Accepted Manuscript MR Imaging for accurate Prediction of Outcome after Perinatal Arterial Ischemic Stroke: Sooner not Necessarily Better Nienke Wagenaar, MD, Niek E. van der Aa, MD PhD, Floris Groenendaal, MD PhD, Manon J.N.L. Benders, MD PhD, Linda S. de Vries, MD PhD PII: S1090-3798(17)30234-9 DOI: 10.1016/j.ejpn.2017.04.002 Reference: YEJPN 2205 To appear in: European Journal of Paediatric Neurology Received Date: 12 July 2016 Revised Date: 16 January 2017 Accepted Date: 4 April 2017 Please cite this article as: Wagenaar N, van der Aa NE, Groenendaal F, Benders MJNL, de Vries LS, MR Imaging for accurate Prediction of Outcome after Perinatal Arterial Ischemic Stroke: Sooner not Necessarily Better, European Journal of Paediatric Neurology (2017), doi: 10.1016/j.ejpn.2017.04.002. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. ACCEPTED MANUSCRIPT MR Imaging for accurate Prediction of Outcome after Perinatal Arterial Ischemic Stroke: Sooner not Necessarily Better Author information: Nienke Wagenaar, MDa; Niek E. van der Aa, MD PhDa; Floris RI PT Groenendaal, MD PhDa,b; Manon J.N.L. Benders, MD PhDa,b; Linda S. de Vries, MD PhDa,b Affiliation: a. Department of Neonatology, Wilhelmina Children’s Hospital, University Medical Centre Utrecht, The Netherlands and b. Brain Center Rudolf Magnus, University Medical Centre SC Utrecht, The Netherlands Linda. S. de Vries Department of Neonatology M AN U Corresponding author: Wilhelmina Children’s Hospital, University Medical Centre Utrecht Internal mail no. KE 04.123.1 P.O. Box 85090 The Netherlands l.s.devries@umcutrecht.nl TE D 3508 AB Utrecht EP Telephone no. 0031 88 75 545 45 Number of words abstract: 100 AC C Number of words report: 1968 Figures: 2 (437 words) Sources of support: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Conflict of Interests: None. 1 ACCEPTED MANUSCRIPT ABSTRACT Two full-term infants with perinatal arterial ischemic stroke (PAIS), with cerebral sinovenous RI PT thrombosis of the superior sagittal sinus in one of them, are reported. Diffusion weighted imaging (DWI)-MRI, performed within 24 hours following onset of seizures and repeated 48 hours later, clearly showed restricted diffusion within the middle cerebral artery territory on both SC MRIs, but clear patterns of signal intensity changes in the descending corticospinal tracts on the second MRI only. Since involvement of these structures is essential for prediction of motor M AN U outcome, we may need to reconsider optimal timing of MR imaging for prediction of neurodevelopmental outcome after PAIS. Key words: MRI; neonate; stroke; PAIS; Wallerian; corticospinal tract • Early MRI is increasingly used to predict neurodevelopmental outcome of newborn infants with PAIS. • TE D Highlights: Signal intensity changes in the descending corticospinal tracts are predictive of adverse EP motor development. This case series shows delayed onset of “pre-Wallerian” degeneration. • Optimal timing of MRI imaging in PAIS patients for diagnosis and prognosis may be AC C • different 2 ACCEPTED MANUSCRIPT 1. INTRODUCTION Perinatal stroke consists of perinatal arterial ischemic stroke (PAIS) and cerebral sinovenous RI PT thrombosis (CSVT), and both are associated with unfavourable neurodevelopmental outcome. Adverse sequelae of PAIS include unilateral spastic cerebral palsy (USCP) cognitive dysfunction, epilepsy and speech problems. In 40-75% of infants, PAIS or CSVT lead to SC abnormal neuromotor and -developmental outcome.(1–3) Early MRI is used for diagnostic purposes, and for dating PAIS, but is also increasingly emphasized as an important prognostic M AN U value to predict the neurodevelopmental outcome of the infant.(4,5) PAIS, and especially middle cerebral artery (MCA) infarction, often involves the descending corticospinal tracts (CST).(4–6) MRI and especially diffusion weighted imaging (DWI) offers the advantage of evaluating the posterior limb of the internal capsule (PLIC) and the cerebral TE D peduncles, i.e. the presence of “pre-Wallerian” degeneration. Involvement of these structures is strongly correlated with adverse motor outcome.(4–9) CSVT is often associated with neurological comorbidity, such as hypoxic-ischemic encephalopathy, venous infarction and EP thalamic haemorrhage.(2,10) The presence of such neurological comorbidity at diagnosis predicts poor outcome in patients with CSVT.(2) AC C The aim of this short communication is to describe two newborns with PAIS who both had two early MRIs showing delayed onset of “pre-Wallerian” degeneration on sequential MRIs performed within 72 hours after onset of symptoms. 2. CASE DESCRIPTIONS 2.1 Case 1 3 ACCEPTED MANUSCRIPT This boy was born at 40+4 weeks of gestation after an uncomplicated pregnancy by secondary caesarean section due to slow dilatation of the cervix and meconium stained amniotic fluid. His birth weight was 3570 gram (p15), length 53 cm (p50), head circumference 36 cm (p50). He had RI PT good Apgar scores of at 9, 10 and 10 at 1, 5 and 10 minutes, respectively. He was admitted to the neonatal unit in a level II hospital for observation, where he developed fluctuations in temperature, frequent apneas and lethargy, suspected for seizures. Amplitude integrated EEG SC (aEEG) showed epileptic activity originating from the left hemisphere. Cranial ultrasound and an early CT-scan showed an area of decreased attenuation in the distribution of the left MCA. He M AN U received phenobarbital to control seizure activity, and antibiotics and anti-viral medication until meningitis was ruled out by negative cerebrospinal fluid cultures, and he was transferred to our level III neonatal intensive care unit. The first MRI was performed on the third day of life, around 20 hours after the onset of apneas TE D (figure 1). In the complete left MCA territory, DWI and T2 weighed imaging showed increased signal intensity in the cortex and white matter. The basal ganglia including globus pallidus and putamen were also mildly affected. The left PLIC showed only very mild highlighting on DWI EP and T2 imaging, while some asymmetry was found laterally in the cerebral left peduncle (figure AC C 1D-E). A small cortical lesion was also found in the upper right hemisphere, not affecting the corticospinal tracts. Reduced flow of the left MCA was seen on MR Angiography (MRA). The infant was included in an imaging study and the MRI was repeated on day 5, around 72 hours after the onset of clinical seizures and 48 hours after the first scan, to additionally perform arterial spin labeling.(11) DWI and T2WI showed the same area of increased signal intensity in the main left MCA territory. DWI hyperintensity in the PLIC had extended, showing a clear 4 ACCEPTED MANUSCRIPT asymmetrical pattern. Additionally, on DWI, the left cerebral peduncle now also clearly showed restricted diffusion, including the middle part. RI PT The aEEG did not show any seizure activity, but the background pattern showed a continuous normal voltage with sleep-wake cycling on the right, while there was discontinuous normal voltage pattern on the left. SC After the second MRI, the child was included in a pilot trial and treated with erythropoietin (EPO) 1000 U/kg per day for three days to improve neuroregeneration.(12) The infant improved M AN U clinically, could be fully breastfed and was discharged home one week after onset of seizures. A thrombophilia screen was performed, showing normal clotting time and homocysteine, no MTHFR, factor V Leiden or prothrombin mutation. Repeat MRI at the age of three months showed cysts in the left hemisphere, especially in the TE D region of the anterior branch of the MCA, and Wallerian degeneration of the left descending CST (Figure 1). On neurological assessment there was a hand preference for his left hand, suggestive of development of USCP, which was subsequently confirmed at two years of age, EP with Manual Ability Classification System score of 2, Gross Motor Function Classification System score of 1 and Hand Assessment for Infants (HAI) of 83% (whereas 0% equals no 2.2 AC C asymmetry).(13) Case 2 This male infant was born at 42+1 weeks’ gestation after a secondary caesarean section because of slow dilatation of the cervix, meconium stained amniotic fluid, and fetal heart rate abnormalities following induction of labor. His birth weight was 3190 gram (