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J Thorac Cardiovasc Surg 1994;107:1036-1043
© 1994 Mosby, Inc.

CARDIOPULMONARY BYPASS, MYOCARDIAL MANAGEMENT, AND SUPPORT TECHNIQUES

Regional cerebral perfusion abnormalities after cardiac operations: Single photon emission computed tomography (SPECT) findings in children with postoperative movement disorders

Boston, Mass.

Received for publication June 1, 1993. Accepted for publication Oct. 8, 1993. Address for reprints: Adre J. du Plessis, MD, Department of Neurology, Fegan 11, Children's Hospital, 300 Longwood Ave., Boston, MA 02115.

Abstract

Despite the clinical and pathologic indicators implicating injury to the basal ganglia in children with hyperkinetic movement disorders, we were previously unable to identify lesions in these structures by means of cranial computed tomography or magnetic resonance imaging. We evaluated regional cerebral perfusion measured by single photon emission computed tomography (SPECT) with technetium 99m hexamethyl propylene amine oxime as a technique to localize functional cerebral abnormalities in eleven children who had a movement disorder after hypothermic cardiac surgery. Perfusion defects of the deep gray matter were noted in six of these eleven patients and cortical perfusion defects in nine. For both cortical and subcortical defects a strong right-sided predilection was present. Our findings suggest functional brain injury not detectable by conventional cranial computed tomography and magnetic resonance imaging in these patients. We speculate that these perfusion defects might relate to the behavioral and developmental sequelae in survivors of this syndrome. SPECT may identify subclinical injury in patients at risk for future neurodevelopmental problems and contribute to our understanding of the mechanisms of cerebral injury in the patient operated on for cardiac disease. (J THORAC CARDIOVASCSURG1994;107:1036-43)

Dramatic improvements in surgical mortality have occurred over the four decades since the introduction of hypothermia and cardiopulmonary bypass (CPB). ¹ Although these advances have been accompanied by decreased neurologic morbidity, the ability to provide cerebral protection for these children has not paralleled the dramatic reduction in mortality. A recent retrospective multicenter survey found a mean prevalence of 8% (and as high as 25% at one center) for neurologic problems in children after cardiac operations. ² In the perioperative period these sequelae include "post-pump" seizures, ^3-5 delayed recovery of consciousness, focal infarcts, and movement disorders such as a choreoathetosis syndrome. ^6-13 We previously reported our clinical experience with choreoathetosis syndrome ¹⁰ and documented focal injury to the basal ganglia at autopsy. ¹⁴ Injury to the basal ganglia, specifically the globus pallidus, was also noted in earlier reports. ^6,11,12 In ourseries, ¹⁰ all patients underwent neurologic study with cranial computed tomography (CT) or magnetic resonance imaging (MRI) or both. Despite the clinical and neuropathologic data suggesting focal injury to the basal ganglia, none of these studies showed lesions of the basal ganglia. The lack of a reliable imaging marker led us to consider other imaging modalities. Brain perfusion single photon emission computed tomography (SPECT) has previously demonstrated regional cerebral perfusion abnormalities in conditions in which results of CT or MRI studies had not yet become abnormal, had returned to normal, or had remained normal. ^15,16 In this study we examined regional cerebral perfusion patterns by technetium 99m hexamethyl propylene amine oxime ( ^99mTc-HMPAO) SPECT in a group of patients with postoperative movement disorders.

PATIENTS AND METHODS

Patients
Patient recruitment was by means of letters sent to the 10 patients from our original cohort who had choreoathetosis syndrome and were living in the New England area. Five families consented to the study. Consent was also obtained to study all six newly diagnosed cases of movement disorders. We studied these 11 patients with ^99mTc-HMPAO brain SPECT. All studies were considered technically adequate. Patients' ages ranged from 3 to 86 months (median age 34 months). Six patients were boys.

Details of the reparative operations for cyanotic congenital heart disease (ten patients) and for ventricular septal defect repair (one patient) are shown in Table I. Deep hypothermia (i.e., less than 20° C) was used for all operations. CPB lasted from 63 to 230 minutes (median 137 minutes) and 10 patients underwent circulatory arrest lasting from 13 to 67 minutes (median 40 minutes). The movement disorder was broadly of two types. A choreoathetoid syndrome refers to involuntary, irregular movements of the limbs, face, and tongue that are rapid (choreiform) or slow and writhing (athetoid) or a combination of these. ¹⁰ Oculogyric crises refer to episodic, sustained spasms of eye deviation, often accompanied by spasms of the neck, mouth, and tongue. The movement disorder was first noted between 2 and 8 days after the operation (median 5 days) and took the form of bilateral choreoathetosis syndrome in nine patients and episodic oculogyric crises in another. One patient had an initial focal dystonic syndrome that evolved into a generalized, symmetric choreoathetosis syndrome. The disorder was considered mild and transient (lasting less than 6 months) in three patients and severe and persistent (lasting longer than 6 months) in five. ¹⁰ In two patients operated on within the past 6 months, severe choreoathetosis syndrome is still present and a persistent or transient status cannot yet be defined. In patients 8 and 10 (Table I), episodes of oculogyric crisis were noted with dystonic posturing of the left arm and leftward head and eye deviation. Neither patient was receiving medication known to cause dystonic crises at the time. These episodes were not associated with alterations of consciousness, and an electroencephalogram in patient 8 was not epileptiform. Detailed neurologic examinations, performed before the SPECT perfusion scans, revealed no lateralizing findings. SPECT was performed in the early (7 to 14 days) postoperative period in seven patients and more remote from the operation in the remaining four patients (28 to 68 months; median 40 months).

Patient preparation.
All patients were sedated with chloral hydrate (50 mg/kg) to ensure studies free of motion artifact.

SPECT methods.
All brain SPECT studies were obtained with a single-headed rotating camera (Orbiter 7500, Siemens Gammasonics, Hoffman Estates, Ill.). A parallel multihole collimator slanted 30 degrees was used to permit a closer approximation of the gamma camera to the patient's head. Consistent positioning of the patients' head was obtained with the aid of laser beams in the sagittal, coronal and transaxial planes. The studies were recorded on an ADAC 3300 computer (ADAC Laboratories, Sunnyvale, Calif.) or, more recently, on a Siemens ICON computer system (Siemens Gammasonics). Studies were recorded on a 64 by 64 by 64 matrix using a circular orbit around the patient's head with 64 stops of 20 seconds' duration. All studies were reconstructed with a Butterworth filter and were displayed on the ICON system for evaluation. No attenuation correction was used. The dose of ^99mTc-HMPAO used was 10.1 to 12.6 mCi, 0.200 mCi/kg. Decreased regional cerebral blood flow was diagnosed by comparing one hemisphere with the contralateral side. Studies were independently evaluated for significant asymmetry of ^99mTc-HMPAO distribution by two experienced observers. For the purpose of this study, perfusion abnormalities were considered only if present on at least two consecutive slices in the coronal or transaxial planes. No interobserver variability was found between two specialists reading these scans.

RESULTS

Among the eleven patients studied, we found decreased perfusion in the deep subcortical basal ganglia regions in six (see Table II). These perfusion defects were all right-sided, although clinically the choreoathetosis syndrome was bilateral in all.

Cerebral cortical perfusion defects were noted in nine of the eleven patients (see Fig. 2). No patient had an isolated subcortical perfusion abnormality, all patients with abnormal perfusion of the basal ganglia also showing cortical perfusion defects. In no case was hypoperfusion confined to the territory of any one major cerebral vessel, abnormalities being present in the frontal (five patients), temporal (six patients), and parietal lobes (seven patients). In all but one of these, the abnormal perfusion involved the right hemisphere. The spatial distribution of the perfusion abnormalities was extensive, involving more than two brain lobes in eight patients.

View larger version (43K): [in this window] [in a new window]   Fig. 2. 99mTc-HMPAO brain SPECT (patient 3). Selected transverse and coronal sections reveal hypoperfusion of right (R) temporoparietal region (*) and right deep gray matter (O). ANT, Anterior; SUP, superior.

Our patients can be divided into two groups on the basis of the interval between the operation and the brain SPECT scan. In four patients this interval ranged from 28 to 69 months (median 40.5 months), and in a second group it ranged from 7 to 16 days (median 8 days). After the immediate postoperative period none of our patients exhibited subsequent new neurologic symptoms or had secondary cerebral insults; all patients showed varying degrees of neurologic improvement. Thus, if these perfusion defects are related to the operative period, then the results in our patients studied a longer time after their operation would suggest that these perfusion defects are enduring. In three patients (patients 1, 2, and 3) the interval between CT scan and SPECT study exceeds 29 months. However, in each of these patients a follow-up CT scan at least 1.5 months after the initial CT study continued to show no features of focal lesions of the cortical or basal ganglia.

DISCUSSION

Deep hypothermia during CPB and circulatory arrest has facilitated advances in pediatric cardiac surgery. During critical periods of heart repair in infants, the ideal of an atonic heart in a bloodless field may be approached with the use of CPB, deep hypothermia, and circulatory arrest. Deep hypothermia depresses cellular metabolism, reduces oxygen demand, ¹⁷ and allows apparently "safe" periods of reduced bypass flow or circulatory arrest. However, the brain is the organ most sensitive to ischemic injury and, despite the protective effect of deep hypothermia, neurologic injury continues to occur. Mechanisms underlying these brain injuries include ischemia, (i.e., insufficient substrate supply because of inadequate suppression of energy demands) or injury related to the extracorporeal circulation such as embolic phenomena and the activation of cellular and humoral cascades (such as leukocyte aggregation and the activation of complement and platelets). ¹⁸ Some authors have implicated deep hypothermia itself as the injurious agent. ^6,9 After deep hypothermic circulatory arrest, reperfusion injury may be a mechanism of ongoing insult. ¹⁹

The neurologic injury after cardiac surgery may present clinically with transient or persistent syndromes ranging from seizures, alterations in muscle tone, and movement disorders (such as choreoathetosis syndrome) to later developing disturbances of behavior, development, and learning. ² Over a 5-year period (1986 to 1990) at our institution, 19 patients with choreoathetosis were seen after 3077 cardiac operations involving deep hypothermia, a prevalence of 0.6%. ¹⁰ Other forms of dyskinesia, such as oculogyric crises, have also been noted. These disorders of movement and tone likely form part of a spectrum, possibly with a common neuropathologic-anatomic basis in the deep gray "extrapyramidal" systems of the brain. Although several autopsy series have reviewed the general neuropathologic state after cardiac operations, ^6,11,20,21 the literature dealing specifically with the neuropathologic characteristics of these movement disorders remains limited. The choreoathetosis syndrome has been associated with injury to the basal ganglia, particularly the globus pallidus, ^6,12,14 but this is by no means a consistent finding. ²² Neuroimaging with CT and MRI has shown a spectrum of findings ranging from focal infarcts and hemorrhagic lesions ²³ to diffuse patterns of atrophy involving both gray and white matter. ^23,24 The most consistent CT/MRI abnormality our population with choreoathetosis syndrome was diffuse atrophy of the gray and white matter (Fig. 1). ¹⁰ No evidence of focal injury to the basal ganglia was noted. Thus our understanding of the movement disorders after cardiac operations remains hampered by the lack of a consistent neuropathologic or neuroimaging marker.

View larger version (152K): [in this window] [in a new window]   Fig. 1. Brain CT scan (patient 3). Transverse view at level of basal ganglia, and at equivalent level to horizontal SPECT views, showing diffuse gray and white matter atrophy without evidence of focal tissue injury. ANT, Anterior; R, right; L, left.

Several mechanisms could underlie these regional perfusion defects; these include brain tissue loss (caused by vasoocclusive disease with infarction or by selective neuronal necrosis) or decreased local metabolic activity in an area of structurally intact brain. If major vessel occlusion (with infarction) were the cause of these perfusion defects, vascular territory perfusion defects on SPECT and visible tissue loss on CT/MRI scan would be expected. Because neither situation was the case in our study, territorial infarct is an unlikely cause of these perfusion defects. Microvascular occlusion by microembolic phenomena could result in injury not visible on conventional CT or MRI. These phenomena have been proposed as the basis for the microvascular dilatations seen in the cortical and deep gray matter of human and animal subjects after CPB. ³⁰ Such an embolic mechanism might also help explain the right hemispheric predominance of perfusion defects. Transcranial Doppler ³¹ and retinal fluorescein angiography ³² have demonstrated substantial numbers of gaseous and particulate emboli passing into the carotid circulation during cardiac operations, particularly during open cardiac procedures such as repair of complex congenital heart defects. If it is postulated that such emboli arising from the aortic cannula, pump, or ejected by the left ventricle pass in greater numbers into the most proximal branches of the aorta, for example, the innominate and right common carotid arteries, then the right cerebral hemisphere would be more vulnerable to such emboli. A greater portion of the total embolic load could thus pass into the right rather than left carotid circulation. An alternative mechanism that might relate to the laterality of these findings is the head position during the operation. Although we cannot be certain about individual cases in a retrospective study such as this, in approximately 80% of our patients the head is turned to the right during the operation. It is thus theoretically possible that right carotid or jugular venous compression, predisposing to right cerebral hemispheric ischemia, could occur in these patients; however, intact collateral circulation through the circle of Willis should minimize these effects. In addition, our present transcranial Doppler experience does not support this latter hypothesis for the right-sided findings.

Selective neuronal necrosis, one form of hypoxic-ischemic injury, ³³ could result in focal hypometabolism (and hence hypoperfusion) in areas not evident as defects on CT/MRI. Although usually following a generalized hypoxic-ischemic insult, selective neuronal necrosis may occur focally in regions rendered vulnerable by local circulatory factors (such as in "watershed" areas) or by the local expression of excitotoxic neurotransmitters. The perfusion defects in our study were not in classic arterial border zones. However, complex patterns of coexisting hyperemia and ischemia have been noted in an animal model during hypothermia and rewarming and may have relevance to our findings. ³⁴ Developmental changes in the microvasculature, neurochemical anatomy, and receptor expression may underlie the age-related and regional vulnerability of the infant brain. It is interesting to note that choreoathetosis syndrome has not been described in adults after deep hypothermic circulatory arrest and appears to have an age-related prevalence and expression of severity in childhood. ¹⁰ Recent data have demonstrated a transient rise in the glutamatergic innervation of the globus pallidus in both human infants and an immature rodent model. ³⁵

Perfusion defects might also occur in areas that are structurally intact but functionally "underactive." Diaschisis refers to the remote inhibition or facilitation (disinhibition) of neuronal activity as a result of a focal cerebral lesion. ^36-39 By this mechanism defects in cortical perfusion could reflect a remote (possibly deep gray matter) injury. A lesion of the efferent basal ganglia nuclei (such as the globus pallidus) would result in hypoperfusion of cortical regions normally under the excitatory influence of that particular glutamatergic thalamocortical loop. In the mature brain, such a lesion would result in frontal lobe hypoperfusion only, because the basal ganglio-thalamo-cortical circuits, while receiving imput from a wide cortical field, focus their output on the frontal lobe. ⁴⁰ The perfusion defects in our study were not restricted to the frontal lobe and thus make diaschisis an unlikely sole cause of these derangements. However, the validity of this argument for the immature brain is not known.

Our original intent was to examine perfusion patterns in the deep grey matter of children with movement disorders after cardiac operations, and we restricted the study to children with these syndromes. Whether these perfusion abnormalities are specific for choreoathetosis syndrome or whether they occur in other neurologic syndromes after deep hypothermic circulatory arrest with CPB is a question not addressed by this study. Another issue beyond the scope of this study is the relationship between the cortical perfusion defects and the pathophysiology of choreoathetosis syndrome. Children having postoperative neurologic syndromes are likely at increased risk of subsequent cognitive impairment. Reports of the choreoathetoid syndrome after cardiac operations (including our own) suffer from small patient numbers and the lack of detailed assessment of neuropsychiatric and developmental outcome. Yet most reports note an increased prevalence of developmental delay in this population. ^8,13,22 Survivors of severe persistent choreoathetosis at our hospital were developmentally delayed, with the range being from "very mild" to a 12- to 24-month cognitive delay. ¹⁰ How these cortical perfusion defects relate to long-term cognitive development in this population, and whether their detection by SPECT could serve as an early marker for children at risk, are questions in need of further study.

In summary, ^99mTc-HMPAO SPECT demonstrated perfusion defects in the cerebral deep gray matter in six of eleven patients with postoperative movement disorders. This study also showed an unexpected prevalence of cerebral cortical perfusion defects with a right-sided predilection in these children. These findings could not be predicted on the basis of clinical neurologic examination, cranial CT scan, or MRI scan. We are unable to determine whether the defects are specific for these hyperkinetic syndromes or whether they occur in a larger population who have survived deep hypothermic circulatory arrest with CPB. The timing of injury (i.e., preoperative, intraoperative or perioperative) underlying these perfusion abnormalities also remains unresolved by this study. We suggest that these movement disorders are a marker for cerebral injury more extensive than the deep gray nuclei. We also speculate that these perfusion defects may form the substrate for the increased cognitive/learning disorders in survivors of childhood cardiac surgery. In this case, these children at risk for future cognitive impairments may not be identified by the clinical neurologic examination or CT/MRI. Thus the occurrence of postoperative neurologic problems, even when transient, should raise the suspicion of more diffuse cerebral injury, and such infants should be subjected to detailed neuropsychologic assessments. Use of perfusion SPECT for the further investigation into the mechanisms of neurologic injury in children undergoing cardiac surgery is warranted.

Footnotes

From the Departments of Neurology, ^a Anesthesia, ^c Cardiovascular Surgery, ^d and Cardiology, ^e Division of Nuclear Medicine, ^b Department of Radiology, Children's Hospital and Harvard Medical School, Boston, Mass.

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This Article Abstract Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Aldo R. Castaneda Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by du Plessis, A. J. Articles by Wessel, D. L. Search for Related Content PubMed PubMed Citation Articles by du Plessis, A. J. Articles by Wessel, D. L.