594.1 Arterial Ischemic Stroke (AIS)

Arterial blood reaches the brain via the anterior (internal carotid) and posterior (vertebrobasilar) circulations, converging at the circle of Willis. Strokes involve the middle cerebral artery (MCA) territory more frequently than either the anterior or posterior cerebral arteries. AIS is the focal brain infarction that results from occlusion of these arteries or their branches. AIS is a leading cause of acquired brain injury in children, with the perinatal period carrying the highest risk (see later).

In children the diagnosis of stroke is frequently delayed or missed. This is due to subtle and nonspecific clinical presentations, a complicated differential diagnosis (Chapter 594.4) and a lack of awareness by primary care pediatric physicians. The acute onset of a focal neurologic deficit in a child is stroke until proven otherwise. The most common focal presentation is hemiparesis but acute visual, speech, sensory, or balance deficits also occur. Children with these presentations require urgent neuroimaging and consultation with a child neurologist as emergency interventions may be indicated. AIS is a clinical and radiographic diagnosis. CT imaging can demonstrate larger mature AIS and exclude hemorrhage, however MRI identifies early and small infarcts and is therefore required to exclude ischemic stroke. Diffusion weighted MRI (DWI) can demonstrate AIS within minutes of onset, and MR angiography can confirm vascular occlusion and suggest arteriopathy as the underlying cause (Fig. 594-1).

Figure 594-1 Arterial ischemic stroke. A healthy 3 yr old boy experienced the sudden onset of left-sided weakness. Examination also demonstrated left-sided hemisensory loss and neglect. Diffusion weighted MRI shows focal increased signal in the right temporal-parietal region in the territory of the middle cerebral artery (MCA, A). Apparent diffusion coefficient map confirms restricted diffusion consistent with infarction (ischemic stroke) (B). MR angiogram shows no occlusion or stenosis and decreased flow in the MCA (C). Follow-up MRI at 3 mo shows atrophy and gliosis in the same region (D).

Most etiologies for AIS are well-established; some represent only potential associations (Tables 594-1 and 594-2). AIS often remains idiopathic although most children have identifiable, frequently multiple risk factors. Three main categories of etiology should be considered: arteriopathic, cardiac, and hematological; full investigation often reveals multiple risk factors in a given individual.

Table 594-1 COMMON RISK FACTORS FOR ARTERIAL ISCHEMIC STROKE IN CHILDREN

Arteriopathy refers to disorders of the cerebral arteries and has emerged as the leading cause of childhood AIS, present in >50% of children. Idiopathic arterial stenosis has been termed focal cerebral arteriopathy (FCA), and may be more specfically identified as transient cerebral arteriopathy (TCA) or postvaricella angiopathy (PVA). These diseases likely represent focal, localized, unilateral vasculitis. More diffuse or bilateral vasculitis may be primary or associated with systemic inflammatory conditions (Table 594-3). Arterial dissection can be spontaneous or post-traumatic and can affect extracranial internal carotid or vertebral arteries, or intracranial arteries. Moyamoya disease may be idiopathic or associated with other conditions (NF-1, trisomy 21, sickle cell anemia, radiation therapy) and demonstrates progressive occlusion of the distal internal carotid arteries (Table 594-4, Fig. 594-2). Congenital malformations of the craniocervical arteries, including PHACES syndrome, may predispose to AIS.

From Roach ES, Golomb MR, Adams R, et al: Management of stroke in infants and children, Stroke 39:2644–2691, 2008, Table 5, p 8.

Table 594-4 RISK FACTORS FOR MOYAMOYA DISEASE

Other syndromes, 1 patient each: Reye (remote), Williams, Alagille, cloacal exstrophy, renal artery fibromuscular dysplasia, and congenital cytomegalic inclusion virus infection (remote). Two patients had unclassified syndromic presentations. There were 4 blacks, 2 of whom had sickle cell disease.

From Roach ES, Golomb MR, Adams R, et al: Management of stroke in infants and children, Stroke 39:2644–2691, 2008, Table 6, p 11.

Figure 594-2 Cerebral angiogram showing idiopathic supraclinoid–internal carotid arteriopathy with classic moyamoya collaterals (arrow).

Cardioembolic stroke comprises about 25% of childhood AIS with embolism occurring either spontaneously, or during catheterization or surgical repair. AIS complicates 1 in 185 pediatric cardiac surgeries, and re-operation increases the risk. Complex congenital heart diseases are the most frequent cause for AIS, however acquired conditions including arrhythmia, cardiomyopathy, and infective endocarditis should also be considered. The presence of a patent foramen ovale provides the possibility of paradoxical venous thromboembolism. All children with suspected AIS require thorough cardiovascular examination, electrocardiogram, and echocardiogram.

Hematologic disorders include iron deficiency anemia and sickle cell anemia (SCA). In SCA the risk of AIS is increased 400-fold. Coagulation disorders are also frequently identified in AIS. They include hereditary (e.g., factor V Leiden) and acquired (e.g., antiphospholipid antibodies) prothrombotic states and prothrombotic medications, including oral contraceptives and asparaginase chemotherapy. Additional AIS risk factors include migraine, acute childhood illnesses, chronic systemic illnesses, illicit drugs and toxins, and rare inborn errors of metabolism.

Treatment of childhood AIS is multifaceted and 3 consensus-based guidelines are now available. Emergency thrombolysis is not yet established for children as there are no safety data available. Antithrombotic strategies depend on the suspected cause but include anticoagulation with heparins or antiplatelet strategies such as aspirin. Neuroprotective strategies are essential to prevent progressive ischemic brain injury. These include careful control of blood glucose, temperature, and seizures and aggressive maintenance of cerebral perfusion pressure, with systolic blood pressures maintained in the high normal range. Malignant cerebral edema in the initial 72 hr is life-threatening and more common in children; emergency surgical decompression can be lifesaving. Disease-specific treatments include transfusion therapy in SCA, immunosuppression in vasculitis, and revascularization surgery in moyamoya disease. Long-term treatment goals include secondary stroke prevention, including antiplatelet therapy or, for cardiogenic causes, anticoagulation. Multimodal, family-centered rehabilitation programs are required for most survivors targeting motor deficits, language and intellectual impairments, behavioral and social disabilities, and epilepsy. Long term attention to arterial health lifestyle factors (avoiding obesity and smoking) is also important. Outcomes after childhood stroke include death in 6-10%, neurological deficits in 60-70%, and seizure disorders in 15%.

Perinatal stroke, the leading cause of term-born cerebral palsy (congenital hemiplegia), requires separate consideration. Acute neonatal stroke typically presents with seizures alone. Presumed perinatal ischemic stroke presents with gradual evolution of hemiparesis in later infancy and remote AIS on neuroimaging. Etiologies for both include cardiac and prothrombotic conditions discussed earlier, but additional maternal, prenatal, perinatal, placental, and neonatal factors must also be considered. Acute neonatal AIS requires neuroprotective treatment, but antithrombotic agents are only provided for cardiogenic embolism. Long-term morbidity is present in most children and requires comprehensive rehabilitation, as deficits continue to emerge with maturation.

594.2 Cerebral Sinovenous Thrombosis (CSVT)

Cerebral venous drainage occurs via superficial (cortical veins, superior sagittal sinus) and deep (internal cerebral veins, straight sinus) systems that converge at the torcula to exit via the paired transverse and sigmoid sinuses and jugular veins. In CSVT, thrombotic occlusion of these venous structures can create increased intracranial pressure, cerebral edema, and, in 50% of cases, venous infarction (stroke). CSVT may be more common in children than in adults, and risk is greatest risk in the neonatal period.

Clinical presentations are often more gradual, variable, and nonspecific compared to AIS. Neonates typically present with diffuse neurologic signs and seizures. Children may present with progressive headache, papilledema, diplopia secondary to 6th nerve palsies (frequently misdiagnosed as idiopathic intracranial hypertension), or acute focal deficits. Seizures, lethargy, and confusion are common. Diagnosis requires a high clinical suspicion and purposeful imaging of the cerebral venous system. Nonenhanced CT is very insensitive for CSVT, and contrast CT venography (CTV) is usually necessary to demonstrate filling defects in the cerebral venous system (Fig. 594-3). However MRI includes diffusion imaging of the brain parenchyma and modern MR venography (MRV) can be comparable to CTV in accuracy. Intraventricular hemorrhage in term infants suggests CSVT.

Figure 594-3 Cerebral sinovenous thrombosis. A 9 yr old girl presented with fever and progressive right-sided headache. She complained of double vision and had papilledema on examination. Axial (A) and coronal (B) CT venography demonstrates a large thrombus in the right transverse sinus that fails to opacify with contrast (arrows). Note normal filling superior sagittal and left transverse sinuses (arrowheads in B) and opacification of the mastoid air cells (arrowhead in A). Cause was otitis media/mastoiditis with septic thrombophlebitis of transverse sinus.

The Virchow triad is helpful in understanding the risk factors for CSVT (Table 594-5). Hypercoagulable states are frequently associated with childhood venous thrombosis including CSVT. Prothrombotic states frequently detected in childhood CSVT include inherited (e.g., prothrombin gene 20210A mutation) and acquired (e.g., antiphospholipid antibodies) conditions, prothrombotic medications (asparaginase, oral contraceptives), and common childhood illnesses, including iron deficiency anemia and severe dehydration. Systemic diseases associated with increased CSVT risk include leukemia, inflammatory bowel disease, and nephrotic syndrome.

Table 594-5 COMMON RISK FACTORS FOR CEREBRAL SINOVENOUS THROMBOSIS IN CHILDREN

Head and neck disorders can directly involve cerebral veins and sinuses causing CSVT. Common infections including meningitis, otitis media, and mastoiditis can cause septic thrombophlebitis of venous channels. CSVT can complicate head trauma especially adjacent to skull fractures. Neurosurgical procedures in proximity to cerebral venous structures may lead to injury and CSVT. Finally, obstruction of the cervical jugular veins and proximal stasis may result in CSVT. In neonates the unfused status of cranial sutures enables compression of underlying venous sinuses during delivery, or postnatally during supine lying when the occipital bone can compress the posterior sagittal sinus, possibly predisposing to CSVT.

Anticoagulation therapy plays an important role in childhood CSVT treatment. Despite no randomized trials, substantial indirect evidence has led to consensus across published guidelines which uniformly recommend anticoagulation with unfractionated or low molecular weight heparins in most children. Hemorrhagic transformation of venous infarcts is not an absolute contraindication to anticoagulation. Treatment is often continued for 3 mo at which time re-imaging either confirms recanalization (treatment usually discontinued) or persistent thrombus (treatment usually extended to 6 mo). However anticoagulation of neonates is more controversial and guidelines differ. New evidence suggests that protocol-based anticoagulants are safe in neonatal CSVT. About 30% of untreated neonates will extend their thrombosis in the 1st week postdiagnosis and additional venous infarction can result. Therefore if anticoagulation is withheld, early repeat venous imaging is paramount. Protocols supporting initial anticoagulation recommend shorter treatment durations in neonates (i.e., 6 weeks, 3 mo). Children with persistent risk factors carry risk for recurrence and may require long-term anticoagulation. Neuroprotective and supportive interventions include aggressive management of infection, maintenance of hydration, and neuroprotective measures (normothermia, normotension, seizure control). Optic neuropathy secondary to increased intracranial pressure is an important and often overlooked complication of CSVT. Regular fundoscopic examination by an ophthalmologist and measures to reduce intracranial pressure (e.g., acetazolamide, serial lumbar puncture) may be required. Most neurologic morbidity is suffered by those incurring venous infarction, and children with bilateral injuries can be devastated. Consistent with other forms of childhood stroke, a comprehensive neurorehabilitation program is required for children with venous infarction.

594.3 Hemorrhagic Stroke (HS)

Hemorrhagic stroke (HS) includes nontraumatic intracranial hemorrhage and is classified by the intracranial compartment containing the hemorrhage. Intraparenchymal bleeds may occur in any location within the brain. Intraventricular hemorrhage may be primary or an extension of intraparenchymal hemorrhage. Bleeding outside the brain may occur in the subarachnoid, subdural, or epidural spaces.

Clinical presentations vary according to location, cause, and rate of bleeding. Acute hemorrhages may feature instantaneous or thunderclap headache, loss of consciousness, and nuchal rigidity in addition to focal neurologic deficits and seizures. HS can be rapidly fatal. In bleeds associated with vascular malformations, pulsatile tinnitus, cranial bruit, macrocephaly, and high-output heart failure may be present. Diagnosis relies on imaging, and CT is highly sensitive to acute HS. However lumbar puncture may be required to exclude subarachnoid hemorrhage. Modern MRI is highly sensitive to even small amounts of acute hemorrhage and it images residual blood products long-term following most parenchymal bleeds (Fig. 594-4). Angiography by CT, MR, or conventional means is often required to exclude underlying vascular abnormalities (e.g., vascular malformations, aneurysms).

Figure 594-4 Hemorrhagic stroke due to vascular malformation. A healthy 1 mo old presented with sudden onset irritability followed by focal left body seizures. Plain CT head demonstrates a large hyperdense lesion in the right parietal region with surrounding edema consistent with acute hemorrhage (A). Axial (B) and sagittal (C) contrast CT scans suggest an abnormal cluster of vessels in the center of the hemorrhage. T2-weighted MRI differentiates the acute hemorrhage from surrounding edema (D). Gradient ECHO MRI, both acutely (E) and at 3 mo (F), demonstrates the presence of blood product.

Abusive (nonaccidental) head trauma with intracranial bleeding in children may present as primary subdural or parenchymal hemorrhage with no apparent history of trauma. Subtle scalp or ear bruising, retinal hemorrhages in multiple retinal layers, and chronic failure to thrive should always be sought, and in small infants with subdural bleeds, x-rays performed to rule out fractures. Epidural hematoma is nearly always due to trauma, including middle meningeal artery injury typically associated with skull fracture. Subdural hematoma can occur spontaneously in children with brain atrophy due to stretching of bridging veins.

Causes of HS include vascular malformations and systemic disorders (Table 594-6). Arteriovenous malformations (AVM) are the most common cause of childhood subarachnoid and intraparenchymal HS and may occur anywhere in the brain. Risk of AVM bleeding is approximately 2-4% per year throughout life. Other vascular malformations leading to HS include cavernous angiomas (cavernomas), dural arteriovenous fistulas, and vein of Galen malformations. Cerebral aneurysms are an uncommon cause of subarachnoid hemorrhage in children and may suggest an underlying disorder (e.g., polycystic kidney disease, infective endocarditis). A common cause for HS is bleeding from a pre-existing brain tumor. Arterial diseases that usually cause ischemic stroke can also predispose to HS including the central nervous system (CNS) vasculitides and moyamoya disease. Additional causes of parenchymal HS include hypertensive hemorrhage and hematologic disorders such as thrombocytopenic purpura, hemophilia, acquired coagulopathies (e.g., disseminated intravascular coagulation, liver failure), anticoagulant therapy (e.g., warfarin), or illicit drug use. Ischemic infarcts may undergo hemorrhagic transformation, particularly in CSVT, and can be difficult to differentiate from primary HS.

Table 594-6 POTENTIAL RISK FACTORS FOR HEMORRHAGIC STROKE IN CHILDREN

Management of childhood HS may include emergent neurosurgical intervention for large or rapidly expanding lesions. The same principles of neuroprotection for vulnerable brain suggested in the ischemic stroke sections also apply to HS. Reversal of anticoagulant therapy may be required (e.g., vitamin K, fresh frozen plasma) but the role of other medical interventions such as factor VII are unstudied in children. Recurrence risk for those with structural lesions is significant and serial imaging may be required. Outcomes from childhood HS are not well studied but likely depend on lesion size, location, and etiology. Compared with ischemic stroke, death is more frequent in HS, however greater degrees of recovery from the initial deficit can be expected.

Neonatal hemorrhagic strokes are different. Cranial ultrasound can detect most significant neonatal bleeds. In the preterm infant, germinal matrix bleeding and intraventricular hemorrhage are common (Chapter 93.3). Subarachnoid and subdural blood may be imaged in up to 25% of normal term newborns. Term HS is poorly studied and includes the etiologies listed earlier, but may be idiopathic in >50% of cases. Term intraventricular bleeding is often secondary to either deep CSVT or choroid plexus angiomas.