prompt suspicion of an underlying vascular cause.

Recognizing stroke in children is difficult because it is infrequent and can resemble other conditions. Stroke mimics such as complex migraines, epileptic postictal paralysis (Todd’s paralysis), encephalitis/meningitis, brain tumors, metabolic encephalopathies (e.g., MELAS), or even conversion disorders should be considered. However, an sudden onset of a focal neurologic deficit in a child should be treated as a stroke until proven otherwise. Healthcare providers must stay highly alert and quickly move to diagnostic testing when faced with acute neurologic symptoms in a child.

Comprehensive Differential Diagnosis of Pediatric Stroke

Pediatric stroke has a wide range of potential causes, including many that are uncommon in adult stroke. These causes can be grouped into main categories that often overlap. About 50–80% of children with AIS have at least one risk factor, and 20–25% have multiple causes at the same time. Below is an overview of key etiologic groups and conditions.

• Cerebral Arteriopathies: Arteriopathies are the leading causes of childhood AIS, identified in up to half of cases. This group includes any structural or inflammatory arterial abnormalities. Common subtypes are:
  
  • Focal cerebral arteriopathy (FCA) of childhood is an acute, often transient unilateral narrowing of a cerebral artery, usually following infection. Notably, post-varicella arteriopathy is a well-known trigger: varicella zoster virus infection is associated with FCA, and varicella-related vasculopathy accounts for approximately 30% of childhood arterial ischemic stroke (AIS). Children who have had a stroke are approximately 18 times more likely to have had chickenpox in the previous nine months compared to controls. FCA is one of the most common causes of childhood AIS, likely due to inflammation of the arterial wall following infections such as VZV and enteroviruses.
    
  • Moyamoya disease is a chronic, idiopathic arteriopathy characterized by progressive bilateral intracranial arterial occlusions and the development of collateral “moyamoya” vessels. Moyamoya can be primary or associated with conditions like Down syndrome or prior cranial radiation (called Moyamoya syndrome). It is a leading cause of stroke in certain ethnic groups, such as East Asian children.
    
  • Vasculitis: Both primary CNS vasculitis (restricted to cerebral vessels) and secondary vasculitis caused by systemic inflammatory diseases can lead to pediatric stroke. Primary angiitis of the CNS (PACNS) in children is rare but presents with recurrent or progressive neurologic deficits and requires specialized evaluation. Secondary vasculitic syndromes include childhood polyarteritis nodosa, Takayasu arteritis (a large vessel arteritis that can involve great vessels and cerebral arteries), and cerebral vasculitis in conditions such as granulomatosis with polyangiitis (Wegener’s) or juvenile temporal (giant cell) arteritis (extremely rare in children). These often present with multifocal strokes and systemic signs of inflammation. For example, children with systemic lupus erythematosus (SLE) or antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis can develop CNS vasculitis and strokes, sometimes involving multiple infarcts at various stages.
    
  • Arterial dissection: Cervico-cerebral arterial dissection (tearing of the arterial wall, often caused by trauma) is an under-recognized cause of stroke in children, particularly in the carotid or vertebral arteries. Even minor trauma (such as sports injuries or sudden neck movements) can trigger a dissection. Dissection should be suspected if there is a history of neck pain or trauma; it can lead to AIS, especially in the posterior circulation (for example, lateral medullary/Wallenberg syndrome in vertebral artery dissection).
    
  • Non-inflammatory arteriopathies include fibromuscular dysplasia (FMD), a rare cause of arterial stenoses mostly affecting renal and carotid arteries, and idiopathic focal stenosis. There are also genetic arteriopathy syndromes: for instance, ACTA2 gene mutations (which cause smooth muscle alpha-actin disease) can lead to early-onset cerebral arteriopathy; PHACE syndrome (characterized by infantile hemangioma with cerebrovascular anomalies) involves arterial dysplasia; and ADA2 deficiency (caused by CECR1 mutation) results in a vasculopathy with recurrent strokes and systemic features. Although rare, these conditions should be considered if strokes occur alongside systemic features, such as PHACE characteristics or ADA2 deficiency signs like livedo reticularis with strokes.
    
    Bottom line: If an arterial infarct is confirmed, it is essential to evaluate for arteriopathies using vascular imaging. Arteriopathies not only cause the initial stroke but also significantly increase the risk of recurrence.
    
• Cardioembolic Sources: Cardiac conditions make up a significant portion of pediatric strokes. Cardioembolic AIS is particularly common in neonates and young children with existing heart disease. In some studies, cardiac disease accounts for as much as ~30% of childhood strokes. Important considerations include:
  
  • Congenital heart disease (CHD): Children with complex CHD—particularly cyanotic heart lesions, those with right-to-left shunts, or post-cardiac surgery patients—are at high risk for stroke. Turbulent flow or shunting can lead to thrombosis or paradoxical embolism. For instance, single-ventricle physiology or Fontan circulations carry a significant stroke risk.
    
  • Cardiac thrombi or emboli: Conditions such as cardiomyopathies with low ejection fraction, ventricular aneurysms, akinetic segments, and prosthetic valves can all lead to clot formation that embolizes to the brain’s arteries. Arrhythmias like atrial fibrillation or flutter, which are uncommon in children outside of post-surgical cases, and myocarditis can also pose an embolic risk.
    
  • Infective endocarditis: Septic emboli from bacterial endocarditis can lead to ischemic stroke or mycotic aneurysms, which may cause hemorrhagic stroke. Any child with stroke and fever or congenital heart disease should be evaluated for endocarditis (e.g., with echocardiogram and blood cultures).
    
  • Other cardiac sources: Cardiac tumors such as atrial myxoma (very rare in pediatrics) have been reported to cause embolic strokes. Additionally, paradoxical embolism through a patent foramen ovale (PFO) could be a mechanism (especially in adolescents), although in children, a PFO is often an incidental finding.
    
    In all children with unexplained AIS, a comprehensive cardiac assessment is necessary, as silent cardioembolic causes may exist even without known heart disease.
    
• Hematologic Disorders: Blood disorders can lead to stroke by affecting coagulability or blood viscosity. The most prominent is sickle cell disease (SCD), a hemoglobinopathy that significantly increases stroke risk. SCD is a major cause of AIS in African and certain Mediterranean pediatric populations. Sickle-shaped RBCs cause vaso-occlusion and damage to the inner blood vessel lining; strokes in SCD patients often involve large intracranial arteries (sometimes leading to Moyamoya vasculopathy). Children with SCD need specialized stroke screening with transcranial Doppler and preventive transfusions to reduce risk. Other hematologic factors include:
  
  • Thrombophilia (Prothrombotic states): Inherited or acquired clotting disorders can increase the risk of arterial and venous strokes. Inherited thrombophilias such as factor V Leiden mutation, prothrombin G20210A mutation, protein C or S deficiency, antithrombin III deficiency, hyperhomocysteinemia (e.g., due to MTHFR mutation), and elevated lipoprotein(a) have all been linked to pediatric stroke. Acquired prothrombotic conditions like antiphospholipid syndrome (APS), often seen in lupus patients, also lead to arterial and venous thromboses. It’s important to note that these thrombophilias rarely directly cause stroke alone but may increase risk when combined with other factors. Still, a thrombophilia work-up is usually part of stroke evaluation in children unless a clear alternative cause is identified.
    
  • Polycythemia or Severe Anemia: Newborns with polycythemia (such as infants of diabetic mothers) have sluggish cerebral blood flow and an increased risk of sinovenous thrombosis. Iron deficiency anemia has been linked to a higher risk of CSVT in children, possibly because of reactive thrombocytosis. Thrombocytosis from any cause could theoretically increase stroke risk. Conversely, thrombocytopenia or coagulopathies (such as hemophilia) are more likely to lead to hemorrhagic stroke due to bleeding.
    
  • Oncologic conditions: Children with leukemia, especially acute lymphoblastic leukemia, may develop strokes due to hypercoagulability caused by the disease and chemotherapy (for example, L-asparaginase induces antithrombin deficiency). Bone marrow transplants and other cancer treatments also carry thrombotic risks. Additionally, hemophagocytic lymphohistiocytosis (HLH), thrombotic microangiopathies (HUS/TTP), and other hematologic disorders have been identified as causes of stroke in some pediatric series. These cases usually involve very ill children in whom stroke is one of multiple complications.
    
• Infectious and Post-Infectious Causes: Infection can trigger a stroke through various mechanisms such as vasculitis, embolism, or a hypercoagulable state. As noted, varicella (chickenpox) is a major post-infectious cause of arteriopathy and AIS. Bacterial meningitis (e.g., pneumococcal meningitis) often leads to cerebral infarcts via inflammation and narrowing of cerebral arteries, especially the basal cerebral arteries. For example, occlusive vasculitis in tuberculous meningitis is notorious for causing strokes in the basal ganglia. Viral encephalitides (such as enterovirus and herpesvirus) can also induce stroke through immune-mediated vasculopathy. Head and neck infections are well-established risks for CSVT: severe otitis media or mastoiditis can cause lateral sinus thrombosis.
• In contrast, sinusitis or a deep neck abscess can lead to thrombosis of the cavernous or sagittal sinuses. Septic thromboses may occur with bacteremia, such as Lemierre’s syndrome, which is caused by a fusobacterial infection and results in jugular vein thrombosis and septic emboli. Endocarditis, as mentioned, can cause septic embolic strokes. Additionally, systemic viruses like HIV or COVID-19 have been linked to strokes in children by vasculitic or coagulopathic mechanisms. For example, hyper-inflammatory states such as Multisystem Inflammatory Syndrome in Children (MIS-C) following COVID-19 can lead to thrombotic complications, including stroke, though this is rare. Post-streptococcal immune syndromes (e.g., cerebral vasculitis after group A strep) and cat-scratch disease (Bartonella) are rare causes of CNS vasculitis or stroke. In any child with stroke, a recent history of infection—especially varicella or a significant head or neck infection—should prompt evaluation for post-infectious arteriopathy or septic thrombosis.
  
• Autoimmune and Systemic Inflammatory Conditions: Various autoimmune diseases can affect the CNS blood vessels or lead to prothrombotic states that result in stroke. We previously mentioned lupus and primary systemic vasculitides; other notable conditions include:
  
  • Antiphospholipid Syndrome (APS): APS can be either primary or secondary (typically associated with SLE) and is characterized by arterial and venous thromboses resulting from antibodies directed against phospholipid-protein complexes. Children with APS may present with strokes, often multiple or recurrent. Testing for antiphospholipid antibodies (lupus anticoagulant, anticardiolipin, β2-glycoprotein) is especially recommended in teenage stroke patients or those exhibiting other autoimmune features.
    
  • Systemic Lupus Erythematosus (SLE): Besides APS, lupus can lead to stroke through immune-complex vasculitis or cardiogenic sources (Libman-Sacks endocarditis). Children with lupus and acute neurologic changes should be evaluated for stroke along with other neuropsychiatric lupus manifestations. High-dose steroids and immunosuppressants are frequently used to treat lupus-related CNS vasculitis.
    
  • Other Collagen Vascular Diseases: Juvenile dermatomyositis, sarcoidosis, or Sjögren’s syndrome sometimes cause CNS vasculopathy. Behçet’s disease, a vasculitic disorder, can result in dural sinus thromboses or arterial aneurysms and should be considered especially in children of Middle Eastern or Asian descent presenting with CSVT and a history of oral/genital ulcers or uveitis.
    
  • Inflammatory bowel disease (Crohn’s, ulcerative colitis) is another systemic condition linked to hypercoagulability and stroke in adolescents.
    
    Overall, any systemic inflammatory condition raises concerns for stroke if neurological symptoms develop. Clues such as systemic rash, arthritis, or organ involvement should prompt a rheumatologic evaluation.
    
• Metabolic and Genetic Disorders: A small but important subset of strokes in children result from inborn metabolic errors or genetic syndromes that affect the brain’s vessels or energy supply. These often present as “stroke-like” episodes and may not follow typical vascular territories. Mitochondrial disorders, such as MELAS (Mitochondrial Encephalopathy with Lactic Acidosis and Stroke-like episodes), cause recurrent stroke-like events often triggered by metabolic stress; they usually have other features like short stature, lactic acidosis, myopathy, and seizures. Consider inherited metabolic diseases like urea cycle disorders, organic acidemias (propionic, methylmalonic aciduria, etc.), homocystinuria (which increases the risk of arterial and venous clots and often presents with lens dislocation and marfanoid habitus), and Fabry disease (an X-linked lysosomal disorder causing strokes, kidney disease, and angiokeratomas in adolescence). Some of these conditions present with diffuse or bilateral infarcts that do not conform to an arterial territory—for example, metabolic strokes may affect gray matter in both hemispheres simultaneously, or the posterior circulation more often, raising suspicion of an underlying metabolic cause. When a metabolic disorder is suspected—especially if signs like developmental delay, hypotonia, dysmorphic features, or multi-organ involvement are present—appropriate metabolic workup should be performed. This may include serum lactate, ammonia, amino acids, urine organic acids, acylcarnitine profile, and genetic testing. Genetic syndromes such as trisomy 21 (Down syndrome) and neurofibromatosis type 1 are also associated with Moyamoya and stroke. COL4A1 mutations can cause hereditary small vessel strokes with infantile hemiparesis, and CADASIL (NOTCH3 mutation) leads to strokes in young adults—extremely rarely manifesting in adolescence. These conditions are rare, but a family history of strokes or consanguinity might warrant genetic consultation.
  

Note: It is important to remember that many children have multiple risk factors working together. For example, a child with minor head trauma might only experience a stroke if they also have an underlying mild hypercoagulability or arterial abnormality. In one international study, 77–79% of children with stroke had a recognizable predisposing condition, and about a quarter had two or more risk factors at the same time. Therefore, a thorough evaluation of all relevant categories is recommended for most pediatric strokes unless a very clear single cause is obvious.

Diagnostic Workup of Pediatric Stroke

The evaluation of a child with suspected stroke should be conducted urgently and alongside initial stabilization. Key elements of the workup include neuroimaging to confirm and classify the stroke, as well as a comprehensive set of studies to determine the underlying cause(s). Recent pediatric stroke guidelines highlight the importance of rapid imaging and early involvement of specialists. Below is a structured approach:

Neuroimaging

Brain imaging is the top priority in any stroke assessment to distinguish ischemic from hemorrhagic stroke and to guide further treatment. The choice of imaging modality may depend on availability and the child’s condition.

• Noncontrast CT (Computed Tomography): A CT scan of the head is the fastest way to detect intracranial hemorrhage and is often the first imaging test used in emergencies. In a child with acute focal deficits without trauma, a CT can quickly confirm a hemorrhagic stroke, which appears hyperdense, or suggest an ischemic stroke, which may appear normal or show subtle early signs within the first few hours. Guideline: For suspected hemorrhagic stroke, perform an urgent noncontrast CT. CT can also identify early signs of large infarction or other conditions like tumors or abscesses that may mimic stroke. However, CT is less sensitive to detecting acute ischemia in children; a normal head CT does not rule out AIS.
  
• MRI (Magnetic Resonance Imaging): MRI is the gold standard for diagnosing ischemic stroke in children due to its superior sensitivity. Diffusion-weighted MRI can detect cerebral infarction within minutes of onset. Guideline: For suspected arterial ischemic stroke, obtain an urgent brain MRI with DWI (diffusion-weighted imaging) if available. MRI can confirm an ischemic lesion and often determine the age of the infarct (acute vs. chronic) through DWI and ADC changes. It is also invaluable for identifying stroke mimics; for example, if MRI shows demyelinating lesions instead of a vascular pattern, a diagnosis such as ADEM might be made. MRI sequences like FLAIR and GRE/SWI can additionally detect prior strokes or microbleeds. The drawback is that MRI may require sedation in young children and is not as immediately available as CT in all centers. If MRI will be delayed, performing a CT first is appropriate. Many protocols recommend CT (with CT angiography) if MRI cannot be performed within 30 minutes in a child with acute stroke symptoms.
  
• Vascular Imaging (MRA/CTA/DSA): Because arteriopathy is very common in pediatric stroke, imaging of the cerebral vasculature is essential.
  
  • MRA (Magnetic Resonance Angiography): MRA of the head and neck is usually performed alongside MRI in stroke protocols. It is noninvasive and can often detect large and medium vessel abnormalities such as occlusion, stenosis, Moyamoya collaterals, and dissection flaps if in the neck. In fact, MRA has been found to have comparable accuracy to conventional angiography for many pediatric vasculopathies, except possibly very small vessel disease. All children with AIS should undergo vascular imaging, either by MRA or CTA, to assess for treatable causes like large vessel occlusion or dissection. Neck MRA is recommended if cervical dissection or arch anomalies are suspected.
    
  • CTA (CT Angiography): CTA can be quickly performed during the initial CT to visualize vessels, including the aortic arch, neck, and cerebral arteries. It is helpful if MRI/MRA is not immediately accessible. Sometimes, CTA shows posterior circulation arterial occlusions more clearly than MRA because of flow artifacts. However, it involves exposure to radiation and contrast. Typically, a stroke code CT includes a CTA of the head and neck to avoid missing a large vessel occlusion that could be treated with thrombectomy (in an older child).
    
  • DSA (Digital Subtraction Angiography): Conventional catheter angiography remains the gold standard for detailed cerebrovascular imaging, especially for small-vessel vasculitis or when noninvasive studies are inconclusive. DSA can identify subtle vasculitic changes, aneurysms, or dissections that are not clear on MRA/CTA. It also permits interventions (e.g., revascularization, angioplasty) if necessary. Drawbacks include its invasive nature and the need for sedation; it is typically reserved for cases where MRA/CTA are inconclusive but clinical suspicion for an arteriopathy remains high, or if endovascular therapy is planned.
    
  • MRV/CTV (Venography): If venous thrombosis (CSVT) is suspected, such as in a child with headache, papilledema, or mental status changes that are out of proportion to focal signs, imaging of the cerebral venous sinuses is necessary. MR venography (MRV) is the preferred method to confirm CSVT and is usually performed with the MRI stroke protocol. MRV can detect the absence of flow in a venous sinus or cortical vein. CT venography is an alternative if MRI is unavailable. In neonates, a cranial ultrasound through the fontanel may sometimes suggest venous sinus thrombosis by revealing a dense echogenic thrombus in the sinus, but MRI/MRV remains essential for confirmation. Guideline: MRI of the brain with MRV of the brain and neck (including jugular veins) is the recommended imaging modality for pediatric CSVT.
    
• Other imaging considerations: For neonates, initial cranial ultrasound can be a useful screening tool (e.g., to detect hemorrhage or major infarcts) since the fontanelle is open, but a follow-up MRI is usually necessary to specify the injury. If arteriovenous malformation (AVM) or aneurysm is suspected as a cause of hemorrhagic stroke, CTA or DSA is often required to locate the lesion and plan treatment (MRI/MRA may miss small AVMs or certain aneurysms). In a child with suspected stroke but normal initial MRI, repeating an MRI after a few days might show evolving changes (especially in cases of suspected vasculitis). Also, transcranial Doppler (TCD) ultrasound is not typically used for acute diagnosis but is important in SCD for screening and can detect occlusion of major intracranial arteries at bedside if needed.
  

Initial Laboratory Studies

While imaging is underway (or immediately afterward), laboratory workup should be started to identify causes and guide urgent treatment. Basic labs in the emergency setting include:

• Complete blood count (CBC) – to check for anemia (e.g., sickle cell crisis, iron deficiency) or polycythemia, and platelet count (thrombocytopenia could suggest hemorrhagic risk, while extreme thrombocytosis may indicate a myeloproliferative disorder).
  
• Serum glucose and electrolytes – to rule out hypoglycemia or electrolyte imbalances that can mimic stroke symptoms and to manage metabolic status.
  
• Coagulation studies (PT, aPTT) – to identify unrecognized coagulopathies (e.g., hemophilia, DIC), especially in hemorrhagic stroke, and as a baseline before any thrombolytic therapy. If a hemorrhagic stroke is present, also obtain fibrinogen and, depending on the context, possibly vitamin K.
  
• Inflammatory markers, such as ESR and CRP, are often ordered early. Although non-specific, an elevated ESR/CRP might support an inflammatory or infectious cause. (Keep in mind ESR/CRP can be normal even in active CNS vasculitis.)
  
• Pregnancy test (in adolescent girls) – before imaging with radiation or certain treatments.
  
• Toxicology screen in adolescents – to rule out drug use, as stimulants like cocaine or meth can trigger stroke or dissection.

Suppose the child presents within a window where thrombolysis or thrombectomy might be considered (generally >~2 years old and within hours of onset). In that case, additional urgent labs include blood type and crossmatch (in case transfusion is needed), as well as frequent repeat neurological exams. According to pediatric acute stroke protocols, labs like CBC, coagulation profile, metabolic panel, and blood glucose should be expedited within minutes, as they are needed to evaluate eligibility for reperfusion therapy.

Targeted Diagnostic Tests

Once the diagnosis of stroke is confirmed (or strongly suspected) and initial stabilization is in progress, a thorough etiologic workup should follow. Many of these tests are guided by clues from history, exam, and initial results.

• Extensive Blood Work: A comprehensive panel of blood tests is usually recommended to identify treatable causes.
  
• Thrombophilia Panel: Even during the acute phase, pediatric stroke guidelines suggest testing for common prothrombotic markers. This typically includes protein C and S levels, antithrombin III, factor V Leiden mutation, prothrombin G20210A mutation, and screening for lupus anticoagulant and anticardiolipin antibodies. Some centers also check homocysteine levels (which are elevated in MTHFR variants) and Factor VIII activity, as high Factor VIII or other clotting factor imbalances can increase risk. Note: If the child is started on anticoagulation (heparin) acutely, protein C and antithrombin levels can be temporarily low. Many protocols still perform the initial panel during this period, but abnormal results should be confirmed at follow-up.
  
• Inflammatory and Autoimmune Markers: If an inflammatory cause is suspected, order ANA (antinuclear antibody) and possibly dsDNA antibodies (for SLE), ENAs (extractable nuclear antigens for specific rheumatic diseases), ANCA (for vasculitides like granulomatosis with polyangiitis), rheumatoid factor, etc., based on clinical suspicion. Antiphospholipid antibodies (lupus anticoagulant, anticardiolipin IgG/M, β2-glycoprotein) should be tested in any arterial stroke in a teenager or if signs of thrombosis are present, given the potential for APS. A vasculitis workup may also include complement levels (C3, C4), ESR/CRP (if not already done), and cytokine profiles, but these are supportive tests. Many of these tests can take days to yield results, but obtaining them early is beneficial. If the initial ANA is positive or if there is strong clinical suspicion of rheumatologic disease, early involvement of pediatric rheumatology is recommended.

• Infectious workup: Based on history and exam, targeted infectious tests should be performed. For example, VZV serology or PCR (serum) if stroke occurred after recent chickenpox, HIV testing in any undiagnosed adolescent stroke, syphilis serology (RPR/VDRL) for neonates or adolescents at risk, and cultures if endocarditis is a possibility. If CSVT or arterial stroke is associated with a sinus or ear infection, obtain relevant cultures (blood, ear drainage) and consider an ENT evaluation. In regions endemic for TB or with risk factors, include TB testing (PPD or IGRA) and, if indicated, PCR for TB or other pathogens in the CSF (if a LP is performed). Less common but noteworthy tests include: Lyme titers (in endemic areas, as neuroborreliosis can rarely cause vasculitis and stroke), echovirus/enterovirus PCR, and various hypercoagulable infection tests (e.g., COVID-19 PCR/antibodies if relevant). Adjust infectious testing based on the clinical context.
  
• Metabolic/Genetic tests: If features suggest a metabolic stroke, order appropriate labs as noted. Examples: plasma amino acids and urine organic acids (for urea cycle disorders or organic acidemias), plasma lactate and pyruvate (for mitochondrial disorders), serum ceruloplasmin (if Wilson’s disease is suspected in basal ganglia stroke), very long chain fatty acids (for ALD in boys with adrenal issues), etc. Serum and urine homocysteine should be checked if homocystinuria is a concern. Many metabolic tests may be performed after the acute phase, but collecting samples early (even freezing them for later analysis) can save time. Ultimately, genetic testing may be indicated for certain suspected conditions (e.g., MELAS m.3243A>G test, ACTA2 gene panel), often in consultation with a genetic specialist.
  
• Miscellaneous: Toxicology (drugs of abuse) screening in adolescents, vitamin levels (B12, folate if homocysteine is elevated), and coagulation factor levels if coagulopathy is suspected (e.g., factor VIII, IX for hemophilia in hemorrhagic stroke). Additionally, consider serum ferritin, triglycerides, and fibrinogen when evaluating for HLH or other hypercoagulable states, such as hyperviscosity.
  
• Lumbar Puncture (CSF analysis): LP is not routinely necessary for every pediatric stroke, but it is essential when CNS infection or primary CNS vasculitis is suspected. If signs point to meningitis or encephalitis (fever, meningismus, altered consciousness), perform an LP after imaging rules out a mass effect. CSF can identify infections (PCR for viruses such as VZV, enterovirus; cultures for bacteria/fungi; antigen tests) and reveal inflammatory changes. In suspected vasculitis, LP can be very informative, as pleocytosis and/or elevated protein may support CNS vasculitis. However, these findings can be mild or even regular in isolated angiitis of the CNS. According to pediatric stroke guidelines, LP should be performed (with opening pressure measurement) when evaluating for CNS vasculitis or infection, and studies such as VZV PCR, EBV PCR, and Mycoplasma PCR should be sent (if these infections are suspected). For example, in one series, reasons for performing LP in young stroke patients included suspicion of infection (e.g., HIV, syphilis, endocarditis) or suspicion of CNS vasculitis (positive autoimmune markers). If intracranial pressure is a concern (such as in CSVT or hemorrhagic stroke with hydrocephalus), measure opening pressure during LP, and CSF removal may be therapeutic. Caution: LP is contraindicated when a large mass lesion or hemorrhage with a mass effect is present; therefore, always perform neuroimaging first. When vasculitis is strongly suspected and noninvasive tests are inconclusive, some cases may even require a brain biopsy for definitive diagnosis, but this is a last resort.
  
• Cardiac Evaluation (ECG and Echocardiography): Because of the contribution of cardiac causes, every child with an ischemic stroke should undergo heart disease assessment. An electrocardiogram (ECG) is performed immediately to detect arrhythmias (e.g., atrial flutter in neonates, atrial fibrillation in adolescents with specific conditions). The key test is echocardiography: a transthoracic echo (TTE) can identify structural heart issues, intracardiac thrombi, shunts, valvular vegetations, or cardiomyopathy. Ideally, for older children with no apparent cause for stroke, a bubble study (agitated saline) may be added to detect a PFO or septal defect with right-to-left shunting. Suppose TTE results are expected, and suspicion remains high. In that case, some cases might require a transesophageal echo (TEE) for enhanced visualization of the atria, atrial appendage, and aortic arch (noting that TEE often requires general anesthesia in young children). Guideline: Pediatric stroke protocols recommend obtaining an ECG and echocardiogram during the subacute phase to identify any cardioembolic source. If an arrhythmic cause is suspected, Holter monitoring or inpatient telemetry can be considered. Close cooperation with pediatric cardiology is essential if any abnormalities are detected or if the child has known heart disease.
  
• Vascular Studies of Head & Neck: Beyond intracranial vessel imaging (MRA/CTA), consider cervical artery imaging, especially if trauma or dissection is a concern. An MRA or CTA of the neck (including the carotid and vertebral arteries) is often performed in conjunction with brain imaging in cases of arterial strokes to assess for dissection, aortic arch anomalies, or cervical fibromuscular dysplasia. Sometimes, carotid ultrasound can be used to screen for carotid dissection or arteriopathy at the bedside; however, its sensitivity is limited in pediatrics. Transcranial Doppler (TCD) ultrasound is widely used in sickle cell disease for stroke risk screening. In the context of acute stroke, TCD may detect occlusion or collateral flow patterns; however, its accuracy is operator-dependent. If an arteriopathy, such as Moyamoya, is identified, formal angiography may be pursued later for surgical planning. If venous thrombosis is present, vascular ultrasound of the limbs can also be done to look for DVT or an underlying thrombophilic source, and abdominal imaging may be considered if there is concern for portal vein thrombosis or other issues in the neonatal thrombosis workup.
  
• Other Consultations for Workup: Early involvement of subspecialists can significantly assist in tailoring the diagnostic approach.
  
  • Neurology: A pediatric neurologist or stroke specialist should be involved as soon as a stroke is suspected. They can assist in coordinating acute management, including decisions on thrombolysis or anticoagulation, and guide the etiologic workup process. Neurologists will also evaluate the EEG if seizures have occurred and plan for rehabilitation. Most hospitals have an immediate “Code Stroke” protocol that includes prompt neurology consultation.
    
  • Hematology: If an overt or potential coagulopathy is present (e.g., stroke in a child with known thrombophilia or any CSVT case), pediatric hematology should be consulted. They guide anticoagulation management and further thrombophilia testing. For example, in cases of CSVT or AIS with a clot, hematology will advise on heparin dosing, the duration of therapy, and interpret subtle abnormalities in coagulation tests. In sickle cell stroke, hematology is crucial for exchange transfusion and chronic transfusion planning.
    
  • Rheumatology: Pediatric rheumatology consultation is essential whenever a vasculitic or autoimmune cause is suspected. If a child’s stroke workup shows positive ANA or other rheumatologic markers, or if there are clinical signs of systemic inflammation (rash, arthritis, etc.), involve rheumatology early. Guideline: Expert recommendations state that prompt consultation with rheumatology should be obtained when evaluating possible CNS vasculitis. Rheumatologists assist in interpreting autoimmune lab results and may recommend immunologic tests (e.g., complement, antiphospholipid panel) to help determine whether a biopsy or empiric immunosuppressive treatment is necessary. They also co-manage conditions like APS or lupus that require long-term therapy.
    
  • Infectious Diseases: If an infectious cause is suspected (e.g., endocarditis, meningitis, varicella, TB), an ID specialist can advise on proper cultures, imaging (to identify the source of the infection), and urgent antimicrobial treatment. For example, in stroke cases caused by endocarditis, ID will oversee antibiotic therapy; in TB meningitis-related stroke, ID guides anti-TB treatment.
    
  • Neurosurgery/Interventional Radiology: These specialists are primarily involved in treating hemorrhagic strokes, including surgical evacuation of hematomas, relieving hydrocephalus, and treating aneurysms and arteriovenous malformations (AVMs). They also manage large ischemic strokes with significant swelling, which may require hemicraniectomy to prevent fatal herniation. In some cases of AIS, interventional radiologists may assist with mechanical thrombectomy for proximal large artery occlusions if the child is a candidate—an evolving area, with some case series indicating thrombectomy is feasible in children promptly. For CSVT that causes intracranial hypertension, neurosurgery may place ICP monitors or perform venous sinus thrombolysis in rare cases. While not all pediatric centers can provide these interventions, having neurosurgery available for hemorrhagic stroke or large infarcts is recommended.
    
  • Metabolic/Genetics: If a metabolic stroke is suspected, consulting a metabolic geneticist can expedite specific testing (enzyme assays, genetic panels) and management (e.g., initiating cofactors like vitamins or specialized diets). The Texas Children’s stroke guideline, for example, recommends a formal genetics/metabolism consultation whenever a stroke related to metabolic disease is suspected.
    
  • Others: Physical medicine and rehabilitation specialists should be involved early in planning post-acute rehab. Occupational and physical therapists, speech therapists, and neuropsychologists will also join the team to manage deficits after the acute phase.
    

Differences in Evaluation Approach: Ischemic vs Hemorrhagic vs CSVT

While there is some overlap in workup, specific aspects of evaluation vary depending on stroke subtype.

Arterial Ischemic Stroke (AIS): The priority is rapid brain imaging to confirm an infarct and exclude hemorrhage. In older children who present very acutely (within hours), adult stroke protocols are cautiously applied – IV tPA (alteplase) can be considered in children ≥2 years old with a confirmed arterial occlusion causing significant deficits, no contraindications, and within 4.5 hours of onset. This decision is made in consultation with neurology and often requires adherence to institutional protocols, as evidence in children is limited. Likewise, mechanical thrombectomy for large vessel occlusion (within 6 hours, sometimes up to 24 hours if imaging shows salvageable tissue) has been reported in pediatric cases, but is determined on a case-by-case basis. Thus, for AIS, time-sensitive steps include obtaining imaging (preferably MRI/MRA or CT/CTA, if MRI is unavailable) and laboratory tests to assess thrombolysis eligibility (coagulation panel, platelet count, etc.). If an arterial occlusion is identified, especially if reperfusion therapy is administered, managing blood pressure, oxygenation, blood glucose, and body temperature is crucial (neuroprotective measures similar to adult stroke care). After initial management, the focus for AIS shifts to identifying risk factors. Comprehensive investigations, including arteriopathy (MRA/angiography), cardiac sources (echocardiography), and prothrombotic states (laboratory tests), are indicated in nearly all AIS cases because the cause is often not immediately apparent. If an arteriopathy, such as focal cerebral arteriopathy, is found, some centers consider immunomodulatory treatment (e.g., steroids) acutely, although evidence is still emerging. In summary, AIS workup is broad and must consider multiple possible simultaneous etiologies.

Hemorrhagic Stroke: The initial assessment for hemorrhagic stroke focuses on stabilizing the patient and identifying the bleeding source. On CT or MRI, it is crucial to differentiate between intracerebral hemorrhage (ICH) and subarachnoid hemorrhage (SAH), as the causes can vary (e.g., SAH in a child may indicate an aneurysm or arteriovenous malformation (AVM). The primary causes of non-traumatic hemorrhagic stroke in children include vascular anomalies (such as AVMs and cerebral aneurysms), blood disorders, and brain tumors. Therefore, if CT confirms hemorrhage:

• Vascular imaging (CTA/MRA/DSA) should be performed as early as possible to investigate for an AVM, aneurysm, or venous sinus thrombosis (the latter can lead to hemorrhagic infarcts). In a child with a lobar hemorrhage, an AVM is the most likely diagnosis until proven otherwise. For deep hemorrhages (in the basal ganglia or thalamus), consider an aneurysm (including pseudoaneurysm in moyamoya or post-infectious cases) or cavernous malformation. Conventional angiography is often ultimately required to evaluate an AVM or aneurysm for complete potential treatment.
  
• Coagulation studies and platelet count are urgent—if the child is coagulopathic (e.g., hemophilia, unrecognized or on warfarin for any reason), reverse the coagulopathy with factor concentrates, vitamin K, or FFP as appropriate. If platelet counts are very low (< 20,000) or dysfunctional, address this with a transfusion.
   
• Managing blood pressure is essential; keep it within a safe range to prevent hemorrhage expansion (often with lower BP targets than in ischemic stroke, but avoid hypotension that could decrease cerebral perfusion in areas of increased pressure).
  
• Neurosurgical evaluation: Involve neurosurgery early. Extensive hemorrhages causing mass effect or hydrocephalus (e.g., intraventricular hemorrhage) may require urgent surgical evacuation or an external ventricular drain. Even if not, neurosurgeons should be involved if an aneurysm needs clipping or an AVM requires resection or embolization.
  
• The etiologic workup in hemorrhagic stroke focuses on identifying a structural lesion. If none is found on initial angiography, a follow-up angiography may be performed later, as micro-AVMs sometimes only become apparent after the clot clears. Also consider systemic causes: for example, was the child hypertensive? (Severe hypertension can cause hemorrhage, although chronic hypertension is rare in children; consider catecholamine surge from an adrenal tumor or medications). Are there any signs of cerebral vasculitis? (Vasculitis like PAN can lead to microaneurysms and hemorrhage). Is there a bleeding disorder? (If not already diagnosed, test for hemophilia, von Willebrand disease, platelet function, etc., in cases of unexplained hemorrhage). The family history and skin exam (for signs of telangiectasia as seen in Osler-Weber-Rendu or neurocutaneous syndromes) might provide clues.
  
• In summary, the evaluation of hemorrhagic stroke relies more heavily on vascular imaging and hematologic testing. The differential diagnosis includes AVM, aneurysm, tumor, coagulopathy, and hypertension/vasculopathy. Notably, in one pediatric series, causes of ICH included AVMs, moyamoya disease, aneurysms (including mycotic aneurysm from endocarditis), arterial dissections, and blood dyscrasias (one child had an MTHFR mutation and another had Evans syndrome with resulting hemorrhage). This underscores the diverse causes of hemorrhagic stroke that need to be investigated.
  

Cerebral Sinovenous Thrombosis (CSVT): The evaluation of CSVT overlaps with AIS because the result is brain infarction, often hemorrhagic, but special attention is paid to provoking factors and hypercoagulability.

• Imaging: MRI/MRV is diagnostic. Often, MRV will reveal the absence of flow in a venous sinus or vein; on MR brain, one might observe venous infarcts, which can be hemorrhagic (e.g., parasagittal frontal lobe hemorrhages in superior sagittal sinus thrombosis). Sometimes, CT shows a hyperdense sinus or hemorrhagic lesion suggesting CSVT, but MRI confirms the diagnosis.
  
• Risk factor investigation: CSVT usually results from a combination of factors. Common risk factors in children include acute systemic illnesses (such as dehydration and severe infections, especially in neonates), head and neck infections (like otitis media, mastoiditis, and sinusitis leading to local septic thrombosis), hematologic or genetic prothrombotic conditions, and mechanical factors, including central venous catheters. For example, a child who is immobilized after surgery with a central line and develops an infection is at very high risk for CSVT. In one pediatric CSVT study, approximately 43% had head or neck infections (otitis, sinusitis), about 12% had inherited thrombophilia, and others had anemia, Behçet’s disease, leukemia, etc., with many cases involving multiple factors. Therefore, the workup needs to be comprehensive: all children with CSVT should be evaluated for infection (e.g., an ENT exam and cultures, as well as cranial imaging to check for mastoiditis); a thrombophilia panel (as described above) should also be ordered. Additionally, assess for anemia, dehydration (high sodium or BUN levels may indicate dehydration in infants), and any inflammatory diseases (elevated ESR and CRP may suggest underlying disorders such as Behçet’s or IBD).
  
• Lumbar puncture is usually not required for diagnosis, as imaging is sufficient. However, if papilledema is present, measuring the opening pressure can confirm intracranial hypertension. LP may also be performed to rule out meningitis if symptoms overlap.
  
• Acute management (beyond just evaluation) of CSVT primarily involves anticoagulation in most cases, even if a hemorrhagic component is present, to reopen the sinus. Therefore, involving hematology early to assist with safe anticoagulation is advisable. Also, treat the underlying cause (such as antibiotics for infection, rehydration for dehydration, etc.).
  
• To summarize, CSVT evaluation focuses on identifying underlying causes: one often finds that a child with CSVT has at least one or two risk factors, such as infection, prothrombotic state, or systemic illness. This differs slightly from arterial AIS, where arteriopathy is predominant; in CSVT, look for factors such as otitis media, mastoiditis, recent ENT infections, iron deficiency, acute leukemia, lupus/Behçet syndrome, nephrotic syndrome, and others, as these are commonly involved. The good news is that many CSVT causes, such as infection and dehydration, are treatable or temporary in nature. Still, it is essential not to miss chronic underlying disorders like occult malignancy or thrombophilia.
  

Multidisciplinary Management and Consultation

Evaluating and managing pediatric stroke is fundamentally a team effort. Inpatient pediatricians will coordinate care across multiple specialties:

• Neurology: Immediately engage pediatric neurology for any suspected stroke. Neurologists direct the acute neurologic care (seizure management, intracranial pressure control, blood pressure targets) and make decisions about reperfusion therapies. They also coordinate neuroimaging protocols and serial exams. Neurology will monitor the child long-term for secondary stroke prevention (e.g., aspirin if appropriate) and rehabilitation. Early neurology input has been shown to improve the speed and accuracy of pediatric stroke diagnosis.
  
• Hematology: The hematologist’s expertise is vital, especially in ischemic stroke requiring anticoagulation or when a coagulopathy is present. They manage heparin or low molecular weight heparin dosing in CSVT or cardioembolic strokes and recommend the duration of therapy. They also interpret complex thrombophilia tests and arrange follow-up testing, as some thrombophilias can only be confirmed after the acute phase or when off anticoagulation. In sickle cell strokes, hematology leads the acute exchange transfusion and chronic transfusion programs to prevent recurrences. If the child has an underlying oncologic or bone marrow disorder causing stroke, hematology/oncology will co-manage that as well. Essentially, for any AIS or CSVT, a hematology consult is recommended to assist with hypercoagulability evaluation and therapy.
  
• Rheumatology: Pediatric rheumatologists are essential when an autoimmune or inflammatory cause is suspected. As soon as there are red flags, such as a positive ANA, elevated inflammatory markers without an infection, or multifocal strokes that may suggest vasculitis, a rheumatology consult should be arranged. They can help differentiate between primary CNS vasculitis and systemic rheumatologic disease and guide immunosuppressive treatment if necessary. For instance, treating primary angiitis of the CNS in children involves high-dose corticosteroids and cyclophosphamide—usually initiated by rheumatology after diagnosis, often requiring a biopsy. Rheumatologists will also co-manage APS (with anticoagulation and immunomodulation if secondary to lupus) and monitor for other systemic features that may develop. Guideline: It is recommended to involve rheumatology promptly during stroke workup if vasculitis is considered, ensuring appropriate tests (such as specialized antibody panels) are performed and that therapy isn’t delayed if an inflammatory condition is confirmed.
  
• Cardiology: For cases with a known or suspected cardiac origin, consultation with pediatric cardiology is recommended. They will perform and interpret the echocardiogram (including advanced imaging, such as transesophageal echo, if needed) and manage any cardiac conditions identified (e.g., initiating anticoagulation in a child with cardiomyopathy and an intracardiac thrombus or arranging closure of a significant atrial septal defect/PFO if deemed causative). If an arrhythmia is detected, they guide antiarrhythmic therapy or device placement. Essentially, any stroke patient with abnormal cardiac findings or a history of congenital heart disease warrants cardiology input. Even if the echo is normal, if no other cause is found, cardiology may assist with more sensitive testing, such as cardiac MRI or prolonged rhythm monitoring to detect subtle cardioembolic sources.
  
• Neurosurgery: Although not explicitly asked in the question, it’s essential to know when to involve neurosurgery. Hemorrhagic strokes often require neurosurgical evaluation for potential intervention, such as evacuating a hematoma, clipping an aneurysm, or resecting or embolizing an AVM in conjunction with interventional radiology. In large malignant ischemic infarcts, like a large MCA territory stroke with significant swelling, neurosurgery is consulted for possible decompressive craniectomy, which can be life-saving. In cases of CSVT with severe intracranial hypertension, neurosurgery might place a ventricular drain. If vasculopathy such as moyamoya is diagnosed, neurosurgeons or vascular neurospecialists perform revascularization surgery (e.g., STA-MCA bypass or encephaloduroarteriosynangiosis) electively to prevent future strokes. Therefore, while neurosurgery may not be necessary in every case, its involvement is vital in many stroke subtypes.
  
• Rehabilitation Services: Early involvement of physiatrists (rehabilitation physicians) and therapists is essential for a successful recovery. Although this occurs after the acute phase, the inpatient team should arrange for PT, OT, and speech therapy evaluations soon after the child stabilizes. Swallowing assessment is essential for safe feeding after a stroke. Establishing a neuropsychology baseline can be helpful, as many children will need cognitive and psychological support due to the impact of stroke on school performance or behavior.
  

In summary, pediatric stroke management is a multidisciplinary effort. The inpatient pediatrician or hospitalist often serves as the coordinator, ensuring that neurology, hematology, rheumatology, and cardiology are involved as needed. Regular team meetings or stroke rounds help coordinate the workup plan, such as deciding the order of tests or interpreting findings together. This team-based approach is supported by evidence and recent guidelines, which highlight the importance of rapid imaging confirmation, involving a pediatric stroke team, and conducting tailored evaluations to find the cause. By determining the etiology, we not only treat the immediate stroke but also initiate specific therapies to prevent future episodes (e.g., anticoagulation for CSVT, immunosuppression for vasculitis, transfusions for sickle cell disease, or surgery for AVM), ultimately improving the child’s long-term outlook.

References: Pediatric stroke evaluation should adhere to established guidelines and consensus statements, including the American Heart Association scientific statement on managing stroke in neonates and children, as well as institution-specific protocols such as the Royal Children’s Hospital Melbourne guideline and the Texas Children’s Hospital pathway, which reflect the most recent evidence. These emphasize a comprehensive, evidence-based approach: confirm the diagnosis with urgent neuroimaging, involve specialists early, broadly investigate for risk factors (arteriopathic, cardiac, hematologic, infectious, autoimmune, metabolic), andmanage collaboratively. This ensures clinicians do not overlook any aspect of a child’s stroke etiology and that targeted, first-line interventions are applied for both acute care and secondary prevention.