Brain Anomalies of Fetal Onset Associated with CHD

Congenital brain anomalies in infants with CHD may result from primary dysgenesis, or from acquired fetal brain insults that result in developmental disruptions, encephaloclastic lesions, or both. In addition, fetal brain growth may be associated with oxygen-glucose deprivation as a consequence of the aberrant cardiac anatomy.

Primary brain dysgenesis in congenital heart disease

The prevalence of cerebral dysgenesis is increased in infants with CHD and brain malformations and should be considered in any child with CHD and unexplained neurologic dysfunction. These brain anomalies may occur as part of syndromic, chromosomal, or genetic conditions. However, in many cases the genetic link between brain and cardiac malformations is presumed, and not currently identifiable. It is possible that some of these presumed primary dysgenetic lesions are acquired disruptions of normal brain development secondary to the underlying cardiac defect.

In earlier autopsy studies of children with CHD, the prevalence of brain malformations ranged from 10 to 29 percent [Glauser et al., 1990b; Jones, 1991; Miller and Vogel, 1999; Terplan, 1976] (Figure 101-1). The prevalence of dysgenetic brain lesions appears to be increased particularly in certain cardiac lesions [Glauser et al., 1990b; Jones, 1991; Terplan, 1976]. For example, a range of cerebral malformations, from microdysgenesis to gross malformations, such as holoprosencephaly, has been described at autopsy in infants with hypoplastic left heart syndrome (HLHS) [Glauser et al., 1990b]. Clinically, these malformations may present in the newborn period with seizures, alterations in level of consciousness, and abnormalities in motor tone, or may remain clinically silent until later infancy and childhood, when they present with developmental delay, epilepsy, and cerebral palsy. The in vivo diagnosis of cerebral dysgenesis is best confirmed by brain magnetic resonance imaging (MRI). Given the decreasing availability and inherent bias of autopsy studies, the increasing sophistication of MRI will be invaluable for the more precise delineation of the relationship between CHD and brain dysgenesis.

Fig. 101-1 T1-weighted magnetic resonance imaging of the brain of a 3-week-old infant with transposition of the great arteries who developed postoperative seizures after an arterial switch operation.

The scan reveals cerebral dysgenesis in the form of agenesis of the corpus callosum (arrows) and a small cerebellar vermis.

Children with certain chromosomal syndromes, particularly aneuploidy, are at increased risk for combined malformations of the heart and brain. Approximately 40 percent of children with trisomy 21 have CHD, typically endocardial cushion defects [Eskedal et al., 2004; Vergara et al., 2006]. The most common cardiac lesions in both trisomies 13 and 18 are ventricular septal defects and patent ductus arteriosus. Conversely, the spectrum of brain malformations in these trisomy syndromes is broad.

With a prevalence of 1:4000–5000, chromosome 22 deletion syndromes are the most common microdeletion disorders in man [Aggarwal and Morrow, 2008], and commonly have features of both cardiac anomalies and neurologic dysfunction.[Morrow et al., 1995] The phenotypic similarities across these syndromes have led to the acronym CATCH-22 spectrum (cardiac defect, abnormal facies, thymic hypoplasia, cleft palate, hypocalcemia, chromosome 22q11 deletions) [Demczuk et al., 1995; Driscoll, 1994; Lindsay et al., 1995; Morrow et al., 1995; Shprintzen et al., 1992]. This spectrum includes the DiGeorge’s and velocardiofacial (Shprintzen’s) syndromes. A second genetic locus for DiGeorge’s syndrome and velocardiofacial syndrome (DGS2) has also been identified on chromosome 10p [Bartsch et al., 2003; Daw et al., 1996].

The most common cardiac defects in DiGeorge’s syndrome are conotruncal lesions, including interrupted aortic arch type B, truncus arteriosus, and tetralogy of Fallot. Features typical of the velocardiofacial syndrome include cleft palate or velopharyngeal insufficiency and a typical facial appearance (Figure 101-2), with a broad prominent nose and retrognathia. Ventricular septal defects and tetralogy of Fallot are the most common cardiac defects in the velocardiofacial syndrome. A range of brain anomalies has been reported [Zinkstok and van Amelsvoort, 2005], the more common of which are midline defects in corpus callosum, septum pellucidum, and vermis development, cerebral and cerebellar “atrophy,” and white-matter abnormalities, including hyperintensities and frontal periventricular cysts [Chow et al., 1999; van Amelsvoort et al., 2001]. In addition, under-opercularization and polymicrogyria (especially of the insula and adjacent cortex) also have been described in chromosome 22 deletion syndromes [Bingham et al., 1997, 1998; Ghariani et al., 2002; Sztriha et al., 2004; Worthington et al., 2000]. The neurologic dysfunction in these syndromes is broad and may evolve over time. These children may present initially with hypocalcemic seizures, and subsequently they develop neurologic or cognitive disturbances, including impaired attention, executive and visuospatial function, and memory [Antshel et al., 2008; Bearden et al., 2001; Moss et al., 1995; Simon et al., 2005]. Early life oromotor dysfunction and expressive language delay is common; however, over time, the most consistent developmental pattern is that of significant discrepancy between verbal IQ and significantly worse performance IQ [Moss et al., 1995]; the mean IQ is around 70. This nonverbal learning disability [Swillen et al., 1999] is in keeping with significant visuoperceptual deficits in many of these children. During childhood, a unusual and inappropriately blunt affect emerges [Golding-Kushner et al., 1985], evolving in some cases into an autistic spectrum disorder, and in adulthood into psychosis [Gothelf et al., 2004; Pulver et al., 1994; Shprintzen et al., 1992; Vorstman et al., 2006].

Fig. 101-2 Facial features of a female with velocardiofacial syndrome include the typical elongated face and broad nasal bridge.

(From Jones KL, editor: Smith’s recognizable patterns of human malformation, ed 4, Philadelphia, 1988, WB Saunders, p 225.)

The most common cardiac lesions seen in Williams’ syndrome are supravalvar aortic stenosis, peripheral pulmonary stenosis, and ventricular/atrial septal defects. These patients are prone to neurologic dysfunction [Ardinger et al., 1994; Chapman et al., 1995; Kaplan, 1995; Soper et al., 1995] and usually have obvious cognitive impairment; the average IQ is around 55. This is compounded further by learning and social disabilities. Gross motor, fine motor, and oromotor dysfunction is common, as are visuospatial and constructional difficulties [Chapman et al., 1995]. Children with Williams’ syndrome also may develop an intracranial arteriopathy with subsequent risk of stroke [Ardinger et al., 1994; Kaplan, 1995; Soper et al., 1995].

Acquired brain lesions in the fetus with congenital heart disease

Many major events in brain development are complete by the onset of the third trimester, but the critical and energy-demanding processes of cortical development and organization have yet to unfold. During the third trimester, these and other processes place escalating demands on the developing cardiovascular system for oxygen-energy substrate supply. Failure to meet these demands may disrupt brain growth and development.

Recent studies have explored the impact of CHD on fetal brain development. In a retrospective review of aortic stenosis-HLHS spectrum cases [Hinton et al., 2008], midgestation (19–22 weeks) fetal ultrasound measurements were compared with neonatal measurements. Several important observations were made in these subjects. First, more than half of these infants had a birth head circumference below the 10th percentile. Second, there was significant decrease in head circumference percentile over the third trimester. Third, fetuses with conditions associated with greater limitation of aortic arch blood flow documented greater impairment of head growth. Finally, there was a tendency for greater restriction of head growth than somatic growth [Hinton et al., 2008]. The only prospective MRI study to date to examine in vivo brain growth in fetuses with CHD versus control fetuses used volumetric measures of brain size and measures of fetal brain metabolism using ¹H-MR spectroscopy [Limperopoulos et al., 2010]. This study revealed a progressive impairment in third-trimester brain growth and metabolism in fetuses with CHD (Figure 101-3). Reduced brain volume and brain N-acetyl aspartate (NAA)/choline ratios were most common in fetuses with HLHS and transposition of the great arteries (TGA); these CHD diagnoses were also responsible for the 20 percent of fetuses with elevated cerebral lactate, suggestive of anaerobic cerebral metabolism. The effects of these CHD diagnoses on cerebral volumetric growth also may underlie the increased incidence of disturbed late-gestation developmental processes in brain development, seen in children with HLHS and TGA. For example, incomplete insular closure, sometimes with polymicrogyria, both late-gestation events, has been described in close to 90 percent of newborns with TGA and HLHS [Licht et al., 2009]. In addition, a high prevalence of disturbances in the third-trimester events of cortical organization has been described in HLHS autopsy studies [Glauser et al., 1990a]. In summary, the findings of these studies suggest that brain growth might be most impaired in those fetuses with CHD resulting in decreased cerebral blood flow and/or hypoxemia. Other studies in newborns with CHD have described decreased pyramidal tract maturation (by diffusion tensor MRI tractography) [Partridge et al., 2006] and biochemical immaturity of the developing white matter (i.e., lower NAA/choline ratio using ¹H-MR spectroscopy) [Miller et al., 2007], suggesting a fetal origin for these brain anomalies.

Fig. 101-3 Relationships between gestational age and ICV, TBV, cerebrospinal fluid, and cerebrospinal fluid:ICV in fetuses with congenital heart disease (green circles) and normal control fetuses (purple diamonds).

Regression equations for fetuses with CHD and controls are as follows. A, ICV CHD = (16.272 × GA) − 265.04; ICV control = (18.744 × GA) − 319.20. B, TBV CHD = (16.081 × GA) − 315.78; TBV control = (20.886 × GA) − 439.41. C, CSF CHD = (0.30052 × GA²) + (−19.936 × GA) + 374.92; CSF control = (0.23769 × GA²) + (−16.768 × GA) + 333.42. D, CSF:ICV CHD = (0.002308 × GA²) + (−0.16478 × GA) + 3.0873; CSF:ICV control = (0.002534 × GA²) + (−0.17985 × GA) + 3.2988. The depicted R² values reflect the goodness of fit for the fitted curve for each group, and not for the adjusted linear regression model. CHD, congenital heart disease; CSF, cerebrospinal fluid; GA, gestational age; ICV, intracanial cavity volume; TBV, total brain volume

(From Limperopoulos C, et al: Brain volume and metabolism in fetuses with congenital heart disease: evaluation with quantitative magnetic resonance imaging and spectroscopy, Circulation 121:26, 2010, Fig. 4.)

Acquired Neurologic Injury Between Birth and Anatomic Intervention

The increase in antenatal diagnosis of CHD has been associated with an improved overall outcome [Montana et al., 1996; Tworetzky et al., 2001; Verheijen et al., 2001], including a decreased rate of neonatal acidosis [Eapen et al., 1998; Kumar et al., 1999] and improved short-term neurologic outcome. This increase is, in large part, due to planned delivery and immediate neonatal care, especially for serious lesions such as HLHS [Mahle et al., 2001]. Furthermore, the advances in neonatal heart repair have reduced the delay to correction, thereby decreasing the brain’s exposure to the deleterious effects of an uncorrected cardiovascular anatomy (e.g., chronic hypoxia). However, while enabling surgical repair in increasingly smaller infants with immature cerebrovascular structure and function, these advances paradoxically have increased the risk of prematurity-related hemorrhagic (e.g., germinal matrix-intraventricular hemorrhage) and ischemic (e.g., periventricular leukomalacia) brain injury.

Preoperative Neurologic Complications

Preoperative neurologic dysfunction has been described in newborns with CHD, in some studies involving more than half of cases [Clancy et al., 2001; Fuller et al., 2009b; Limperopoulos et al., 1999a, 2000, 2001; Newburger et al., 1993; Robertson et al., 2004]. Clinical abnormalities described include muscle tone abnormalities, jitteriness, motor asymmetries, abnormal behavioral state regulation, decreased sensory (visual and auditory) responsiveness, and feeding difficulties. In one study, neurologic compromise was more prominent among newborns with acyanotic CHD [Limperopoulos et al., 1999a]. Congenital microcephaly, despite appropriate birth weight, has been reported in one-third or more of neonates with CHD, suggesting fetal-onset impaired brain growth [Licht et al., 2004; Limperopoulos et al., 1999b; Manzar et al., 2005; Shillingford et al., 2007]. Likewise, preoperative electroencephalographic (moderate, diffuse, background disturbances) and evoked potential abnormalities have been reported in over 40 percent of newborns with CHD [Limperopoulos et al., 1999b, 2000].

Neuroimaging studies in newborns with CHD, using either cranial ultrasound or MRI, have depicted a significantly increased prevalence of brain injury, largely clinically silent. Cranial ultrasound studies performed preoperatively and postoperatively in a cohort of infants undergoing cardiac surgery identified a 24 percent incidence of new lesions after cardiac surgery, with new hemorrhagic lesions in 6 percent of cases [Krull et al., 1994]. Preoperative cranial ultrasound abnormalities, including cerebral atrophy (41 percent), enlarged cerebrospinal fluid (CSF) spaces (26 percent), linear deep gray-matter echodensities (20 percent), intraventricular hemorrhage (16 percent), and parenchymal echodensities (16 percent), have been reported in 40–60 percent of newborns with CHD [Te Pas et al., 2005; van Houten et al., 1996]. The incidence of these cranial ultrasound abnormalities is greatest in newborns with aortic coarctation (especially with ventricular septal defect) or HLHS, ranging from 63 percent [Te Pas et al., 2005] to 71 percent [van Houten et al., 1996].

Recent MRI studies have confirmed this high prevalence of preoperative brain injury [Mahle et al., 2002; McConnell et al., 1990; McQuillen et al., 2006, 2007; Miller et al., 2004; Tavani et al., 2003], especially in infants with certain CHD lesions, including HLHS and TGA, as well as those with low preoperative oxygenation and longer time to surgery [Cheng, 2006; McQuillen et al., 2006]. In an MRI study of infants with HLHS, 23 percent documented preoperative evidence of focal or diffuse brain injury [Dent et al., 2005]. Procedures such as preoperative balloon-atrial septostomy also have been associated with evidence of infarction on MRI in some [Cheng, 2006; McQuillen et al., 2006], but not all, studies [Beca et al., 2009; Petit et al., 2009]. Prospective MRI studies have also increased the detection of periventricular leukomalacia (PVL) [Mahle et al., 2002; McConnell et al., 1990; McQuillen et al., 2006, 2007; Miller et al., 2004; Tavani et al., 2003], with some studies reporting a prevalence as high as 20 percent [Galli et al., 2004; Mahle et al., 2002]. PVL characteristically is a lesion of the premature infant, mediated by an interplay between the vulnerability of immature oligodendrocytes and insults such as cerebral ischemia. The fact that the preoperative PVL described in infants with CHD has been in term or near-term newborns has led to speculation that oligodendrocyte maturation is delayed in infants with CHD [du Plessis, 1997; Licht et al., 2009; Miller et al., 2007]. The notion of cerebral hypoperfusion in the newborn with CHD has been supported by studies indicating decreased cerebral perfusion (by arterial MRI spin-labeling) [Licht et al., 2004], as well as elevated cerebral lactate (by preoperative ¹H-MR spectroscopy) in up to 53 percent of newborns with CHD – most commonly, those with TGA and single ventricle physiology [Ashwal et al., 1996, 2003; Mahle et al., 2002; Miller et al., 2004, 2007]. Table 101-1 summarizes the prevalence and type of preoperative brain injury in infants with CHD.

Mechanisms of Neurologic Injury during Deep Hypothermic Cardiac Surgery

Regardless of its frequency, intraoperative brain injury remains a major concern for children undergoing surgery for severe CHD. Intra- and perioperative hypoxic-ischemic/reperfusion (HI/R) insults generally are considered the principal cause of postoperative neurologic dysfunction. During open-heart surgery, a multitude of complex, dynamic, and interrelated phenomena may impact simultaneously on cerebral oxygen delivery and demand (Box 101-1) during the core cooling, low or no-flow bypass, and rewarming phases of deep hypothermic cardiac surgery. In individual infants sustaining intraoperative brain injury, the precise role and contribution of each of these phenomena are often unclear. The potential mechanisms for the development of HI/R are multiple and include both global (Box 101-1) and focal insults (Box 101-2). In adults undergoing cardiac surgery, the predominant form of brain injury is focal embolic ischemia, resulting when atheromatous debris dislodged from the aorta enters the arteriosclerotic cerebrovascular bed. Conversely, in the young infant undergoing open-heart surgery, the cerebral HI/R insults are mediated primarily by global hypoperfusion. Normally, the delicate balance between cerebral oxygen supply and utilization is controlled by intrinsic cerebral autoregulatory systems. These systems are likely overwhelmed by the major hemodynamic and metabolic changes induced during infant open-heart surgery. During the intraoperative period, it becomes the responsibility of the anesthesiologist-perfusionist team to maintain a positive balance of cerebral energy supply and demand. Guidelines for this extrinsic regulation of cerebral oxygenation remain based largely on theoretical safety parameters of aspects, such as duration of circulatory arrest, as well as rate and depth of cooling. The complex and dynamic intraoperative changes in both oxygen substrate demand and supply, as well as the lack of reliable and validated intraoperative monitoring techniques, make it challenging in the individual patient to identify imminent cerebral hypoxia-ischemia before injury occurs [du Plessis et al., 1995b; Sakamoto et al., 2001, 2004; Wardle et al., 1998].

Box 101-1 Intraoperative Determinants of Global Cerebral Oxygen Delivery and Use

Factors That Decrease Cerebral Oxygen Use

Hypothermia

Drugs (e.g., barbiturates)

After hypoxia or ischemia

Factors That Decrease Cerebral Oxygen Supply

Cerebral Perfusion Pressure Decreases

Deep hypothermic circulatory arrest or low-flow cardiopulmonary bypass

Nonpulsatile perfusion

Disturbed autoregulation

Increased central venous pressure

Oxygen-Carrying Capacity Decreases

Hemodilution

Oxygen Delivery Decreases

Increased oxyhemoglobin affinity (i.e., hypothermia and alkalosis)

Box 101-2 Potential Mechanisms for Focal Intraoperative Vaso-occlusive Insults

Embolic Insults

From Bypass Circuit

Synthetic debris

Platelet emboli

Air emboli

From Surgical field

Fat emboli

Air emboli

Platelet emboli

From Venous System

Systemic veins after deep hypothermic circulatory arrest

Pulmonary veins after bypass

Thrombotic Insults

Arterial: possible inflammatory vascular changes

Venous: increased central venous pressure

Over the last two decades, there has been intense research into techniques that reduce the risk of intraoperative hypoxia-ischemia. Clinical trials have focused on strategies for optimizing intraoperative cerebral oxygen availability, which is most tenuous during periods of low-flow cardiopulmonary bypass (LFB) or deep hypothermic circulatory arrest (DHCA). Since longer periods of both DHCA and LFB have their own attendant risks, the neurologic outcome associated with LFB and DHCA was compared in a randomized clinical trial of 171 infants with TGA undergoing neonatal cardiac repair. Based on the findings of this trial, in which DHCA was associated with higher perioperative morbidity [Newburger et al., 1993] and worse developmental outcome at age 1 year, most centers adopted a strategy that minimized DHCA. The longer-term outcomes of this study are discussed below [Bellinger et al., 1997, 1999b, 2003].

Deep hypothermia has significant acid–base effects, and different intraoperative management strategies have been used to manipulate these acid–base changes with the goal of optimizing tissue metabolism. Both the more alkalotic alpha-stat strategy and the more acidotic pH-stat strategy have theoretical advantages. The alpha-stat approach is based on the natural alkaline shift in tissue that accompanies hypothermia and is thought to optimize enzyme function at low temperatures. Conversely, the pH-stat technique utilizes the addition of CO₂ to counter this alkaline shift and is used to enhance tissue oxygen delivery. The more hypercarbic perfusate increases cerebral perfusion and increases oxygen release in tissues by countering the increased oxygen-hemoglobin affinity associated with hypothermia. A randomized clinical trial comparing these two pH management strategies suggested that infants managed by the pH-stat strategy had less perioperative morbidity and a shorter time to recovery of electrocortical activity [du Plessis et al., 1997]. As a result, the pH-stat strategy has become incorporated into the intraoperative acid–base management protocols of many centers, particularly during the induction of hypothermia on CBP.

Hemodilution is used widely in CBP to improve blood flow in the microcirculation. However, the benefits of improved perfusion are countered by the risks of reduced oxygen-carrying capacity of the circulation. A randomized clinical trial of different hematocrit levels in infants undergoing hypothermic CBP found that hemodilution was associated with greater perioperative hemodynamic instability and worse psychomotor development at age 1 year [Jonas et al., 2003]. However, at longer-term follow-up, the neurodevelopmental outcomes were similar in both groups [Newburger et al., 2008].

Besides global HI/R insults, several other mechanisms have been implicated in intraoperative brain injury. Compared with those in adults, vaso-occlusive insults play a lesser role in intraoperative brain injury during cardiac surgery in infants. CPB and the surgical field may generate particulate (e.g., platelet, synthetic, or fat) (Figure 101-4) or gaseous (e.g., air) emboli [Boyajian et al., 1993; Fish, 1988; Moody et al., 1990; Padayachee et al., 1987]. Inflammatory mechanisms triggered during CPB also have been investigated for their role in intraoperative brain injury, an interest stimulated by the growing body of evidence for cytokine-mediated neurotoxicity in animal studies [Back, 2006; Back et al., 2007; Den et al., 2009]. A post-bypass systemic inflammatory syndrome [Kirklin et al., 1983; Westaby, 1987], with systemic vascular injury manifesting with marked edema, is common, particularly in young infants. This syndrome is related to the relatively large blood volume required for priming bypass pumps and the prolonged exposure of this blood to artificial surfaces. The elevated levels of cytokines (interleukins-6 and 8, tumor necrosis factor-α, and endothelin-1) measured in bypass blood [Bando et al., 1998; Elliott, 1999; Elliott and Finn, 1993; Jansen et al., 1992; Journois et al., 1996; Kirklin et al., 1983; Millar et al., 1993; Steinberg et al., 1993] potentially may mediate vascular, as well as cellular, injury. Ultrafiltration of blood during or after CPB reduces both cytokine levels and excess free plasma water [Gaynor, 2003]. Ultrafiltration has been associated with improved postoperative hemodynamics [Bando et al., 1998] and improved myocardial function [Chaturvedi et al., 1999; Davies et al., 1998]. It is not known whether the beneficial effects of ultrafiltration result primarily from a reduction in postoperative cytokine levels or from hemoconcentration. To date, the potential contribution of this systemic inflammatory response to intraoperative brain injury has not been demonstrated convincingly in clinical trials with long-term follow-up.

Fig. 101-4 Aneurysmal dilatations (arrows) in the cerebral microvasculature after cardiopulmonary bypass.

(From Moody D, Bell M, Challa VR, et al: Brain microemboli during cardiac surgery or aortography, Ann Neurol 28:477–486, 1990. Copyright © 1990 Wiley–Liss, Inc., a Wiley Company. Reproduced with permission of John Wiley & Sons, Inc.)

Mechanisms of Neurologic Injury with Extracorporeal Membrane Oxygenation

Extracorporeal oxygenation-circulation devices are used increasingly in children with critical heart disease as a “bridge” to recovery, surgery, or transplantation. Extracorporeal life-support devices were introduced into clinical practice by Kirklin and Lillehei in the mid-1950s for the CPB support of patients undergoing open-heart surgery [Lillehei, 1982; Moller et al., 2009]. On-going technological advances expanded the applications of these devices, and in the 1980s they emerged from the operating room to become established for the intensive care management of severe but potentially reversible cardiorespiratory failure. In the early years, the principal target population in children was the term newborn with respiratory failure due to meconium aspiration and persistent pulmonary hypertension, and subsequently congenital diaphragmatic hernia [Bartlett et al., 1977]. Since its inception, an estimated 20,000 infants have had extracorporeal membrane oxygenation (ECMO) for respiratory failure [Lequier et al., 2008]. The advent of nitric oxide pulmonary vasodilators obviated the need for ECMO in many cases of respiratory failure due to pulmonary hypertension [Christou et al., 2000; Clark et al., 2000]. Coinciding with its waning use for respiratory failure, ECMO became used increasingly for critical but potentially reversible circulatory failure. There are two broad indications for so-called cardiac ECMO in children. Most commonly, cardiac ECMO is used to support children with severe cardiovascular failure, for which spontaneous recovery or effective intervention is possible. Included in this group are newborn infants who fail to transition effectively from a fetal to an extrauterine circulation; children with intractable cardiac failure awaiting transplant; and children who fail to wean off CPB after cardiac surgery. Another indication for cardiac ECMO, employed in some centers, is cardiorespiratory arrest refractory to conventional resuscitative measures (cardiopulmonary resuscitation [CPR]-ECMO) [del Nido et al., 1992]. The use of CPR-ECMO has been recommended by the American Heart Association for in-hospital cardiac arrest that is potentially reversible or amenable to transplant.

Two types of ECMO circuit are used, depending on the primary underlying pathophysiology. A veno-venous (VV) circuit is used to provide oxygenation for respiratory failure, whereas veno-arterial (VA) ECMO provides circulatory support, as well as oxygenation, in cases of severe circulatory failure. In both VV and VA circuits, venous blood is drained from the right atrium through a catheter advanced down the right internal jugular vein. Following oxygenation and removal of CO₂ across the ECMO membrane, blood is pumped into either the right atrium through the second lumen of a double-lumen catheter (VV circuit), or into the aortic arch through a catheter in the right common carotid artery (VA circuit). Systemic heparinization is required to prevent clotting in the ECMO circuit. The rostral segments of the cannulated vessels (i.e., jugular vein and, in VA ECMO, the right common carotid) are ligated as part of the procedure.

ECMO may injure the brain through multiple mechanisms that promote either ischemic or hemorrhagic injury. Carotid ligation causes an immediate reduction in blood flow to the ipsilateral middle cerebral artery, which may be restored only partially by collateral flow through the circle of Willis and the external carotid artery. This reduced flow may cause direct ischemia and may interfere with cerebral autoregulation, rendering that hemisphere vulnerable to systemic hypotension. Jugular vein ligation can result in cerebral venous hypertension, which may predispose to venous infarction, and which further decreases the cerebral arteriovenous pressure gradient. Systemic heparinization increases the risk of intracranial hemorrhage, which may be either primary or due to hemorrhagic transformation of an ischemic lesion. Finally, ECMO causes elevated levels of inflammatory cytokines, which may contribute to the development of PVL [Fortenberry et al., 1996; Kinney and Back, 1998].

The Neurologic Outcome of Children Undergoing Extracorporeal Membrane Oxygenation

An important determinant of long-term neurologic outcome following ECMO is the underlying indication for its use. Given the significant clinical instability and illness severity preceding ECMO, and the difficulty obtaining definitive brain imaging acutely, it remains difficult to distinguish between brain injury associated with the ECMO technique itself and that due to the underlying critical illness. For a number of reasons, the outcome after cardiac ECMO is less favorable than for respiratory ECMO. This finding is perhaps not surprising since cerebral ischemia is known to be a more potent cause of brain injury than is cerebral hypoxemia, a notion supported by the fact that the severity of arterial metabolic acidosis prior to ECMO is a significant predictor of adverse neurologic outcome [Cengiz et al., 2005].

Intracranial hemorrhage and infarction are the primary neurologic complications of ECMO, with previous estimates ranging from 25 to 50 percent overall, and severe lesions in 10–20 percent of infants [Volpe, 2001]. The most common sites of intracranial hemorrhage are into the lateral ventricles and posterior fossa structures. Cerebral ischemia may be global or focal, and may manifest as PVL [Jarjour and Ahdab-Barmada, 1994; Kinney and Back, 1998]. Clinical seizures occur in approximately 10 percent of both cardiac and respiratory ECMO cases [Dalton, 2004]. However, given the overall morbidity and the use of sedating-paralyzing drugs, it is not surprising that electrographic seizures have been detected in up to 70 percent of cases. [Kim and Stolar, 2000]. Despite this high risk for acute seizures, the risk for subsequent epilepsy is low. Sensorineural hearing impairment, often reversible, is reported in 4–15 percent of neonates after ECMO [Desai et al., 1997; Hofkosh et al., 1991; Schumacher et al., 1991]. ECMO survivors are at significant risk for neurocognitive delays; between 10 and 29 percent have developmental quotients below 70, the greatest risk being in the smaller infants [Hamrick et al., 2003; Revenis et al., 1992].

The short-term benefit of respiratory (VV) ECMO was established early, with multicenter survival rates around 75–80 percent; of note, a major criterion for ECMO eligibility was a predicted mortality of greater than 80 percent [Dalton et al., 2005; Stolar et al., 1991]. However, reports of neurologic injury in infants undergoing ECMO soon emerged, and this occurrence remains a major complication among survivors of ECMO. The reported long-term neurologic morbidity has ranged from 15 to 30 percent [Hanekamp et al., 2006; McNally et al., 2006; Robertson et al., 1995].

There is a relative paucity of data for the long-term outcome of cardiac (VA) ECMO. Overall survival is lower than for respiratory ECMO, and ranges from 30 to 55 percent [Balasubramanian et al., 2007; Chen et al., 2008; Taylor et al., 2007], but varies with the specific underlying indication. Children with dilated cardiomyopathy or myocarditis requiring ECMO may have survival rates as high as 80–90 percent [Duncan et al., 2001; McMahon et al., 2003]. Neurologic deficits have been described in up to 60 percent of cardiac ECMO survivors [Chow et al., 2004; Hamrick et al., 2003; Ibrahim et al., 2000], with mental retardation in 30–50 percent of survivors, depending on the indication [Hamrick et al., 2003; Lequier et al., 2008].

Not surprisingly, survival is significantly higher when ECMO is started before cardiac arrest than after, CPR-ECMO having the highest mortality and morbidity risks. While conventional CPR lasting 30 minutes or more has a survival of 5 percent or less [de Mos et al., 2006; Morris et al., 2004], survival after CPR-ECMO in patients who had failed conventional CPR is around 30–40 percent [Alsoufi et al., 2007; Chan et al., 2008; Lequier et al., 2008; Thiagarajan et al., 2007]. Risk factors for death in CPR-ECMO cases are severe metabolic acidosis (pH ≤ 7.00) prior to ECMO, persistent metabolic acidosis despite CPR-ECMO, and the development of multisystem organ failure [Kolovos et al., 2003; Kulik et al., 1996; Thiagarajan et al., 2007]. In a recent study of outcome following cardiac ECMO, including CPR-ECMO, survival to discharge was 46 percent, but more than 50 percent of survivors had mental retardation at long-term follow-up, with time to normalization of circulating lactate and the degree of inotropic support needed being significant predictors [Lequier et al., 2008].

With improved technology, the incidence of neurologic complications has decreased, but these remain a poor prognostic factor. However, the expanded indications for ECMO support, including more critical circulatory failure, are likely to increase the development of problems arising from the antecedent illness.

Delayed Recovery of Consciousness

Prolonged delay in the recovery of consciousness after cardiac surgery, anesthesia, and sedation is not uncommon. The standard diagnostic guidelines [Plum and Posner, 1985] for the evaluation of altered mental status should be applied to these patients, although the precise mechanism(s) remains unclear in most cases. Ultimately, some of these children demonstrate clinical and neuroimaging features suggestive of cerebral HI/R injury. However, because intraoperative events specific for HI/R often are lacking, other potentially reversible etiologies should be excluded, including postoperative hepatic or renal impairment with accumulation of toxic metabolites, or impaired metabolism or excretion of sedating drugs. Prolonged use of neuromuscular blocking agents for ventilatory management may be associated with delayed recovery of motor function [Gooch et al., 1991; Partridge et al., 1990; Waitling and Dasta, 1994], and, in severe cases, may mimic impaired consciousness. Neuromuscular blockade may be excluded with a bedside peripheral nerve stimulator or nerve conduction studies. A significant minority of infants develop postoperative seizures, which may recur serially and often are clinically silent [Newburger et al., 1993]. In the absence of other causes to explain persistent impairment of consciousness, occult seizures or a prolonged postictal state should be considered.

Postoperative Seizures

Seizures are among the most common manifestations of neurologic dysfunction after infant open-heart surgery. Past series have reported clinical seizures in up to 15 percent of infants in the early postoperative period [Ehyai et al., 1984; Miller et al., 1995; Newburger et al., 1993], whereas clinically silent, electrographic seizures were detected by continuous electroencephalographic (EEG) monitoring in up to 20 percent of infants [Helmers et al., 1997]. More recent studies from large pediatric cardiac surgery centers report widely disparate postoperative seizure rates ranging from 1.2 to 17.7 percent [Clancy et al., 2003; Menache et al., 2002]. Risk factors for postoperative seizures include the use of DHCA, prolonged DHCA times, the presence of a ventricular septal defect, and pre-existing genetic conditions [Clancy et al., 2003; Helmers et al., 1997]. The recent decline in seizure incidence observed in some centers also may be attributable to refinements in extracorporeal perfusion support, such as the minimization of DHCA.

Two forms of early postoperative seizures may be distinguished, i.e., seizures with a readily identifiable cause and those without (so-called “postpump seizures”). The usual etiologies of seizures should be excluded, particularly reversible causes such as hypoglycemia and electrolyte disturbances. Cyclosporine A toxicity is a common cause of seizures in heart transplant recipients [Menache et al., 2002].

Postpump seizures

Postpump seizures (i.e., those without an identifiable etiology) were the most common form of postoperative seizures in previous years, but their incidence appears to be decreasing. Postpump seizures tend to have certain characteristic clinical features and are confined almost exclusively to young infants. Conversely, postoperative seizures in older infants and children usually are associated with an identifiable cause. Postpump seizures often are assumed to reflect intraoperative HI/R injury; however, they differ from other post-HI/R (e.g., birth asphyxia) seizures in several ways. First, the onset of postpump seizures (including EEG seizures) is typically delayed until 24–48 hours postoperatively. This is significantly later than postasphyxial seizures, which often present within the first 12 hours after birth. Second, although not always benign, the long-term outcome of postpump seizures [Bellinger et al., 1995] is markedly better than the 50 percent incidence of adverse neurologic outcome seen after postasphyxial seizures [Andre et al., 1990; Bergman et al., 1983; Volpe, 2001].

The temporal predilection for postpump seizures is relatively circumscribed to a “window” of several days (Figure 101-6). During this period, seizures tend to recur and, not uncommonly, status epilepticus develops. After several days, the tendency for further seizures decreases rapidly. The clinical manifestations of postpump seizures may be subtle, especially in infants receiving sedating or paralyzing drugs. Behavioral changes may be confined to paroxysmal changes in autonomic function, such as tachycardia, hypertension, and pupillary dilatation. Convulsive activity, when evident, is often focal or multifocal. Bedside EEG helps distinguish true epileptic phenomena from other behavioral or autonomic changes [Mizrahi, 1987; Scher and Painter, 1990]. Furthermore, the ability of EEG to detect clinically occult seizure activity helps guide anticonvulsant drug therapy. Finally, highly focal EEG abnormalities may reflect an underlying structural lesion (e.g., stroke), indicating the need for neuroimaging.

Fig. 101-6 Diagram of the circumscribed postoperative susceptibility period for electroencephalographic and clinical seizures.

The therapeutic approach to postpump seizures is dictated best by their typical clinical course. After reversible etiologies, such as hypoglycemia, hypomagnesemia, and hypocalcemia, [Lynch and Rust, 1994; Satur et al., 1993] have been excluded, anticonvulsant therapy should commence. In view of the tendency toward repeated seizures and status epilepticus, the initial goal is rapid achievement of therapeutic anticonvulsant levels by an intravenous route. The vast majority of postoperative seizures are controlled by standard anticonvulsant regimens used in infants. Careful cardiorespiratory monitoring is essential when using potentially cardiotoxic anticonvulsants during the postoperative period, when myocardial dysfunction or arrhythmias are prevalent. Specifically, in infants with established myocardial dysfunction, cautious administration of phenobarbital is advisable, whereas pre-existent conduction disturbances, particularly bradyarrhythmias, necessitate careful monitoring of phenytoin therapy [Cranford et al., 1978]. The apparently circumscribed window of susceptibility for these postpump seizures and the rarity of subsequent epilepsy allow successful early withdrawal of anticonvulsant agents, often before hospital discharge.

Stroke in the Early Postoperative Period

Vaso-occlusive stroke in children with CHD diagnosed in the early postoperative period likely has an etiologic profile that differs from stroke occurring prior to or remote from cardiac surgery. The latter category of stroke is discussed later in this chapter. Since strokes diagnosed in the early postoperative period are likely to be clinically silent during the operation and early postoperative recovery [Chen et al., 2009], their incidence is likely underestimated. A recent 10-year review described a 5.4 per 1000 incidence of arterial and venous occlusive brain injury within the first 3 days of cardiac surgery [Domi et al., 2008]. Another study using MRI in the first 14 days after surgery found a 10 percent incidence of stroke that included both vaso-occlusive and global hypoperfusion (“watershed”) injuries; vaso-occlusive lesions comprised less than half these “strokes” [Chen et al., 2009] (Figure 101-7). Of interest, the vast majority of these lesions were clinically silent in the acute phase.

Fig. 101-7 Illustrative magnetic resonance imaging findings of infarcts (arrows).

A, Apparent diffusion coefficient map from axial diffusion-weighted image documents large acute middle cerebral artery territory infarct. B, Left caudate lacunar infarct on axial T2 image. C, Remote right middle cerebral-anterior cerebral artery watershed zone infarct on axial T2 image.

(From Chen J, Zimmerman RA, Jarvik GP, et al: Perioperative stroke in infants undergoing open heart operations for congenital heart disease, Ann Thorac Surg 88:823, 2009, Figure 1. Reprinted with permission.)

Certain features of open-heart surgery and the immediate postoperative period may predispose to stroke and warrant brief review. During the intraoperative period, both embolic and thrombotic mechanisms may cause cerebral vaso-occlusive injury. Particulate and gaseous emboli originating from the CPB apparatus or surgical field bypass the normal pulmonary filtration system during CPB and thus enter the systemic circulation directly [Boyajian et al., 1993; Moody et al., 1990; Padayachee et al., 1987; Solis et al., 1975]. Improvements in bypass circuits, particularly the replacement of bubble oxygenators by membrane oxygenators, have decreased the incidence of macroembolic injury [Nussmeier and McDermott, 1988]. The impact of these advances on the incidence of microvascular injury [Fish, 1988] is unclear. The marked inflammatory response triggered by the extensive and prolonged exposure between bypass blood and artificial surfaces [Kirklin et al., 1983; Millar et al., 1993; Steinberg et al., 1993] is known to trigger complex cascades, including endothelial-leukocyte interactions [del Zoppo, 1994; Elliott and Finn, 1993; Feuerstein et al., 1994; Lucchesi, 1993]. The resulting microvascular dysfunction may predispose to intravascular thrombosis or thromboembolism, manifesting with vaso-occlusive brain injury.

In the early postoperative period, several factors predispose to cardiogenic stroke. First, vascular stasis may result from localized areas of low flow within the heart [du Plessis et al., 1995a; Rosenthal et al., 1995a, 1995b], or global ventricular dysfunction. Prolonged postoperative immobility predisposes to systemic venous stasis and thrombosis. Transient pulmonary hypertension is common after CPB, elevating venous pressure and decreasing the rate of blood flow through the right heart chambers and central veins. Injury to native tissue or the presence of prosthetic tissue alters vascular surfaces in contact with the circulation. A number of these stroke risk factors may be present after the Fontan procedure, the most common final operation for CHD with a single ventricle physiology [Day et al., 1995; Dobell et al., 1986; du Plessis et al., 1995a; Hutto et al., 1991; Mathews et al., 1986; Rosenthal et al., 1995a, 1995b], and is discussed in more detail below.

Movement Disorders After Cardiac Surgery

For many years, movement disorders have been considered an uncommon but dreaded complication of deep hypothermic cardiac surgery [Barrat-Boyes, 1990; Bergouignan et al., 1961; Bjork and Hultquist, 1962; Brunberg et al., 1974; Chaves and Scaltsas-Persson, 1988; Curless et al., 1994; DeLeon et al., 1990; Donaldson et al., 1990; Huntley et al., 1993; Medlock et al., 1993; Robinson et al., 1988; Wical and Tomasi, 1990; Wong et al., 1992]. Although less commonly described in recent years, these postoperative movement disorders are often dramatic, frequently intractable, and ultimately debilitating, with severe forms associated with substantial mortality.

Choreoathetosis is the most frequently reported dyskinesia after cardiac surgery, but a spectrum of movement disorders, including oculogyric crises [du Plessis et al., 1994b], akathisia, and parkinsonian syndromes [Straussberg et al., 1993], may be encountered. These dyskinesias are likely under-diagnosed and under-reported, making the true incidence difficult to ascertain; however, in reported case series, the incidence of postoperative choreoathetosis has ranged from 0.5 percent [Wessel and du Plessis, 1995] to 19 percent [Brunberg et al., 1974].

Postoperative choreoathetosis has a fairly stereotypic presentation and clinical course (Figure 101-8). The temporal course of choreoathetosis is relatively stereotypic after cardiac surgery, with subacute mental status changes, including often severe insomnia and irritability, emerging after a usually unremarkable period of 2–7 days; these are followed by “restlessness,” progressing to frankly abnormal involuntary movements, even ballismus, which typically commence in the distal extremities and orofacial muscles and progress proximally to the girdle muscles and trunk. The dyskinesia is confined to wakefulness, increases with stress, and resolves during the brief and fitful periods of sleep. Oculomotor, faciomotor, and oromotor apraxia may be prominent, raising concerns of “blindness” because these children appear not to “look at” or show recognition of familiar faces; in addition, oral feeding and expressive language may be disrupted. The involuntary movements intensify over days to a week, and then plateau over 1–2 weeks, before a gradual and variable recovery may begin. Mild dyskinesia usually resolves completely over days to weeks, and by 6 months at the latest. Severe postoperative dyskinesia may gradually improve for up to 2 years, after which further meaningful recovery is unlikely.

Fig. 101-8 Diagram of the time course and evolution of postoperative dyskinesia.

Diagnosis of these postoperative hyperkinetic syndromes is essentially clinical. Currently available adjunctive neurodiagnostic techniques have been useful only in so far as they exclude other disorders. Neuroimaging studies may be normal or depict nonspecific and nonfocal changes, most commonly diffuse cerebral atrophy [Medlock et al., 1993; Robinson et al., 1988; Wong et al., 1992]. Single-photon emission computer tomography (SPECT) functional brain imaging studies document a high incidence of both cortical and subcortical perfusion defects [du Plessis et al., 1994b]. EEG is usually normal or documents diffuse slowing. Neuropathologic findings have been limited and inconsistent, and have not elucidated the mechanisms of injury [Chaves and Scaltsas-Persson, 1988; Kupsky et al., 1995]. The basal ganglia do not undergo infarction; selective neuronal loss and gliosis may be seen in the external globus pallidus, an uncharacteristic region for HI/R injury, at least at normothermia [Kupsky et al., 1995]. Interestingly, an animal model of deep hypothermic circulatory arrest [Johnston et al., 1995; Redmond et al., 1994] has suggested that, when HI/R occurs at deep hypothermia, selective neuronal necrosis is prominent in the globus pallidus.

The prognosis of these conditions depends largely on their initial severity. Based on the severity and persistence of the dyskinesias, two forms of postpump choreoathetosis may be distinguished: a mild transient form and a severe persistent form [Wong et al., 1992]. In the mild transient form, involuntary movements are confined to the distal extremities or face, and tend to resolve over several weeks to months in virtually all cases [du Plessis et al., 2002]. However, a significant minority of these children have persistent disturbances in gait, fine motor function, and language. Severe postpump choreoathetosis has a much worse prognosis, with a mortality approaching 40 percent (due to aspiration pneumonia, massive caloric consumption, and infection); amongst survivors, long-standing dyskinesias, pervasive behavioral and cognitive disturbances, and even mental retardation are common [du Plessis et al., 2002]. Furthermore, these severe cases are associated with older age (beyond early infancy) at surgery, cyanotic heart disease, and shorter time from onset of CPB to DHCA (Wong et al., 1992). [Wong et al., 1992].

Dyskinesias also have been associated with the use of fentanyl and midazolam, widely used postoperative analgesics and sedatives. These medication-associated forms of movement disorder have a good prognosis, with less prominent sensorium changes and mild involuntary movements that resolve over days to weeks [Bergman et al., 1991; Lane et al., 1991; Petzinger et al., 1995].

Prevention of postoperative dyskinesias is limited by the current lack of a discernible mechanism of injury. Identified risk factors in retrospective studies include:

Acute and long-term management of postoperative dyskinesias remains frustrating; currently, no agents consistently control the involuntary movements while preserving alertness. In the acute phase, essential management goals should be amelioration of the agitated delirium, protection of the airway, and anticipation of the skin breakdown and increased nutritional demands. The often-prominent oromotor dyskinesia impairs feeding and predisposes to aspiration. Nasogastric or even gastrostomy tube feedings may be necessary to meet the high caloric demands of the constant involuntary movements. General measures against the profound irritability should include a decrease in the level of external (e.g., noise, light) and internal (e.g., pain) stimuli. Sedation should be used judiciously and should aim to restore the fragmented sleep-wake cycle. During the acute phase, mild dyskinesias can be managed by sedating agents alone, such as benzodiazepines and chloral hydrate. In severe movement disorders, a cautious trial with more specific antidyskinetic agents (e.g., haloperidol) is a reasonable approach.

Equally exasperating has been the pursuit of long-term pharmacologic control of residual dyskinesias. A wide spectrum of medications has been tried, including dopamine receptor antagonists, dopamine depleting agents, dopamine agonists, benzodiazepines, and other agents, including valproic acid, carbamazepine, phenytoin, diphenhydramine, and chloral hydrate. More recent anecdotal reports suggest that levetiracetam may be effective.

Spinal Cord Injury

Spinal cord injury is fortunately a rare complication of cardiac surgery in infants and children, and is most commonly, but not exclusively [Puntis and Green, 1985], seen after aortic coarctation repair, occurring in 0.4 percent [Brewer et al., 1972] to 1.5 percent [Lerberg et al., 1982; Pennington et al., 1979] of such cases. During aortic surgery, spinal cord injury results from a watershed-type of HI/R insult. In the spinal cord, end-zone or watershed territories of arterial supply are located transversely at a lower thoracic level, and longitudinally between the supply territories of the anterior and posterior spinal arteries. Transverse ischemia at the thoracic level is the usual form of cord injury seen after coarctation repair. The highly variable, inconsistent collateral arterial supply of the distal cord may predispose to transverse cord ischemia during clamping of the aorta distal to the subclavian arteries, resulting in postoperative paraplegia with pyramidal features, with or without a thoracolumbar sensory level and bladder and bowel dysfunction.

The longitudinal cord syndrome is rare and occurs after systemic hypotension, as occurs with birth asphyxia [Sladky and Rorke, 1986] or with cardiac defects [Rousseau et al., 1993]. Injury is maximal in the ventral gray matter with selective anterior horn cell loss. Unlike the predominant pyramidal features of transverse cord ischemia, longitudinal cord injury causes a prominent lower motor neuron syndrome, with hypotonia (acute and long-term) and weakness with decreased or absent reflexes; posterior column sensory function is relatively spared. Intraoperative somatosensory-evoked potentials sometimes are used to monitor spinal cord function during coarctation surgery [Guerit et al., 1997; Laschinger et al., 1983, 1988], but, since these evaluate the posterolateral spinal pathways, rather than the more vulnerable anterior horn cells, this approach has not been adopted universally [Laschinger et al., 1988].

Peripheral Neuromuscular Injury

The often prolonged periods of immobility during and after cardiac procedures expose the peripheral nervous system to pressure and traction injuries. In addition, the child with CHD is at risk for toxic/metabolic injury to the peripheral nerve, neuromuscular junction, and muscle.

Late Postoperative Stroke

The overall annual incidence of childhood stroke ranges from 2.5 [Schoenberg et al., 1978] to 7.9 per 100,000 children [Giroud et al., 1995]. CHD is a major risk factor for stroke in childhood, being present in 25–30 percent of cases [Lanska et al., 1991; Riela and Roach, 1993; Schoenberg et al., 1978]. Stroke in the child with CHD, including stroke in the late postoperative period, is predominantly thromboembolic in origin. Less commonly, arteriopathic or stenotic lesions of the intracranial vasculature may be seen in certain congenital heart lesions. Both these forms of stroke are discussed.

Thromboembolic cardiogenic stroke

Although thromboembolic stroke may complicate CHD at any time in the preoperative, intraoperative, and early postoperative periods, the majority of cardiogenic strokes occur remote from surgery. Risk factors for cardiogenic stroke in earlier years (e.g., polycythemia and right-to-left shunt) [Berthrong and Sabiston, 1951; Cottrill and Kaplan, 1973; Martelle and Linde, 1961; Phornphutkul et al., 1973; Terplan, 1976; Tyler and Clark, 1957a, 1957b] have decreased with the surgical correction of heart lesions in early infancy. Autopsy studies from earlier decades described cerebrovascular ischemic lesions in up to 20 percent of children with CHD [Berthrong and Sabiston, 1951; Terplan, 1976]; given the paucity of recent neuropathologic studies in this population, the current rate of strokes at autopsy is unknown.

In patients who survive cyanotic CHD into adulthood, the risk for stroke persists and likely increases. In a study of patients older than 18 years with cyanotic CHD, a stroke incidence of 1/100 patient-years was described [Ammash and Warnes, 1996]. Similar to earlier studies in children [Cottrill and Kaplan, 1973; Linderkamp et al., 1979], the strongest risk factor for stroke in this cyanotic population was microcytosis. The proposed mechanism is a procoagulant shift resulting from an increased blood viscosity caused by the microcytic erythrocytosis.

The major physiologic and anatomic risk factors for stroke, including the three elements of Virchow’s triad (i.e., altered vascular surface, stasis [du Plessis et al., 1995a; Rosenthal et al., 1995a, 1995b] and hypercoagulability [Cromme-Dijkhuis et al., 1990; Komp and Sparrow, 1970; Linderkamp et al., 1979]), are commonly present in children with CHD. The presence of paradoxical vascular pathways between the systemic venous system and the cerebral arteries constitutes a further major risk factor for cardiogenic stroke. In broad terms, cardiogenic stroke may be mediated by three mechanisms (Figure 101-9). First, arterial emboli may emanate from an intracardiac embolic source (cardioembolic stroke). Second, emboli may arise from a systemic venous or right-heart source and bypass the pulmonary circulation through a right-to-left shunt (paradoxic embolic stroke). Finally, cerebral venous thrombosis may result from a combination of central venous hypertension, venous stasis, and polycythemia. In earlier autopsy reports, venous thrombosis was the most common form of cerebral vaso-occlusive lesion, usually occurring around 2–3 years of age and particularly in the setting of iron-deficiency anemia [Cottrill and Kaplan, 1973].

Fig. 101-9 The three broad mechanisms of cardiogenic stroke: cardioembolic (i.e., intracardiac embolic source), paradoxical (i.e., systemic venous embolic source), and cerebral vein thrombosis.

Thromboembolic events, including stroke, are known long-term complications of the Fontan operation [Day et al., 1995; Dobell et al., 1986; du Plessis et al., 1995a; Hutto et al., 1991; Mathews et al., 1986; Rosenthal et al., 1995a, 1995b]. The Fontan procedure redirects venous blood returning to the right atrium into the pulmonary arterial system, thereby bypassing the single ventricle, which then serves as the systemic perfusion pump. Consequently, right atrial pressure is often elevated, slowing flow through this chamber and the central veins supplying it. The procoagulant effect of this slow venous flow is enhanced further by the use of a prosthetic “tunnel” or baffle within the atrium to redirect flow. These factors combine to predispose to thrombus formation within the right atrium and central veins. In the fenestrated Fontan modification, a right-to-left interatrial defect is created in the baffle or “tunnel.” This fenestrated modification, which has markedly reduced the mortality of the Fontan operation, essentially connects the thrombogenic right atrium to the cerebral arterial supply. Protein-losing enteropathy, a complication of the Fontan physiology, may result in a decrease in circulating protein C and S, as well as antithrombin, particularly in the setting of infection.

Another potential area of thrombus formation after the Fontan procedure results when the main pulmonary artery is ligated, leaving a blind-ending, low-flow stump. Thrombi in this location (Figure 101-10A) are capable of generating emboli directly into the aorta and cerebral circulation (Figure 101-10B). Retrospective studies of post-Fontan patients confirm the increased stroke risk, with a prevalence ranging from 2.6 percent [du Plessis et al., 1995a] to 8.8 percent [Day et al., 1995]. This risk for stroke after the Fontan operation persists for up to 3 [du Plessis et al., 1995a] to 15 years [Rosenthal et al., 1995b] after the procedure.

Fig. 101-10 Recurrent strokes after a Fontan procedure for congenital heart disease with single-ventricle physiology with persistent or recurrent thrombus in the pulmonary artery stump.

A, The echocardiogram documents a thrombus (arrow) in the proximal, blind-ending stump of the ligated main pulmonary artery. AAo, arch of aorta; LV, left ventricle; PV, pulmonary valve. B, Computed tomographic brain scan with contrast demonstrates a recurrent stroke (arrow) in the right middle cerebral artery distribution. This stroke occurred 14 months after an initial large, left-sided stroke, despite therapeutic levels of anticoagulation. It was presumably caused by an embolus from the persistent or recurrent pulmonary artery thrombus in A.

Stroke therapies may be considered in broad terms as rescue or preventive strategies. Rescue strategies aim to limit the extent of stroke by salvaging injured but potentially viable brain. Rescue therapies include thrombolytic agents [del Zoppo et al., 1988; Mori et al., 1988] or agents directed at limiting the injurious biochemical cascades triggered by HI/R insults [Gerlach et al., 1995; Vannucci, 1990]. Preventive therapies for stroke may be primary (i.e., treatment of high-risk patients to prevent a first stroke) or secondary (i.e., aimed at preventing stroke recurrence) [Anderson, 1991]. A review of the various preventive and rescue therapies for stroke, including that in children with CHD, is provided elsewhere in this text.

Chronic Headache

In general, headache is mediated by stimulation of nerve endings in the dura and blood vessels, by processes as diverse as inflammation and tension/pressure. As many of the physiologic changes capable of stimulating these structures (e.g., vasodilatation and intracranial hypertension) occur in CHD, it is not surprising that headaches are a common complication of CHD. For example, both decreased cerebral oxygen delivery and hypercarbia cause vasodilatation. Elevated cerebral venous pressure may cause headaches by venous distention and, if sustained, by causing communicating hydrocephalus due to impaired CSF absorption [Rosman and Shands, 1978]. Headaches are particularly common in adolescent and adult survivors of earlier palliative procedures, in whom progressive pulmonary hypertension, central venous hypertension, and polycythemia develop over time. Certain surgical procedures (e.g., the Fontan and Glenn operations) are prone to central venous hypertension and commonly are complicated by headaches. In patients with venous hypertension and polycythemia, the development of headaches may herald dural vein thrombosis. The intensity and frequency of headaches associated with progressive polycythemia tend to parallel the rising hematocrit and respond to erythropheresis.

Headache is the most common initial complaint in the often-subtle clinical presentation of brain abscess [Aicardi, 1992b]. Consequently, it is mandatory that a diagnosis of brain abscess be excluded before the direct measurement of CSF pressure when doing a lumbar puncture in CHD patients with papilledema. Sudden-onset severe headaches should always raise concern about subarachnoid hemorrhage, particularly in patients with infective endocarditis [Bohmfalk et al., 1978; Jones and Sieker, 1989] and in hypertensive patients with coarctation of the aorta [LeBlanc et al., 1968; Shearer et al., 1970; Tomlinson et al., 1992; Young et al., 1982].

Long-Term Neurodevelopmental Dysfunction

Although children with acute postoperative neurologic manifestations are at risk for long-term neurodevelopmental dysfunction, it is likely that, in many cases, structural brain injury in early (even fetal) life and the acute perioperative period remains clinically silent until the later functional consequences are detected. Examples include the delayed neurodevelopmental impact of neonatal stroke and PVL. The few prospective studies to examine the neurodevelopmental outcome of infants with CHD longitudinally over time have been, for the most part, in the context of randomized clinical trials. Most studies have been cross-sectional in design and have focused primarily on two high-risk populations: namely, children with TGA and HLHS. However, others have reported increased risk for long-term developmental disabilities in all CHD subtypes severe enough to require open-heart surgery in early life [Fuller et al., 2009a; Gaynor et al., 2007; Limperopoulos et al., 2001, 2002; Majnemer et al., 2006, 2008, 2009; Massaro et al., 2008]. Children at greatest risk for long-term neurodevelopmental disability appear to be those with complex CHD requiring palliative procedures and staged repair, including patients with HLHS [Dittrich et al., 2003; Limperopoulos et al., 2002; McCusker et al., 2007].

Previously, outcome studies focused primarily on cognitive scores (i.e., intelligence quotients), the neuromotor examination in survivors of open-heart surgery, or both. Recent studies have used more comprehensive testing instruments to examine a broader spectrum of long-term outcome, including performance in motor, learning, behavior, socialization, functional skills in day-to-day activities, and quality of life. Not surprisingly, children with CHD exhibit a wide range of long-term developmental outcomes overall. Mean IQ scores at follow-up generally are in the low-average range [Bellinger et al., 1999a, 2009; Majnemer et al., 2008], while neuromotor abnormalities, such as hypotonia and motor delay, are reported in up to 50 percent of subjects and may persist well into school age [Bellinger et al., 1999a, 2009; Limperopoulos et al., 2002; Majnemer et al., 2006]. Conversely, severe neuromotor impairments (e.g., hemiplegia, restricted mobility) are less common (<5 percent) [Majnemer et al., 2006, 2009]. Increasingly reported are attentional problems, executive function deficits, and visual-spatial and visual motor impairments, as well as speech and language delays (e.g., oromotor apraxia) [Bellinger et al., 1999a; Mahle and Wernovsky, 2004]. Behavioral problems have been described in up to 27 percent of subjects [Bellinger et al., 2009; Majnemer et al., 2008]. Functional limitations in socialization, communication, adaptive behavior skills, and daily living skills are also described in close to 20 percent [Majnemer et al., 2008]. These studies suggest that children with CHD are at increased risk for learning difficulties and decreased social participation at school age. Recent reports suggest that a significant proportion of survivors of open-heart surgery for CHD are at risk for psychological maladjustment and impaired quality of life, including autonomy and motor, social, and emotional functioning [Landolt et al., 2008; Latal et al., 2009].

Of great interest in the few longitudinal studies published to date is the evolving neurodevelopmental profile in survivors of CHD surgery. For example, in the Boston Circulatory Arrest Study comparing outcome in infants with TGA randomized to intraoperative strategies of DHCA versus LFB, testing at 1 year of age revealed that infants assigned to DHCA were at higher risk of delayed motor development and neurologic abnormalities [Bellinger et al., 1995, 1997]. However, subsequent evaluations in this cohort at 4 and 8 years indicated no difference between the two groups in IQ scores, neurological status, academic achievement, memory, problem solving, or visual-motor integration [Bellinger et al., 1999a, 2009]. Assignment to DHCA was associated with lower gross and fine motor function and more severe speech abnormalities, while assignment to LFB was associated with a more impulsive response style and worse behavior. Risk factors for behavioral problems in middle childhood included postoperative seizures and intraoperative management with severe hemodilution and an alpha-stat acid–base management strategy [Bellinger et al., 2009]. The authors concluded that both the DHCA and LFB strategies are associated with increased risk of neurodevelopmental vulnerabilities. The evolving nature of neurodevelopmental function in these infants exposed to early-life CHD repair is of great interest, especially when considered in the context of other studies in premature infants that document similar evolving patterns of long-term outcome over time [Ment et al., 2003].

Over the past decades, the search for predictors of long-term neurodevelopmental impairment in survivors of CHD surgery has focused largely on intraoperative factors (see above). More recently emerging data suggest that predictors of adverse neurodevelopmental outcome are multifactorial, and include preoperative, intraoperative, and postoperative factors. In fact, several studies have reported that the strongest predictors of worse neurodevelopmental outcome are patient-specific factors that outweigh intraoperative management-related factors [Gaynor, 2003; Gaynor et al., 2007; Zeltser et al., 2008]. Such patient-specific factors have included genetic syndromes, low birth weight, gender, ethnicity, age at surgery, socioeconomic status, and parental factors such as mental health and IQ, amongst others [Ballweg et al., 2007; Forbess et al., 2002; Hovels-Gurich et al., 2006; Limperopoulos et al., 2002; McCusker et al., 2007; Newburger et al., 1993; Wernovsky et al., 2000]. In addition, preoperative factors, such as Apgar score, birth weight, microcephaly, and neurologic status, amongst others, also have been identified as predictors of long-term outcome [Fuller et al., 2009a; Limperopoulos et al., 2002; Majnemer et al., 2006, 2008; Neufeld et al., 2008; Robertson et al., 2004].

Of particular interest is a series of reports from prospective studies in infants with CHD undergoing brain MRI during the pre- and early postoperative periods [Licht et al., 2004, 2009; Mahle et al., 2002; McQuillen et al., 2006, 2007; Miller et al., 2004; Tavani et al., 2003]. These studies have shown a significant and previously under-recognized prevalence of structural brain abnormalities that, for the most part, have been clinically silent in the perioperative period. Among the most common findings have been focal infarctions, micro-hemorrhages, and PVL [Licht et al., 2009; McQuillen et al., 2006; Miller et al., 2006, 2007; Tavani et al., 2003]. Early postoperative MRI studies have depicted a striking prevalence of periventricular white-matter injury, particularly after neonatal cardiac surgery. In some studies, the prevalence of PVL on early postoperative MRI exceeded 50 percent in newborns following cardiac surgery [Galli et al., 2004; Mahle et al., 2002] (Figure 101-11), and was associated with hypotension and hypoxemia in the first 48 hours postoperatively [Galli et al., 2004]. Unfortunately, the long-term neurodevelopmental impact of these perioperative MRI findings has yet to be reported. Two recent reports from prospective studies in which MRI was performed after the early postoperative period have evaluated the functional associations of specific structural brain lesions. Volumetric MRI performed several months following open-heart infant cardiac surgery indicated a significant reduction in cerebral cortical gray matter (but interestingly, not white matter), particularly in the frontal lobes, which was associated with impaired psychomotor development on later testing [Watanabe et al., 2009]. Another MRI study 1 year after infant cardiac surgery described a 38 percent incidence of subtle hemorrhagic lesions, which were associated with lower motor developmental scores at age 1 year [Soul et al., 2009]. Further studies of the long-term significance of perioperative MRI lesions are needed before this imaging technique can be used for meaningful prognostication.

Fig. 101-11 Postoperative periventricular leukomalacia.

A, Axial magnetic resonance image (MRI; T1-weighted) demonstrating two small areas of increased signal intensity in the periventricular white matter consistent with periventricular leukomalacia, classified as mild (arrows). B, Axial MRI (T1-weighted) demonstrating multiple larger areas of increased signal density in the periventricular white matter consistent with periventricular leukomalacia, classified as moderate (arrows).

(From Galli KK, Zimmerman RA, Jarvik GP, et al: Periventricular leukomalacia is common after neonatal cardiac surgery, J Thorac Cardiovasc Surg 127:692, 2004, Figure 1.)

Infective Endocarditis

Neurologic injury complicates between 20 and 40 percent of infective endocarditis cases [Derex et al., 2009; Francioli, 1991; Hart et al., 1990; Horstkotte et al., 2004; Kanter and Hart, 1991; Saiman et al., 1993; Salgado et al., 1989; Thuny et al., 2007]. The neurologic manifestations of infective endocarditis are protean and include meningitis, brain abscess, seizures, and, most commonly, cerebrovascular injury. Systemic embolization occurs in up to 50 percent of patients with infective endocarditis [Lutas et al., 1986; Pelletier and Petersdorf, 1977; Roy et al., 1976], with as many as 65 percent of embolic events targeting the brain, usually the middle cerebral artery territory [Pruitt et al., 1978] (Figure 101-12).

Fig. 101-12 Echocardiogram demonstrating the aortic valve.

A, During systole. B, During diastole. Vegetations on the valve leaflets are indicated by arrows. AAo, aortic arch; LV, left ventricle.

Cerebrovascular complications are not only the most common form of neurologic injury, but also the most lethal [Pruitt et al., 1978]. Stroke complicates up to 40 percent of left-sided endocarditis [Derex et al., 2009; Hart et al., 1990; Horstkotte et al., 2004; Kanter and Hart, 1991; Salgado et al., 1989; Thuny et al., 2007]. For these reasons, anticoagulant therapy has been controversial to date for children with infective endocarditis. Strokes occur as a result of arterial infected embolus or mycotic aneurysm. The risk of stroke is highest in the first week of antibiotic treatment and decreases rapidly thereafter. Risk factors for embolization and stroke include vegetations over 10 mm in size, especially on the anterior mitral leaflet, and certain organisms such as Staphylococcus aureus or Staph. bovis, Enterococcus, or Candida albicans [Pruitt et al., 1978]. Although cerebral hemorrhage complicates only 5 percent of infective endocarditis, the mortality of this complication exceeds 50 percent [Hart et al., 1990; Horstkotte et al., 2004; Kanter and Hart, 1991; Salgado et al., 1989; Thuny et al., 2007]. The mechanisms of hemorrhage include arteritis, hemorrhagic transformation of a stroke, or rupture of a mycotic aneurysm. In children with endocarditis who develop neurologic symptoms, these risks for intracranial hemorrhage have long been considered a contraindication for anticoagulation. In addition, the benefit of anticoagulation has never been demonstrated in cases of native valve endocarditis, but may be beneficial for mechanical valve vegetations [Baddour et al., 2005].

Cerebral mycotic aneurysms are an infrequent but often lethal complication of infective endocarditis. Although mycotic aneurysms complicate only 1.2–5 percent of cases of infective endocarditis, the overall mortality of this lesion approaches 60 percent [Bohmfalk et al., 1978]. Two-thirds of cerebral mycotic aneurysms occur at the more distal bifurcations, particularly the middle cerebral artery. The remaining aneurysms are more centrally located at the branches of the circle of Willis [Corr et al., 1995]. Angiographic studies have determined that, in approximately 30 percent of cases, multiple aneurysms are present [Corr et al., 1995]. The clinical presentation is highly variable, with features ranging from those of sudden catastrophic hemorrhage (Figure 101-13), a mass lesion, or an embolic lesion. Presentation and outcome depend primarily on the location and integrity of the aneurysm. The mortality rate in patients with intact aneurysms is about 30 percent, and increases to 90 percent if the aneurysm ruptures [Bohmfalk et al., 1978; Jones and Sieker, 1989]. Aneurysms that leak rather than rupture are associated with a sterile meningeal syndrome, with elevations of CSF protein and of red cell and white cell counts.

Fig. 101-13 Cerebral hemorrhagic infarction in a 16-year-old boy with bacterial endocarditis.

A, Echocardiogram of the aortic (AO) root demonstrates vegetations on the aortic valve leaflets (arrows). LA, left atrium. B, Computed tomography (CT) of the brain reveals large area of hemorrhage in the right occipitoparietal region several days after the development of seizures. C, Follow-up CT of the brain 3 months later depicts a large residual area of encephalomalacia in the right occipitoparietal region.

Mycotic aneurysms should be excluded in all cases of infective endocarditis complicated by severe headaches, “sterile” meningitis, strokelike events, or cranial nerve abnormalities. Currently, the screening technique of choice is high-resolution, contrast-enhanced CT, because it is capable of identifying both the presence of cerebral hemorrhage and the location of mycotic aneurysms. The definitive diagnostic test remains four-vessel angiography. MR angiography techniques are insensitive to aneurysms smaller than 5 mm [Huston et al., 1994].

Management of mycotic aneurysms is complex and includes both medical and surgical approaches [D’Angelo et al., 1995; Elowiz et al., 1995; Utoh et al., 1995]. A 6-week course of antimicrobial therapy directed at the organism responsible for the underlying endocarditis should be completed. Hereafter, follow-up angiography is indicated to assess the response to treatment and to detect enlarging or new aneurysms [Corr et al., 1995]. Subsequent treatment is based on these angiographic findings. When angiograms are repeated after a full course of appropriate antimicrobial therapy, up to 20 percent indicate enlargements, 17–29 percent decrease in size, and one third to 50 percent indicate complete resolution [Bingham, 1977; Corr et al., 1995]. Up to 50 percent of patients experience full clinical recovery of their neurologic deficits after a 6-week course of treatment [Corr et al., 1995]. Indications for surgical intervention remain controversial [Wilson et al., 1982], but include the presence of single or multiple aneurysms distal to the first middle cerebral artery bifurcation that persist, enlarge, or bleed, despite appropriate antibiotic therapy [Corr et al., 1995; Scotti et al., 1996]. The usual surgical approach to these aneurysms is direct excision or clip application. More recently, endovascular procedures [Scotti et al., 1996] have been used to manage selected, severe cases of deep or distal mycotic aneurysms.

Brain Abscess

Brain abscess has become a rare complication of CHD in childhood [Ghosh et al., 1988]. However, among those children diagnosed with brain abscess, almost half have CHD [Aebi et al., 1991]. In children with CHD, brain abscess is rare before the age of 2 years, with a peak incidence between 4 and 7 years of age [Kagawa et al., 1983]. The risk is highest in cyanotic CHD; earlier studies reported that brain abscess developed in 2–6 percent of patients [Shu-yuan, 1989]. The risk for brain abscess is highest in children with polycythemia and right-to-left shunts [Tyler and Clark, 1957a], particularly tetralogy of Fallot [Aebi et al., 1991]. The incidence, morbidity, and mortality of brain abscess in CHD are correlated inversely with circulating arterial oxygenation [Shu-yuan, 1989]. Infants with higher oxygen saturations are less likely to develop brain abscess and more likely to recover. During periods of systemic illness and dehydration, polycythemia may disturb cerebral microvascular perfusion critically, with subsequent localized areas of ischemia. A right-to-left shunt allows organisms to bypass the pulmonary filtration system and thus to gain direct access to the brain. In areas of necrosis, organisms breach the disrupted blood–brain barrier, passing into necrotic areas to form focal septic cerebritis that may evolve to frank cerebral abscess. The recent marked decrease in incidence of brain abscess among children with CHD is likely due to a number of factors, including earlier corrective surgery, decreased exposure to polycythemia and hypoxia, and more aggressive rehydration.

Clinical manifestations of brain abscess are determined by the degree of intracranial hypertension, focal neurologic injury, and sepsis. The location of the abscess influences the neurologic presentation. A total of 75 percent of brain abscesses are supratentorial. Posterior fossa abscesses are less common but more dangerous because they often remain clinically silent until the onset of rapid deterioration from tonsillar herniation and brainstem compression (Figure 101-14). Cerebral abscesses are multifocal in about 20 percent of patients.

Fig. 101-14 T1-weighted magnetic resonance imaging reveals multiple brain abscesses in the cerebellum and fourth ventricle of an infant with cyanotic congenital heart disease.

A, Coronal view. B, Sagittal view.

The presentation of brain abscess is usually subtle (with the exception of seizures) and slowly progressive. The most common presenting features are headache and vomiting [Aicardi, 1992a]. Up to 75 percent of patients are afebrile and have minimal peripheral leukocytosis. Diagnosis of brain abscess is best established by contrast-enhanced CT or MRI scan. With CT scan, brain abscess presents as an area of hypodensity with contrast ring enhancement. The lesion is often surrounded by marked cerebral edema. Once brain imaging has excluded significant mass effect, CSF should be obtained. Typically, the CSF contains elevated protein but only mild leukocytosis.

Optimal management of brain abscess remains controversial [Dodge and Pomeroy, 1992]. Surgery is still considered the definitive first-line treatment in many centers, either by direct resection or CT-guided aspiration. Advances in both antibiotic therapy and neuroimaging surveillance have allowed a more conservative approach [Berg et al., 1978; Rosenblum et al., 1980]. This approach remains controversial, but may prove effective in early cases of focal cerebritis without rapid progression. Whether combined with surgery or not, high-dose antibiotic therapy should be maintained for at least 6 weeks.

Initial antimicrobial management should be directed at the most common causative organisms (i.e., mixed aerobic and anaerobic streptococci and staphylococci) [Ghosh et al., 1988]. Third-generation cephalosporins, used in combination with antistaphylococcal and anaerobic agents, have superseded earlier antibiotic regimens largely. Subsequent antibiotic treatment should be guided by microbial culture results. In immunosuppressed patients (e.g., after cardiac transplantation), other lower-virulence organisms, as well as fungi (e.g., Aspergillus) and parasites (e.g., Toxoplasma), should be considered. As the clinical presentation of brain abscess may closely resemble stroke in up to 30 percent of patients [Kurlan and Griggs, 1983], it has been suggested that children with cyanotic CHD and a strokelike presentation should be managed with antibiotic therapy until a brain abscess is excluded [Kurlan and Griggs, 1983].

Diagnostic and therapeutic advances have reduced the mortality of brain abscess from 40 percent [Kagawa et al., 1983] to 10 percent [Dodge and Pomeroy, 1992]. However, in survivors, the prevalence of neurologic sequelae largely has remained unchanged at about 35–45 percent [Aebi et al., 1991; Dodge and Pomeroy, 1992]. Epilepsy may develop, often years later, in up to 30 percent of survivors [Aebi et al., 1991].

Rheumatic Heart Disease

Sydenham’s chorea, the major neurologic complication of acute rheumatic fever [Special Writing Group of the Committee on Rheumatic Fever Endocarditis and Kawasaki Disease of the Council on Cardiovascular Disease in the Young of the American Heart Association, 1992] was, in earlier years, the most common form of acquired chorea in childhood [Eschel et al., 1993]. For several decades, there has been a global decline in the incidence of rheumatic fever and in the incidence of chorea as a complication of rheumatic fever [Eschel et al., 1993]. Possible reasons for this decline are an alteration in the virulence or epitopes of rheumatogenic streptococci and a decrease in antigen cross-reactivity with the basal ganglia. However, outbreaks of rheumatic fever in the United States [Ayoub, 1992] and elsewhere [Karademir et al., 1994] focused attention on this condition.

Chorea complicates rheumatic fever in only 10–25 percent of patients [Eschel et al., 1993]. Chorea may emerge from 1 week to 8 months after the onset of rheumatic fever, and then persist for 1–6 months [Eschel et al., 1993]. Sydenham’s chorea is rare under the age of 3 years and occurs more commonly in girls than in boys. In some patients, chorea may be the only clinical manifestation of rheumatic fever. The onset of this disorder is often subtle, and the abnormal movements tend to be preceded by psychoemotional symptoms, such as anxiety, emotional lability, distractibility, the emergence or exacerbation of attention-deficit hyperactivity disorder, obsessive-compulsive symptoms, and sleep disturbances [Swedo, 1994; Swedo and Kiessling, 1994]. On occasion, both the psychoemotional prodrome and the dyskinesia may be explosive in onset. The motor activity, which at first is described as “fidgety,” soon becomes choreiform, evolving from initial brief, myoclonic-like proximal muscle jerks to more complex, writhing distal movements. The handgrip often has a rippling character due to inconsistently sustained finger pressure (“milkmaid’s grip”). The chorea may be asymmetric and, in some cases, pure hemichorea develops. Muscle hypotonia and mild to moderate weakness often are present. Patients may have difficulty initiating and sustaining spontaneous motor activity. Speech and oral motor activity often are affected; an explosive dysarthria may develop, evolving in severe cases to complete mutism. These symptoms usually begin to subside after about 2–6 months, but may recur in the setting of subsequent illnesses, particularly streptococcal infections, pregnancy (chorea gravidarum), or oral contraceptive use.

The diagnosis of acute rheumatic fever is based on specific (Jones’) criteria [Special Writing Group of the Committee on Rheumatic Fever Endocarditis and Kawasaki Disease of the Council on Cardiovascular Disease in the Young of the American Heart Association, 1992], which may be major or minor, depending on their diagnostic importance. A patient with two major criteria, or one major and two minor criteria, has a high probability of rheumatic fever. The major criteria are carditis, polyarthritis, chorea, erythema marginatum, and subcutaneous nodules. The minor criteria are based on clinical features (fever, arthralgia, previous rheumatic fever) or laboratory features (acute-phase reaction, elevated erythrocyte sedimentation rate, leukocytosis, C-reactive protein, and prolonged P–R interval on electrocardiogram). Additional laboratory findings, such as an elevated antistreptolysin O titer or positive throat cultures for group A beta hemolytic streptococci, may be helpful. Diagnosis of chorea, on the other hand, is purely clinical. Despite the causal relationship to streptococcal infection, the onset of chorea is often delayed. Consequently, serologic evidence of streptococcal disease may be absent in 25 percent of patients. Rheumatogenic strains of group A streptococci contain particular (M-type) proteins that share antigenic determinants with neurons in the basal ganglia, particularly in the caudate and subthalamic nuclei. Autoantibodies against these neurons (antineuronal antibodies) have been detected in up to 90 percent of patients in some studies [Swedo, 1994; Swedo et al., 1997]. As this condition is seldom fatal, neuropathologic data are limited. However, neuronal loss, with vascular and perivascular inflammatory changes, has been described in the caudate and putamen, as well as the frontoparietal cortex. The topography of these earlier neuropathologic findings has been supported by MRI [Giedd et al., 1995; Heye et al., 1993] and SPECT [Heye et al., 1993]. These techniques have also demonstrated disturbances in the blood–brain barrier, with localized edema, presumably resulting from vasculitis [Heye et al., 1993].

Current management of the chorea includes dopamine-blocking agents (e.g., haloperidol, 0.5–1 mg twice a day) for 2–6 months and then gradually withdrawn. Other agents used include carbamazepine and valproic acid [Aicardi, 1992b; Swedo et al., 1993]. These agents often diminish the intensity of the chorea, but fail to control it completely. In severe cases, prednisone has been used with limited success. Prophylaxis against group A streptococcal infections with penicillin or monthly intramuscular benzathine penicillin is recommended because even asymptomatic future infections may precipitate recurrence of chorea. The high incidence of antineuronal [Swedo, 1994; Swedo and Kiessling, 1994] and anticardiolipin antibodies [Diniz et al., 1994; Figueroa et al., 1992] in these patients has led to trials of plasmapheresis and intravenous immunoglobulin therapy; results from these studies are not yet available.

Inborn Errors of Metabolism

Cardiac dysfunction may be a prominent feature and often the cause of death in several inherited metabolic disorders [Lyon et al., 1996]. The inheritance of these conditions is usually recessive (autosomal or, rarely, X-linked) or mitochondrial. The cardiac dysfunction results from a hypertrophic or dilated cardiomyopathy due to myocardial infiltration or energy failure, rather than from a primary structural lesion. The cardiac involvement in these conditions manifests clinically with myocardial failure, valvular insufficiency, arrhythmias, or coronary insufficiency (in storage disorders) with myocardial ischemia. Neurologic manifestations may be due primarily to the underlying enzyme defect or, conversely, may be secondary to global or focal cerebral hypoperfusion caused by diminished cardiac output.

Disorders of Energy Production

Storage Disorders of the Heart and Nervous System

Inherited Neuromuscular Disorders with Cardiac Complications