Predictive Value of Multimodality Evoked Potentials in Asphyxiated Term Newborns

Transcription

1 Ann Ali Abdel Kader et al. Predictive Value of Multimodality Evoked Potentials in Asphyxiated Term Newborns Ann Ali Abdel Kader 1, Saly El-Kholy 1, Dahlia El-Sebaie 2, Shahira Mostafa 1, Amira El-Gohary 1, Lamia Afifi 1, Hebatallah Raafat 1 Departments of Clinical Neurophysiology 1, Pediatrics 2, Cairo University ABSTRACT Background: Hypoxic-ischemic events may cause permanent brain damage, and it is difficult to predict the longterm neurological outcome of survivors. Multimodality evoked potentials using flash visual evoked potential (VEP), somatosensory evoked potential (SSEP), and brainstem auditory evoked potential (BAEP) may assess the cerebral function in term neonates. Objectives: The aim of the present study was to determine the predictive value of multimodality evoked potentials in asphyxiated term infants with respect to the neurodevelopmental outcome. Methods: The study was conducted on 30 asphyxiated infants and 15 normal controls. Thorough history taking, neurological examination, cranial ultrasonography, and multimodality evoked potentials were done to controls and patients in order to predict the neurological outcome. Results: There was a statistically highly significant association between VEP and neurodevelopmental outcome on one hand (P=0.000) and SSEP results and neurodevelopmental outcome on the other hand (P=0.000). However, BAEP results revealed no statistical significance with the neurodevelopmental outcome (P>0.05). Sensitivity of SSEP and VEP was 96.4% and 90.5%, respectively. Specificity of SSEP and VEP was 79.8% and 70%, respectively. Conclusion: This study concluded that both flash VEP and SSEP are more accurate as prognostic indicators for term newborns. (Egypt J. Neurol. Psychiat. Neurosurg., 2009, 46(2): ) Key words: multimodality evoked potentials; VEP; SSE; BAEP; asphyxiated infants INTRODUCTION Perinatal asphyxia is an insult to the fetus or newborn due to lack of oxygen (hypoxia) and/or lack of perfusion to various organs. It is associated with tissue lactic acidosis, accompanied by hypoventilation, and maybe associated with hypercapnia 1,2. The clinical neurological sequelae in the immediate neonatal period following perinatal asphyxia are known as hypoxic-ischemic encephalopathy (HIE). HIE events may cause permanent brain damage, and it is difficult to predict the long-term neurological outcome of survivors 3. Several methods have been used for the early prediction of neurological outcome after perinatal asphyxia; these methods include estimation of HIE based on clinical assessment and imaging techniques 3. Neuroimaging techniques such as computed tomography, ultrasonography, and magnetic resonance imaging provide information about the morphology of the nervous system without assessing its function 3. This can be done by electrophysiological techniques including flash visual evoked potentials (fveps), brainstem auditory evoked potentials (BAEPs) and somatosensory evoked potentials (SSEPs) 3. They are easy, noninvasive and constitute an early aid in the assessment of systemic or neurological diseases involving somesthetic, visual, and auditory pathways without demanding cooperation from the infants. In addition, they could be easily performed during spontaneous sleep following feeding, not requiring any sedation 4,5. Flash visual evoked potentials reflect the hemispheric structures, SSEPs reflect different levels of neuraxis and BAEPs reflect the cochlea and the brainstem auditory pathways. The use of one modality gives only a focal cerebral assessment, because it only looks at the visual, sensory or Correspondence to Amira M. El-Gohary, Clinical Neurophysiology Unit, Cairo University. elgoharyamira@gmail.com 385

2 Egypt J. Neurol. Psychiat. Neurosurg. Vol. 46 (2) - July 2009 auditory pathway; while multimodality evoked potentials give a more global assessment 3. Multimodality evoked potentials have been employed not only to assess the sensory pathways but also as a marker of global neurological status, thus formulating the prognosis of global neurological outcome. This study aimed precisely at analyzing and determining the predictive value of multimodality evoked potentials with respect to the studied neurological and developmental outcome in asphyxiated newborns at 3 months of age. METHODS Subjects: The present study is a case controlled study carried out on 30 asphyxiated infants-admitted in the neonatal intensive care unit of Kasr El-Aini Hospital-after their condition was stabilized. All of them were over 36 weeks of gestation with appropriate weight for gestational age. The study also included 15 age matched normal controls. Inclusion criteria: Asphyxia was diagnosed according to Scalais et al. 3 by the presence of fetal distress including: late decelerations in fetal monitoring, metabolic acidosis, the 5 minute Apgar score < 7, passage of meconium, together with HIE for example prolonged altered tone or consciousness. Exclusion criteria: Infants with malformations, metabolic derangements, or systemic infections were excluded. Methods: The studied newborns were subjected to the following: Thorough history taking including: maternal history, obstetric history, and Apgar score. Neurological examination including: level of consciousness, sucking reflex, presence of cyanosis, presence of seizures and its type, tone, motor weakness, Moro reflex, grasp reflex, and deep tendon reflexes. Cranial ultrasonography was done for the asphyxiated group to detect brain edema, increased brain echogenicity, intra-cranial hypertension, or any cystic changes. Multimodality evoked potentials for both patients and control group including: flash visual evoked potentials, brainstem auditory evoked potentials, somatosensory evoked potentials. The initial multimodality evoked potential tests were done at the first visit for all the patients (age range: 2-6 weeks) and the control group (age range: 2-4 weeks). Multimodality evoked potentials were done using Schwarzer-myos 4 medical diagnostic equipment, 4 channels, manufactured in Munich, Germany. The recording electrodes used were gold cup-disk electrodes. Flash visual evoked potentials: The stimulation was performed using LED goggles at a rate of 1 Hz. P1 or P200 was identified as the single most prominent positive peak after 100 milliseconds. For each test latency of the P200 and peak to peak amplitude were calculated by manual adjustment of cursers. The most prominent and consistent peak was the P200 and therefore statistical correlations and associations were calculated using this prominent P1 or P200 peak. Brainstem auditory evoked potentials: Hearing threshold was identified by lowering the intensity until all waves were not identified except wave V was prominent. The positive uppeaks of waves I, III, and V were identified and the following measurement took place: absolute latencies (I, III, V), interpeak latencies (I-III, III-V, I- V), and amplitude ratio (V/I). Somatosensory evoked potentials: SSEPs were recorded after stimulation of the median nerve. Erb's, cervical, N20, and P22 points were identified. Criteria of abnormal evoked potentials: Considering mean±lsd for each of the evoked potentials results, the upper normal value was calculated and number of abnormal cases were therefore calculated and concluded. Then the mean±2sd was reassessed changing the upper normal value and the number of abnormal cases was recalculated. 386

3 Ann Ali Abdel Kader et al. Follow-up: The clinical and neurological outcomes as well as the multimodality evoked potentials were reassessed at the age of 3 months for all of the asphyxiated newborns studied. Neurodevelopmental assessment was done to detect any developmental delay or neurological disabilities such as: cerebral palsy, epilepsy, visual or hearing impairment. The control group was subjected at the age of 3 months to multimodality evoked potentials only. Statistical Analysis: Data were tabulated and statistically analyzed to evaluate the difference between the groups under study as regards the various parameters. The statistical analysis included: the arithmetic mean, standard deviation, standard error, hypothesis Student's "t", X2, Mann -Whitney test and Pearsons' correlation tests. RESULTS The present study included 30 asphyxiated infants, all of them over 36 weeks gestation with appropriate weight for gestational age and 15 normal controls, table (1). Neurological examination of asphyxiated infants: Summarized in table (2). Neurodevelopmental assessment: At the age of 3 months all patients were neurodevelopmentally assessed: 12 out of 30(40%) were normal and 18 out of 30(60%) were abnormal; the findings are shown in table (3). Electrophysiological results: Evoked potentials Initial control and initial patients test According to the criteria of abnormality; mean±lsd, there were 23 out of 60(39%) abnormal eye responses representing 14 out of 30(47%) infants. Considering mean±2sd there were 21 out of 60(35%) abnormal eye responses representing 11 out of 30(37%) infants. There was no statistical significance between the two groups as regards the latency and amplitude of fveps. According to the criteria of abnormality, mean±1sd there was 1 out of 60(2%) ear response abnormal representing one patient. The abnormality was in the form of delayed III-V interval. There was no statistical significance between patients and control group regards BAEPs. According to the criteria of abnormality, mean±lsd there was 16 out of 60(27%) median nerve responses abnormal representing 16 patients. Considering mean±2sd there were 12 median nerve abnormal responses representing 12 patients. The mean value of SSEP- N20 was significantly higher in the asphyxia group (P<0.05), while the Erb's, cervical and SSEP-P22 showed no statistically significant difference between the two groups (Table 4). Follow up control and follow up patients test: There was a statistical significance between the two groups as regards the P200 latency with the control group being of shorter latency than the patients group. There was no statistically significant difference between the follow up patients and control group regarding the BAEP results. There was a statistical significant difference between the two groups as regarding the N20 and P22, the control group having shorter N20 and P22 latency than the patients group (Table 5). Initial and follow up patients test: These data are summarized in table (6). There was no statistical significance between the initial and follow up patients fveps. Follow up fvep revealed reappearance of 2 previously absent responses representing 2 patients. According to the criteria of abnormality, mean±lsd, there were 21 out of 60(35%) eyes representing 12 infants showing delayed mean latency. Considering mean±2sd, there was 16 out of 60(27%) eyes representing 8 infants showing delayed mean latency of P200 response. There was a statistically significant difference between the initial and follow up patients BAEPs as regards wave III and wave V latencies and intervals I-III and I-V. There was a statistically significant difference between the initial and follow up test as regards the Erb's and P22 values. Association results: Neurodevelopmental outcome with: - Clinical variables: There was a highly significant association between neurodevelopmental outcome and chest compression, abnormal Moro 387

4 Egypt J. Neurol. Psychiat. Neurosurg. Vol. 46 (2) - July 2009 reflex, presence of motor dysfunction, presence of seizures, deep tendon reflexes (hyporeflexia) and disturbed level of consciousness. Associations with different clinical variables are shown in table (7). - Evoked potentials: There was a statistically highly significant association between the VEP and SSEP results together with the neurodevelopmental outcome. On the other hand, BAEP results revealed no statistical significance with neurodevelopmental outcome (Table 8). Associations between different evoked potentials: Associations between different evoked potentials for the initial tests revealed a statistically significant association between the VEP and SSEP results (P=0.007), while the VEP with BAEP (P=0.285) or the SSEP with BAEP (P=1.00) did not show. Follow up at the age of 3 months showed neurodevelopmental abnormalities in 18 patients (60%). 16 of them had abnormal SSEP (88.9%). 14 of them had abnormal VEP (77.8%) and 1 patient had abnormal BAEP (5.6%) (Fig. 1). One patient had 3 abnormal tests (VEP, BAEP, and SSEP), 11 patients had 2 abnormal tests (VEP and SSEP) and 7 patients had one abnormal test (VEP or SSEP). Sensitivity and Specificity: Sensitivity of SSEP and VEP in predicting neurodevelopmental outcome was 96.4% and 90.5% respectively. Specificity of SSEP and VEP was 79.8% and 70% respectively. Concerning the positive and negative predictive power, the positive predictive power of SSEP and VEP was 97.3% and 80.5% respectively and the negative predictive power of SSEP and VEP was 95.0% and 86.2%, respectively. Table 1. Comparisons of demographic factors among patients and controls. Patients Control (n=15) Item Mean±SD (n=30) Mean±SD T value P value Age (months) 4±2.01 3± >0.05 Weight (grams) ± ± >0.05 Sex No. (%) No. (%) Male 10(33.3) 9(60) 2.91 >0.05 Female 20(66.7) 6(40) Table 2. Neurological examination of the asphyxiated infants. Item Abnormal Normal No. (%) Comment No. (%) Level of consciousness 16(53.4) Depressed Lethargic 10(33.3) 4(13.3) Suckling reflex 27(90) 3(10) Cyanosis 30(100) 0(0) Seizures 22(73.3) 8(26.7) Tone 18(60) Floppy Hypertonia 8(26.7) 4(13.3) Motor weakness 23(76.7) 7(23.3) Moro and grasp reflex 21(70) 9(30) 388

5 Ann Ali Abdel Kader et al. Deep tendon reflexes 24(80) Hyporeflexia 6(20) Table 3. Abnormal neurodevelopmental outcome in the patients group. No. (%) Cerebral palsy (CP) 8(26.6) - Alone 1(3.3) - CP & visual impairment 3(10) - CP & epilepsy 3(10) - CP & hearing impairment 1(3.3) Epilepsy & visual impairment 4(13.3) Hypotonia 1(3.3) Developmental delay (DD) 4(13.3) - Alone 2(6.7) - DD & visual impairment 1(3.3) - DD & Epilepsy 1(3.3) Died before next examination 1(3.3) Table 4. Mean and standard deviation of initial VEP, BAEP and SSEP of patients and control group (latency in msec, amplitude in μv). VEP BAEP Item Patients Initial test (n=30) Mean±2SD Control Initial test (n=15) t value P value Mean±2SD P200 latency ± ± >0.05 P200 amplitude 5.54± ± >0.05 Wave I 1.5± ± >0.05 Wave III 4.3± ± >0.05 Wave V 6.49± ± >0.05 Interval I-III 2.8± ± >0.05 Interval III-V 2.2± ± >0.05 Interval I-V 4.99± ± >0.05 V/I amplitude 2.46± ± >

6 Egypt J. Neurol. Psychiat. Neurosurg. Vol. 46 (2) - July 2009 SSEP Erb's 7.7± ± >0.05 Cervical 13.45± ± >0.05 N ± ± <0.05* P ± ± >0.05 Table 5. Mean and standard deviation of follow up control and patients VEP, BAEP and SSEP (latency in msec, amplitude in μv). Item Patients Follow up test (n=30) Control Follow up test (n=15) t value P value Mean ± 2SD Mean ± 2SD VEP P200 latency ± ± <0.05* P200 amplitude 6.32± ± >0.05 BAEP Wave I 1.39± ± >0.05 Wave III 3.6± ± >0.05 Wave V 5.8± ± >0.05 Interval I-III 2.3± ± >0.05 Interval III-V 2.1± ± >0.05 Interval I-V 4.5± ± >0.05 V/I amplitude 2.59± ± >0.05 SSEP Erb's 8.4± ± >0.05 Cervical 12.98± ± >0.05 N ± ± <0.05* P ± ± <0.05* Table 6. Mean and standard deviation of initial and follow up patients tests. Item Patients Initial test (n=30) Patients Follow up test (n=30) t value P value Mean ± 2SD Mean ± 2SD VEP P200 latency ± ± >0.05 P200 amplitude 5.54± ± >0.05 BAEP Wave I 1.5± ± >0.05 Wave III 4.3± ± <0.001** Wave V 6.49± ± <0.01* Interval I-III 2.8± ± <0.001** Interval III-V 2.2± ± >

7 Ann Ali Abdel Kader et al. Interval I-V 4.99± ± <0.001** V/I amplitude 2.46± ± >0.05 SSEP Erb's 7.7± ± <0.05* Cervical 13.45± ± >0.05 N ± ± >0.05 P ± ± <0.01* Table 7. Associations between different clinical variables and neurodevelopmental outcome. Abnormal clinical variable Neurodevelopmental outcome Frequency Percent P-value Mann- Whitney Test Chest compression * Moro reflex ** Motor dysfunction ** Seizures ** Deep tendon reflexes ** Level of consciousness ** Respiratory distress Jitteriness Suckling Meconium Aspiration Table 8. Association between multimodality evoked potentials and neurodevelopmental outcome. Neurodevelopmental outcome Frequency Percent P-value VEP ** SSEP ** BAEP

8 Egypt J. Neurol. Psychiat. Neurosurg. Vol. 46 (2) - July DISCUSSION The evaluation of neonatal asphyxia is problematic. Asphyxia is a clinical diagnosis and the correlation with neurological outcome remains difficult 4. Most of the asphyxiated infants either develop mild or severe encephalopathy. The remaining infants developed moderate encephalopathy. This intermediate group is the most interesting one, as it is especially difficult to predict neurodevelopmental outcome in these infants 6. This can be done by electrophysiological techniques including flash visual evoked potentials, somatosensory evoked potentials and brainstem auditory evoked potentials 4,5. Gibson et al. 7 stated that patients with abnormal neurodevelopmental outcome were 7(23.3%), including three/thirty infants with cerebral palsy and four/thirty infants with dystonia. Our results showed that the abnormal neurodevelopmental outcome was in 18(60%) patients including 8 patients with cerebral palsy. Other abnormalities were epilepsy, visual impairment, hearing impairment or just developmental delay. The follow up at 3 months for P200 latency for the control group showed that the mean P200 latency was ±25.3 which was statistically Fig. (1): Percentage of SSEP, VEP, and BAEP abnormalities among patients with neurodevelopmental abnormalities. shorter than that of the patients group. Kraemer et al. 8 reported that P200 latency reaches 100 msec. by 8 to 12 weeks post-term age. However, the mean latency of P200 in this study is much higher. Follow up at 3 months for BAEPs of the patients group showed significant reduction in latency of wave III and V and interval I-III and I-V which indicates that these waves mature rapidly during the first 3 months. This is in agreement with Jiang et al. 9,10, as they stated that wave III and V show rapid decrease in latency over the first several months. In the present study, follow up at 3 months demonstrated a significant difference in N20 and P22 between the patients and the control group. This finding corresponds with the findings of Gibson et al. 7, who found that delayed cortical responses persisted on follow up as compared with the controls. Follow up at 3 months showed significant increase in Erb's point latency as compared to the initial test. Such finding was elicited in the patients and control group, which could be explained by the elongation of the infants' limb at the age of 3 months. Abnormal SSEPs or VEPs were associated with abnormal outcome. In contrast, neurological sequelae were found in many patients with normal BAEPs. The only patient who died had absent SSEPs. All patients who had normal VEPs or SSEPs had normal outcome on follow-up at 3 months.

9 Ann Ali Abdel Kader et al. The present study agrees with the findings of Majnemer et al. 11 and Gibson et al. 7 in a way that abnormalities that persisted correlated with severe neurologic impairment. This study also showed that visual evoked responses that improved in 3 months age were associated with mild to moderate neurologic impairment a finding which was met by McCulloch et al. 12. On the other hand, all abnormal SSEPs persisted during follow up and did not show any improvement. Taylor et al. 13 came to the conclusion that the combination of VEPs and SSEPs yields a powerful means of prognostication for asphyxiated term infants. Such finding corresponds well with the present finding that there is a strong relation between the VEP and SSEP results which concludes that they are complementary. They mentioned that both VEPs and SSEPs should be included in the assessment of patients with hypoxic-ischemic encephalopathy. On the other hand, there was no significant relation between the VEP or the SSEP results and the BAEP results. Furthermore, the BAEPs were less sensitive than the VEPs and SSEPs. They were not as effective in predicting neurological outcomes in asphyxiated infants because of false negatives. This conclusion met with the conclusion of Scalais et al. 3. The discrepancy of accuracy between fveps, SSEPs and BAEPs could be expected because subcortical and cortical injury in parasagittal distribution is the principle ischemic lesion in term neonates, the postcentral gyri (somesthetic) and the calcarine (visual) being particularly vulnerable 14. In the literature, the sensitivity of SSEPs and VEP in predicting neurodevelopmental outcome ranged between % and 77-91% respectively 6,13,15,16. In the present study the sensitivity was almost comparable to previous results, 96.4% for SSEP and 90.5% for VEP. Specificity was stated in the literature as 73.3% for SEP and 66.7% for VEP 6. In the present study the specificity was a little bit higher. It was 79.8% for SSEP and 70% for VEP. Concerning the positive predictive power, it was mentioned in the literature as 81.8% to 100% for SSEP and 77.3% to 100% for VEP 6,13. This means that abnormal VEPs or SSEPs guaranteed abnormal outcome. The positive predictive power in this study was 97.3% for SSEP and 80.5% for VEP, which met that of the literature. In the literature, the negative predictive power for SSEP ranged from 91.7% to 97% 6,13 and that of VEP was 83.3% 6. This means that normal SSEPs virtually guaranteed normal outcome. In the present study the negative predictive power is 95% for SEP and 86.2% for VEP. This corresponds to the former literature results. An examination by both flash VEP and SSEP has a higher predictive power than either alone, and is accurate as a prognostic indicator for term newborns 6,13, a conclusion that was made in our study. REFERENCES 1. Evans, DJ, Levene, MJ: Hypoxic-ischaemic injury. In: Rennie JM, Roberton NRC eds. Textbook of Neonatology. 3 rd edition. London: Churchill Livingston, 1999: Aurora S, Snyder EY: Perinatal asphyxia. In: Cioherty JP, Eichenwald EG, Stark AR eds. Manual of Neonatal Care. 5 th edition. Lippincott. Williams and Wilkins, 2004: Scalais E, Francois-Adant A, Nuttin C, et al.: Multimodality evoked potentials as prognostic tool in term asphyxiated newborns. Electroencephalogr. Clin. Neurophysiol. 1998; 108: Levene MI, Kornberg, Williams THC: The incidence and severity of post-asphyxial encephalopathy in full term infants'. Early Hum. Dev. 1985; 11: Mercuri E, Siebenthal K, Daniels H, et al.: Multimodality evoked responses in the neurological assessment of the newborn. Eur. J. Pediatr. 1994; 153: Eken P, Toet MC, Groenendaal F et al.: Predictive value of early neuroimaging, pulsed Doppler and neurophysiology in full term infants with hypoxic-ishaemic encephalopathy. Archives of Disease in Childhood 1995; 73: F75-F Gibson NA, Brezinova V, Levene ML: Somatosensory evoked potentials in the term newborn. Electroencephalogr. Clin.Neurophysiol. 1992; 84: Kraemer M, Abrahamsson M, Sjostrom A: The neonatal development of the light flash visual evoked potentials. Doc. Ophthalmol. 1999; 99:

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