Chapter 57: Cerebrovascular Syndromes

• Both ischemic and hemorrhagic strokes occur in children. In US children, hemorrhagic strokes have an incidence of 2.9/100, 000 per year for hemorrhagic events versus 2.8/100,000 per year for ischemic.

• Ischemic strokes are caused by vascular occlusion of an artery, usually because of thromboembolism (arterial ischemic stroke [AIS]) or occlusion of venous sinuses or cerebral veins (sinovenous thrombosis).

• A history of complex congenital heart disease, prosthetic heart valve, recent cardiac surgery, or ECMO should raise suspicion of an embolic phenomenon. Twenty-five percent of patients with sickle cell disease will develop cerebrovascular problems.

• Magnetic resonance imaging (MRI) with diffusion-weighted imaging is more sensitive in detecting small infarcts, infarcts of the brain stem and cerebellum, infarcts that become hemorrhagic, and is more sensitive for acute ischemia than a CT scan.

• A computed tomography (CT) scan will show a tumor, large bleed, or abscess, and may show loss of gray/white differentiation and dense triangle sign (hyperdense thrombus in posterior part of superior sagittal sinus), but may not detect an acute hemorrhage.

• Magnetic resonance angiography (MRA) can be done at the time of the MRI to visualize the flow through the cerebral arteries. MRI can also be used with magnetic resonance venography (MRV) to diagnose sinovenous thrombosis.

• For patients in whom a hemorrhagic stroke is suspected and in whom the CT scan is negative, a lumbar puncture is indicated. Particularly with a small subarachnoid hemorrhage, the CT scan may not reveal blood.

• The key function of the emergency department is stabilization of the patient's respiratory and cardiovascular status, especially the blood pressure. In the event of an ischemic infarct, a precipitous decline in blood pressure is avoided, since it can worsen cerebral ischemia, but if hypotension is present, careful fluid resuscitation and inotropic support may be needed.

• Serum glucose should be monitored closely as hypoglycemia can worsen the effect of the stroke, and hyperglycemia can increase infarct size.

• Specific therapy is directed at the etiology of the stroke, such as correction of clotting abnormalities, antibiotics for infections, antiepileptic medication for seizures, and surgery for evacuation of a hematoma. For patients with sickle cell disease, exchange transfusion is indicated for ischemic stroke.

Although they are uncommon in children when compared to adults, both ischemic and hemorrhagic strokes occur. In US children, hemorrhagic strokes have an incidence of 2.9/100,000 per year for hemorrhagic events versus 2.8/100,000 per year for ischemic events.^1–3 Ischemic strokes can be categorized as arterial ischemic strokes (AIS) and cerebral sinovenous thrombosis (CSVT). In the pediatric population, arterial ischemic stroke usually results from a thromboembolism. Occlusion of venous sinuses or cerebral veins can result in CSVT. The majority of ischemic and hemorrhagic strokes occur in the neonatal period, but both occur in older children and adolescents; so this chapter will focus on those from 29 days to adolescence.³ The signs of AIS vary with age and the area of the brain affected by ischemia; they include focal neurologic findings such as hemiparesis, cranial nerve palsies, visual field deficits, and aphasia. Seizures may or may not occur.^1,4 CSVT may present with diffuse neurologic signs and seizures, but symptoms vary with age and etiology. Infants present with seizures, or lethargy, while older children have headaches, vomiting, altered level of consciousness, seizures, papilledema, and focal neurologic deficits.^1,5 Strokes that can result from vascular rupture are classified as hemorrhagic. The two main types are intracerebral and subarachnoid hemorrhage. Signs of hemorrhagic stroke include severe headache, decreased level of consciousness, vomiting, focal neurologic signs, and seizures.^1,6

The arterial circulation to the brain is via the anterior carotids and the posterior vertebral and basilar arteries, which link via communicating arteries to form the circle of Willis. Cerebral arteries can thrombose due to damage to the arterial wall, emboli, or prothrombotic conditions. Infarction occurs when loss of blood supply to cerebral tissue results in ischemia, hypoxia, and depletion of energy and carbohydrate stores. The extent of neuronal damage depends on the severity and length of time of ischemia, the availability of collateral circulation, and the metabolic needs of the brain.¹

In children, risk factors are associated with 90% of AIS and include cardiac disease, prothrombotic states, arteriopathy, vasculitis, acute head and neck infections and trauma, metabolic disorders, moyamoya, chronic medical disorders (sickle cell disease, iron deficiency, cancer), and indwelling central lines.⁷ In some cases, no risk factor is defined, whereas in others there may actually be multiple risk factors.^2,7 This is in stark contrast to adults, in whom arteriosclerosis is the leading risk factor for AIS, along with hypertension, smoking, diabetes, and hypercholesterolemia.^1,4,8

Sinovenous thrombosis can occur due to thrombophlebitis, hemoconcentration, or coagulation abnormalities. Occlusion of the sinuses or other cerebral vessels results in increased venous pressure and blood–brain barrier disruption, which leads to vasogenic edema. As pressure continues to increase, cerebral edema and decreased cerebral perfusion result. In some cases, the vessels leak and the infarcts become hemorrhagic. In addition, there is a risk of developing communicating hydrocephalus after sinovenous thrombosis of the sagittal sinus or with sinus hypertension, because the arachnoid granulations, which absorb CSF, become nonfunctional.¹

Risk factors associated with CSVT are prothrombotic disorders, dehydration, systemic infection, otitis media, mastoiditis, sinusitis, hematologic disorders, drugs, cardiac disease, cancer, and perinatal complications.^1,5,9 The underlying diseases that cause AIS and CSVT are listed in Tables 57-1 and 57-2, respectively.

Hemorrhagic strokes involve the rupture of cerebral blood vessels with leakage of blood into the brain parenchyma, subarachnoid space, or ventricular system. The location of the hemorrhage defines the two major types of stroke as intracerebral/intraparenchymal or subarachnoid, and determines the pathophysiology, risk factors, and clinical findings.¹

Intracerebral hemorrhage occurs when arteries or veins rupture into intracerebral areas or brain parenchyma. Damage occurs to the blood–brain barrier, resulting in cerebral edema; when large, the hematoma can cause a mass effect. In children the greatest risk factor is head trauma, followed by aneurysms and vascular malformations.

Subarachnoid hemorrhage results from rupture of an aneurysm (usually proximal arteries at the circle of Willis) or an arteriovenous malformation (AVM). Secondary effects include ischemic infarction due to blood in the subarachnoid space that causes vasospasm of the cerebral arteries and hydrocephalus. Risk factors include disorders associated with vascular malformations, aneurysms, sickle cell disease, and hypertension. However, hemorrhagic strokes are occasionally associated with systemic diseases and coagulopathies.¹ These conditions are summarized in Table 57-3.

History

The presenting signs and symptoms of a stroke depend somewhat on the type of stroke and the age of the patient. AIS usually have a rapid onset, so there may be little in the history to warn of the impending event. Patients often suffer sudden seizures, or focal neurologic findings, especially hemiplegia. A history of recurrent headaches, transient ischemic attacks, or focal seizures may be obtained, but these do not provide a specific diagnosis, and often confuse the issue.¹ An AIS involving a large vessel may present with loss of consciousness and multiple focal neurologic deficits.⁴ A stroke due to a metabolic disorder may have an episodic or progressive course. A prenatal AIS often does not present until age 4 months to 8 months as an evolving hemiparesis.⁴

An older child with a CSVT may present with slowly progressive signs, such as fever, vomiting, or headache. A young infant may have dilated scalp veins, eyelid swelling, and a large anterior fontanelle.¹

An older child with a hemorrhagic stroke may have a history of severe headache or, especially in the case of subarachnoid hemorrhage, neck pain. A large bleed will usually result in a sudden alteration in consciousness and perhaps seizures, but a small bleed may result in subtle focal neurologic signs, including cranial nerve palsies.¹

A history of cardiac disorders, especially complex congenital heart disease, prosthetic heart valve, or recent cardiac surgery should raise suspicion of an embolic phenomenon. The presence of an indwelling catheter is a risk factor for a thrombotic event.⁷ The presence of fever and headache should raise concern about meningitis. However, systemic infections, such as mycoplasma, Rocky Mountain spotted fever, and others, have been associated with cerebral infarction due to thrombophlebitis of cerebral vessels.¹ A recent throat, peritonsillar, or parapharyngeal infection could lead to thrombophlebitis of the jugular vein (Lemierre's syndrome).¹⁰ A recent infection with varicella is of concern, because postvaricella angiopathy (also called transient cerebral arteriopathy) can include basal ganglia infarction and stenosis of large arteries.¹¹ Inherited coagulation disorders such as deficiency of protein C, protein S, antithrombin III, and plasminogen, or the presence of factor V Leiden, lipoprotein (a), anticardiolipin antibody, or lupus anticoagulant can all lead to thromboembolism.^1,2,5,9 A history of sickle cell disease is extremely important to elicit, because 25% of patients will develop cerebrovascular problems.¹ The presence of systemic lupus erythematosus and other forms of vasculitis such as polyarteritis nodosa, mixed connective tissue disease, or Takayasu's arteritis have all been associated with arterial ischemic and sinovenous thrombosis.

Metabolic disorders, such as homozygous homocystinuria (hyperhomocysteinemia), which have a thrombotic effect, can cause arterial and venous thrombosis. Fabry's disease (deficiency of α-galactosidase A) can lead to lacunar infarcts, and hyperlipidemia has also been associated with childhood strokes. The MELAS syndrome (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes) is due to a mitochondrial disorder and is characterized by episodes of nausea, vomiting, headaches, seizures, and hemiparesis, which initially resolve, but ultimately lead to persistent deficits and cortical blindness.^1,4 Neurocutaneous disorders such as neurofibromatosis, Sturge–Weber syndrome, and tuberous sclerosis are all associated with both ischemic and hemorrhagic strokes.

Any history of trauma is significant and suggests a hemorrhagic lesion. Intraoral trauma can cause dissection of the carotid artery, and injury to the vertebral arteries can occur after neck trauma. Recent head or neck trauma can also lead to AIS.⁷

Children who have had radiation for optic gliomas or pituitary or suprasellar tumors can develop postradiation vasculitis.³

Adolescents in particular are questioned regarding illicit drug use, particularly cocaine. Additional questions are directed toward detecting one of the underlying etiologies noted in Tables 57-1, 57-2, and 57-3.

Physical Examination

Stabilization of the patient is the first priority, since seizures may occur in younger children at the time of, or shortly after, the stroke. Complete vital signs include temperature and blood pressure. If trauma is suspected, the head and neck are immobilized. A thorough examination includes auscultation over the head, eyes, and carotid arteries listening for bruits, as well as a careful auscultation of the heart for murmurs, clicks suggestive of valvular disease, arrhythmias, or indications of prior cardiac surgery. The eyes are examined for extraocular movements, pupillary responses, and the visual fields. The eyes will look toward the lesion if the cerebral hemisphere is involved, but away with brain stem involvement. The skin is examined for petechiae, café au lait spots, neurofibromas, or telangiectasias.

Neurologic assessment includes determination of degree of weakness, cranial nerve dysfunction, and the side and extent to which the extremities are involved. If the facial muscles and tongue are involved, there is dysarthria, but involvement of the basal ganglia, thalamus, or cerebral hemispheres can result in aphasia. It may be difficult to assess sensory impairment due to aphasia.

Some disorders that can be confused with a stroke include complicated migraines, partial seizures, Todd's paralysis, brain tumors, brain abscesses, and subdural hematoma. Most will be diagnosed during the workup of the suspected stroke (Fig. 57-1).

Diagnostic Evaluation

Baseline laboratory studies include a complete blood count with differential and platelet count and coagulation studies (PT, activated PTT, INR, fibrinogen, and D-dimer).^2,12 If sickle cell disease is a possibility, a sickle cell preparation and hemoglobin electrophoresis are performed. Further coagulation studies are indicated if other coagulopathies, such as protein S or C or antithrombin III deficiencies, are suspected. Other studies should include electrolytes, BUN, creatinine, glucose, sedimentation rate, and CRP, as well as a urinalysis looking for red cells or protein, and a urine pregnancy test in females.^1,4,8 Studies evaluating a hypercoagulable/prothrombotic state include antinuclear antibodies, protein S, protein C, factor V Leiden mutation, prothrombin 20210A, antithrombin III activity, lipoprotein (a), anti-beta 2 glycoprotein-1 antibodies, homocysteine concentration, anticardiolipin antibodies (IgG and IgM), and lupus anticoagulant.^1,2,4,5,9,12 If a fever is present, blood culture, urine culture, and CSF studies are indicated. Blood and CSF viral titers of varicella zoster, herpes, EBV, enterovirus, and parvovirus may be helpful.⁴ If a metabolic disorder is suspected, blood lactate, pyruvate, carnitine, and serum amino acids are ordered, and urine is sent for organic acids.⁴ A urine toxicology screen should be sent if cocaine use is suspected. An electrocardiogram and an echocardiogram should be performed on all children in whom underlying heart disease is suspected.¹²

Imaging studies provide information that will help differentiate an ischemic from a hemorrhagic stroke. MRI with diffusion-weighted imaging is more sensitive than a CT scan in detecting small infarcts, infarcts of the brain stem and cerebellum, and infarcts that become hemorrhagic, and is more sensitive for acute ischemia.^1,3,4,12 A CT scan will show a tumor, large bleed, or abscess, and may show loss of gray/white differentiation and the dense triangle sign (hyperdense thrombus in the posterior part of superior sagittal sinus).^5,13 However, a CT scan may not detect a small acute hemorrhage.^1,4,5 CT scan is also normal in up to 40% of CSVT, so MRI is the preferred study in these cases.^3,5 MRA correlates well with angiography, and can be done at the time of the MRI to visualize the flow through the cerebral arteries.^1,12 MRI can also be used with MRV to diagnose CSVT.^3,5 The visualization of a thrombus and the absence of a flow-related signal provide the diagnosis.¹³ (Fig. 57-2).

Due to the availability of MRV and MRA, cerebral angiography to visualize intracranial and extracranial vessels is needed less often.¹³ For patients in whom a hemorrhagic stroke is suspected, in whom the CT scan is negative, and who have no signs of increased intracranial pressure, a lumbar puncture is indicated. Particularly in a small subarachnoid hemorrhage, the CT scan may not reveal blood. The CSF is evaluated for the presence of red blood cells, which, in the absence of a traumatic lumbar puncture, indicates hemorrhage, especially if the blood does not clear during CSF collection. In some cases, the CSF may appear xanthochromic, which is also consistent with hemorrhage.¹

The key function of the ED is stabilization of the patient's respiratory and cardiovascular status, especially the blood pressure. In the event of an ischemic infarct, a precipitous decline in blood pressure is avoided, since it can worsen cerebral ischemia.^1,4 If hypotension is present, careful fluid resuscitation and inotropic support may be needed. If there are signs of impending herniation, mannitol (0.25–1 g/kg intravenously over 20 minutes) and controlled ventilation may be required. Serum glucose should be monitored closely because hypoglycemia can worsen the effect of the stroke, and hyperglycemia can increase the infarct size. Maintenance of normal body temperature is also important, since hyperthermia can worsen ischemic brain damage. The patient should be kept with the bed at 0 to 15 degrees of head elevation for AIS.^3,8 Specific therapy is directed at the etiology of the stroke, such as correction of clotting abnormalities, antibiotics for infections, antiepileptic medication for seizures, and surgery for evacuation of a hematoma.³ In patients with sickle cell disease, hydration and exchange transfusion to reduce hemoglobin S to <30% is indicated.^4,12,14 (see Chapter 104). The American College of Chest Physicians (ACCP) recently published updated evidence-based clinical practice guidelines.¹⁵ ACCP recommends treatment of children with AIS with or without a prothrombotic state with unfractionated heparin (UFH), low-molecular-weight heparin (LMWH), or aspirin until dissection or embolic etiologies are excluded. This should be followed by aspirin for 2 years. For those with an AIS due to an embolic etiology, treatment includes anticoagulation with LMWH or vitamin K antagonist for at least 3 months.¹⁵ The American Heart Association recommends the use of LMWH or UFH, whereas the Royal College of Physicians recommends initial treatment with aspirin.^3,4,12

Treatment of CSVT includes hydration, antibiotics for cases due to infection, control of seizures, and elevated intracranial pressure.^3,13 Initial anticoagulation with UFH or LMWH for those without significant intracranial hemorrhage bleeding, followed by 3 months of LMWH or Vitamin K antagonist. For those with CSVT and hemorrhage, treatment is with UFH or LMWH with close monitoring of the thrombosis at 5 to 7 days.^3,13,15

Children who have suffered strokes are admitted to an intensive care setting for close monitoring of blood pressure, fluid status, temperature, glucose, neurologic function, and antithrombotic therapy.

For children with AIS, overall mortality is approximately 3%.¹¹ Those with an AIS of the middle cerebral artery territory with a stroke volume >10% of intracranial volume and initial presentation with altered level of consciousness are predictors of poor outcome.⁹ The risk of recurrence ranges from 6% to 40%; the presence of vasculopathy or arteriopathy appears to be an important risk factor, since children with evidence of abnormal vessels had a stroke recurrence rate of 66%, while those with normal vascular imaging had no recurrence.^2,11,12

For CSVT, outcome depends on etiology, but mortality ranges from 4% to 20%, with a recurrence rate of 17%.⁹ For children with sickle cell disease, effective prevention of recurrent stroke includes chronic transfusion therapy and measures to prevent iron overload.^3,14

Moyamoya

Moyamoya is characterized by an abnormal network of small collateral vessels, which develop due to progressive stenosis and occlusion of large cerebral arteries involving the circle of Willis. The “puff of smoke” appearance on angiogram is due to the collateral vessels.^1,3,16 The etiology is unknown, but there is a relatively high incidence in Asian and Japanese populations, with a family history in 10% of patients.¹⁶ In children, the presentation is more often with ischemic events such as TIA or stroke, rather than a hemorrhagic stroke, which occur more in adults.¹⁵ Moyamoya syndrome includes the typical angiographic pattern, but is secondary to an etiology such as trisomy 21, sickle cell disease, cranial radiation, neurofibromatosis type 1, autoimmune diseases, connective tissue disorders, and other neurocutaneous disorders.^3,4,16

In children with AIS, cerebral arteriopathies account for up to 64% of cases.¹¹ Included in this classification are focal cerebral arteriopathy of childhood (FCA), moyamoya, postvaricella angiopathy, arterial dissection, and vasculitis.¹¹ Focal cerebral arteriopathy is stenosis not due to a specific diagnosis, and the cause is unknown, however, it may be related to a recent viral illness.¹¹

Transient cerebral angiopathy is characterized by unilateral focal or segmental stenosis of the distal carotid arteries and vessels in the proximal circle of Willis vessels. These lesions may resolve or stabilize within 6 months.^4,8 This results in infarction in the internal capsule or basal ganglia. The average age of onset is 5 years, and etiology is thought to be viral, and when preceded by varicella within 12 months is termed postvaricella angiopathy.^1,11