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Original Articles Indian Pediatrics 2001; 38: 705-713 |
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Role of brain spect in neonates with hypoxic ischemic encephalopathy and its correlation with neurodevelopmental outcome |
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From
the Division of Neonatology, Lokmanya Tilak Municipal General Hospital,
Sion, Mumbai 400 022, India.
Objective: To study cerebral blood flow pattern seen on single photon emission computed tomography (SPECT) scan in neonates with hypoxic ischaemic encephalopathy (HIE) and to correlate it with immediate neurological status and neurodevelopmental outcome; and to compare it with Ultrasonogaphy (USG). Design: Prospective cohort study. Setting: Tertiary level Neonatal Intensive Care Unit. Methods: All the neonates HIE stage 2 or 3 underwent SPECT scan and USG between the ages of 1-2 weeks. The pattern of deficit seen on SPECT scan was correlated with neurological status, duration of altered sensorium, severity of seizures and short-term neurodevelopmental outcome at 3 months. Results: The commonest pattern of defect noted was parasagittal hypoperfusion. Babies with severe perfusion defect had higher incidence of difficult to control seizures and longer duration of altered sensorium. The positive predictive value of SPECT scan was 75% while that of USG was 60% and the negative predictive value of SPECT was 100% while that of USG was 76%, when neurodevelopmental outcome at 3 months was considered. Conclusion: SPECT scan is superior to ultrasonography in predicting neurodevelopmental outcome in babies with HIE.
PERINATAL asphyxia is a very common problem encountered in our tertiary referral Neonatal Intensive Care Unit and is seen in almost 40% of all admissions. Hypoxic ischemic encephalopathy (HIE) is the most important consequence of perinatal asphyxia(1). The syndrome of HIE has a spectrum of clinical manifestations ranging from mild to severe, that correlates with severity of the insult(2). Recognition of perinatal asphyxia depends on information gained from careful history and thorough neurological examination(3). Determination of site or sites and extent of injury is made to considerable degree by history and neuro-logical examination, but supplementary evaluations including Electroencephalography (EEG), Computed Tomography (CT scan), Magnetic Resonance Imaging (MRI) and radionuclide scanning are important(3). In infants who have experienced perinatal injury, it is often difficult on the basis of clinical examination and conventional investi-gations, to diagnose those with brain damage and to predict type and severity of further neurological handicap(3). Hence, several variables have been used to assess prognosis and outcome(3). These include Apgar score, neurological examination and neurodiagnostic studies such as EEG, evoked potentials, ultrasonography (USG) and CT scan(3,4). However, each of these has its own limitations and is not 100% sensitive and specific in diagnosing hypoxic ischemic lesions. Also, most of the radiological changes may not correlate with the future neurological status(3,4). Perinatal asphyxia is associated with high mortality and morbidity(5). However, not all survivors manifest later neurological handicaps, even following apparently severe neonatal neurological symptomatology(5). It would be of considerable clinical and aca-demic value to be able to identify in the neonatal period which neurological sympto-matic neonates show evidence of organic cerebral lesions and which do not, and to be able to relate such information to later neurological function(5). Brain single photon emission computed tomography (SPECT) is a method of reconstructing cross sectional images of radiotracer distributions in sagittal, coronal and transaxial images(6). It provides a non invasive direct measure of regional blood flow(6). Radionuclide scanning has become widespread only recently with development of improved instrumentation and suitable radio-tracers that cross normal as well damaged blood brain barrier, distribute proportionally to regional blood flow, and remain fixed in the brain for a sufficiently long time to permit SPECT imaging(6,7). In perinatal asphyxia, changes seen on SPECT and other imaging modalities reflect permanent cerebral injury(6). The clinical value of this new method, clearly established in adults and children, is still to be evaluated in neonates, more particularly in those at risk for neurological handicaps where the need for an early diagnostic tool is real(4,7,8). The present study was conducted to evaluate the cerebral blood flow pattern seen on SPECT scan in neonates with HIE and to correlate it with immediate neurological status; to evaluate the role of SPECT scan in predicting early neurodevelopmental outcome in cases of HIE; and to compare the results of SPECT scan with USG findings in determining early neurodevelopmental outcome. Subjects and Methods This study was carried out in the Neonatal Intensive Care Unit of the Lokmanya Tilak Municipal General Hospital, Sion, Mumbai, from a period of September 1996 to December 1997. This was a prospective cohort study which included 24 term neonates born in this hospital who satisfied the inclusion criteria. The hospital ethics committee approved the study. Informed consent was obtained from the parents before entry in to the study. The neonatologist involved in the immediate and follow-up examination did not know the results of ultrasonography and SPECT. The inclusion criteria were full term newborn with manifestations of HIE (Sarnat and Sarnat stage 2 or 3) who survived till the age of 2 weeks. Sarnat and Sarnat stage 2 encephalopathy was defined as neurological syndrome characterized by lethargy or obtundation, occurrence of seizures, para-sympathetic overactivity, overactivity of deep tendon reflexes and absence of complex neonatal reflexes(9). Sarnat and Sarnat stage 3 encephalopathy was defined as neurological syndrome characterized by severe stupor or coma, flaccid tone, absent deep tendon reflexes, intermittent decerebration, absent complex neonatal reflexes and evidence of autonomic or bulbar dysfunction(9). History of perinatal asphyxia was available in all babies with HIE. Perinatal asphyxia was diagnosed if all of the following criteria were satisfied(10): (i) Umbilical cord arterial pH less than 7; (ii) Persistence of an Apgar score of 0-3 > 5 minutes; (iii) Neurological sequelae in form of HIE; and (iv) Evidence of multiorgan dysfunction in the neonatal period. Neonates with major congenital malforma-tions, congenital cyanotic heart disease, intracranial infections, intrauterine infections and intrauterine growth retardation were excluded from the study. All the neonates in the study group were evaluated with USG and SPECT, once clinical status was stablized. The average age of performing the study was between 1-2 weeks. Sonographic studies of the head were performed with 7.5 MHz real time probe. These studies were performed within 1-3 days of SPECT studies and the reporting sonologist was unaware of other imaging examinations. The ultrasound studies were evaluated with specific attention to size and configuration of ventricles, presence and extent of parenchymal abnormalities, relative sulcoparenchymal differentiation, presence of extra-axial fluid and presence of cystic encephalomalacia. For SPECT studies, babies were sedated using oral trichlorofos (50 mg/kg) one hour prior to the study and simultaneously an intravenous line was inserted. 5 mCi of Technetium 99 Hexamethyl Propyleneamine (HMPAO) (Ceretac, Amersham) was injected within 30 minutes of preparation. The baby was shifted to camera room 1 hour after injection of technetium 99 HMPAO and head was gently wrapped in cushion to avoid motion artefacts. SPECT imaging was performed using a triple head, rotating gamma camera with ultra-high-resolution fan beam collimator [Picker, Prism 3000]. Forty frames of 22.5 seconds were acquired. Transaxial, sagittal and coronal slices 2 pixels thick (corresponding to 0.5 to 1 cm) were reconstructed. Scans were read by a nuclear physician unaware of the clinical data and USG findings, taking into account the normal brain blood flow in the neonatal age group(4,11). A record of clinical status of the neonates and course in ward was kept. A neurological examination was done before sending the patient for SPECT scan and subsequent correlation was done with the SPECT scan results at the end of the study. The pattern of deficit seen on SPECT scan was correlated with the neurological status, duration of altered sensorium, type and severity of seizures. Seizures easily controlled were defined as those controlled with single anticonvulsant. Seizures difficult to control were defined as those requiring more than 1 anticonvulsant. All infants were seen in high risk follow up clinic for a minimum period of 3 months and neurological and developmental status was recorded at 1 and 3 months of age. Neuro-logical examination was performed using the Amiel Tisons method(12,13) while develop-mental status was assessed by recording various age appropriate milestones(14). A Neonatologist (SS) trained in the art of neurological examination carried out both the examinations. The neurological and develop-mental status at follow up was classified as follows(13):
Results The mean weight of the babies enrolled in the study was 2520 g (±145 g) and the mean gestational age was 38.3 weeks (±1.1 week). Thirteen (54.16%) of the 24 neonates were males, while 11 (45.84%) were females,. The mean age of performing USG was 10 days (± 3 days) while that of SPECT scan was 12 days (±2 days). There were 18 babies with HIE stage 2 and 6 babies with HIE stage 3. The results of the study are summarized in Tables I to IV. Of the 24 neonates, who had undergone SPECT examination, perfusion pattern was normal in 12 (50%) of the babies and abnormal in 12 (50%). The commonest pattern of defect noted was parasagittal hypoperfusion, followed by global and focal hypoperfusion (Table I). The SPECT scan findings were correlated with the neurological status of the baby at the time of study. It was found that babies with severe perfusion defects (global, unilateral focal or bilateral focal hypo-perfusion) had higher incidence of multiple seizures, difficult to control seizures and longer duration of altered sensorium. The topography of SPECT findings correlated with the clinical examination when the defect was global or focal hypoperfusion (Table I). However, there was no correlation with the neurological examination when the pattern of defect was parasagittal hypoperfusion. Table I - Correlation of SPECT Findings with Clinical Status of the Baby
All the 24 neonates were followed up to the age of 3 months. Fifteen (62.5%) of the 24 neonates were normal on follow-up, while 4 (16.6%) had minor neurological dysfunction and 5 (20.8%) had major neurological dys-function. In the present study, normal SPECT scan was associated with normal neuro-developmental outcome in 12/12 cases (Table II). However, only 9 of 12 (75%) cases with abnormal SPECT scan had minor or major dysfunction (abnormal neurodevelop-mental outcome). There were 3/12 (25%) false positive patients with SPECT scan. Thus, SPECT scan has a sensitivity of 100% and specificity of 80% as far as neuro-developmental outcome is concerned. On correlating the pattern of perfusion deficits seen on SPECT scan with neurodevelopmental outcome, it was found that all babies with global hypoperfusion or bilateral focal hypoperfusion on SPECT scan had impaired neurological outcome (Table II). Table II - Scan Results and its Correlation with Neurodevelopment Outcome
Ultrasonography of brain was performed in all the neonates included in the study group. It was found that among 19 neonates with normal USG brain, 13 (68.4%) had normal outcome, while 3 (15.7%) each had minor and major dysfunction (Table III). USG examination was abnormal in 5 neonates. In 3 neonates the ventricles were increased in size but retained the normal angulations, indicating that this was not due to increased pressure. The sulci appeared more echogenic and thicker than usual relative to brain. The brain parenchymal echogenicity was diffusely abnormal and heterogenous. In 2 neonates the only abnormality noticed was increased echogenicity in the thalamic region. Among 5 neonates with abnormal USG brain, 1 neonate had minor dysfunction and 2 neonates had major dysfunction. Thus, the sensitivity and specificity of sonography in diagnosing abnormal outcome was 33.3% and 76%, respectively. Three patients with abnormal USG (ventriculomegaly, abnormal echo-genicities) had congruent SPECT abnor-malities. All 3 were abnormal on follow-up. However, thalamic hyperechogenicities found on USG brain were not associated with abnormal SPECT findings. Both these neo-nates were subsequently normal on follow-up. Of the 19 neonates with normal USG, SPECT scan was normal in 10 neonates, the remaining 9 neonates showed evidence of perfusion defects (Table IV). Thus, SPECT scan can reveal perfusion defects not diagnosed by sonography. Among the 9 neonates with abnormal SPECT, 6 neonates (66.6%) had minor or major dysfunction. Out of the 24 neonates evaluated with both SPECT and USG, 10 neonates had normal SPECT and USG findings. All (100%) were normal on follow-up. Both USG and SPECT were abnormal in 3 neonates. All had either major dysfunction or minor dysfunction. In this study, a normal SPECT scan was found to be predictive of normal neuro-developmental outcome (negative predictive value of 100%). However, an abnormal SPECT scan did not correlate well with abnormal neurodevelopmental outcome (Positive predictive value of 75%). The nega-tive predictive value of SPECT scan was 100%, while that of USG was 75%. The positive predictive value of SPECT scan was 75%, while that of USG was 60%.
Discussion Our study shows that in cases of hypoxic ischemic encephalopathy, perfusion abnor-malities are very commonly seen on SPECT scan. The commonest pattern of defect noted on SPECT scan in term babies with HIE was parasagittal hypoperfusion, followed by global and focal hypoperfusion. This is due to the fact that, in full term infants the lesions are usually located in the watershed areas of major cerebral arteries, i.e. in the parasagittal and parietooccipital areas. Similar findings were noted earlier(4). Babies with severe perfusion defects (global, unilateral focal or bilateral focal hypoperfusion) had higher incidence of multiple seizures, difficult to control seizures and longer duration of altered sensorium. The topography of SPECT findings correlated with the clinical examination when the defect was global, unilateral focal or bilateral focal hypoperfusion. However, there was no correlation with the neurological examination when the pattern of defect was parasagittal hypoperfusion. Majority of patients with parasagittal hypoperfusion had generalized hypotonia, disturbed suck and swallow move-ments. This could be possibly due to cerebral edema causing generalized neuronal depres-sion. Since SPECT is a relatively newer modality there is a paucity of studies cor-relating SPECT scan findings with immediate neurological status of the baby. Though the follow-up in our study is not of very long duration, babies requiring early intervention can be accurately diagnosed at 3 months of age(15,16). The predictive value of the 3 month assessment for normal develop-ment at 12 months is excellent, 96.9%(16). Thus, at 3 months babies can be accurately assigned to normal or abnormal group, the latter requiring more elaborate evaluation and further therapeutic interventions. In our study, SPECT scan had a sensitivity of 100% and specificity of 80% as far as neurodevelopmental outcome is concerned. Shankaran et al.(6) also noted that in neonates with perinatal asphyxia, sensitivity and specificity of SPECT scan was 83% when neurological outcome was used as the primary outcome variable. On correlating pattern of perfusion deficits seen on SPECT scan with neurodevelopmental outcome, it was found that among 2 babies with global hypoperfusion on SPECT scan, both had impaired neurological outcome. Similar findings were noted when unilateral focal or bilateral focal hypoperfusion was the defect. However, amongst 5 babies with parasagittal hypoperfusion, 3 were normal, while only 2 were neurologically impaired. It is possible that in the neonates who showed parasagittal hypoperfusion on SPECT scan but were subsequently normal on follow-up, SPECT scan may detect more subtle areas of ischemia that revert to normal(3,6). The plasticity of the neonatal brain is such that ischemia and mild perfusion abnormalities could recover(6,17). The sensitivity and specificity of sono-graphy in predicting abnormal neurodevelop-mental outcome in our study was 33.3% and 76%, respectively. Shankaran et al.(6) found that sensitivity and specificity of USG in predicting neurological outcome in babies with HIE was 83%. Backcock et al.(18) found that when USG was abnormal in 16 neonates, only 8(50%) had severe handicap. The remaining 50% had no severe handicap. Volpe et al.(3) found that USG is not useful in the identification, either of selective neuronal necrosis, because the cortical and brain stem lesions are too restricted or too peripherally localized to be visualized, or of parasagittal cerebral injury for similar reasons. The low sensitivity and specificity of USG in predicting neurodevelopmental outcome, found in our study could be due the fact that the lesions located in the watershed areas, i.e., the parasagittal and parietooccipital areas are in most cases not revealed by USG. Thalamic hyperechogenicities found on USG brain in our study were not associated with abnormal SPECT findings. Both these neonates with this lesion were subsequently normal on follow-up. However, babies with ventriculomegaly and diffusely abnormal echoes on USG were abnormal on follow-up. In our study we found that SPECT scan can reveal perfusion defects not diagnosed by sonography. Similar findings were noted earlier(4). These workers found that out of 16 patients with normal sonography, only 8 (50%) had normal SPECT findings, while the remaining 8(50%) had perfusion defects(4). Among the 9 neonates with abnormal SPECT in our study, 6 neonates (66.6%) had minor or major neurological dysfunction. In our study the sensitivity and specificity of combined USG and SPECT to diagnose normal and abnormal neurodevelopmental outcome was 100%. A normal SPECT scan was found to be predictive of normal neuro-developmental outcome. (negative predictive value of 100%). However, an abnormal SPECT scan did not correlate well with abnormal neuro-developmental outcome (positive predictive value of 65%). This low positive predictive value could be due to the fact that neonatal brain can preserve functional integrity at very low cerebral blood flow rates, as compared to adults(17). Thus, it is likely that these abnormalities in regional blood flow do exist but are not sufficient enough to result in deficits(17). Because these infants have been followed up only upto the age of 3 months, continued follow-up of these subjects may detect subtle cognitive defects that are not discernible at this age. In conclusion, SPECT scan is superior to ultrasonography in predicting neuro-develop-mental outcome at the age of 3 months in newborns with HIE. However, its routine use is limited by availability and high cost. Acknowledgements We are grateful to Dr. V.R. Lele and Department of Nuclear Medicine of Jaslok Hospital, Mumbai for organization and analysis of SPECT scans. We are also thankful to Radiology Department of Lokmanya Tilak Municipal General Hospital for organizing and analyzing the ultrasound scans. Contributors: SS was involved in writing up the project, organization of SPECT scans, clinical evaluation and neurodevelopmental follow-up of the babies involved. AF and DC were involved in setting up the project and clinical and neurodevelopmental evaluation of the babies. SS wrote the final manuscript under the supervision of AF. SS will act as the guarantor for the manuscript.
Funding: None.
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