Strokes in Children

Isolated Venous Ectasia

It is now well-recognized that orbital lymphangiomas can be accompanied by intracranial venous ectasia.455,802,906 Intraocular vascular anomalies affecting the iris or retina rarely coexist.802 The long-term prognosis and corresponding treatment implications for these intracranial venous ectasia are unknown.

Craniocervical Arterial Dissection

Arterial dissection is probably an underrecognized cause of stroke in children. Rafay et al706 studied 213 children with arterial ischemic stroke and found 16 (7.5%) attributable to arterial dissection. The etiology of craniocervical arterial dissection in children was usually traumatic or idiopathic. Dissection involved the extracranial vessels in 75% and the anterior circulation in 56%. Most were treated with antithrombotic therapy. Followup showed a complete recovery in 43%, mild to moderate deficits in 44%, and severe deficits in 13%. Total occlusion had the worse prognosis for recanalization. Anterior dissection was more common in the traumatic group and posterior dissection in the spontaneous group, suggesting that the posterior circulation, especially the extracranial portion, might be more vulnerable to injury by trivial trauma, often causing there to be no associated history.706 Carotid dissection should be considered in the infant with a history of traumatic birth delivery and congenital Horner syndrome.372

Strokes in Children

The advent of modern neuroimaging has led to the appreciation that childhood neurovascular disorders are more common than previously thought, perhaps approaching or exceeding childhood brain tumors in incidence.151,742 Strokes may be classified by the pathophysiologic mechanisms of the vascular dysfunction into cerebral embolism, arterial embolism, venous thrombosis, intraparenchymal hemorrhage, and subarachnoid hemorrhage. Unlike adults, in whom hypertension and atherosclerosis are the major risk factors for stroke, children have a wide array of risk factors, including vascular and metabolic etiologies (Table 11.4).797 While vascular causes of stroke have been discussed, a number of metabolic conditions warrant diagnostic consideration in the child with stroke.626,797 The pathogenesis of stroke in these disorders is not certain but may include mechanisms such as alterations in vascular endothelial wall integrity, platelet dysfunction, and alterations in cerebral perfusion

Table 11.4  Risk factors for pediatric cerebrovascular disease

Congenital heart disease

Ventricular or atrial septal defects Patent ductus arteriosus

Valvular stenosis Cardiac rhabdomyoma

Acquired heart disease Rheumatic heart disease Infectious endocarditis Cardiomyopathy Arrhythmia

Kawasaki disease Atrial myxoma

Systemic vascular disease Systemic hypertension, hypotension

Diabetes

Progeria

Superior vena cava syndrome Vasculitis

Meningitis, sepsis, varicella Systemic lupus erythematosis

Polyarteritis nodosa, granulomatous angiitis Takayasu arteritis

Drug abuse (cocaine) Vasculopathies

Homocystinuria, Fabry disease, pseudoxanthoma elasticum

Moyamoya syndrome Vasospastic disorders

Migraine

Vasospasm due to subarachnoid hemorrhage Hematologic disorders/hypercoagulopathies

Sickle cell diseases Platelet disorders Neoplasms (e.g., leukemia)

Protein C deficiency, protein S deficiency Lupus anticoagulant, anticardiolipin antibodies Antiphospholipid antibody syndrome Ornithine transcarbamylase deficiency

Cerebrovascular structural anomalies Fibromuscular dysplasia Intracranial aneurysms Arteriovenous malformations Sturge–Weber syndrome

Trauma

Shaken baby syndrome Penetrating intracranial trauma

Metabolic

Cerebrotendinous xanthomatosis Familial hypercholesterolemia Hashimoto encephalitis

Fabry disease

Glutaric acidemia type 1 Homocystinemia Homocystinuria

Mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS) syndrome

Methylmalonic acidemia

Organic-acid disorders (hyperammonemia, methylmalonic acidemia, propionic acidemia, isovaleric acidemia, glutaric aciduria)

Ornithine transcarbamylase deficiency Tangier disease

or metabolism caused by the accumulation of toxic metabolites.179

Hashimoto thyroid-related autoantibodies cause encephalopathy with a relapsing course and normal cerebral angiography.811 Fabry disease and homocystinuria are associated with thrombosis.608 Elevated plasma levels of homocysteine secondary to gene variants that disrupt folate metabolism can produce a thrombo-coagulative predisposition and manifest as perinatal stroke.803 In the carbohydrate-deficient glycoprotein syndromes, there is evidence of abnormal coagulation.417 The concept of “metabolic stroke,” proposed to explain the focal lesions in patients with methylmalonic acidemia, postulates that an accumulation of toxic metabolites causes infarction in the absence of hypoxia or vascular insufficiency.387,445

Organic acid disorders occur because of defects in mitochondrial metabolism, resulting in impairment of oxidative metabolism. Acute or subacute encephalopathy in the neonatal period or infancy is a common presentation, often with hyperammonemia. The clinical spectrum is broad, however, and includes progressive psychomotor retardation and seizures. Certain organic-acid disorders have been associated with stroke like episodes, including methylmalonic acidemia, propionic acidemia, isovaleric acidemia, and two forms of glutaric aciduria (Types 1 and II).113,899 Clinical features of these disorders include an extrapyramidal syndrome characterized by dystonia and tremor and pyramidal tract signs such as spastic quadriparesis. Neuroimaging shows predominant involvement of basal ganglia in cases with stroke, and diffuse deep white-matter involvement is typical.387,397

The mitochondrial encephalomyelopathies (discussed in Chap. 10) are a heterogenous group of disorders that can cause central nervous system and neuromuscular disease.797 Although any tissue in the body can be affected, brain tissue and muscle are particularly vulnerable. The syndrome of mitochondrial encephalopathy, lactic acidosis, and strokelike episodes has seizures and strokelike episodes as prominent features (MELAS).682 The hallmark of this syndrome is the occurrence of strokelike episodes that result in hemiparesis, hemianopia, or cortical blindness. Focal or generalized seizures, recurrent migraine-like headaches, vomiting, short stature, hearing loss, and muscle weakness are common. The syndrome usually develops during childhood and has a relapsing and remitting course, with strokelike episodes separated by periods of variable resolution but resulting in neurologic dysfunction and dementia.797 The pathogenesis of strokelike episodes in patients with MELAS remains controversial.

Ornithine transcarbamylase deficiency, the most common urea-cycle defect, is an X-linked disorder. The spectrum of severity of symptoms in heterozygous female carriers is broad, with some having severe symptoms. Patients may have a history of protein avoidance and complicated migraine

headaches. Recurrent strokelike episodes and seizures can be triggered by intercurrent infection and increased metabolic demand. Hyperammonemic episodes can lead to cerebral edema and increased intracranial pressure. The sequelae of severe hyperammonemic episodes includes cortical blindness, which is usually transient.18,140

The neuro-ophthalmologic complications of strokes in children are the same as those in adults, with the caveats that acquired homonymous hemianopia in children more commonly results from trauma or tumors (and their neurosurgical resection) than from vascular disease462,544 and that children tend to show greater recovery of function and superior abilities to compensate for their deficits. Disorders of higher cortical dysfunction, such as alexia without agraphia, are increasingly recognized in children with stroke.639,665 Prosopagnosia may accompany periventricular leukomalacia426,583,767 or occur as a congenital hereditary condition of unclear etiology in children.366,367

Cerebral Venous Thrombosis

Cerebral venous thrombosis (CVT) is an important cause of stroke and of idopathic intracranial hypertension in children.242 CVT-venous infarction is often hemorrhagic and typically causes increased intracranial pressure.16 It affects primarily neonates and results in neurologic impairment or death in approximately 50% of cases.242 Hypoxic–ischemic encephalopathy is the most common perinatal complication.242 The occurrence of venous infarcts or seizures portends a particularly poor outcome.242 Perinatal risk factors are usually present (birth hypoxia, premature rupture of membranes, maternal infection, placental abruption), as well as gestational diabetes in neonates, infectious disorders of the head and neck, or chronic systemic diseases in older patients.242 In one study,166 the most common risk factors included mastoiditis, persistent pulmonary hypertension, cardiac malformations, and dehydration. Coagulation studies are also often abnormal (presence of anticardiolipin antibody, decreased levels of protein C, antithrombin, protein S, fibrinogen, and plasminogen, lupus anticoagulant, factor V Leiden, and G20210A prothrombin gene mutation).

Deficiencies of antithrombin, protein C, and protein S are, in many cases, caused by an acquired disorder such as liver disease, nephrotic syndrome, prothrombotic drugs (asparaginase, oral contraceptives) or by disseminated intravascular coagulation.242 Children may present with decreased level of consciousness, focal neurological signs, and cranial nerve palsies, while neonates tend to present with seizures and diffuse neurological signs.242 MR imaging with MR venography (MRV) is recognized as the optimal technique for establishing the diagnosis of cerebral venous sinus

thrombosis,23 but there are several pitfalls to using it. MRV may show dominance of the transverse sinus on one side and hypoplasia or atresia of transverse sinuses as variants of normal.940 Moreover, fenestrations and arachnoid granulation may simulate thrombi. For this reason, it may be advisable to perform MRV in conjunction with MR imaging with gadolinium enhancement.

In neonates, CT scans may show false positive results because of increased hematocrit, decreased density of unmyelinated white matter, and slower venous flow, resulting in findings that mimic the dense-triangle sign.554 Contrary to ischemic arterial stroke, cerebral venous thrombosis carries a good neurological prognosis once the acute phase is survived.851 Lumbar puncture is important to check CSF pressure and rule out infection and carcinomatous meningitis.211

A recent multicenter study of cerebral venous sinus thrombosis in children found that predisposing factors were identifiable in (90%) of cases.924 They included infection in 40%, perinatal complications in 25%, hypercoagulable or hematologic diseases in 13%, and other conditions in 10%. Presenting features included seizures (59%), coma (30%), headache (18%), and motor weakness (22%). Hemorrhagic infarcts occurred in 40% of patients, and hydrocephalus in 10%. Transverse sinus thrombosis was more common (73%) than sagittal sinus thrombosis (35%). Fifty-five percent were younger than 6 months of age. Seizures and coma were poor prognostic indicators. Only 25% were treated with anticoagulation and thrombolysis, while 70% were treated with antibiotics and hydration. Mortality was 13% overall but 25% in neonatal cerebral venous thrombosis. Mortality is generally higher (25%) in neonatal cerebral venous thrombosis.166

Symptomatic treatment includes antiepileptic medications for treatment of seizures, antibiotics for treatment of infection (when present), and heparin for anticoagulation which, although its systematic use remains debated, has been shown to be safe even in patients with large hemorrhagic infarctions.91 Decompressive craniotomy may be needed acutely for severe cases with intractable intracranial hypertension and herniation.91

Cerebral Dysgenesis and Intracranial

Malformations

Malformations caused by abnormalities of cortical development comprise a heterogenous group of multifactorial disorders.660,661 These malformations can arise from derangements in neuronal or glial proliferation, neuronal migration, or subsequent cortical organization can result in a cortical malformation.47 Their causes are protean. Chromosomal mutations, destructive events arising from ischemia or infection, and tox-

ins (both exogenous toxins such as drugs or alcohol, or endogenous toxins in metabolic disorders) can interfere with stem cell production, radial glial development, neuronal migration, or the disengagement of neurons from radial glial fascicles and their subsequently organization.47 Destructive events, arising from ischemia or infection can damage the germinal matrix, the radial glial fibers, the molecular layer, or the overlying “pial-glial barrier.” The type, timing, and severity of injury and its potential for impact at different stages of cortical development all influence the final histopathology.660,661

Classfications of this complex group of malformations have been based on histopathology, embryological timing, or neuroimaging descriptions, and genetic aspects.660,661 Barkovich47 had classified these disorders based primarily upon the step in which cortical development is most likely perturbed. This classification system comprises disorders of stem cell proliferation or apoptosis (microcephaly with normal to thin cortex or with polymicrogyria/cortical dysplasia, hemimegalencephaly, cortical hamartomas of tuberous sclerosis, ganglioglioma/gangliocytoma); disorders of neuronal migration (lissencephaly, cortical heteroptopia); and disorders of late migration and cortical organization (polymicrogyria, schizencephaly, cortical dysplasia).47 Although they may overlap with disorders of neuronal migration such as lissencephaly,402,755 cerebellar malformations are generally classified into a discussed in a separate category.

These complex classification schemes for malformations of cortical development are undergoing almost continuous revision, with a trend toward reclassifying them by causative gene, rather than by clinical phenotype, wherever possible. Clinically, malformations of cortical development are common causes of epilepsy and developmental delay that were considered idiopathic before modern neuroimaging. The availability of MR imaging has enhanced our ability to identify dysgenetic anomalies and CNS malformations in vivo and to correlate them with their associated neuro-ophthalmologic findings.66 New genes for most of the disorders have been mapped or cloned, but some cases clearly result from intrauterine ischemia or infection.

Congenital or perinatal brain injury may affect the developing visual system at multiple levels. Optic disc anomalies, cortical visual loss, and homonymous hemianopia in children frequently reflect a primary dysgenesis or intrauterine injury of the developing brain. Many midline or hemispheric brain malformations directly or secondarily involve the developing visual system and produce congenital visual loss associated with small optic nerves. Other brain malformations are associated with additional malformations of one or both optic nerves at the junction with the globe, as in the morning glory disc anomaly, optic disc coloboma, and multiple malformation syndromes (e.g., Aicardi syndrome, Walker–Warburg syndrome, linear sebaceous nevus syndrome). The type of

optic disc malformation can often be predicted from the associated brain anomalies.117 Conversely, the appearance of the anomalous optic disc may be used in conjunction with other associated systemic and neurological abnormalities to predict that a specific constellation of CNS abnormalities will be found on neuroimaging. While considerable progress has been made in correlating malformations of the brain with those of the optic discs, little is known about the pathogenesis of each malformation complex.

Depending also on their location, prenuclear and infranuclear ocular motor signs can arise from congenital malformations. As discussed in Chap. 1, children with cortical visual loss or congenital homonymous hemianopia do not generally develop nystagmus but often manifest a constant exotropia which should raise suspicion of CNS disease. Ocular motility disturbances such as periodic alternating nystagmus, A-pattern strabismus with superior oblique muscle overaction, congenital ocular motor apraxia, or skew deviation can reflect structural malformations within the posterior fossa that can disrupt the system at a preor postnuclear level. Ischemic injury to the developing brainstem in the intrauterine or perinatal period can even be associated with a congenital ocular motor nerve palsy. While congenital third nerve palsy may be the presenting sign of intrauterine or perinatal brainstem injury,41 congenital fourth nerve palsy and congenital sixth nerve palsy (including Duane syndrome) generally do not portend CNS malformations.

In the following section, the common malformations encountered in neuro-ophthalmological practice are discussed.

Destructive Brain Lesions

Destructive injuries to the developing brain include porencephaly, hydranencephaly, colpocephaly, and encephalomalacia.47 Because the fetal brain has limited capacity for astrocytic reaction, necrotic tissue is completely reabsorbed by liquefaction necrosis. The ability to mount an astrocytic response begins somewhere during the late second or early third trimester.47 Earlier injuries tend to produce porencephaly or hydranencephaly, consisting of a smooth-walled cyst, while later injuries result in encephalomalacia (with astroglial cells and an irregular wall consisting primarily of reactive astrocytes). In the mature brain, injury results in gliosis with no appreciable cystic component.

Porencephaly

The term porencephaly refers to a smooth-walled, fluid-filled cavity that communicates with the ventricular system, the subarachnoid space, or both.5,47 The finding of porencephaly

signifies localized brain injury during the first two trimesters of gestation when the brain has limited capacity to mount a glial reaction, and necrotic tissue is completely reabsorbed by liquefaction necrosis.47 On MR imaging, porencephalic cysts appear as smooth-walled cavities that are isointense to CSF on all pulse sequences (Fig. 11.27).

Although porencephaly is caused by perinatal vascular insults, it may also have a genetic underpinning. Several familial cases have been described, and autosomal inheritance linked to chromosome 13q has been suggested. A recent study linked porencephaly in two families to mutations in COL4A1, an essential component of basement membrane stability that has been associated with perinatal hemorrhage or porencephaly when mutated in a mouse model.361 COL4A1 may be a major locus for genetic predisposition to perinatal cerebral hemorrhage and porencephaly in humans.111

When posterior porencephalic cysts involve the optic radiation or occipital cortex, affected patients have congenital homonymous hemianopia with homonymous hemioptic hypoplasia.406,862 Davidson et al226 documented porencephaly and optic nerve hypoplasia in four infants who were found to have neonatal isoimmune thrombocytopenic purpura.

Hydranencephaly

Hydranencephaly is a devastating condition in which most of the brain mantle (cortical plate and hemispheric white matter) has been damaged, liquefied, and resorbed.47 The cerebral hemispheres are almost completely replaced by thin-walled sacs containing CSF (Fig. 11.27).315,717 The brainstem is usually atrophic, but the thalami and cerebellum are fairly well preserved.47 Although some have considered this condition to be a congenital anomaly, hydranencephaly represents a destructive process that can be conceptualized as porencephaly of the entire cerebral hemispheres. A similar condition has been induced in laboratory animals by occlusion of both cerebral hemispheres in utero. The optic nerves are formed but severely hypoplastic.388a Neurologically, children with hydranencephaly are severely developmentally delayed from birth and may be macrocephalic, normocephalic, or microcephalic, depending upon the degree of associated hydrocephalus.47 When hydranencephaly is associated with hydrocephalus, shunting does not improve intellectual development but may prevent the development of a grotesquely enlarged head.47 In other cases, severe hydrocephalus can produce extreme thinning of the cortical mantle and simulate hydranencephaly.

Encephalomalacia

Unlike porencephaly and hydranencephaly, encephalomalacia is characterized pathologically by astroglial proliferation and,