Ischemic stroke in children: Clinical presentation, evaluation, and diagnosis

INTRODUCTION — While more common in older adults, stroke also occurs in neonates, infants, children, and young adults, resulting in significant morbidity and mortality.

An overview of the presentation, evaluation, and diagnosis of arterial ischemic stroke in children one month of age or older is provided here.

Other aspects of ischemic stroke in children and young adults are reviewed elsewhere:

Ischemic stroke in children and young adults: Epidemiology, etiology, and risk factors
Ischemic stroke in children: Management and prognosis
Hemorrhagic stroke in children
Cerebral venous thrombosis: Etiology, clinical features, and diagnosis
Stroke in the newborn: Classification, manifestations, and diagnosis

CLINICAL PRESENTATION — Infants and young children with stroke may present with focal weakness, but are more likely than older children to present with seizures and altered mental status [1,2]. Older children usually have hemiparesis or other focal neurologic signs such as aphasia, visual disturbance, or cerebellar signs, although seizures, headache, and lethargy are more common among children than adults [3-7].

●Focal manifestations – In various reports, the frequency of focal neurologic manifestations with acute stroke in children include the following [2,7]:

•Hemiparesis and hemifacial weakness in 67 to 90 percent

•Speech or language disturbance in 20 to 50 percent

•Visual disturbance in 10 to 15 percent

•Ataxia in 8 to 10 percent

●Nonlocalizing manifestations – The most frequent nonlocalizing manifestations in arterial ischemic stroke are the following [2,7]:

•Headache in 20 to 50 percent

•Altered mental status in 17 to 38 percent

•Vomiting in approximately 10 percent

●Seizures – Seizures at stroke onset occur in 15 to 25 percent of children with arterial ischemic stroke; the frequency is highest in younger children, particularly those less than six years of age [2,4,7].

Certain presentations may be associated with mechanism or localization:

●Cardiac etiology – Arterial ischemic stroke caused by cardiac disease tends to occur predominantly among younger children (median age six months to three years) with complex congenital heart disease and is associated with a relatively high frequency of seizures (up to 40 percent) and bilateral strokes in the anterior and posterior circulation, and a tendency to hemorrhagic transformation of ischemic infarcts [8-11].

●Posterior circulation infarcts – In children, most posterior circulation infarcts (63 to 77 percent) occur in boys for reasons that are unknown [7,12-15]. Common presenting manifestations of posterior circulation infarcts in children include hemiparesis, ataxia, dysarthria, visual field deficits, and oculomotor involvement [7,13,15]. Frequent nonlocalizing symptoms include headache, vomiting, and altered mental status. Common causes include vertebral artery dissection, often with a history of recent head or neck trauma, and cardioembolic stroke [7,12,15,16].

URGENT EVALUATION

Goals of initial evaluation — Urgent evaluation and neuroimaging is important for confirming the diagnosis of acute arterial ischemic stroke (algorithm 1) and excluding stroke mimics; numerous conditions can mimic ischemic stroke, particularly with regard to children, including but not limited to migraine, seizure with Todd paralysis, Bell's palsy, and infection [17,18]. (See 'Differential diagnosis' below.)

The diagnosis of stroke is often delayed or initially misdiagnosed in children [19,20]. In a retrospective series of 209 children (one month to 18 years old) who presented with acute arterial ischemic stroke, the mean interval from symptom onset to diagnosis was 22.7 hours [21].

The urgent evaluation proceeds in tandem with consideration of immediate interventions – once the diagnosis of ischemic stroke is confirmed – that may improve stroke outcome (algorithm 1), including possible hyperacute reperfusion therapies with intravenous thrombolysis (within 4.5 hours of the time the patient was last seen well) and mechanical thrombectomy (within 24 hours of last seen well).

Brain imaging

Choice of imaging study — We obtain a brain magnetic resonance imaging (MRI) with diffusion weighted imaging and vascular imaging with magnetic resonance angiography (MRA) as the initial studies, which should be obtained as soon as possible in children who present with suspected ischemic stroke. Head computed tomography (CT) is generally considered inadequate to diagnose ischemic stroke in children, and MRI may be required to reliably exclude stroke mimics [17,22-27].

Brain MRI is more sensitive for acute ischemia than CT, particularly with use of diffusion-weighted imaging in the hyperacute time period. In addition, brain MRI provides better visualization of the posterior fossa. Head CT with CT angiography (CTA) should be obtained if MRI/MRA is not tolerated or will not be available within one hour after arrival. For children with complex congenital heart disease, CT/CTA may be used as the initial imaging study if determination of cardiac hardware compatibility with MRI would entail significant delay. In young adults, either CT or MRI may be used as the initial study, but we prefer brain MRI with diffusion-weighted imaging (DWI) if available because it is more sensitive for the diagnosis of acute stroke than CT.

Availability of urgent neuroimaging of children is a challenge and may influence clinical algorithms for suspected stroke in a child. Australian guidelines recommend MRI as the diagnostic imaging modality of choice for suspected arterial ischemic stroke, but CT imaging including CTA and CT perfusion can be considered as an alternative where urgent MRI is not possible [28]. UK guidelines recommend cranial CT, including CTA, within one hour of arrival at hospital for every child with suspected stroke; they note that brain MRI can be used as the initial study if it is available within one hour of arrival [22]. The guidelines also recommend that brain MRI, including MRA, should be obtained within 24 hours if the initial head CT is negative and stroke is still suspected.

MRI appearance of ischemic stroke — On brain MRI, acute stroke is associated with restricted diffusion in an arterial territory on DWI, just as in older adults. This can persist for 7 to 14 days after stroke onset, at which time restricted diffusion transitions to increased diffusion. Subacute stroke is associated with increased T2-weighted signal and enhancement with gadolinium. Chronic stroke is associated with increased diffusion, increased T2 signal, and evidence of volume loss, including ex vacuo dilatation of the lateral ventricles or porencephaly. Gradient echo imaging is sensitive to the presence of blood products. (See "Neuroimaging of acute stroke", section on 'Assessment of early infarct signs'.)

MRI with gadolinium contrast may be helpful in identifying conditions that can mimic stroke clinically, but gadolinium is not necessary for the diagnosis of ischemic stroke.

CT appearance of ischemic stroke — Early infarct signs, such as cortical effacement with loss of gray-white differentiation, loss of the insular ribbon, and hyperdense artery sign, may be observed on noncontrast head CT acutely, and within 24 hours hypodensity in an arterial territory may be appreciated. (See "Neuroimaging of acute stroke", section on 'Assessment of early infarct signs'.)

Data from a prospectively identified cohort of 63 children with acute arterial ischemic stroke suggest that hemorrhagic transformation is observed in approximately 30 percent of children within one month of stroke onset [29]. In most cases, the hemorrhage is clinically asymptomatic and has a petechial appearance on brain imaging with CT or MRI [30].

CT safety considerations — When clinically indicated, CT is considered a relatively safe procedure in children with proper application of radiation protection, appropriate use of nonionic contrast agents, proper administration of sedation or anesthesia when needed, and monitoring of vital signs.

Relative contraindications to CT in children are unusual but include certain syndromes in which radiation could induce chromosome breaks and increase the genetic predisposition to tumors (eg, ataxia telangiectasia, Nijmegen breakage syndrome) [31-37]. However, such studies should not be withheld if they are required to provide optimal management. (See "Ataxia-telangiectasia" and "Nijmegen breakage syndrome".)

●Radiation dose – Radiation dose is particularly important in children because radiation exposure from CT scanning appears to be associated with a small increased lifetime risk of cancer, including central nervous system tumors [38-41].

In addition, there is some evidence that early radiation to the brain may impair long-term cognitive function [42,43]. Although pediatric CT accounts for approximately 15 percent of radiographic examinations, it contributes to an estimated 70 percent of the total radiation dose to the population [44,45].

●Minimizing radiation exposure – Every effort must be made to minimize the radiation dose to children from CT examinations. The policy of "as low as reasonably achievable" (ALARA), or "least radiation dose necessary" to produce a diagnostic scan should always be followed [46,47]. This concept employs the following methods:

•Use weight-based protocols and improved shielding

•Consider alternative nonradiating imaging modalities, such as MRI

•When clinically appropriate, use focused and/or limited-view studies

•Dissuade repeat CT studies

The Image Gently campaign (www.imagegently.org) offers information for practitioners, radiology technicians, and parents regarding opportunities to use lower radiation doses in the imaging of children [48].

Vessel imaging — In addition to brain imaging, a neurovascular evaluation should be done urgently, particularly if the child is a candidate for reperfusion with thrombolysis or mechanical thrombectomy. We suggest MRA of the neck and head (three-dimensional time-of-flight) without and with contrast enhancement to evaluate the extracranial and intracranial large arteries. CTA can be substituted depending on availability and local expertise, but MRA is preferred because CTA incurs the hazards of radiation and contrast exposure [7]. Cerebrovascular imaging with CTA or MRA should cover the aortic arch to the vertex (ie, the extracranial and intracranial cerebral vessels) [22].

Triage for hyperacute reperfusion therapies — Hyperacute reperfusion therapies may be appropriate for selected children with arterial ischemic stroke. Older children and adolescents within 6 hours of ischemic stroke onset who have a causative large artery occlusion on CTA or MRA may be eligible for mechanical thrombectomy if neuroimaging is consistent with a small infarct core (ie, there are limited signs of early ischemic change on diffusion-weighted MRI or CT without contrast). Mechanical thrombectomy may still be an option for selected children presenting within 6 to 24 hours of stroke onset who meet the eligibility criteria used in adults, other than age (algorithm 2). However, thresholds for estimating core infarct versus penumbra using processed perfusion imaging may differ in young patients compared with older adults, and thresholds for benefit in children have not been established [49]. Young patients with good pial collaterals may transiently present with smaller perfusion deficits despite a large artery occlusion. In healthy children without stroke, typical values for quantitative perfusion studies change with age and brain maturity [50]. Selection for mechanical thrombectomy in the extended time window should be done in consultation with neurologists and neuro-interventionalists who have expertise in treating children with stroke.

Reperfusion therapies are reviewed in greater detail elsewhere. (See "Ischemic stroke in children: Management and prognosis", section on 'Reperfusion with thrombolysis and thrombectomy' and "Mechanical thrombectomy for acute ischemic stroke".)

Laboratory studies — The initial evaluation for stroke in children should include the following studies [22,23]:

●Complete blood count including platelets

●Electrolytes, urea nitrogen, creatinine

●Serum glucose

●Prothrombin time (PT) and international normalized ratio (INR)

●Partial thromboplastin time (PTT)

●Oxygen saturation

In selected patients, particularly those with a confirmed diagnosis of arterial ischemic stroke, additional studies may be useful [22,23]:

●Lumbar puncture if there is suspicion for an infectious etiology of stroke

●Electroencephalogram if seizures are suspected (eg, involuntary movements)

●Hemoglobin electrophoresis in patients with possible sickle cell disease (eg, if suggested by personal or family history)

●Toxicology screen if etiology remains unclear

●Pregnancy test in girls of childbearing potential

●Thrombin time and/or ecarin clotting time for rare pediatric patients who might be taking a direct thrombin inhibitor or a direct factor Xa inhibitor

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of ischemic stroke is broad, as numerous other conditions can present with acute neurologic deficits. In addition, the differential is further extended in young children because stroke may present with nonspecific signs such as seizures or lethargy.

Hemorrhagic stroke can mimic ischemic stroke and is best differentiated by neuroimaging.

●Intracranial hemorrhage (due in most cases to vascular malformation or hematologic abnormalities) can present much like arterial ischemic stroke. Hemorrhagic stroke is differentiated from ischemic stroke by imaging with cranial magnetic resonance imaging (MRI) or noncontrast computed tomography (CT) scan. MRI with gradient echo and/or susceptibility-weighted sequences is equally sensitive to CT for acute parenchymal hemorrhage. (See "Hemorrhagic stroke in children" and "Cerebral venous thrombosis: Etiology, clinical features, and diagnosis".)

Lumbar puncture is indicated if there is clinical suspicion for subarachnoid hemorrhage (eg, severe or sudden-onset headache) and CT or MRI scan is negative for blood. (See "Aneurysmal subarachnoid hemorrhage: Clinical manifestations and diagnosis", section on 'Need for lumbar puncture when early CT is negative'.)

●Cerebral venous sinus thrombosis is highly variable in presentation. The onset can be acute, subacute, or chronic. Headache is the most frequent symptom and may occur as part of an isolated intracranial hypertension syndrome, with or without vomiting, papilledema, and visual problems. In other cases, headache may be accompanied by focal neurologic deficits, focal or generalized seizures, and encephalopathy. The combination of an abnormal signal in a venous sinus on brain MRI and the corresponding absence of flow on magnetic resonance (MR) venography confirms the diagnosis. (See "Cerebral venous thrombosis: Etiology, clinical features, and diagnosis".)

●Seizure with postictal paresis (Todd paralysis) can mimic stroke, particularly when the seizure itself is very brief, unwitnessed, or occurs during sleep. Manifestations of the postictal period typically include confusion and suppressed alertness. Postictal paresis often involves weakness of a hand, arm, or leg that appears following a focal motor seizure involving the one side of the body. The degree of weakness is usually moderate but can be severe. Other focal postictal symptoms vary according to the location of the seizure and may include aphasia, hemianopsia, or numbness. Although there is a broad range, most patients begin to recover responsiveness and alertness within 10 to 20 minutes of a generalized seizure and show gradual, consistent improvement in postictal symptoms as time elapses. Neuroimaging with MRI is helpful to evaluate for acute stroke and for structural abnormalities that cause seizures; electroencephalography (EEG) and lumbar puncture, as clinically indicated. (See "Seizures and epilepsy in children: Clinical and laboratory diagnosis".)

●Migraine can be confused with stroke and other causes of acute neurologic symptoms, particularly in the setting of the emergency department, where children may be more likely to present with a first episode of moderate to severe headache. Migraine aura, when it occurs, is most often visual and gradually progressive. By contrast, stroke typically has a sudden onset of symptoms rather than a gradual progressive spread of one aura symptom after another. Ischemic events are less likely to have positive symptoms such as visual scintillations or paresthesia and are less likely to have migrainous symptoms such as nausea, vomiting, photophobia, and phonophobia. Unlike stroke, the symptoms of migraine are fully reversible, and neuroimaging is typically unrevealing. (See "Pathophysiology, clinical features, and diagnosis of migraine in children".)

Hemiplegic migraine is rare; it is distinguished from other types of migraine with aura by the presence of motor weakness as a manifestation of aura in at least some attacks. (See "Hemiplegic migraine".)

●Bell's palsy can mimic stroke with onset of unilateral facial paralysis, typically over hours. Common findings include diffuse involvement of all of the distal branches of the facial nerve, with sagging of the eyebrow and inability to close the eye. Decreased tearing, hyperacusis, and/or loss of taste sensation on the anterior two-thirds of the tongue may also occur. These features help to distinguish Bell's palsy (a peripheral nerve lesion) from stroke (a central lesion), which normally spares the forehead muscles and does not affect tearing, taste sensation, or hearing. (See "Facial nerve palsy in children".)

●Alternating hemiplegia of childhood (AHC) is a rare genetic condition characterized by periodic episodes of hemiplegia or quadriplegia [51]. Onset in infancy, recurrent episodes, and associated symptoms (dystonia, paroxysmal eye movements, seizures, cognitive impairment, and ataxia) help to distinguish it from stroke.

●Brain tumors in children may present with nonspecific signs and symptoms that occur commonly in children (eg, headache, nausea and vomiting, developmental and behavioral problems) and symptoms that are more suggestive of central nervous system pathology (eg, ataxia, cranial nerve palsies, impaired vision, seizures, papilledema, macrocephaly). The diagnosis of a brain tumor is based upon identification of the lesion by neuroimaging, preferably by MRI, or CT if MRI is not an option. (See "Clinical manifestations and diagnosis of central nervous system tumors in children".)

●Central nervous system infection (meningitis, encephalitis, abscess) can cause headache and hemiparesis, but clinical signs (eg, rash, fever, nuchal rigidity), cerebrospinal fluid (CSF) analysis (eg, pleocytosis), and neuroimaging findings (eg, meningeal enhancement or parenchymal lesion) usually point to the correct diagnosis. In some cases, however, infection can trigger stroke from a variety of etiologies, and meningitis can cause an infectious arteritis of vessels in the subarachnoid space, which in turn may result in thrombosis, ischemia, and infarction. (See "Ischemic stroke in children and young adults: Epidemiology, etiology, and risk factors", section on 'Infection' and "Ischemic stroke in children and young adults: Epidemiology, etiology, and risk factors", section on 'Diffuse vasculitis'.)

●Posterior reversible encephalopathy syndrome (PRES; also called reversible posterior leukoencephalopathy syndrome) is a neurologic syndrome that most often presents with headache, confusion, visual symptoms, and seizures. Typical MRI findings are consistent with vasogenic edema in the subcortical white matter and are predominantly localized to the posterior cerebral hemispheres. The differentiation of vasogenic versus cytotoxic edema with diffusion-weighted MRI is helpful in distinguishing reversible posterior leukoencephalopathy syndrome from stroke. (See "Reversible posterior leukoencephalopathy syndrome".)

●Acute disseminated encephalomyelitis (ADEM) is a demyelinating disease of the central nervous system that typically presents as a monophasic disorder associated with multifocal neurologic symptoms and encephalopathy. ADEM is preceded by a viral or bacterial infection in approximately 75 percent of cases. Unlike stroke, brain MRI in ADEM typically shows diffuse, poorly demarcated, large (>1 to 2 cm) lesions predominantly involving the white matter. (See "Acute disseminated encephalomyelitis (ADEM) in children: Pathogenesis, clinical features, and diagnosis".)

●Idiopathic intracranial hypertension typically presents in obese woman of childbearing age with headaches and papilledema, though it can occur in children. Other common features are transient visual obscurations, pulsatile tinnitus, and diplopia. MRI with and without contrast including postcontrast MR venography is the preferred imaging study; suggestive findings for the diagnosis include empty sella, flattening of the posterior aspect of the globe, distension of the perioptic subarachnoid space, and transverse venous sinus stenosis. (See "Idiopathic intracranial hypertension (pseudotumor cerebri): Clinical features and diagnosis".)

●Acute cerebellar ataxia in children is a clinical syndrome characterized by the sudden onset of ataxia, usually manifested as gait disturbance; associated symptoms may include nystagmus, slurred or garbled speech, vomiting, irritability, dysarthria, or headache. Fever, meningismus, and seizures are absent. Most cases occur in toddlers or school-aged children; in many cases the symptoms develop a few days or weeks after a viral illness. CSF analysis in acute cerebellar ataxia is typically normal or shows a mild lymphocytic pleocytosis, with or without elevations in protein. Neuroimaging is not necessary for children with typical features. (See "Acute cerebellar ataxia in children".)

Other nonvascular conditions that may mimic stroke in children include drug toxicity, musculoskeletal conditions, and psychogenic disorders [17].

EVALUATION FOR ETIOLOGY

Essential evaluation for all patients — The evaluation of children with arterial ischemic stroke should screen for the most common causes, including imaging of intracranial and extracranial cerebral arteries (if not already done as part of the urgent evaluation), assessment of heart structure and function, and hypercoagulable testing [7].

Stroke in children is a multifactorial disease, and the presence of multiple risk factors for stroke increases recurrence risk [52], so the full diagnostic evaluation should be completed even if one risk factor is identified. In support of this, a case-control study of 38 children with underlying cardiac disease and ischemic stroke found more than one hemostatic abnormality consistent with a prothrombotic state in 11 percent of cases and in none of the 100 age-matched controls [53].

For all children with a diagnosis of arterial ischemic stroke, United Kingdom guidelines from the Royal College of Paediatrics and Child Health (RCPCH) recommend evaluation for a history of prior infection (especially varicella zoster virus), immunization, dysmorphic features, neurocutaneous stigmata, autoimmune disease, and evidence of vascular disease in other organ systems [22]. These evaluations are useful in the work-up for focal cerebral arteriopathy (see 'Focal cerebral arteriopathy' below) and for some less common underlying causes of stroke (see 'Rare causes of stroke' below), including ACTA2 mutations and other genetic diseases.

Cardiac evaluation — Children with arterial ischemic stroke should have a cardiac evaluation including electrocardiogram with inpatient cardiac monitoring, and transthoracic echocardiography (TTE) with agitated saline study to evaluate for possible cardiac source of embolism, including right to left shunt. The most common cardiac causes of stroke are cardiac anomalies (congenital or acquired) and arrhythmia. (See "Ischemic stroke in children and young adults: Epidemiology, etiology, and risk factors", section on 'Cardiac'.)

The role of patent foramen ovale (PFO) as a cause of stroke in childhood is not settled. Nevertheless, some experts advise four-extremity Doppler ultrasound in children with cryptogenic stroke who have a positive bubble study on TTE [7]. Others advise consideration of transesophageal echocardiography (TEE) if TTE is nondiagnostic, or if there is a high index of suspicion for a cardioembolic source.

Cardiac enzymes and troponin should be obtained if there is clinical suspicion of myocardial ischemia [22,23]. Patients at heightened risk for myocardial ischemia include those with known congenital heart disease, heart transplant, substance abuse, or prior Kawasaki disease. Clinical features suggesting myocardial ischemia include the presence of chest pain and abnormalities on cardiac examination or electrocardiogram (ECG).

The management of acute ischemic stroke due to cardiogenic embolism is reviewed separately. (See "Ischemic stroke in children: Management and prognosis", section on 'Cardioembolic source'.)

Arteriopathy evaluation — As noted above (see 'Vessel imaging' above), the preferred vessel imaging modality for arteriopathy is magnetic resonance angiography (MRA) of the neck and head (three-dimensional time-of-flight) without and with contrast enhancement of the extracranial and intracranial large arteries. Computed tomography angiography (CTA) can be substituted depending on availability and local expertise, but MRA is preferred because CTA incurs the hazards of radiation and contrast exposure [7].

Important etiologic considerations in the evaluation for arteriopathy are extracranial dissection, focal cerebral arteriopathy (including inflammatory and intracranial dissection subtypes), moyamoya, and Takayasu arteritis [7]. Neck pain can be associated with cervical artery dissection, and a Horner syndrome may accompany carotid dissection. (See "Ischemic stroke in children and young adults: Epidemiology, etiology, and risk factors", section on 'Arteriopathy' and "Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis" and "Clinical features and diagnosis of Takayasu arteritis".)

A segmental banding pattern (image 1) is considered a pathognomonic feature of focal cerebral arteriopathy-inflammatory type (FCA-i), but is only present in a minority of cases [54]. Magnetic resonance imaging (MRI) with arterial wall imaging is useful when an inflammatory arteriopathy or intracranial dissection is suspected. Axial T1 MRI of the neck with fat saturation increases the likelihood for detecting extracranial dissection [26].

Treatment for ischemic stroke caused by arteriopathy is reviewed separately. (See "Ischemic stroke in children: Management and prognosis", section on 'Arteriopathy'.)

Arterial wall imaging — Where available at centers with sufficient expertise, MRI with arterial wall imaging is valuable because it can detect nonstenotic lesions that are not apparent on angiography using MRA, CTA, or DSA; arterial wall imaging can further characterize stenotic lesions that have already been visualized using angiography [55,56]. Arterial wall imaging can help differentiate between various types of intracranial arterial lesions, including vasculitis, arterial dissection, moyamoya, and other causes of intracranial arterial narrowing.

The MRI techniques to visualize thin intracranial arterial walls require high contrast-to-noise and high spatial resolution, which are best achieved with a minimum magnetic field strength of 3 Tesla. In addition, arterial wall visualization requires suppression of signal in luminal blood and cerebrospinal fluid ("black-blood" sequences). MRI protocols vary among centers; one technique for arterial wall imaging involves high-resolution, two-dimensional T1-weighted fluid-attenuated inversion recovery (FLAIR) fast spin echo sequences before and after intravenous gadolinium contrast [26,57]. Arterial wall imaging should focus on the abnormal vessel detected by angiography (if present) that supplies the location of acute brain infarct, or, if there is no abnormality on angiography, on the major artery supplying the vascular territory of the infarct.

Hypercoagulable evaluation — Numerous prothrombotic conditions are risk factors for ischemic stroke in children. We suggest the following studies as part of the evaluation for a hypercoagulable state in children with arterial ischemic stroke:

●Protein C functional

●Protein S free and total or protein S functional

●Antithrombin activity

●Lipoprotein (a)

●Prothrombin G20210A variant

●Factor V Leiden

●Antiphospholipid antibody panel

●Factor VIII activity

We screen for a hypercoagulable state in most children with ischemic stroke except those with sickle cell disease. In our clinical experience, this approach is especially important for children with congenital heart disease. These children undergo frequent instrumentation and line placement. While the cardiac defect is a strong risk factor for stroke, identification of a prothrombotic abnormality that may be a second risk factor for stroke can influence management. As an example, anticoagulation may be instituted in children with congenital heart disease and a prothrombotic state to prevent clot formation and possible stroke during high-risk periods.

However, the evidence supporting this approach is limited, and the precise role of prothrombotic states in stroke pathophysiology remains unclear. The American Heart Association/American Stroke Association (AHA/ASA) scientific statement notes that an evaluation for thrombophilia is helpful in every case of childhood stroke, yet may not be clinically indicated if there is an alternative explanation for the stroke [7]. (See "Thrombophilia testing in children and adolescents" and "Ischemic stroke in children and young adults: Epidemiology, etiology, and risk factors", section on 'Hematologic'.)

Note that antiphospholipid antibodies (ie, lupus anticoagulant, anticardiolipin antibodies, and beta2-glycoprotein I antibodies) may be positive after viral infections or acute stroke [7,58]. Therefore, testing should be repeated 12 weeks after a positive test performed immediately after an acute stroke in order to determine whether antiphospholipid antibody syndrome is the underlying condition. (See "Diagnosis of antiphospholipid syndrome".)

The management of children with arterial stroke due to a confirmed hypercoagulable state is reviewed elsewhere. (See "Ischemic stroke in children: Management and prognosis", section on 'Hypercoagulable state'.)

ADDITIONAL EVALUATION FOR SELECTED PATIENTS — Additional studies may be indicated for children with certain findings – or no identified cause – of arterial ischemic stroke.

Inflammation evaluation — For select children with suspicion for an inflammatory cause of arterial ischemic stroke or for those with otherwise unexplained (cryptogenic) stroke, the initial evaluation includes testing for erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) level, and antinuclear antibody (ANA) assay.

Repeated testing at one month may be indicated when the cause for stroke is unclear, as persistent elevation of these inflammatory markers beyond one month after stroke onset raises suspicion for inflammatory conditions including primary angiitis of the central nervous system, systemic lupus erythematosus, adenosine deaminase 2 (ADA2) deficiency, and polyarteritis nodosa [7]. (See 'Rare causes of stroke' below.)

Focal cerebral arteriopathy — For children with focal cerebral arteriopathy of uncertain origin, additional studies include the following [7]:

●Magnetic resonance imaging (MRI) with arterial wall imaging. (See 'Arterial wall imaging' above.)

●Herpes simplex virus (HSV) and varicella zoster virus (VZV) polymerase chain reaction (PCR) and antibodies (immunoglobulin M [IgM] and immunoglobulin G [IgG] antibodies) tested in the blood or cerebrospinal fluid.

●Early follow-up vascular imaging (five to seven days after initial imaging) for progressive narrowing or stenosis.

Diffuse or multifocal cerebral vasculitis — Diffuse or multifocal vasculitis in children is typically secondary to infection, predominantly from meningitis or other central nervous system (CNS) infections (eg, tuberculous meningitis), and sepsis. Diffuse vasculitis may be secondary to autoimmune disease such as systemic lupus erythematosus. Rarely, it may be due to a primary angiitis of the central nervous system. (See "Ischemic stroke in children and young adults: Epidemiology, etiology, and risk factors", section on 'Diffuse vasculitis'.)

Multifocal vasoconstriction mimicking vasculitis may be seen in cases of reversible cerebral vasoconstriction syndrome (RCVS). (See "Reversible cerebral vasoconstriction syndrome", section on 'Neurovascular imaging'.)

The following studies are suggested whenever there is clinical suspicion of diffuse vasculitis, inflammation, or infection as the cause of ischemic stroke in children:

●ESR, CRP level, and ANA; although nonspecific, persistent elevation of these markers beyond one month raises suspicion for primary angiitis of the central nervous system, systemic lupus erythematosus, ADA2 deficiency, and polyarteritis nodosa.

●Cerebral digital subtraction angiography, if there is concern for moyamoya syndrome or disease, to confirm the diagnosis and to guide planning for revascularization surgery.

●Lumbar puncture and cerebrospinal fluid (CSF) examination with cell count, differential, protein concentration, acid-fast bacilli testing, and CSF analysis for herpes simplex virus via PCR and varicella-zoster virus via PCR and IgM and IgG antibodies; in rare adolescents with suspected or known history of HIV infection or neurosyphilis, testing should include determination of the CSF-Venereal Disease Research Laboratory (VDRL) titer. While a reactive CSF-VDRL establishes the diagnosis of neurosyphilis, a nonreactive test does not exclude the diagnosis. Neurosyphilis, if suspected, is also evaluated by serum nontreponemal tests (eg, VDRL or Rapid Plasma Reagin [RPR]) and serum treponemal tests (eg, fluorescent treponemal antibody absorption [FTA-ABS] or Treponema pallidum particle agglutination assay [TPPA]). (See "Neurosyphilis", section on 'Diagnosis'.)

●HIV testing. (See "Diagnostic testing for HIV infection in infants and children younger than 18 months" and "Screening and diagnostic testing for HIV infection" and "Acute and early HIV infection: Treatment".)

Multiple posterior circulation infarctions — Multiple acute or sequential posterior circulation infarcts should raise suspicion for vertebral artery dissection or rotational vertebral arteriopathy [7]. Transcranial Doppler ultrasonography and/or vessel imaging with magnetic resonance angiography (MRA) or computed tomography angiography (CTA) may detect arterial irregularity or dissection; axial T1 MRI of the neck with fat saturation increases the likelihood for detecting extracranial dissection [26].

Rotational vertebral artery syndrome (bow hunter syndrome) is a potential cause of stroke due to pseudoaneurysm and/or dissection involving the V3 segment of the vertebral artery that typically affects boys (see "Ischemic stroke in children and young adults: Epidemiology, etiology, and risk factors", section on 'Other vascular abnormalities'). When bow hunter syndrome is suspected, we obtain a dynamic study using digital subtraction angiography (DSA; catheter angiography with contrast) or CTA of the neck with head turning, which can establish the diagnosis by showing cessation of flow within the VA with rotation. While this procedure is associated with a risk of recurrent posterior circulation ischemia and stroke, we have not observed this complication. When bow hunter syndrome is suspected, we also obtain flexion-extension films of the cervical spine to evaluate for instability or bony anomalies (eg, congenital arcuate foramen).

Rare causes of stroke — Further evaluation for rare causes of stroke is directed by specific clinical findings [7]:

●ADA2 deficiency, diagnosed by testing for CECR1 mutations and plasma ADA2 activity, in cases with elevated inflammatory markers and variable features that may include intermittent fevers, proteinuria, hypertension, peripheral neuropathy, humoral immunodeficiency, and skin disease (ie, livedo reticularis, hand nodules) [59-61].

●Multisystem smooth muscle dysfunction syndrome, diagnosed by testing for ACTA2 mutations, in cases of straight ectatic internal carotid arteries, aortic disease, congenital mydriasis, hypotonic bladder, and/or pulmonary hypertension [62,63].

●Fabry disease, diagnosed by biochemical and molecular genetic testing, in cases of stroke with painful neuropathy. (See "Fabry disease: Clinical features and diagnosis" and "Fabry disease: Neurologic manifestations".)

●Connective tissue disorders, in cases of hyperextensibility and dissection. Considerations include Ehlers-Danlos type IV disease, with genetic testing for COL3A1 mutations, and Loeys-Dietz syndrome, with genetic testing for TGFBR1, TGFBR2, and SMAD3 mutations. Alternatively, a gene panel for connective tissue disorders may be obtained. (See "Clinical manifestations and diagnosis of Ehlers-Danlos syndromes", section on 'Vascular EDS' and "Genetics, clinical features, and diagnosis of Marfan syndrome and related disorders", section on 'TGFBR1 or TGFBR2 mutation: Loeys-Dietz syndrome'.)

●PHACE (syndrome of posterior fossa brain malformations, hemangiomas, arterial anomalies, coarctation of the aorta and cardiac defects, and eye abnormalities); the evaluation should include ophthalmology and dermatology consultations. The diagnosis can be made based upon the presence of a facial hemangioma greater than 5 cm in diameter plus one major or two minor criteria (table 1). (See "PHACE syndrome", section on 'Diagnosis'.)

●Mitochondrial disorders should be suspected when ischemic stroke does not conform to vascular territories.

•MELAS – The stroke-like episodes that occur in patients with mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) are characterized by the acute onset of neurologic symptoms and high signal on diffusion-weighted MRI brain imaging. These episodes are different from typical embolic or thrombotic ischemic strokes:

-The brain lesions typically do not respect vascular territories

-The apparent diffusion coefficient on MRI is not always decreased (as it would be with tissue infarction) but may be increased or demonstrate a mixed pattern

-The acute MRI signal changes are not static and may migrate, fluctuate, or resolve more quickly and more often than would occur in a typical ischemic stroke

MELAS is discussed in greater detail elsewhere. (See "Mitochondrial myopathies: Clinical features and diagnosis", section on 'MELAS'.)

When MELAS is suspected, the evaluation includes lactate levels from serum and cerebrospinal fluid, molecular genetic testing (of blood leukocytes, cultured skin fibroblast, skeletal muscle, urine sediment, and/or cheek mucosa), and muscle biopsy, particularly if genetic testing is nondiagnostic. These studies are not always abnormal in patients with MELAS because of heteroplasmy for mitochondrial mutations. (See "Mitochondrial regulation and functions", section on 'Heteroplasmy'.)

•POLG-related disorders – Mutations in the POLG1 gene are a rare cause of childhood stroke or stroke-like episodes with predominant involvement of the occipital lobes [7,64,65]. Seizures, status epilepticus, and liver dysfunction or failure are frequently reported among children affected by stroke. The diagnosis is made by molecular genetic testing for POLG mutations.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Stroke in children".)

SUMMARY AND RECOMMENDATIONS

●Clinical presentation

•Infants and young children – Infants and young children with stroke may present with focal weakness but are more likely than older children to present with seizures and altered mental status.

•Older children – Older children usually have hemiparesis or other focal neurologic signs such as aphasia, visual disturbance, or cerebellar signs. However, seizures, headache, and lethargy are more common among children with stroke compared with adults. (See 'Clinical presentation' above.)

●Urgent evaluation

•Goals – The urgent evaluation starts with confirmation of the diagnosis of ischemic stroke (excluding hemorrhage and stroke mimics) and consideration of immediate interventions that may improve stroke outcome (algorithm 1), including possible hyperacute reperfusion therapies with intravenous thrombolysis (within 4.5 hours of the time the patient was last seen well) and mechanical thrombectomy (within 24 hours of last seen well). (See 'Goals of initial evaluation' above.)

Hyperacute reperfusion therapies in children are reviewed separately. (See "Ischemic stroke in children: Management and prognosis", section on 'Reperfusion with thrombolysis and thrombectomy'.).

•Brain and vessel imaging – We suggest magnetic resonance imaging (MRI) of the brain with diffusion weighted imaging and vascular imaging with magnetic resonance angiography (MRA) as the initial studies, which should be obtained as soon as possible for children who present with suspected ischemic stroke. Head computed tomography (CT), including CT angiography (CTA), should be obtained if MRI and MRA are not tolerated or will not be available within one hour after arrival. (See 'Brain imaging' above.)

•Laboratories – In all patients, we obtain complete blood count, electrolytes, urea nitrogen, creatinine, serum glucose, prothrombin time (PT) and international normalized ratio (INR), partial thromboplastin time (PTT), and oxygen saturation. Additional studies in selected patients include hemoglobin electrophoresis and toxicology screen. (See 'Laboratory studies' above.)

●Etiologic evaluation

•All patients – Evaluation of children with arterial ischemic stroke should screen for the most common causes, including imaging of intracranial and extracranial cerebral arteries (if not already done as part of the urgent evaluation), assessment of heart structure and function, hypercoagulable testing, and evaluation of inflammatory markers. (See 'Essential evaluation for all patients' above and 'Cardiac evaluation' above.)

•Selected patients – For children with vasculopathy or those with no identified cause of arterial ischemic stroke, additional studies may be indicated to further characterize the underlying etiology. (See 'Evaluation for etiology' above and 'Additional evaluation for selected patients' above.)

●Differential diagnosis – Numerous other conditions can present with acute neurologic deficits. Hemorrhagic stroke can mimic ischemic stroke and is best differentiated by neuroimaging. Nonvascular conditions that mimic stroke in children include tumors and other structural brain lesions, seizures with prolonged postictal paresis (Todd), and other conditions. (See 'Differential diagnosis' above.)