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Neonatal arterial ischemic stroke secondary to carotid artery dissection: a case report and systematic literature review

  • Author Footnotes
    ˆ Joint first authors: These authors were equally responsible for the work described in this paper, contributed equally and share the first authorship
    Laura Baggio
    Footnotes
    ˆ Joint first authors: These authors were equally responsible for the work described in this paper, contributed equally and share the first authorship
    Affiliations
    Paediatric Neurology and Neurophysiology Unit, Department of Women's and Children's Health, University Hospital of Padova, Padova, Italy

    Master in Pediatrics and Pediatric Subspecialties, University of Padova, Padova, Italy
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  • Author Footnotes
    ˆ Joint first authors: These authors were equally responsible for the work described in this paper, contributed equally and share the first authorship
    Margherita Nosadini
    Correspondence
    Corresponding author: Margherita Nosadini, MD, PhD, Department of Women's and Children's Health, Paediatric Neurology and Neurophysiology Unit, University Hospital of Padova, Padova, Italy. Neuroimmunology group, Paediatric Research Institute “Città della Speranza”, Padova, Italy. Via Giustiniani 3, 35128 Padova, Italy.
    Footnotes
    ˆ Joint first authors: These authors were equally responsible for the work described in this paper, contributed equally and share the first authorship
    Affiliations
    Paediatric Neurology and Neurophysiology Unit, Department of Women's and Children's Health, University Hospital of Padova, Padova, Italy

    Neuroimmunology group, Paediatric Research Institute “Città della Speranza”, Padova, Italy
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  • Maria Federica Pelizza
    Affiliations
    Paediatric Neurology and Neurophysiology Unit, Department of Women's and Children's Health, University Hospital of Padova, Padova, Italy
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  • Jacopo Norberto Pin
    Affiliations
    Paediatric Neurology and Neurophysiology Unit, Department of Women's and Children's Health, University Hospital of Padova, Padova, Italy
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  • Anna Zarpellon
    Affiliations
    Paediatric Neurology and Neurophysiology Unit, Department of Women's and Children's Health, University Hospital of Padova, Padova, Italy
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  • Clarissa Tona
    Affiliations
    Paediatric Neurology and Neurophysiology Unit, Department of Women's and Children's Health, University Hospital of Padova, Padova, Italy
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  • Giorgio Perilongo
    Affiliations
    Paediatric Neurology and Neurophysiology Unit, Department of Women's and Children's Health, University Hospital of Padova, Padova, Italy
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  • Paolo Simioni
    Affiliations
    General Internal Medicine and Thrombotic and Hemorrhagic Unit, University of Padua, Padua, Italy
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  • Irene Toldo
    Affiliations
    Paediatric Neurology and Neurophysiology Unit, Department of Women's and Children's Health, University Hospital of Padova, Padova, Italy
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  • Giacomo Talenti
    Affiliations
    Neuroradiology Unit, University Hospital of Padova, 35128 Padova, Italy
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  • Stefano Sartori
    Affiliations
    Paediatric Neurology and Neurophysiology Unit, Department of Women's and Children's Health, University Hospital of Padova, Padova, Italy

    Neuroimmunology group, Paediatric Research Institute “Città della Speranza”, Padova, Italy

    Department of Neuroscience, University of Padova, Padova, Italy
    Search for articles by this author
  • Author Footnotes
    ˆ Joint first authors: These authors were equally responsible for the work described in this paper, contributed equally and share the first authorship
Open AccessPublished:October 28, 2022DOI:https://doi.org/10.1016/j.pediatrneurol.2022.10.008

      Highlights

      • Neonatal arterial ischaemic stroke due to carotid artery dissection (NAIS-CAD) is rare
      • Instrumental/traumatic delivery or urgent caesarean section often precede NAIS-CAD
      • Most frequent clinical presentation of NAIS-CAD is with seizures and systemic signs/symptoms
      • Neuroradiology is characterised in most cases by extensive ischaemic brain lesions
      • Neurovascular imaging should be carried out in all patients with NAIS
      • Definite evidence and recommendations on antithrombotic treatment for NAIS-CAD are lacking

      Abstract

      Background

      Carotid artery (CA) dissection is a rare aetiology of neonatal arterial ischemic stroke (NAIS). Diagnosis is challenging due to low level of suspicion and difficult interpretation of neonatal vascular studies.

      Aim

      To collect data on clinical-radiological presentation, treatment and outcome of NAIS due to CA dissection.

      Methods

      We describe one novel case and conduct a systematic literature review on NAIS attributed to CA dissection, complying with the PRISMA guidelines.

      Results

      8 published cases of NAIS attributed to CA dissection were identified, and analysed with our case. All patients (9/9) were born at term, and 8/9 experienced instrumental/traumatic delivery or urgent caesarean section. None had foetal problems during pregnancy or thrombophilia. Signs and symptoms at presentation (between day of life 0-6) included: seizures (8/9), respiratory distress or irregular breathing (5/9), hyporeactivity, decreased consciousness or irritability (4/9), focal neurological signs (2/9). At MRI, stroke was unilateral in 7/9, extensive in 5/9. CA dissection was documented in 7/9 by neuroimaging or at post-mortem studies, and hypothesised by the treating physicians based on delivery and neuroradiology characteristics in the remaining 2/9. Antithrombotic treatment was used in 2/9. According to available follow-up, 1/8 died at age 7 days, 7/8 had neurologic or epileptic sequelae, and CA recanalisation occurred in 3/4.

      Conclusions

      NAIS attributed to CA dissection is rarely identified in the literature, often preceded by traumatic/instrumental delivery, presenting with seizures and systemic signs/symptoms, and characterised by extensive MRI lesions and neurologic sequelae. Definite evidence and recommendations on antithrombotic treatment are lacking.

      Key words

      INTRODUCTION

      Perinatal stroke comprises a group of cerebrovascular diseases occurring between 20 weeks of foetal life and 28 days postnatal life. Perinatal stroke can be categorised into arterial or venous, ischaemic or haemorrhagic, and also according to the timing of clinical presentation, into acute symptomatic perinatal strokes and presumed perinatal strokes [
      • Dunbar M.
      • Kirton A.
      Perinatal stroke: mechanisms, management, and outcomes of early cerebrovascular brain injury.
      ,
      • Ferriero D.M.
      • Fullerton H.J.
      • Bernard T.J.
      • Billinghurst L.
      • Daniels S.R.
      • DeBaun M.R.
      • deVeber G.
      • Ichord R.N.
      • Jordan L.C.
      • Massicotte P.
      • Meldau J.
      • Roach E.S.
      • Smith E.R.
      American Heart Associa-tion Stroke Council and Council on Cardiovascular and Stroke Nursing. Management of Stroke in Neonates and Children: A Scientific Statement From the American Heart Associa-tion/American Stroke Association.
      ]. Acute symptomatic perinatal strokes present shortly after onset, manifesting clinically within 28 days after birth typically with focal seizures; they can be distinguished into neonatal arterial ischaemic stroke (NAIS), neonatal cerebral sinovenous thrombosis and neonatal haemorrhagic stroke. Whereas, presumed perinatal strokes refer to chronic strokes diagnosed in a delayed manner and presumed to have occurred in the perinatal period, typically presenting clinically in infancy as hemiparetic cerebral palsy, pathological early handedness, developmental delay or seizures with imaging confirmation of remote stroke; they include arterial presumed perinatal ischaemic stroke, periventricular venous infarction and presumed perinatal haemorrhagic stroke [
      • Dunbar M.
      • Kirton A.
      Perinatal stroke: mechanisms, management, and outcomes of early cerebrovascular brain injury.
      ,
      • Ferriero D.M.
      • Fullerton H.J.
      • Bernard T.J.
      • Billinghurst L.
      • Daniels S.R.
      • DeBaun M.R.
      • deVeber G.
      • Ichord R.N.
      • Jordan L.C.
      • Massicotte P.
      • Meldau J.
      • Roach E.S.
      • Smith E.R.
      American Heart Associa-tion Stroke Council and Council on Cardiovascular and Stroke Nursing. Management of Stroke in Neonates and Children: A Scientific Statement From the American Heart Associa-tion/American Stroke Association.
      ,
      • Fluss J.
      • Garcia-Tarodo S.
      • Granier M.
      • Villega F.
      • Ferey S.
      • Husson B.
      • Kossorotoff M.
      • Mueh-lethaler V.
      • Lebon S.
      • Chabrier S.
      Perinatal arterial ischemic stroke related to carotid artery occlusion.
      ] (Figure 1).
      Figure thumbnail gr1
      Figure 1Subtypes of perinatal strokes. According to the timing of clinical presentation and diagnosis, perinatal stroke includes the categories of acute symptomatic perinatal strokes (neonatal arterial ischaemic stroke [NAIS], neonatal cerebral sinovenous thrombosis and neonatal haemorrhagic stroke), manifesting clinically within 28 days after birth typically with focal seizures, and presumed perinatal strokes (arterial presumed perinatal ischaemic stroke, periventricular venous infarction and presumed perinatal haemorrhagic stroke), typically presenting in infancy as hemiparetic cerebral palsy with imaging confirmation of remote stroke [
      • Dunbar M.
      • Kirton A.
      Perinatal stroke: mechanisms, management, and outcomes of early cerebrovascular brain injury.
      ,
      • Ferriero D.M.
      • Fullerton H.J.
      • Bernard T.J.
      • Billinghurst L.
      • Daniels S.R.
      • DeBaun M.R.
      • deVeber G.
      • Ichord R.N.
      • Jordan L.C.
      • Massicotte P.
      • Meldau J.
      • Roach E.S.
      • Smith E.R.
      American Heart Associa-tion Stroke Council and Council on Cardiovascular and Stroke Nursing. Management of Stroke in Neonates and Children: A Scientific Statement From the American Heart Associa-tion/American Stroke Association.
      ,
      • Fluss J.
      • Garcia-Tarodo S.
      • Granier M.
      • Villega F.
      • Ferey S.
      • Husson B.
      • Kossorotoff M.
      • Mueh-lethaler V.
      • Lebon S.
      • Chabrier S.
      Perinatal arterial ischemic stroke related to carotid artery occlusion.
      ].
      NAIS is characterised by a vascular focal brain ischaemic infarction corresponding to one or more arterial territories, and accounts for about 80% of acute neonatal strokes [
      • Dunbar M.
      • Kirton A.
      Perinatal stroke: mechanisms, management, and outcomes of early cerebrovascular brain injury.
      ,
      • Ferriero D.M.
      • Fullerton H.J.
      • Bernard T.J.
      • Billinghurst L.
      • Daniels S.R.
      • DeBaun M.R.
      • deVeber G.
      • Ichord R.N.
      • Jordan L.C.
      • Massicotte P.
      • Meldau J.
      • Roach E.S.
      • Smith E.R.
      American Heart Associa-tion Stroke Council and Council on Cardiovascular and Stroke Nursing. Management of Stroke in Neonates and Children: A Scientific Statement From the American Heart Associa-tion/American Stroke Association.
      ,
      • Dunbar M.
      • Kirton A.
      Perinatal Stroke.
      ,
      • Dunbar M.
      • Mineyko A.
      • Hill M.
      • Hodge J.
      • Floer A.
      • Kirton A.
      Population Based Birth Prevalence of Disease-Specific Perinatal Stroke.
      ,
      • Biswas A.
      • Mankad K.
      • Shroff M.
      • Hanagandi P.
      • Krishnan P.
      Neuroimaging Perspectives of Perinatal Arterial Ischemic Stroke.
      ]. Despite advances in perinatal care and increased awareness, NAIS still represents an important cause of injury to the developing brain and accounts for a high morbidity rate.
      Different risk factors for NAIS have been recognised, including both maternal and neonatal factors, none with a definite causative relation, and aetiology is considered to be multifactorial [
      • Ferriero D.M.
      • Fullerton H.J.
      • Bernard T.J.
      • Billinghurst L.
      • Daniels S.R.
      • DeBaun M.R.
      • deVeber G.
      • Ichord R.N.
      • Jordan L.C.
      • Massicotte P.
      • Meldau J.
      • Roach E.S.
      • Smith E.R.
      American Heart Associa-tion Stroke Council and Council on Cardiovascular and Stroke Nursing. Management of Stroke in Neonates and Children: A Scientific Statement From the American Heart Associa-tion/American Stroke Association.
      ,
      • Clive B.
      • Vincer M.
      • Ahmad T.
      • Khan N.
      • Afifi J.
      • El-Naggar W.
      Epidemiology of neonatal stroke: A population-based study.
      ]. Thromboembolism arising from the placenta and direct vessel injury occurring during birth or due to an underlying arteriopathy are the two main pathophysiological processes hypothesised in NAIS [
      • Fluss J.
      • Garcia-Tarodo S.
      • Granier M.
      • Villega F.
      • Ferey S.
      • Husson B.
      • Kossorotoff M.
      • Mueh-lethaler V.
      • Lebon S.
      • Chabrier S.
      Perinatal arterial ischemic stroke related to carotid artery occlusion.
      ,
      • Biswas A.
      • Mankad K.
      • Shroff M.
      • Hanagandi P.
      • Krishnan P.
      Neuroimaging Perspectives of Perinatal Arterial Ischemic Stroke.
      ,
      • Chabrier S.
      • Saliba E.
      • Nguyen The Tich S.
      • Charollais A.
      • Varlet M.N.
      • Tardy B.
      • Presles E.
      • Renaud C.
      • Allard D.
      • Husson B.
      • Landrieu P.
      Obstetrical and neonatal characteristics vary with birth-weight in a cohort of 100 term newborns with symptomatic arterial ischemic stroke.
      ]. Among the latter, carotid artery dissection is a rarely described aetiology in neonates, also in view of the challenges related to vascular imaging in this age.
      In this study we report one novel case of NAIS related to a carotid artery dissection and we review the pertinent literature, in order to identify clinical and neuroradiological features suggestive for NAIS attributed to carotid artery dissection, and collect data on treatment and outcome.

      METHODS

      We retrospectively analysed data of patients with NAIS diagnosed at our tertiary care centre (Padova, Italy) with the aim of identifying the frequency of NAIS due to carotid artery dissection in our centre, and we describe a novel case of NAIS related to carotid artery dissection (the identity of this case cannot be retrieved from the data provided).
      We subsequently conducted a systematic literature review of neonatal cases with NAIS due to carotid artery occlusion/dissection. The search was carried out in Pubmed independently by two researchers (LB and MN), up to date to 15.08.2022, with the search terms ((carotid dissection) or (carotid occlusion)) and (stroke or infarction or ischemia or ischemic) and (neonatal or neonate or newborn or perinatal). Articles in English, Italian, French and Spanish were included.
      The available articles were filtered manually for patients in neonatal age (≤28 days) with stroke attributed to carotid artery dissection. Demographics, clinical, radiological and treatment data were collected. Studies on animals, and articles reporting neonatal patients with stroke and carotid occlusion not clearly attributed to dissection by the authors [
      • Bukari S.
      • Siddiqui A.
      • Rajpurkar M.
      • Chitlur M.
      Perinatal arterial ischemic stroke and multiple thrombo-emboli in a term newborn.
      ,
      • Raets M.M.
      • Lequin M.H.
      • Plaisier A.
      • Dudink J.
      • Govaert P.
      Incidental sonographic diagnosis of neonatal carotid occlusion.
      ,
      • Amlie-Lefond C.M.
      • Basir M.A.
      • Franciosi R.A.
      Fatal neonatal stroke from a prenatal cardiac thrombus.
      ,
      • Lee E.J.
      • Lim G.Y.
      • Kim S.Y.
      Extensive unilateral cerebral infarct in a full-term newborn.
      ,
      • Suppiej A.
      • Toffoli E.
      • Festa I.
      • Cervesi C.
      • Cappellari A.
      • Manara R.
      • Magarotto M.
      • Cainelli E.
      Perinatal carotid artery ischemic stroke: Report of two cases.
      ,
      • Ebert J.J.
      • Varma H.
      • Sisk R.A.
      Unilateral Terson-Like Syndrome in a Patient With a Perinatal Ischemic Stroke.
      ], or neonatal patients with carotid dissection in the absence of an associated stroke, were excluded [
      • Ryerson L.M.
      • Sanchez-Glanville C.
      • Huberdeau C.
      • Aklabi M.A.
      Carotid Artery Dissection Following Neck Cannulation for Extracorporeal Life Support.
      ] (Figure 2). The systematic literature review complies with the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines.
      Figure thumbnail gr2
      Figure 2Identification of studies via Pubmed search (PRISMA).

      RESULTS

      Case presentation

      From May 2010 to September 2021, among 49 cases of NAIS diagnosed in our tertiary care centre, carotid artery dissection was diagnosed in 1/49 (2%). This patient is described below.
      A 40-gestational-week-old female was born in 2021 after an uneventful pregnancy from an urgent caesarean section due to a pathological cardiotocographic tracing. At birth she was hypotonic, hyporeactive and had respiratory distress. Apgar scores were 8-9-10 (at minutes 1, 5 and 10 respectively) and arterial cord pH was 7.09 with base excess -12,8 mmol/L. She was diagnosed with a mild hypoxic ischemic encephalopathy (Sarnat score 1). At birth, weight was 3970 g (90-97th centile), length 50 cm (10th centile), head circumference 35 cm (50-97th centile).
      A transcranial ultrasound showed hyperechogenicity of the left parietal lobe. During her day of life (DOL) 1, she experienced focal electroclinical seizures, thus phenobarbital was started.
      Brain magnetic resonance imaging (MRI) with MR angiography on DOL 1 (Figure 3) showed a left middle cerebral artery (MCA) acute cortico-subcortical ischaemic lesion in the insular, parietal, temporal lobes and in the striatum. A focal dissection in the proximal part of the left carotid artery was detected with secondary thrombosis of the left MCA.
      Figure thumbnail gr3
      Figure 3A. Brain MRI at day of life 1: left middle cerebral artery (MCA) acute cortical-subcortical ischemic lesion in the insular, parietal, temporal lobes and in the striatum. B. MR Time of Flight Angiography demonstrates absence of flow in the left middle cerebral artery (MCA). C. MR Time of Flight Angiography shows focal flow signal defect (arrow) of the internal carotid artery (ICA) just after the bifurcation, in keeping with dissection. D. Axial T1 fat-sat showing spontaneous arterial wall hyperintensity (arrow) in the left internal carotid artery (ICA) consistent with intramural hematoma.
      Antithrombotic therapy with low molecular weight heparin 150 IU/kg/day was started.
      Follow-up brain MRI on DOL 12 showed partial recanalization of the left M1 segment and complete recanalisation of the left internal carotid artery (ICA).
      The supra-aortic vessels and transcranial doppler sonography performed on DOL 15 were suggestive for an intimal flap of the extracranial portion of the left ICA.
      At age 1 month, brain MRI showed further MCA recanalisation with mild residual stenosis of the proximal third of the M1 segment. Thus, heparin was discontinued and aspirin 2.5 mg/kg/day was administered for 1 month. Phenobarbital was discontinued at age 4 months due to the absence of seizures.
      At age 7 months, the girl has right hemiparetic cerebral palsy with mild developmental delay and is not yet able to sit unsupported.

      Literature review

      The literature search yielded a total of 375 results. Among these, 6 articles reporting a total of 8 cases of NAIS attributed to carotid dissection were identified [
      • Fluss J.
      • Garcia-Tarodo S.
      • Granier M.
      • Villega F.
      • Ferey S.
      • Husson B.
      • Kossorotoff M.
      • Mueh-lethaler V.
      • Lebon S.
      • Chabrier S.
      Perinatal arterial ischemic stroke related to carotid artery occlusion.
      ,
      • Mann C.I.
      • Dietrich R.B.
      • Schrader M.T.
      • Peck W.W.
      • Demos D.S.
      • Bradley Jr., W.G.
      Posttraumatic carotid artery dissection in children: evaluation with MR angiography.
      ,
      • Lequin M.H.
      • Peeters E.A.
      • Holscher H.C.
      • de Krijger R.
      • Govaert P.
      Arterial infarction caused by carotid artery dissection in the neonate.
      ,
      • Hamida N.
      • Hakim A.
      • Fourati H.
      • Ben Thabet A.
      • Walha L.
      • Bouraoui A.
      • Mnif Z.
      • Gargouri A.
      Dissection artérielle cervicale néonatale secondaire à un traumatisme obstétrical [Neonatal cervical artery dissection secondary to birth trauma].
      ,
      • Piris-Borregas S.
      • Vicente-Santamaría S.
      • Martínez de Aragón A.
      • Camacho-Salas A.
      Disección carotídea como causa de ictus perinatal [Carotid dissection as the cause of perinatal strokes].
      ,
      • Benavente-Fernández I.
      • Zuazo Ojeda A.
      • Lubián-López S.P.
      Ischemic stroke caused by arterial dissection of the internal carotid artery diagnosed by Doppler sonography in a newborn.
      ] (Figure 2). These 8 literature cases were analysed and described together with our novel patient below and in Table 1.
      Table 1Published cases of NAIS attributed to carotid artery dissection retrieved from the literature review, (n=8) and our case (n=1)
      ReferenceSex, GA and weight at birth

      Apgar score UCBGA
      DeliveryRisk factorsTiming and type of clinical presentationNeuroimaging (timing)Carotid artery occlusionNeuroradiologic demonstration of dissectionVascular territory involved by the strokeAntithrombotic treatmentAge at last follow-up

      Neurological outcome

      Epilepsy

      Vascular studies
      Mann 1993M, 42 gw

      3300 g

      Apgar s. 1-9
      Urgent C-section after vacuum delivery attemptStained meconiumDOL 6: seizures and right hemiparesis involving the face, arm and legDUS (DOL 9): tapering of the left ICA immediately distal to the bifurcation, with undetectable flow 5 mm distal to the bifurcation

      MRI (N/A): infarct in the left MCA distribution with absent signal void in the left ICA

      MRA (N/A): occlusion of the left ICA just superior to the CA bifurcation, with a positive string sign; decreased calibre of the left MCA
      Left ICA (DUS, MRA)Yes: string sign (DUS, MRA)Left MCANone10 m

      Outcome and epilepsy N/A

      MRA (10 m): left ICA recanalization, persistent attenuation of the left MCA

      MRI (10 m): encephalomalacia in the left MCA stroke region
      Lequin 2004F, at term

      3240 g

      Apgar s. 5-7 pH 7.16 BE 10.9
      Instrumental (vacuum and forceps extraction)NoneDOL 0-2: irregular breathing due to pneumothorax

      DOL 3: hypertonia and convulsions (PB, MDZ)
      CUS (DOL 3): slit ventricles and a slightly increased basal ganglia echogenicity, no midline shift

      MRI (DOL 4): infarctions in the territory of left MCA and ACA, and right ACA and pial segments of the right MCA, caused by a complete occlusion of the ICA on the left and a partial occlusion on the right, best seen on the T2 weighted spin echo (SE) images.

      MRA (DOL 4): loss of signal in left carotid artery at petrous level (C2); the right carotid artery shows signal loss at supraclinoid level (C4)

      DUS: no sign of dissection at the C1 level

      Postmortem confirmation of brain infarction due to dissection with ICAs thrombosis
      Left ICA, complete

      Right ICA, partial (MRA)
      No (postmortem demonstration)Left MCA + ACA

      Right MCA (extensive)
      NoneDied at DOL 7
      Lequin 2004M, 41 gw

      4900 g

      Apgar s. 9-10
      VaginalProlonged rupture of membranes

      Stained meconium
      DOL 0 (2 h): right cervical lump, respiratory distress, irritabilityCUS (DOL 4): right basal ganglia hyperechogenicity with some mass effect

      DUS (DOL 4): thrrombus distal to the right carotid bulb (C1) due to dissection at this level, collateral vessels

      CT (DOL 4): infarction in the area of the right MCA

      MRI (DOL 13): early right hemisphere atrophy due to right ICA occlusion

      MRA (DOL 13): narrowing of the right CA due to dissection and thrombosis
      Right ICAYes: narrowing of the right CA (DUS, MRA)Right MCANone4 y

      Left spastic hemiplegia, language delay, special schooling

      Epilepsy under control with CBZ
      Hamida 2014M, 38 gw

      4600 g

      Apgar s. 7-9
      InstrumentalPoorly followed pregnancy, maternal hypertension

      Difficult extraction with right humeral fracture and right brachial palsy, shoulder dystocia
      DOL 0: mild respiratory distress, weak sucking reflex, Moro reflex asymmetry (right brachial palsy)

      DOL 1: generalised convulsive seizures (PB, VPA)
      CT (DOL 1): hypodense areas in the right occipital and capsulo-lenticulo-caudate regions and left fronto-temporo-parietal regions, in keeping with ischaemic cerebrovascular accidents, with haemorrhagic changes on the left

      DUS (DOL 1): extensive thrombosis affecting the left CCA and its two branches and partially the right ICA; vertebral arteries patent in their cervical tract

      MRI (N/A): signal hyperintensity at the level of the right posterior territories, right ICA and left superficial sylvian region

      MRA (N/A): dissection of the left CCA and its two external and internal branches. An anomaly of signal at the level of the third portion of the right vertebral artery evoked a dissection at its level but the partial thrombus of the right CCA was not visualized on this exam.
      Left CCA, ICA, ECA, complete

      Right ICA, partial (DUS, MRA)
      Yes (MRA)Right PCA + MCA

      Left MCA
      None11 m

      Microcephaly, motor delay (not yet sitting unsupported), right upper limb paresis

      No epilepsy

      DUS (1 m): recanalization of the carotids
      Piris-Borregas 2015F, at term

      4194 g

      Apgar s. 9-10 pH 7.22
      Instrumental (forceps)Stained meconiumDOL 2: seizures (PB)CT (DOL 2): extensive hypodensity in the territory of the left MCA and PCA

      MRI (DOL 3): infarction in the left MCA territory: left basal ganglia and cerebral hemisphere

      MRA (DOL 3): absent flow in the left CCA and left ICA
      Left CCA and ICA (MRA)Yes (MRA)Left MCA (extensive)None4 y

      Right hemiparesis

      No epilepsy (no ASM)
      Fluss 2016M, 39 gw

      3250 g

      Apgar s. 10-10
      Instrumental (forceps)Shoulder dystociaDOL 1: right-sided hypotonia and focal convulsionsCT (DOL 2), MRI (DOL 12): extensive ischemic stroke involving both the superficial and deep territories of the left MCA

      MRA (DOL 15): occlusion of the left ICA, presumably related to arterial wall injury upon obstetrical trauma although not formally confirmed by imaging
      Left ICA (MRA)NoLeft MCA (extensive)None8 y

      Right-sided spastic cerebral palsy, behavioural issues, mild intellectual disability

      Refractory epilepsy
      Fluss 2016F, 40 gw

      4560 g

      Apgar s. 7-9-10 pH 7.12
      VaginalShoulder dystocia, macrosomiaDOL 0: respiratory distress and focal seizures (apnoea, right hand clonia)CUS (N/A): diffuse hyperechogenicity on the right hemisphere

      MRI (DOL 5): major right hemispheric infarction with absent flow in the right ICA but sparing of the deep MCA territory; right PCA territory involvement

      MRA (DOL 5): absent right ICA flow, with visible flow along the right MCA

      CT (DOL 11): confirmed carotid occlusion at the cervical level
      Right ICA (MRA, CT angiography)NoRight MCA + ACA (extensive)ASA for 3 months (no side effects)14 m

      Left hemiparesis, left hemianopsia, microcephaly

      No epilepsy

      MRA (3 m): persistence of right ICA occlusion

      MRI (14 m): atrophy of the whole superficial MCA territory, partially sparing the deep MCA territory
      Benavente-Fernández 2019M, 39+4 gw

      3550 g

      Apgar s. 6-8
      Urgent C-section after vacuum delivery attemptNoneDOL 2: decreased level of consciousness, hypertonia, bulging fontanelle, electrical focal seizures (PB, LEV, lidocaine)CUS (DOL 2): large triangular wedge-shaped echogenic area in the right hemisphere with collapsed right ventricular system and sulci, causing mass effect and left midline shift

      DUS: no flow signal in the right MCA and in the right ICA

      MRI (DOL 4): extensive ischemic injury in the right MCA territory

      MRA (DOL 4): confirmed the US suspicion of dissection and thrombosis of the right ICA (carotid dissection with findings of irregular stenosis, “string sign”)
      Right ICA (DUS)Yes: string sign (MRA)Right MCA (extensive)None6 m

      Infantile spasms (ASM)
      Our caseF, 40+4 gw

      3940 g

      Apgar s. 8-9-10 pH 7.09 BE -12.8
      Urgent C-sectionPathological cardiotocographic tracing, maternal feverAt birth: hyporeactivity, hypotonia, respiratory distress

      DOL 1: focal seizures
      CUS (DOL 1): hyperechogenicity of the left parietal lobe

      MRI (DOL 1): left MCA acute cortico-subcortical ischaemic lesion in the insular, parietal, temporal lobes and in the striatum

      MRA (DOL 1): focal dissection in the proximal part of the left ICA, secondary thrombosis of the left MCA

      DUS (DOL 15): intimal flap of the extracranial portion of the left ICA
      Left ICA + MCA (MRA)Yes (MRA, DUS)Left MCALMWH, then ASA (no side effects)7 m

      Right hemiparesis

      No epilepsy (no ASM)

      MRI (DOL 12 partial recanalization of the left M1 segment and complete left ICA recanalisation
      ACA: anterior cerebral artery; ASA: acetylsalicylic acid; ASM: antiseizure medications; BE: base excess; CA: carotid artery; CCA: common carotid artery; C-section: caesarean section; CT: cerebral computed tomography; CUS: cerebral ultrasound; DOL: day of life; DUS: doppler ultrasound; ECA: external carotid artery; F: female; GA: gestational age; gw: gestational weeks; ICA: internal carotid artery; LEV: levetiracetam; m: months; M: male; MCA: median cerebral artery; MDZ: midazolam; MRA: cerebral magnetic resonance angiography; MRI: cerebral magnetic resonance imaging; N/A: not available; PB: phenobarbital; PCA: posterior cerebral artery; UCBGA: umbilical cord blood gas analysis; VPA: valproic acid; y: years.
      All cases (9/9) were born at term and 8/9 experienced an instrumental or traumatic delivery or an urgent caesarean section; foetal problems during pregnancy were not reported, and maternal problems during pregnancy were reported only in 1/9 case (hypertension); thrombophilia assessment was normal in 9/9.
      Signs and symptoms at clinical presentation (ranging between DOL 0 and 6) included: seizures (8/9), respiratory distress or irregular breathing (5/9), hyporeactivity, decreased level of consciousness or irritability (4/9), focal neurological signs (unilateral hypotonia or hypertonia) (2/9).
      The first brain parenchymal neuroimaging was cranial ultrasound in 5/9, showing pathological findings in all 5/5, cerebral computed tomography (CT) in 3/9, revealing an ischaemic lesion in 3/3, and brain MRI in 1/9. Brain MRI was carried out in all 9/9 patients, showing an ischaemic lesion in all (left-sided in 4/9, right-sided in 3/9 and bilateral in 2/9), described as extensive in 5/9.
      Regarding vascular studies, doppler sonography was carried out in 6/9, detecting absent blood flow in the ICA and/or MCA in 4/6, and MR angiography was done in 9/9 cases, revealing pathological findings in all.
      Neuroradiology-demonstrated carotid artery dissection was reported in 6/9 patients including our case [
      • Mann C.I.
      • Dietrich R.B.
      • Schrader M.T.
      • Peck W.W.
      • Demos D.S.
      • Bradley Jr., W.G.
      Posttraumatic carotid artery dissection in children: evaluation with MR angiography.
      ,
      • Lequin M.H.
      • Peeters E.A.
      • Holscher H.C.
      • de Krijger R.
      • Govaert P.
      Arterial infarction caused by carotid artery dissection in the neonate.
      ,
      • Hamida N.
      • Hakim A.
      • Fourati H.
      • Ben Thabet A.
      • Walha L.
      • Bouraoui A.
      • Mnif Z.
      • Gargouri A.
      Dissection artérielle cervicale néonatale secondaire à un traumatisme obstétrical [Neonatal cervical artery dissection secondary to birth trauma].
      ,
      • Piris-Borregas S.
      • Vicente-Santamaría S.
      • Martínez de Aragón A.
      • Camacho-Salas A.
      Disección carotídea como causa de ictus perinatal [Carotid dissection as the cause of perinatal strokes].
      ,
      • Benavente-Fernández I.
      • Zuazo Ojeda A.
      • Lubián-López S.P.
      Ischemic stroke caused by arterial dissection of the internal carotid artery diagnosed by Doppler sonography in a newborn.
      ], and demonstrated at post-mortem studies in an additional 1/9 case [
      • Lequin M.H.
      • Peeters E.A.
      • Holscher H.C.
      • de Krijger R.
      • Govaert P.
      Arterial infarction caused by carotid artery dissection in the neonate.
      ]; in in the remaining 2/9 cases, a carotid artery dissection was hypothesised by the treating physicians based on the delivery modality and the characteristics of the cerebral lesion [
      • Fluss J.
      • Garcia-Tarodo S.
      • Granier M.
      • Villega F.
      • Ferey S.
      • Husson B.
      • Kossorotoff M.
      • Mueh-lethaler V.
      • Lebon S.
      • Chabrier S.
      Perinatal arterial ischemic stroke related to carotid artery occlusion.
      ].
      In 2/9 patients including our case [
      • Fluss J.
      • Garcia-Tarodo S.
      • Granier M.
      • Villega F.
      • Ferey S.
      • Husson B.
      • Kossorotoff M.
      • Mueh-lethaler V.
      • Lebon S.
      • Chabrier S.
      Perinatal arterial ischemic stroke related to carotid artery occlusion.
      ], antithrombotic treatment was used, with aspirin and heparin followed by aspirin, respectively.
      One patient died at DOL 7 [
      • Lequin M.H.
      • Peeters E.A.
      • Holscher H.C.
      • de Krijger R.
      • Govaert P.
      Arterial infarction caused by carotid artery dissection in the neonate.
      ]. Data on outcome were available in 7/8 remaining patients (duration of follow-up: range 0.5-8 years): 6/7 had hemiparetic/unilateral cerebral palsy, 5/7 had developmental delay and 3/7 developed epilepsy.
      In patients with available follow-up neuroimaging, carotid recanalisation occurred in 3/4.

      Discussion

      Neonatal arterial ischemic stroke (NAIS) secondary to carotid artery dissection is a rare clinical entity associated with direct vessel injury. We have described one novel case of NAIS due to carotid artery dissection and carried out a systematic review of the pertinent literature, identifying 8 additional published cases [
      • Fluss J.
      • Garcia-Tarodo S.
      • Granier M.
      • Villega F.
      • Ferey S.
      • Husson B.
      • Kossorotoff M.
      • Mueh-lethaler V.
      • Lebon S.
      • Chabrier S.
      Perinatal arterial ischemic stroke related to carotid artery occlusion.
      ,
      • Mann C.I.
      • Dietrich R.B.
      • Schrader M.T.
      • Peck W.W.
      • Demos D.S.
      • Bradley Jr., W.G.
      Posttraumatic carotid artery dissection in children: evaluation with MR angiography.
      ,
      • Lequin M.H.
      • Peeters E.A.
      • Holscher H.C.
      • de Krijger R.
      • Govaert P.
      Arterial infarction caused by carotid artery dissection in the neonate.
      ,
      • Hamida N.
      • Hakim A.
      • Fourati H.
      • Ben Thabet A.
      • Walha L.
      • Bouraoui A.
      • Mnif Z.
      • Gargouri A.
      Dissection artérielle cervicale néonatale secondaire à un traumatisme obstétrical [Neonatal cervical artery dissection secondary to birth trauma].
      ,
      • Piris-Borregas S.
      • Vicente-Santamaría S.
      • Martínez de Aragón A.
      • Camacho-Salas A.
      Disección carotídea como causa de ictus perinatal [Carotid dissection as the cause of perinatal strokes].
      ,
      • Benavente-Fernández I.
      • Zuazo Ojeda A.
      • Lubián-López S.P.
      Ischemic stroke caused by arterial dissection of the internal carotid artery diagnosed by Doppler sonography in a newborn.
      ].
      Our main results, derived from pooling together the literature patients and our novel case, show that most patients experienced an instrumental or traumatic delivery or an urgent caesarean section, and the great majority presented with seizures accompanied by systemic signs/symptoms such as respiratory distress, hyporeactivity, decreased consciousness or irritability. Neuroradiology was characterised in most cases by extensive ischemic brain lesions, mostly unilateral, with documented carotid artery dissection in the majority of cases, by neuroimaging or at post-mortem confirmation. Antithrombotic therapy was used in the minority, and outcome was characterised by severe neurological sequelae.
      The low frequency of carotid artery dissection among NAIS cases in our centre (2%, n=1 case), and the very limited number of published cases of NAIS attributed to carotid artery dissection identified by our literature review (n=8 published cases), confirm that carotid artery dissection is a rare aetiology of NAIS.
      It is well established that the detection of vascular lesions in general is infrequent in NAIS, with intraluminal thrombi in cerebral arteries, evidence for vessel wall injuries, or arteriopathy being seldom documented on angiographic sequences in neonatal age [
      • Fluss J.
      • Garcia-Tarodo S.
      • Granier M.
      • Villega F.
      • Ferey S.
      • Husson B.
      • Kossorotoff M.
      • Mueh-lethaler V.
      • Lebon S.
      • Chabrier S.
      Perinatal arterial ischemic stroke related to carotid artery occlusion.
      ,
      • Chabrier S.
      • Saliba E.
      • Nguyen The Tich S.
      • Charollais A.
      • Varlet M.N.
      • Tardy B.
      • Presles E.
      • Renaud C.
      • Allard D.
      • Husson B.
      • Landrieu P.
      Obstetrical and neonatal characteristics vary with birth-weight in a cohort of 100 term newborns with symptomatic arterial ischemic stroke.
      ]. In a previous work collating novel and literature cases [
      • Fluss J.
      • Garcia-Tarodo S.
      • Granier M.
      • Villega F.
      • Ferey S.
      • Husson B.
      • Kossorotoff M.
      • Mueh-lethaler V.
      • Lebon S.
      • Chabrier S.
      Perinatal arterial ischemic stroke related to carotid artery occlusion.
      ], patients with NAIS and documented carotid occlusion due to any cause were identified in less than 0.5% (n=16; of these, 6/16 cases were attributed to traumatic arterial injury) [
      • Fluss J.
      • Garcia-Tarodo S.
      • Granier M.
      • Villega F.
      • Ferey S.
      • Husson B.
      • Kossorotoff M.
      • Mueh-lethaler V.
      • Lebon S.
      • Chabrier S.
      Perinatal arterial ischemic stroke related to carotid artery occlusion.
      ,
      • Mann C.I.
      • Dietrich R.B.
      • Schrader M.T.
      • Peck W.W.
      • Demos D.S.
      • Bradley Jr., W.G.
      Posttraumatic carotid artery dissection in children: evaluation with MR angiography.
      ,
      • Lequin M.H.
      • Peeters E.A.
      • Holscher H.C.
      • de Krijger R.
      • Govaert P.
      Arterial infarction caused by carotid artery dissection in the neonate.
      ,
      • Hamida N.
      • Hakim A.
      • Fourati H.
      • Ben Thabet A.
      • Walha L.
      • Bouraoui A.
      • Mnif Z.
      • Gargouri A.
      Dissection artérielle cervicale néonatale secondaire à un traumatisme obstétrical [Neonatal cervical artery dissection secondary to birth trauma].
      ]. The frequency of MR angiography abnormalities in patients with NAIS was higher (35%, 29/81) in a recent monocentric retrospective analysis conducted by the International Pediatric Stroke Study, although it should be noticed that this included both pathological and not clearly pathological anatomical variants, with presumed ICA dissection in only 2/29 [
      • Siddiq I.
      • Armstrong D.
      • Surmava A.M.
      • Dlamini N.
      • MacGregor D.
      • Moharir M.
      • Askalan R.
      Utility of Neurovascular Imaging in Acute Neonatal Arterial Ischemic Stroke.
      ].
      The radiological diagnosis of carotid artery dissection is based on the evidence of an intimal flap, vessel wall hematoma, double lumen and geometric changes at follow-up [
      • Bernard T.J.
      • Beslow L.A.
      • Manco-Johnson M.J.
      • Armstrong-Wells J.
      • Boada R.
      • Weitzenkamp D.
      • Hollatz A.
      • Poisson S.
      • Amlie-Lefond C.
      • Lo W.
      • deVeber G.
      • Goldenberg N.A.
      • Dowling M.M.
      • Roach E.S.
      • Fullerton H.J.
      • Benseler S.M.
      • Jordan L.C.
      • Kirton A.
      • Ichord R.N.
      Inter-Rater Reliability of the CASCADE Criteria: Challenges in Classifying Arteriopathies.
      ,
      • Nash M.
      • Rafay M.F.
      Craniocervical Arterial Dissection in Children: Pathophysiology and Man-agement.
      ]. There are several reasons explaining the difficulties identifying these findings, and vascular lesions in general, in neonates. First of all, neonatal circulation assessment is challenging because of its anatomy, the smaller and/or more tortuous vessels and the lower blood flow velocities compared with older children and adults. Secondly, stroke in newborns is characterised by peculiar elements such as quick thrombus resolution, thus the affected artery is often patent and cerebral vessels exhibit normal anatomy at the time of first acute imaging [
      • Fluss J.
      • Garcia-Tarodo S.
      • Granier M.
      • Villega F.
      • Ferey S.
      • Husson B.
      • Kossorotoff M.
      • Mueh-lethaler V.
      • Lebon S.
      • Chabrier S.
      Perinatal arterial ischemic stroke related to carotid artery occlusion.
      ,
      • Chabrier S.
      • Saliba E.
      • Nguyen The Tich S.
      • Charollais A.
      • Varlet M.N.
      • Tardy B.
      • Presles E.
      • Renaud C.
      • Allard D.
      • Husson B.
      • Landrieu P.
      Obstetrical and neonatal characteristics vary with birth-weight in a cohort of 100 term newborns with symptomatic arterial ischemic stroke.
      ,
      • Van der Aa N.E.
      • Porsius E.D.
      • Hendrikse J.
      • van Kooij B.J.
      • Benders M.J.
      • de Vries L.S.
      • Groenendaal F.
      Changes in carotid blood flow after unilateral perinatal arterial ischemic stroke.
      ]. Further challenges in neonatal imaging may be represented by scanner unavailability or unsuitability for a neonate who is clinically unstable, or the absence of an expert team for critical ill neonates [
      • Bukari S.
      • Siddiqui A.
      • Rajpurkar M.
      • Chitlur M.
      Perinatal arterial ischemic stroke and multiple thrombo-emboli in a term newborn.
      ,
      • Srivastava R.
      • Dunbar M.
      • Shevell M.
      • Oskoui M.
      • Basu A.
      • Rivkin M.J.
      • Shany E.
      • de Vries L.S.
      • Dewey D.
      • Letourneau N.
      • Hill M.D.
      • Kirton A.
      Development and Validation of a Prediction Model for Perinatal Arterial Ischemic Stroke in Term Neonates.
      ].
      Moreover, angiographic sequences are often not routinely performed in stroke study protocols, especially at the cervical level [
      • Fluss J.
      • Garcia-Tarodo S.
      • Granier M.
      • Villega F.
      • Ferey S.
      • Husson B.
      • Kossorotoff M.
      • Mueh-lethaler V.
      • Lebon S.
      • Chabrier S.
      Perinatal arterial ischemic stroke related to carotid artery occlusion.
      ], despite its importance has been previously highlighted [
      • Chabrier S.
      • Saliba E.
      • Nguyen The Tich S.
      • Charollais A.
      • Varlet M.N.
      • Tardy B.
      • Presles E.
      • Renaud C.
      • Allard D.
      • Husson B.
      • Landrieu P.
      Obstetrical and neonatal characteristics vary with birth-weight in a cohort of 100 term newborns with symptomatic arterial ischemic stroke.
      ]. For all these reasons, the use of cranial ultrasound and doppler sonography is supported as a useful, inexpensive, noninvasive and easily available tool for a first evaluation in newborns with concern for stroke, possibly to be identified also based on proposed prediction models [
      • Srivastava R.
      • Dunbar M.
      • Shevell M.
      • Oskoui M.
      • Basu A.
      • Rivkin M.J.
      • Shany E.
      • de Vries L.S.
      • Dewey D.
      • Letourneau N.
      • Hill M.D.
      • Kirton A.
      Development and Validation of a Prediction Model for Perinatal Arterial Ischemic Stroke in Term Neonates.
      ]; MRI could be then performed for an essential more detailed definition [
      • Benavente-Fernández I.
      • Zuazo Ojeda A.
      • Lubián-López S.P.
      Ischemic stroke caused by arterial dissection of the internal carotid artery diagnosed by Doppler sonography in a newborn.
      ].
      As regards the general characteristics of our cohort, the high rate of instrumental or traumatic delivery is noteworthy. To date, the role of instrumental delivery as a risk factor for NAIS is uncertain. However, by analogy with childhood ischemic stroke, it could be reasonably supposed that mechanical stretching during traumatic delivery may cause or favour a direct arterial injury, especially in the presence of macrosomia and shoulder dystocia [
      • Fluss J.
      • Garcia-Tarodo S.
      • Granier M.
      • Villega F.
      • Ferey S.
      • Husson B.
      • Kossorotoff M.
      • Mueh-lethaler V.
      • Lebon S.
      • Chabrier S.
      Perinatal arterial ischemic stroke related to carotid artery occlusion.
      ]. Furthermore, no foetal problems (and rare maternal problems) were reported during pregnancy, and thrombophilia screening was normal in our cohort, further supporting the hypothesis that stroke might have resulted from an insult occurring in the perinatal frame [
      • Chabrier S.
      • Saliba E.
      • Nguyen The Tich S.
      • Charollais A.
      • Varlet M.N.
      • Tardy B.
      • Presles E.
      • Renaud C.
      • Allard D.
      • Husson B.
      • Landrieu P.
      Obstetrical and neonatal characteristics vary with birth-weight in a cohort of 100 term newborns with symptomatic arterial ischemic stroke.
      ,
      • Pascal A.
      • Govaert P.
      • Ortibus E.
      • Naulaers G.
      • Lars A.
      • Fjørtoft T.
      • Oostra A.
      • Zecic A.
      • Cools F.
      • Cloet E.
      • Casaer A.
      • Cornette L.
      • Laroche S.
      • Samijn B.
      • Van den Broeck C.
      Motor outcome after perinatal stroke and early prediction of unilateral spastic cerebral palsy.
      ].
      Similar to the previously mentioned cohort of NAIS due to carotid occlusion [
      • Fluss J.
      • Garcia-Tarodo S.
      • Granier M.
      • Villega F.
      • Ferey S.
      • Husson B.
      • Kossorotoff M.
      • Mueh-lethaler V.
      • Lebon S.
      • Chabrier S.
      Perinatal arterial ischemic stroke related to carotid artery occlusion.
      ], and differently to more common NAIS aetiologies in which neonates mostly experience isolated seizures [
      • Bernson-Leung M.E.
      • Rivkin M.J.
      Stroke in Neonates and Children.
      ,
      • López-Espejo M.A.
      • Chávez M.H.
      • Huete I.
      Short-term outcomes after a neonatal arterial ischemic stroke.
      ], most of our patients presented with seizures accompanied by other nonspecific signs and generalised illness (respiratory distress, hyporeactivity, depressed consciousness, irritability, hypotonia).
      Indeed, it has been observed that occlusion of a large vessel such as carotid artery may cause a less transient vascular occlusion than thromboembolic mechanism, and this could be responsible for more extensive lesions, more frequently associated with encephalopathy or generalised signs/symptoms beside seizures, as opposite to isolated focal seizures as a more common presentation in other aetiologies of NAIS [
      • Fluss J.
      • Garcia-Tarodo S.
      • Granier M.
      • Villega F.
      • Ferey S.
      • Husson B.
      • Kossorotoff M.
      • Mueh-lethaler V.
      • Lebon S.
      • Chabrier S.
      Perinatal arterial ischemic stroke related to carotid artery occlusion.
      ].
      As previously reported in literature, we could find no side prevalence of the NAIS and no specific MRI lesion pattern, with possible involvement of different areas and of both superficial and deep territories [
      • Fluss J.
      • Garcia-Tarodo S.
      • Granier M.
      • Villega F.
      • Ferey S.
      • Husson B.
      • Kossorotoff M.
      • Mueh-lethaler V.
      • Lebon S.
      • Chabrier S.
      Perinatal arterial ischemic stroke related to carotid artery occlusion.
      ].
      All the patients of our series developed important neurological deficits such as unilateral cerebral palsy associated with a severe intellectual disability. When considering NAIS due to other (more frequent) aetiologies, disabilities in motor, learning, behaviour, language, and mental health are otherwise reported in different grades of severity, in relation with the infarction dimensions [
      • Ferriero D.M.
      • Fullerton H.J.
      • Bernard T.J.
      • Billinghurst L.
      • Daniels S.R.
      • DeBaun M.R.
      • deVeber G.
      • Ichord R.N.
      • Jordan L.C.
      • Massicotte P.
      • Meldau J.
      • Roach E.S.
      • Smith E.R.
      American Heart Associa-tion Stroke Council and Council on Cardiovascular and Stroke Nursing. Management of Stroke in Neonates and Children: A Scientific Statement From the American Heart Associa-tion/American Stroke Association.
      ,
      • Dunbar M.
      • Kirton A.
      Perinatal Stroke.
      ,
      • Pascal A.
      • Govaert P.
      • Ortibus E.
      • Naulaers G.
      • Lars A.
      • Fjørtoft T.
      • Oostra A.
      • Zecic A.
      • Cools F.
      • Cloet E.
      • Casaer A.
      • Cornette L.
      • Laroche S.
      • Samijn B.
      • Van den Broeck C.
      Motor outcome after perinatal stroke and early prediction of unilateral spastic cerebral palsy.
      ,
      • Grunt S.
      • Mazenauer L.
      • Buerki S.E.
      • Boltshauser E.
      • Mori A.C.
      • Datta A.N.
      • Fluss J.
      • Mercati D.
      • Kel-ler E.
      • Maier O.
      • Poloni C.
      • Ramelli G.P.
      • Schmitt-Mechelke T.
      • Steinlin M.
      Incidence and outcomes of symptomatic neonatal arterial ischemic stroke.
      ]. As regards epilepsy, it was reported at follow-up in nearly half of patients in our literature cohort, similarly to what reported for other types of arterial ischemic stroke, which is considered the most frequent stroke category associated with structural epilepsy development (50% of presumed perinatal AIS and 71% of NAIS), probably because of the involvement of the cerebral cortex.
      To date, only supportive treatment is recommended for neonates with a first episode of NAIS, especially because of the low recurrence rate, except in cases with a documented thrombophilia or complex congenital heart disease [
      • Ferriero D.M.
      • Fullerton H.J.
      • Bernard T.J.
      • Billinghurst L.
      • Daniels S.R.
      • DeBaun M.R.
      • deVeber G.
      • Ichord R.N.
      • Jordan L.C.
      • Massicotte P.
      • Meldau J.
      • Roach E.S.
      • Smith E.R.
      American Heart Associa-tion Stroke Council and Council on Cardiovascular and Stroke Nursing. Management of Stroke in Neonates and Children: A Scientific Statement From the American Heart Associa-tion/American Stroke Association.
      ,
      • Monagle P.
      • Chan A.K.C.
      • Goldenberg N.A.
      • Ichord R.N.
      • Journeycake J.M.
      • Nowak-Göttl U.
      • Vesely S.K.
      Antithrombotic therapy in neonates and children: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines.
      ], and thrombolysis and mechanical thrombectomy are rarely considered in neonates due to the lack of evidence and the small artery size in this age [
      • Ferriero D.M.
      • Fullerton H.J.
      • Bernard T.J.
      • Billinghurst L.
      • Daniels S.R.
      • DeBaun M.R.
      • deVeber G.
      • Ichord R.N.
      • Jordan L.C.
      • Massicotte P.
      • Meldau J.
      • Roach E.S.
      • Smith E.R.
      American Heart Associa-tion Stroke Council and Council on Cardiovascular and Stroke Nursing. Management of Stroke in Neonates and Children: A Scientific Statement From the American Heart Associa-tion/American Stroke Association.
      ]. However, the potential utility of early antithrombotic treatment in NAIS due to a direct vascular lesion like dissection has been hypothesised [
      • Fluss J.
      • Garcia-Tarodo S.
      • Granier M.
      • Villega F.
      • Ferey S.
      • Husson B.
      • Kossorotoff M.
      • Mueh-lethaler V.
      • Lebon S.
      • Chabrier S.
      Perinatal arterial ischemic stroke related to carotid artery occlusion.
      ,
      • Bukari S.
      • Siddiqui A.
      • Rajpurkar M.
      • Chitlur M.
      Perinatal arterial ischemic stroke and multiple thrombo-emboli in a term newborn.
      ,
      • Siddiq I.
      • Armstrong D.
      • Surmava A.M.
      • Dlamini N.
      • MacGregor D.
      • Moharir M.
      • Askalan R.
      Utility of Neurovascular Imaging in Acute Neonatal Arterial Ischemic Stroke.
      ], similar to recommendations for paediatric and adult stroke due to arteriopathy and in particular arterial wall injury such as dissection [
      • Ferriero D.M.
      • Fullerton H.J.
      • Bernard T.J.
      • Billinghurst L.
      • Daniels S.R.
      • DeBaun M.R.
      • deVeber G.
      • Ichord R.N.
      • Jordan L.C.
      • Massicotte P.
      • Meldau J.
      • Roach E.S.
      • Smith E.R.
      American Heart Associa-tion Stroke Council and Council on Cardiovascular and Stroke Nursing. Management of Stroke in Neonates and Children: A Scientific Statement From the American Heart Associa-tion/American Stroke Association.
      ,
      • Monagle P.
      • Chan A.K.C.
      • Goldenberg N.A.
      • Ichord R.N.
      • Journeycake J.M.
      • Nowak-Göttl U.
      • Vesely S.K.
      Antithrombotic therapy in neonates and children: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines.
      ], but definite evidence and recommendations in neonatal age are lacking. Therefore, the best treatment strategy in NAIS attributed to carotid artery dissection represents a knowledge gap due to the lack of evidence on the efficacy/safety profile and of definite recommendations, and a challenging decision for the treating physician which appears to be often taken on a case-by-case basis.

      Limitations

      The main limitations of our study include the heterogeneous data availability for the literature patients included due to the retrospective study design, and the limited number of cases identified, hindering definite conclusions. Furthermore, data collected refer to a large literature timeframe, during which knowledge on perinatal stroke, its diagnosis and management have improved substantially. Finally, as mentioned earlier, it should also be acknowledged that in our literature cohort carotid artery dissection was not documented at neuroimaging in all cases, and in 2/9 it was hypothesised by the authors of the articles included in the literature review based on the extension of the neuroradiological characteristics and the presence of risk factors.

      Conclusions

      Despite the above-mentioned limitations, in the present study we sought to collect data on NAIS attributed to carotid artery dissection, potentially useful for its characterisation and understanding. Indeed, poor understanding of the underlying primary mechanism in stroke represents an important limitation for prevention, recognition and acute management.
      Our study confirms the rarity of NAIS secondary to carotid artery dissection, the possible association with instrumental or traumatic delivery in the absence of maternal or foetal risk factors, the characteristic presentation with seizures associated with systemic signs/symptoms, the relatively large parenchymal lesions and the severe neurological sequelae. These factors may aid a timely clinical suspicion of this rare entity. More importantly, despite the intrinsic challenges in this age, neurovascular imaging remains be essential to identify the aetiologic mechanism in NAIS, including large or medium vessel occlusion, vascular anomalies such as tortuosity or malformation, and craniocervical arteriopathy including dissection [
      • Biswas A.
      • Mankad K.
      • Shroff M.
      • Hanagandi P.
      • Krishnan P.
      Neuroimaging Perspectives of Perinatal Arterial Ischemic Stroke.
      ].
      Our study confirms and highlights a knowledge gap in the best treatment strategy for NAIS secondary to carotid artery dissection as regards the potential indication for antithrombotic treatment, whose efficacy and safety in this clinical setting is still to be properly assessed in larger studies.

      Acknowledgements

      We thank the Master in Pediatrics and Pediatric Subspecialties, University of Padova, Italy.

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