FETAL A N D N E O N A T A L M E D I C I N E Richard E. Behrman, Editor S t r o k e in neonates Five neonates with large cerebral infarctions o f arterial origin are presented. Four had severe focal seizures on the first day o f life. The fifth, a premature infant, was asymptomatic. The diagnoses were made by computed tomography (CT) scans between 5 and 12 days o f life; CT scans obtained in the first few days of life were normal. In the fifth infant, the infarct was hemorrhagic and was also noted by cranial ultrasound. Three o f the infants had a history o f trauma to the head or neck during labor and birth. Only one was severely asphyxiated at birth. Two apparently are doing well at 1 year of age. Cerebral infarcts of arterial origin in neonates probably have been missed in living patients in the past, but now are recognized in the newborn period by properly timed CT examination. (J PEDIATR 102:605, 1983)) Frank L. Mannino, M.D., and Doris A. Trauner, M.D. San Diego, Calif. CEREBRAL INFARCTS OF ARTERIAL ORIGIN are rarely documented in the neonatal period, and then usually at autopsy,', 2 because of the frequent lack of specific clinical signs such as hemiparesis and, in the past, the difficulty and danger of making the diagnosis by arteriogram. In a recent large neonatal autopsy series) the incidence of cerebral infarcts with arterial occlusion was 5.4% (17% in term infants); a quarter of the infarcts involved a major vessel thrombosis. This incidence indicates t h a t m a n y focal cerebrovascular ischemic events are being missed in surviving infants?, 3 T h e cause of such infarcts is frequently unclear and usually inferred. Clinical and pathologic sequelae of presumed neonatal cerebral infarction may be noted later in infancy or childhood, b u t an etiologic diagnosis is even more difficult to m a k e at t h a t t i m e ? T h e recent availability of noninvasive diagnostic techniques, such as computed tom0graphy (CT) and cranial ultrasound, have m a d e it possible to m a k e this diagnosis safely. W e present five neonates with localized cerebral infarction diagnosed over the last year in our I n f a n t Special C a r e Center. A s u m m a r y and follow-up of the five patients is given in T a b l e I. From the Departments of Pediatrics and Neurosciences, University o f California Medical Center, San Diego. Reprint requests: Frank L. Mannino, M.D., Department of Pediatrics/H638A, University Hospital, 225 Dickinson St., San Diego, CA 92103. CASE REPORTS Patient 1. The patient was a 3.0 kg term boy. Late in labor a prolonged variable deceleration in fetal heart rate occurred, and a low/mid forceps delivery was attempted unsuccessfully. A cesarean section was performed. Extraction of the infant was difficult and required traction on the body with manual, upward pushing through the vaginal canal to disengage the head. Apgar scores were 8 and 9 at one and five minutes, respectively. The infant was noted initially to have a right cephalohematoma and a left peripheral facial weakness. At 18 hours of life he had a generalized tonic-clonic seizure, followed by frequent focal rightsided seizures over the next 12 hours. Occasional clinical and electrographic seizure activity persisted for the first four days of life, despite treatment with phenobarbital, phenytoin, and amobarbital. A CT scan at 32 hours showed small ventricles and a minimally depressed skull fracture in the right parietal region. Cranial ultrasound examination was normal. An electroencepha logram on day 4 was abnormal over the left hemisphere. A C T scan on day 5 showed a large area of low density in the left parietotemporal area (Fig. 1). Patient 2. The patient was a term, 3.1 kg boy. During labor thick meconium was noted and late fetal heart rate decelerations were detected. Fetal scalp pH was 7.17, and an emergency cesarean section was performed. The infant had a tight nuehal cord (• Apgar scores at one and five minutes were 6 and 8; umbilical artery pH was 7.16. A large succenturiate lobe was present in the placenta. Microscopically, there were severe focal proliferative villitis and chorioamnionitis with fetal capillary occlusions. The infant appeared normal until 4 hours of age, when he developed focal right-sided tonic-clonie seizures, which recurred over the next 18 hours despite treatment with phenobarbital, The Journal of P E D I A T R I C S 605 606 Mannino and Trauner The Journal of Pediatrics April 1983 Fig. 2, Patient 2. CT scan without contrast on day 7 of life. Note left parietooccipital area of low density. Fig. 1. Patient 1. Ct scan without contrast on day 5 of life. Note wedge-shaped left parietotemporal low-density region. Table I. S u m m a r y o f clinical findings in five patients with n e o n a t a l stroke _ _ Patient Apgar Scores 1 8/9 2 6/8 3 2/7 4 7/8 5 5/6 (Premature infant) [ Seizures EEG CT diagnosis 18 hr ~ 4 days; Left hemisphere Day 5: Left parietotemporal right focal, spikes and sharp infarct (left middle cerebral general waves artery) 4 hr ~ 18 hr; Bilateral spikes and Day 7: Left parietooccipital Right focal, sharp waves, infarct (left middle cerebral general maximal left artery) central area 5 hr ~ 12 days; Bilateral temporal Day 12: Right posterior parietal Left focal spikes; less activity infarct (right middle cerebral over right artery) hemisphere Day 5: Left midparietal infarct 8 hr ~ 2 days; Left temporal and (left middle cerebra/ artery) Right focal central spikes Day 10: Left occipital None Normal hemorrhagic infarct. (left posterior cerebral artery); no intraventricular hemorrhage (day 6: Ultrasound) Follow-up 12 mo: Normal physical and developmental* exam; seizure free without anticonvulsants 15 too: Normal physical and developmental* exam; seizure free without anticonvulsants 21 mo: Microcephalic with generalized hypotonia and developmental* delay; recurrent seizures Newborn 15 too: Minimal right shoulder hypotonia; normal development~ *Revised Developmental Screening Interview, 1980. ~Bayley Scales of Infant Development. phcnytoin, paraldehyde, and diazepam. The EEG on day 2 demonstrated multi focal epileptiform activity. A C T scan on day l demonstrated only a subarachnoid hemorrhage, but on day 7 demonstrated a low-density area in the left parietooccipital region (Fig. 2). Patient 3. This was a 2.9 kg postterm girl, delivered of a mother with a history of mitral valve replacement for acute rheumatic fever. Maternal medications included quinidine (first trimester), coumadin (changed to heparin two months prior to delivery), persantine, and hicillin. A prolonged labor was complicated by Volume 102 Number 4 Stroke in neonates 607 Fig. 3. Patient 3. CT scan with contrast at 12 days of life. Note enlarged right occipital horn and right posterior parietal, peripheral low-density area with small regions of contrast enhancement. preeclampsia and maternal fever. Ten hours prior to delivery a severe late deceleration of four minutes' duration occurred, but heart rate normalized and scalp pH was 7.33. The infant was delivered with the aid of a Malmstrom vacuum extractor. Meconium-stained amniotic fluid was present. Apgar scores at one and five minutes were 2 and 7; umbilical venous pH was 7.26. Mechanical ventilation was necessary for the first 30 minutes of life, after which the infant did well. There was evidence of chorioamnionitis and umbilical vasculitis on examination of the placenta. At 5 hours the infant developed focal, left-sided tonic-clonic seizures, which recurred frequently for the first 21/2 days of life and persisted until day 12 despite treatment with phenobarbital, phenytoin, and paraldehyde. The C T scans on days 1 and 3 were unremarkable. A scan at 12 days revealed a right posterior parietal low-density region (Fig. 3). Cranial ultrasound examination on days 2 and 3 revealed only a small right choroid plexus hemorrhage. An EEG on day 2 was severely abnormal. Patient 4. This was a 3.8 kg term girl. Meconium-stained amniotic fluid was noted. A loose nuchal cord was cut during the vaginal vertex delivery. Apgar scores at one and five minutes were 7 and 8. The placenta was meconium stained. At 8 hours the infant had tonic-clonic seizure activity of the right arm, which recurred over the next 11/2days despite treatment with phenobarbital and phenytoin. An EEG at 14 hours of age revealed left focal epileptiform discharges. The C T scan on day 1 was normal but on day 5 revealed a localized left midparietal low-density area extending through the gray matter. Fig. 4. Patient 5. A, Cranial ultrasound on day 6 of life, left sagittaI section (anterior cranium oriented to right). Note echodense area in posterior parietooccipital region, indicative of intracerebral blood. There is no evidence of intraventricular or subarachnoid hemorrhage. (Line represents orientation of "coronal" section in B.) B, Forty-five degree "coronal" section in same patient, with echodense material in left occipital region. Patient 5. The patient was a 1.1 kg boy of 30 weeks' gestation who was small for gestational age. The mother had severe preeclampsia (BP 200/110), necessitating premature delivery of the infant by cesarean section with epidural anesthesia. Apgar scores at one and five minutes were 5 and 6; umbilical arterial pH was 7.29. The placenta was circumvallate with many infarcts and a small, old abruptio. The first few days of life were complicated by severe respiratory distress syndrome, interstitial emphysema, and a patent ductus arteriosus. The infant required mechanical ventilation for seven days. Cranial ultrasound examination on day 3 revealed no intraventricular hemorrhage but on day 6 revealed a left parietooccipital echodensity compatible with an isolated intracerebral hemorrhage (Fig. 4). A C T scan on day 10 demonstrated an area of increased density in the same area (Fig. 5) with no contrast enhancement. The EEGs at 6 and 22 days of life were normal. At 1V2 months of age, repeat ultrasound examination revealed reabsorption of the blood and an early cystic lesion. At 7 months of age, the area of the lesion could not be approached by ultrasound, 608 Mannino and Trauner The Journal of Pediatrics April 1983 Table 11. Causes of stroke in neonates Reference Embolization Placental tissue/vessel thrombus Twin-to-twin transfusion syndrome Patent ductus arteriosus Congenital heart discase Sepsis Thrombosis Traumatic vascular damage PoIycythemia* Stasis/shock Meningitis/encephalitis* Tumors Consumption coagulopathy lschemia Postintraventricular hemorrhage Hypotension/shock Hypoxia 2, 6, 8 35 7 2, 3 10, 12 2, 13, 32 33 36, 37, 38 14 *Venous circulation more commonly affected. Fig. 5. Patient 5. CT scan without contrast on day 10 of life. Note wedge-shaped left occipital area of increased density, indicative of a hemorrhagic infarct. but a CT scan revealed an area of porencephaly in the left parietooccipital region, with slightly prominent ventricles. DISCUSSION Cerebral arterial vascular disease with infarction is well documented in older infants and children? ,6 In neonates, only about 50 cases of cerebral infarction of vascular origin have been reported in the English literature (excluding those resulting from meningitis). ~-4,6-14 All but five9, 10.12.14 of the diagnoses were made at autopsy; most have involved infarcts of the middle cerebral circulation. The high incidence of cerebral infarction in the autopsy series by Barmada et al. 3 suggests underdiagnosis or a change in the occurrence rate. With the advent of neonatal intensive care, neonates who might previously have died are kept alive longer, perhaps allowing time for the infarcts to become apparent. In our series all five infants survived and the infarcts were diagnosed during the acute episode by C T scan. The four term infants with ischemic infarcts had severe focal seizures in the first day of life, and had localizing features on EEG. Initial CT scans were negative, but became positive for infarction at 5 to 12 days of age. Information on the appearance and evolution of localized ischemic infarcts by C T exists mainly for adults. ~s-j7 Initially the scans are normal, but by two days after the ictus, the ischemic area appears as a homogenous, low- density (low attenuation coefficient), usually wedgeshaped region, with irregularly defined borders. By four to 10 days, the lesion reaches maximum size; a mass effect may be noted. With small lesions, by three to four weeks the C T scan may return to normal. Larger lesions may progress to cavity formation and cystic degeneration. A variety of enhancement patterns occur with contrast in up to 65% of ischemic infarcts, between one and four weeks after the event~8; 11% may be appreciated only with contrast. 19 Noncontrast studies are required to avoid obscuring a lesion with minimal hypodensity? 9 The diagnostic accuracy of C T in supratentorial ischemic infarcts is about 90% in adults, if the scan is done at the appropriate time, with and without contrast. ~v Hemorrhagic infarcts are seen as wedge-shaped areas of high-density, sometimes surrounded by a low-density rim; there is usually no contrast enhancement, lntracerebral bleeds are usually more dense, have a greater mass effect, and do not have the characteristic shape or location of hemorrhagic infarcts. Although neither will be missed on CT, a distinction between the two cannot always be made. ~6 Recent autopsy and clinical correlation of C T head studies in term neonates with severe perinatal asphyxia revealed that a diffuse pattern of low-density areas with gray matter involvement may represent brain ischemia or infarction.20 22 These changes are thought to result from a general hypoxic-ischemic encephalopathy. Diffuse lowdensity areas on C T of premature infant brains and periventricular low density in both term and premature infants may be normal findings and are difficult to interpret. 22,23 However, four of our infants had large Volume 102 Number 4 localized hypodensities with shapes and locations suggestive of cerebral infarction of vascular origin. Cranial ultrasound may aid in the diagnosis of hemorrhagic infarction, as in patient 5. The nonhemorrhagic infarcts in our other patients were not appreciated with cranial ultrasound. Ultrasound has been used to diagnose isolated intracerebral hemorrhage in neonates. However, some of the recently reported cases of intracerebral hemorrhages in term infants may in fact represent hemorrhagic infarcts? 5-2~ Radionuclide brain scans can be used to diagnose cerebral infarcts, but the scans also are usually negative in the first week after the infarct? The resolution of newer CT scanners may be greater than that of radionuclide scans, making C T the diagnostic test of choice for detection of cerebral infarction, However, the timing of the C T scan is important. Two scans may be necessary, one early to rule out other disease in need of acute treatment (perhaps obviated by cranial ultrasound), and the second seven days later to document infarction. The presence of an early, normal C T scan in term neonates with severe focal seizures clinically and on E E G should suggest infarction and the need for a repeat C T scan. Possible causes of stroke in neonates are listed in Table II. Our first two patients (and perhaps the fourth) had direct trauma to the head and neck. Traumatic occlusion of the internal carotid and middle cerebral arteries in older children with nonpenetrating head injuries has been documented.Z9,30 The mechanism of occlusion is thought to be stretching of the vessel wall or emboli from the internal carotid artery. Haas 3~ described middle cerebral artery occlusion in children with migraine headaches after head trauma. Traumatic injury to cerebral vessels during the birth process has been documented in vertebral vessels 32 and in the internal carotid artery, with intimal damage and thrombus formation. ~3 The cause in patient 3 is less clear, but could relate to trauma and stretching of the neck secondary to use of the Malmstrom vacuum extractor. Some in utero asphyxia also occurred. In utero hypotension, stasis, and vessel thromboses (systemic or placental) may have occurred secondary to the severe bradycardia. In this infant a dysplastic left kidney was diagnosed later, indicating the possibility of multiple embolic phenomena at some time, resulting in damage to more than one organ system. Maternal medications may also have had some effect. Patient 5 differed from the others in that he was premature and had no obvious birth trauma. The infarct could have been secondary to a placental thromboembolus at the time of birth (with secondary hemorrhage later), as there were many placental infarcts and an old abruption present. Stroke in neonates 609 Many instances of older infants with mild hemiparesis or focal seizures are seen with no apparent cause. With the advent of the CT scan, porencephaly or focal areas of atrophy can be demonstrated. A t least some of these findings may result from cerebral vascular occlusions associated with difficult deliveries and other perinatal factors.33.~4 It is encouraging that two of our five patients are normal on brief follow-up. Three have no significant evidence of hemiparesis, indicating that many infarcts may not only be missed in the neonatal period, but also may not be detected clinically later in infancy. The possibility exists, however, that neurologic deficits will become apparent later in childhood; long-term follow-up will be needed to determine the prognosis of neonatal stroke. ADDENUM: Since submission of this article, left cerebral infarctions have been diagnosed in two additional term infants. Both infants had good Apgar scores (8/9, 7/8) and appeared well until right-sided seizures occurred at 10 and 18 hours of age. The infants continued to do well generally, but seizures persisted (10 and 2 days, respectively) despite anticonvulsant medication. The infarcts were diagnosed with C T scans done at 30 hours of age. A large left hemisphere infarction encompassing most of the left middle cerebral artery circulation was present in one infant, and a high left parietal lobe infarction in the other. The C T scans were done on a fourth-generation scanner (Deltascan 2020, Johnson & Johnson) and may account for the early appreciation of the infarcts. REFERENCES 1. Harvey FH, Alvord EC: Juvenile cerebral arteriosclerosis and other cerebral arteriopathies of childhood: Six autopsied cases. Acta Neurol Scand 48:479, 1972. 2. Friede RL: Developmental neuropathology. New York, 1975, Springer-Verlag, pp 122-149. 3. Barmada MA, Moosy J, Shuman RM: Cerebral infarcts with arterial occlusion in neonates. Ann Neurol 6:495, 1979. 4. Cocker J, George SW, Yates PO: Perinatal occlusion of the middle cerebral artery. Dev Med Child Neurol 7:235, 1965. 5. Davie JC, Coxe W: Occlusive disease of the carotid artery in children. Arch Neurol 17:313, 1967. 6. Banker BQ: Cerebral vascular disease in infancy and childhood. J Neuropathol Exp Neurol 20:127, 1961. 7. Gross RE: Arterial embolism and thrombosis in infancy. Am J Dis Child 70:61, 1945. 8. Clark RM, Linell EA: Case report: Prenatal occlusion of the internal carotid artery. J Neurol Neurosurg Psychiatr 17:295, 1954. 9. Harwood-Nash DC, Fitz CR: Neuroradiology in infants and children. St. Louis, 1976, CV Mosby, p 568. 10. Prian GW, Wright GB, Rumack CM, O'Meara OP: Apparent cerebral embolization after temporal artery catheterization. J PEDIATR93:115, 1978. I I. Ruff RL, Shaw CM, Beckwith JB, Iozzo RV: Cerebral 6 10 Mannino and Trauner infarction complicating umbilical vein catheterization. Ann Neurol 6:85, 1979. 12. Schrumpf JD, Sehring S, Killpack S, Brady JP, Hirata T, Mednick JP: Correlation of early neurologic outcome and CT findings in neonatal brain hypoxia and injury. J Comput Assist Tomogr 4:445, 1980. 13. Roessmann U, Miller RT: Thrombosis of the middle cerebral artery associated with birth trauma. Neurology 30:889, 1980. 14. Volpe J J: Neurology of the newborn. Philadelphia, 1981, WB Saunders, ch 8, 9, 19. 15. Davis KR, Taveras JM, New PF, Schnur JA, Roberson GH: Cerebral infarction diagnosis by computerized tomography. Am J Roentgenol 124:643, 1975. 16. Weisberg LA, Nice C, Katz M: Cerebral computed tomography: A text-atlas. Philadelphia, 1978, WB Saunders, pp 53-86. 17. lnoue Y, Takemoto K, Miyamoto T, Yoshikawa N, Taniguchi S, Saiwai S, Nishimura Y, Komatsu T: Sequential computed tomography scans in acute cerebral infarction. Radiology 135:655, 1980. 18. Weisberg LA: Computerized tomographic enhancement patterns in cerebral infarction. Arch Neurol 37:21, 1980. 19. Wing SD, Norman D, Pollock JA, Newton TH: Contrast enhancement of cerebral infarcts in computed tomography, Radiology 121:89, 1976. 20. Flodmark O, Becket LE, Harwood-Nash DC, Fitzhardinge PM, Fitz C, Chuang SH: Correlation between computed tomography and autopsy in premature and full term neonates that have suffered perinatal asphyxia. Radiology 137:93, 1980. 21. Flodmark O, Fitz CR, Harwood-Nash DC: CT diagnosis and short term prognosis of intracranial hemorrhage and hypoxic/ ischemic brain damage in neonates. J Comput Assist Tomogr 4:775, 1980. 22. gitzhardingc PM, Fitz CR, Ashby S: The prognostic value of computed tomography as an adjunct to assessment of the term infant with postasphyxial encephalopathy. J PEDIATR99:777, 1981. 23. Estrada M, El Gammal T, Dyken P: Periventricular low attenuations: A normal finding in computerized tomographic scans of neonates? Arch Neurol 37:754, 1980. The Journal of Pediatrics April 1983 24. Fitzhardinge PM, Flodmark O, Ashby S: The prognostic value of computed tomography of the brain in asphyxiated premature infants. J PEDIATR 100:476, 1982. 25. Grant EG, Borts F, Schellenger D, McCullough DC, Smith Y: Cerebral intraparenchymal hemorrhage in neonates: Sonographic appearance. Am J Neuroradiol 2:129, 1981. 26. Cartwright GW, Culbertson K, Schreiner RE, Garg BP: Changes in clinical presentation of term infants with intracranial hemorrhage. Dev Med Child Neurol 21:730, 1979. 27. Chaplin ER, Goldstein GW, Norman P: Neonatal seizures, intracerebral hematoma and subarachnoid hemorrhage. Pediatrics 63:812, i979. 28. Miller GM, Block VD, Lubchenco LO: lntracerebral hemorrhage in a term newborn with hyperviscosity. Am J Dis Child 135:377, 1981. 29. Frantzen E, Jacobsen HH, Therkelsen J: Cerebral artery occlusions in children due to trauma to the head and neck. Neurology 11:695, 1962. 30. Zimmerman AW, Kumar A J, Gadoth N, Hodges F J: Traumatic verebrobasilar occlusive disease in childhood. Neurology 28:185, 1978. 31. Haas DC, Pineda GS, Lourie H: Juvenile head trauma syndromes and their relationship to migraine. Arch Neurol 32:727, 1975. 32. Yates PO: Birth trauma to the vertebral arteries. Arch Dis Child 34:436, 1959. 33. Amit M, Camfield P: Neonatal polycytbemia causing multiple cerebral infarcts. Arch Neurol 37:109, 1980. 34. Simmons MA, Levine RL, Lubchenco LO, Guggenheim MA: Clinical note: Serious sequelae of temporal artery catheterization. J PEOIATR 92:284, 1978. 35. Benirschke K, Driscoll SG: The pathology of the human placenta. New York, 1974, Springer-Verlag. 36. Berman PH, Banker BQ: Neonatal meningitis: A clinical and pathological study of 29 cases. Pediatrics 38:6, 1965. 37. Friede RL: Cerebral infarcts complicating neonatal leptomeningitis: Acute and residual lesions. Acta Neuropathol (Berlin) 23:245, 1973. 38. Brown LW, Zimmerman RA, Bilaniuk LT: Polycystic brain disease complicating neonatal meningitis: Documentation of evolution by computed tomography. J PEDIATR 94:757, 1979.