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Neonatal (perinatal)

NICH-NINDS: “a group of heterogeneous conditions with focal disruption of cerebral blood flow secondary to arterial or cerebral venous thrombus or embolization between 20w of fetal life through the 28th postnatal day The newborn and confirmed by NEUROIMAGING or neuropathological studies.”

«neonatal stroke» - It can be focal or multifocal and both ischaemic and Andrea Righini MD, Elisa Scola MD*, Cecilia Parazzini MD, Fabio Triulzi MD. PhD* haemorrhagic. Radiology and Neuroradiology Dept., Children’s Hospital V. Buzzi, Milan, Italy - The first week of life carries the highest period risk for *Neuroradiology Dept., University Hospital-Policlinic, Milan, Italy [email protected] stroke in paediatric age 1 2

Lancet Child Adolesc Classification Health. 2018. Perinatal stroke: «typical-common» arterial acute stroke «Typical-common» arterial acute stroke (AIS) mechanisms, AJNR 2009 management, and Evolution of Unilateral Perinatal Arterial Ischemic Stroke on Conventional outcomes of early «Atypical-uncommon» arterial acute stroke and Diffusion-Weighted MR Imaging J. Dudink et Al.. cerebrovascular brain and arterial acute ischemia–PLUS injury. Dunbar M et AL.

T1

Deep medullary vein territory -haemorrhages 2d old

Periventricular venous T2 (mostly prematures)

Sinus thrombosis and related haemorrhagic DD DWI infarctions Rapid necrosis (T1-hyper) Rapid and malacia (T1-CSF like signal) wallerian degen. 3 4

«typical-common» arterial acute stroke «typical-common» arterial acute stroke often asymptomatic or acute symptoms nonspecific presentation such as hypotonia, lethargy, apnea - perinatal arterial ischemic stroke (AIS) occurs in or feeding difficulties. around 1 in 1600 to 5000 births - Typically a term baby with a “normal “ «presumed perinatal stroke» prenatal history who - male predominance of approximately 60% appears well.

- are the most haemorrhagic - left hemisphere predominates. common symptoms of arterial venous infarction AIS in term infants (25- ischemia 40%)

- Hemiparesis is rarely periventricular left found in acute phase venous infarction late detection 5 6

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«typical-common» arterial acute stroke «typical-common» arterial acute stroke aetiologies Often not so «normal» history J Pediatr. 2016 In more than 50% of AIS the cause is never found. Risk Factors for Neonatal Arterial - More frequent family history of seizures/neurologicIschemic Stroke: The Normal neonates already have risk factors for thrombus formation including: raised Importance of the diseases, primiparous Intrapartum Period. hematocrit, presence of fetal hemoglobin, high procoagulant proteins, and increased blood Martinez-Biarge M et Al. viscosity. mothers, and male sex. Placental factors Maternal factors/condition Placental thrombosis - More intrapartum complications: prolonged rupture of Infertility and infertility treatment membranes, fever, thick meconium, prolonged second Autoimmune disorders Placental infection stage, tight nuchal cord, and abnormal disorders (Protein C deficiency, Protein S deficiency, Factor V Leiden) cardiotocography. Anticardiolipin antibodies Fetal/ Neonatal Cardiac disorders Preeclampsia Congenital heart disease Placental abnormalities more common than Infection, chorioamniositis Patent ductus arteriosus J Pediatr. 2018 Prolonged rupture of membrane (>24h) in controls: Placental Pathology Pulmonary valve atresia in Neonatal Stroke: A Twin-to-twin transfusion syndrome Cardiac surgery (associated with cardiac - Fetal vascular malperfusion. Retrospective Case-Control Study. In utero cocaine exposure bypass, atrial balloon, septostomy) - Amniotic fluid Bernson-Leung ME et Al.

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Thrombophilic factors? Arterial ischemic stroke topography Blood. 2017 NeurodevelopmentAfter Perinatal Arterial Ischemic Stroke posterior risk is not increased in children after perinatal stroke. Nienke Wagenaar, M et Al.. PEDIATRICS 2018 anterior Curtis C et Al.. cerebral cerebral Thrombophilia evaluations: MCA territory 90% artery 9% artery 1% proteins C and S, antithrombin, factors VIII/IX/XI, fibrinogen, lipoprotein(a), homocysteine, lupus , anticardiolipin antibodies and genotyping of factor V Leiden (FVL), factor II G20210A (FII), and methylenetetrahydrofolate reductase C677T.

”minimal association between perinatal stroke and thrombophilia.” Multiple infarctions: 6% to 25% of perinatal are bilateral.

Arch Pediatr. 2017. [Neonatal arterial ischemic stroke: Review of the current guidelines]. Saliba E The extent and location of the stroke influence the long-term AIS has a low recurrence rate (1%), except in children with congenital outcome. Therefore MRI is crucial for the assessment of the heart disease or multiple genetic thrombophilia. topography of the chronic infarct area. 9 10

Eur J Radiol. 2016 MR angiography findings «typical-common» arterial acute stroke MR-angio variability in infants with neonatal arterial ischemic stroke in the middle cerebral artery territory: A prospective Frequent post-rolandic involvement and prognosis issue MRA should be performed BUT often of the arterial defects study using circle of Willis MR angiography. Three-Dimensional Map of Neonatal Arterial Ischemic can quickly regress. Husson B et Al.. Stroke Distribution From Early Multimodal Brain Imaging “33 arterial changes, occlusion in 6 thrombus-type flow defect in 9, and Christian Stephan-Otto et Al.. Stroke. 2017 unilateral increased flow in enlarged insular arteries in 8”. “71% lesions posterior to central sulcus”

complete carotid none to mild MCA asymmetry occlusion

exemplificative cases remarkable MCA asymm. MCA ditation Dev Med Child Neurol. 2019 ”new evidence that children with remarkable periph. reactive Neuroanatomical correlates of sensory deficits in AIS may experience difficulty processing branches asymm. Hyper children with neonatal arterial ischemic stroke. perperfusion Giudice C et Al.. sensory information” MCA perf. arteries involvement (basal ganglia) 11 12

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«typical-common» arterial acute stroke» Pathophysiology spot Arterial Spin Labeling perfusion in AIS early phases of wallerian degeneration Arterial Spin Labeling Perfusion Magnetic Resonance Imaging Performed in Acute Perinatal 73% demonstrated Stroke Reveals very fast in neonates! Hyperperfusion Associated With hyperperfusion... Ischemic Injury Christopher G. Watson et Al. higher freq. than Stroke. 2016 adults. NEWBORN FOCAL INFARCTION (15 DAYS) ASL Reperfusion effect?, Excitoxicity? Seizures? FSE-T2

adult studies: lambda 1 lambda 2 and 3 (Thomalla G. et Al., 2004)

pCASL-3D Fractional Anisotropy 13 14

Pathophysiology spot «typical-common» arterial acute stroke AIS secondary changes ADC and cortical / axonal damage Acute changes are also seen within the medial thalamus and (early wallerian degeneration) hypothesis pulvinar, which are likely attributable to secondary degeneration of ACUTE SUBACUTE corticothalamic projections.

AJNR 2009 Evolution of Unilateral Perinatal Arterial Ischemic Stroke on Conventional and Diffusion-Weighted MR Imaging J. Dudink et Al..

In the chronic phase contralateral cerebellar hemisphere atrophy may be seen as a result of crossed cerebellar diaschisis following MCA infarction. Cortical ADC pseudonormalization

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DTI/RGB/FA maps may help in prognosis Differential diagn. I Signs of cortical-spinal tract degeneration are not good signs for Some of the more tricky cases for neuroradiologists motor prognosis

Acute infective Encephalopathies 15d old 15d old 13d old no CST, but optic rad.degen. moderate to severe degen. moderate degen. neonat. Herpes encephalitis

atypical but true hypoglycaemic encephalopathy*

5d old 4w old *hypoglycaemia itself is a risk factor for none to mild degen.? AIS or can be associated with AIS none to mild degen.? 5d old prolonged hypoglycaemia 17 18

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Differential diagn. II Some of the more tricky cases for neuroradiologists «shaken baby syndrome» cortical necrosis «Atypical» arterial acute stroke

Molybdenum defic. and arterial acute ischemia–PLUS acute SBS phase especially if asymmetric

Some neurometabolics: Clinical Neuroimaging Features and Outcome molybdenum defic., mitochondria in Molybdenum Cofactor Deficiency Kayal Vijayakumar MBBSa, et al.. Focal prolonged seizures (overlapping effect). ? 19 20

«Atypical» arterial acute stroke «Atypical» arterial acute ischemia and arterial acute ischemia–PLUS and arterial acute ischemia–PLUS AIS may present with uncommon features complete sparing of the cortex with cavitation of the underlying or with associated additional findings was observed in 3 preterms Stroke. 2016 Risk Factors, Clinical Presentation, and Neuroimaging Cortical Sparing in Findings of Neonatal Perforator Stroke Preterm Ischemic Arterial Ginette M. Ecury-Goossen, et Al.. Stroke. 2013 Stroke. pure perforator art. stroke: van der Aa NE et Al. mostly detected by US, AIS-PLUS perivenular lesions in no heralding symptoms cortical mild unclear HIE history sparing

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Deep medullary vein territory infarctions-haemorrhages

- Premature and term newborn

- Rarerly secondary to intracranial sinus thrombosis - Sometime associated with central venous hyepertension – jugular v. occlusion - May be associated with CHD Deep medullary vein territory - Unclear relation with - Sometime with systemic infections

infarctions-haemorrhages - Neonatal immature deep medullary vein system more susceptible than in adult.

deep medullary veins: - congestion - rupture - thrombosis

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Deep medullary veins territory infarctions-haemorrhages Deep medullary veins territory infarctions-haemorrhage

perivenular radially SWI acute phase oriented haemmorrhagic- infarctions

Case a DD classic PVL Case 1 (not radially ADC map oriented) Case 3 SWI

Case 2 Case b

ADC map

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Periventricular venous infarction (mostly prematures)

Pathophysiol.: germinal matrix hemorrhage with secondary medullary venous infarction.

Periventricular venous Well characterized already by Ulstrasound. infarction (mostly prematures) The same mechanism commonly occurs in delivered preterm infants as well as in-utero.

If isolated and of limited extension, lower risk of cognitive and behavioral disorders

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Periventricular venous infarction Periventricular venous infarction (mostly prematures) (mostly prematures) severe case

EG:31

acute

follow-up at term of ex-premature 26w milder case

sequelae

Roze E. Pediatrics 122:e46 (2008)

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Periventricular venous infarction (mostly prematures) potential neurodevelopmental impact Periventricular haemorr. in fronto- occipital associative, cortico- striatal, and corticopontine Sinus thrombosis and related projection pathways may result in in cognitive and motor deficit. Developmental Dynamics of Radial Vulnerability in the Cerebral Compartments in Preterm Infants and Neonates haemorrhagic infarction Frontiers in Neurology 2014 Ivica Kostovic et al..

Periventricular haemorr. also interfere with proliferation (germ. matrix) and migration, which contributes to the complexity of the lesion.

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Sinus thrombosis and related haemorrhagic Sinus thrombosis and related haemorrhagic infarction infarction most frequent locations • 40 cases per 100,000 live births per year More often sagitt. sinus cortical-subcortical parasagitt. haematom., • transeverse-sigmoid sinus temporal-basal haematom. Comorbidities and risk factors in 62%: - dehydration - - sepsis - cardiac malformations - higher incidence of MTHFR mutations than controls • internal cerebral veins- straight sinus thalamic haematom. - Brain injuries related to CSVT is likely due to the increased venous pressure, which results in an increase in the net capillary filtration, with Bilthalamic haematomas in subsequent vasogenic edema and a reduction in arterial perfusion newborn means CVT if not pressure, with subsequent tissue damage. proven differently - A mixed MRI pattern with both cytotoxic and vasogenic edema.

Arch Dis Child Fetal Neonatal Ed 2012, 97:F377-384 33 34

Sinus thrombosis and related haemorrhagic infarction Sinus thrombosis and related haemorrhagic infarction most frequent locations

Internal cereb. veins-straight sinus thrombosis and Blood invading bithalamic involvement subarachnoid sudural space Early thrombosis resolution Transverse sinus normal venogram thrombosis and temporal lobe involvement

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Differential diagn. I Differential diagn. II Peripartum spontaneous haematomas-haemorrhages AJNR 2004 Subpial haemorrhage - term healthy neonates Spontaneous Superficial Parenchymal and Leptomeningeal Hemorrhage in - spontaneous delivery Term Neonates . Amy H. Huang and Richard L. Robertson - superficial parenchymal leptomeningeal haemorrhage - most common temporal lobe, parietal lobe next to sutures - no sinus thrombosis - relative good outcome - Labor trauma with contusion or venous compression/occlusion

Three-dimensional magnetic resonance imaging of fetal head Subpial molding and brain shape changes Subpial Hemorrhage of Angio-ven-TOF during the second stage of labor the Neonate haemorr. Olivier Ami et Al. PLOS ONE 2019 Donald W. Cain et Al. Stroke DWI cranial deformation January 2020 3d old at term and suture overlap acute thrombocytopenia and coagulation abnormalities were common 37 38

Differential diagn. III congenital cavenomas- angiomas in newborn (rare)

partial haemorragic-transformation of subacute AIS thank you (reperfusion, tissue haemorr. necrosis, etc.)

11d

T2* 39 40

Pathophysiology spot Spot on tech. perspective Oscillating-gradient diffusion magnetic resonance imaging detects acute subcellular structural changes in the mouse forebrain after neonatal hypoxia-ischemia Diffusion tensor imaging of early changes in corpus callosum after acute cerebral hemisphere lesions in newborns Dan Wu et Al. Journal of Cerebral Blood Flow & Metabolism 2018 Andrea Righini, Chiara Doneda, Cecilia Parazzini, Filippo Arrigoni, Ursula Matta & Fabio Triulzi HUMAN OBSERVATION Neuroradiology July 2010 Short diffusion time with MRI-oscillating gradients

While mean AXIAL D value in lesioned splenium was significantly lower than in normal controls (1.61 SD 0.52 versus 2.36 SD 0.14 μm2/s, p < 0.0001), mean RADIAL D value did not change significantly, with just a trend towards a decrease (0.60 SD 0.21 versus 0.73 SD 0.12 μm2/s, p < 0.0590).

Double Oscillating Diffusion Encoding and Sensitivity to Microscopic Anisotropy Andrada Ianu ̧ et Al. Neurite beading is sufficient to decrease the apparent diffusion coefficient after ischemic stroke Matthew D. Budde and Joseph A. Frank Magnetic Resonance in Medicine 78:550–564 (2017) PNAS August 2010

normal axons beading axons IN-VITRO DEMONSTRATION 41 42

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Cerebellar Haemorrhages bilat. with vermis

EG:27 monolat with vermis

EG:26 monolat no vermis Analogies with fetal ones: <27 week onset Caudal cerebellum. Mono or bilat, w/wout vermian involvement 43

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