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Pediatric Neurology 49 (2013) 469e473

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Pediatric Neurology

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Clinical Observations

Stroke by Carotid Artery Complete Occlusion in Kawasaki Disease:Case Report and Review of Literature

Isabelle Sabatier MD a,b, Stéphane Chabrier MD, PhD c,d, Amandine Brun MS e, Laure Hees MD f,Anne Cheylus PhD e, Randy Gollub MD, PhD g, Nouchine Hadjikhani MD, PhDh,Jian Kong MD, MS, PhD g, Vincent des Portes MD, PhD a,b,e, Daniel Floret MD, PhD i,Aurore Curie MD, PhD a,b,e,h,*

aHospices Civils de Lyon, HFME, Service de Neuropédiatrie, Bron, FrancebUniversité Claude Bernard Lyon 1, Lyon, Francec Inserm CIE3, Saint Etienne, FrancedCentre Hospitalier Universitaire de Saint-Étienne, Service de Médecine Physique et Réadaptation Pédiatrique, Saint-Étienne, FranceeCNRS UMR5304, Institut des Sciences Cognitives, L2C2, Bron, FrancefHospices Civils de Lyon, HFME, Unité d’Hospitalisation de Courte Durée, Bron, Franceg Psychiatric Neuroimaging, Department of Psychiatry, Massachusetts General Hospital, Charlestown, MassachusettshA. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Charlestown, MassachusettsiHospices Civils de Lyon, HFME, service de réanimation pédiatrique, Bron, France

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abstract

BACKGROUND: Kawasaki disease is an acute and time-lim

ited systemic vasculitis primarily affecting young children.PATIENT: We describe an 18-month-old girl with Kawasaki disease who developed cerebral infarction followingcomplete occlusion of her right internal carotid artery. RESULTS: The occlusion occurred 10 days after the onset offever, while she was on high-dose aspirin, and the day after she received intravenous immunoglobulin treatment.We present the first literature review on this very rare complication. CONCLUSION: Stroke is a rare neurologicalcomplication in Kawasaki disease. Optimal treatment should be begun as soon as possible after diagnosis. Intra-venous immunoglobulins seem to reduce the cerebrovascular complications, but evaluation of hydration status isstrongly recommended before performing such treatment.

Keywords: Kawasaki disease, infant, stroke, carotid artery occlusion, immunoglobulin

Pediatr Neurol 2013; 49: 469-473

� 2013 Elsevier Inc. All rights reserved.

Introduction

Kawasaki disease is an acute and time-limited systemicvasculitis primarily affecting young children.1,2 Recentstudies have suggested that an ubiquitous infectious agent,which is asymptomatic in most people, leads to Kawasakidisease in some genetically predisposed children.2 Diag-nosis is based on a set of clinical criteria: fever for at least5 days; bilateral conjunctival injection; dryness of mucousmembranes with fissured lips, strawberry tongue, injected

ory:May 2013; Accepted in final form 11 August 2013nications should be addressed to: Dr. Curie; Institut desgnitives; L2C2, CNRS 5304; 67 Boulevard Pinel; 69675 Bronce.

ddress: aurorecurie@yahoo.fr

- see front matter � 2013 Elsevier Inc. All rights reserved..org/10.1016/j.pediatrneurol.2013.08.011

pharynx; voluminous cervical adenopathy, polymorphousrash, peripheral erythema, peripheral edema, and desqua-mation.1 The main complications are cardiac aneurysms.However, neurological complications, such as asepticmeningitis and facial palsy, have been described, in 1% to30% of cases.3,4 Very rare arterial strokes have been reportedin the literature and only one symptomatic case has beenreported since immunoglobulin treatment has becomeavailable (Table).

We describe a stroke occurring the day after immuno-globulin infusion in an 18-month-old girl with Kawasakidisease.

Case Report

An 18-month-old girl with an unremarkable medical history andup-to-date vaccinations presented with a prolonged fever, deterioration

TABLE.Literature review of cerebral infarction and intracranial hemorrhage associated with Kawasaki disease

Reference Sex Age Type of Stroke Stroke Onset* Initial Treatment Stroke Treatment

Hosaki (1978) M 4 mo Occlusion of the right middle cerebral artery 45 days Corticosteroidsand antibiotics

Anticoagulants

Lauret (1979) F 5 yr Occlusion of the right internal carotid artery 10 days Antibiotics Corticosteroids

Boespflug (1984) F 9 mo Occlusion of the left middle cerebral artery 25 days Antibiotics Anti-platelet

Laxer (1984) F 26 mo Stenosis of the right middle cerebral artery 18 days ? Corticosteroidsand antibiotics

Lapointe (1984) M 4 mo Occlusion of the distal branches of the leftmiddle cerebral artery

45 days Corticosteroidsand antibiotics

Immunosuppressivetherapy

Templeton (1987) ? 6 mo Infarction of the whole territory of the rightmiddle cerebral artery

3 weeks ? ?

Suda (2003) M 8 mo Irregular stenosis of the left middle cerebralartery

20 days d Aspirin, immunoglobulin,and intracoronarythrombolysis

Wada (2006) M 3 yr Infarction of territory of the left middlecerebral artery

10 days Aspirin andimmunoglobulin

d

Fujiwara (1992) M 22 mo Systematic discovery of infarction of theright middle cerebral artery’s deep territory

59 days Aspirin, immunoglobulin,and then anticoagulants

d

Muneuchi (2006) M 4 yr Systematic discovery of infarction of theright anteroinferior cerebellar arteryocclusion

21 days Aspirin, immunoglobulin,and then anticoagulants

d

Tanaka (2007) M 3 yr Meningeal hemorrhage by rupture of leftposterior cerebral artery aneurysm

9 yr ? Surgery

Ahn (2010) M 6 mo Intracerebral and meningeal hemorrhageby rupture of left middle cerebral arteryaneurysm

7 mo Aspirin (stopped 1 mobefore hemorrhage)and immunoglobulins

Surgery

Abbreviations:F ¼ FemaleM ¼ Male

* Since the beginning of the disease.

I. Sabatier et al. / Pediatric Neurology 49 (2013) 469e473470

of general status, and skin rash associated with peripheral edema. Theblood tests revealed anemia (hemoglobin 7.5 g/dL), thrombocytopenia(platelets 107 G/L), hyponatremia, functional renal failure, hypo-albuminemia, and hypertriglyceridemia. Given the lipid abnormality andthe presence of bicytopenia, a myelogram was obtained to rule out amacrophagic activation syndrome. The myelogram revealed a bonemarrow reaction related to HHV6 primary infection (positive polymerasechain reaction gene amplification in bone marrow and blood). Lumbarpuncture revealed lymphocytic meningitis (36 white cells/mm3, highprotein level 0.62 g/L, and normal glucose level). The inflammatorysyndrome was major (C-reactive protein level 260 mg/L, hyper-leukocytosis 20 G/L). Treatment with cephalosporins was started. Thechild also received a transfusion of red blood cells and two perfusions ofalbumin. Based on the presence of cervical lymphadenopathies associ-ated with peripheral predominant eruption, edemas, fissured lips, andbilateral conjunctival injection, Kawasaki syndrome was finally diag-nosed. Intravenous immunoglobulin (2 g/kg) and aspirin treatment werestarted 10 days after the onset of hyperthermia.

When she awoke the next morning, a right hemiplegia associatedwith a left ptosis was noted, but without other clinical signs of ClaudeBernard-Horner syndrome. Blood tests showed thrombocytopenia(platelets at 113 g/L) without other signs of disseminated intravascularcoagulation, elevated C-reactive protein, and high protein level (72 g/L).Brain magnetic resonance imaging showed an extended infarct in theterritory of the left middle cerebral artery (Fig A). Magnetic resonanceangiography revealed a complete ipsilateral occlusion of the internalcarotid artery extending from its origin to the distal middle cerebralartery (Fig B-D). There was no sign of carotid dissection.

Echocardiography was normal, without any coronary dilatation orintracavity thrombus. Search for constitutional thrombophilia wasnegative. Lipid analysis showed a decreased high-density lipoproteincholesterol level (0.22 mmol/L) and ApoA1 (0.42 g/L). Thrombolysiscould not be performed because of a lack of precise informationregarding the time of stroke onset. The child received treatment withenoxaparin (1000 U anti-Xa per 12 hours) for a week, followed by aspirin(75 mg per day).

Three days later, brain magnetic resonance imaging showed recan-alization of the middle cerebral artery, whereas carotid occlusionremained stable. C-reactive protein returned to normal (1 mg/L), but athrombocytosis was noted (platelets 592 g/L). Hemoglobin electro-phoresis, nuclear antibodies, complement assay, auto cytoplasmicantibodies, homocysteinemia, plasma amino acids chromatography,ammonemia, and lactate/pyruvate ratio were normal.

The girl recovered slowly and could walk without support andperform a palm grip after 2 months. One year later, she still exhibitedright hemiplegia associated with right facial paralysis and right hom-onymous lateral hemianopia. Brain imaging was unchanged. After18 months, brain and arterial imaging remained unchanged and aspirinwas stopped.

Discussion

Only 10 examples of arterial ischemic stroke have beenreported in pediatric patients with Kawasaki disease(Table).5-14 Several potential mechanisms may explain the

Evolution Suspected Stroke Mechanism Comments

Epilepsy, motor deficit, dilatedmyocardiopathy

? Severe and diffuse formwithmyocardial infarction and disseminatedarterial aneurysm

Motor deficit ? Important digestive symptoms

Motor deficit, dilated myocardiopathy Cardio-embolic þ thrombocytosis Myocardial infarction and multiple systemic embolisms

Motor deficit Cerebral arteritis Classical form

Motor deficit, developmental delay Cardioembolic � cerebral arteritis Disseminated arterial aneurysms

Death ? Massive myocardial infarction and disseminated arterial aneurysms

Motor deficit Cerebral arteritis or cardioembolic Severe coronary injury

Asymptomatic 12 mo later Kawasaki’s cerebral arteritis or post-chickenpox � blood hyperviscosityrelated to immunoglobulin

High risk of coronary injury at the initial phase, but nonconfirmedafter treatment

Asymptomatic Disseminated intravascularcoagulation?

Severe and diffuse form with disseminated arterial aneurysms anddisseminated intravascular coagulation

Asymptomatic Cerebral arteritis, thrombocytosis First-line treatment resistant form with coronary aneurysms

Motor deficit Some inflammatory signs in theaneurysm wall

Language delay ?No inflammatory signs in theaneurysm wall

Classical form

TABLE. (CONTINUED).

I. Sabatier et al. / Pediatric Neurology 49 (2013) 469e473 471

occurrence of strokes in Kawasaki disease (Table): car-dioembolic (from a thrombus occurring on hypokineticmyocardia), artery occlusion (resulting from inflammationof the arterial wall); or acquired thrombophilia (related toinflammatory syndrome with major hyperthrombocytosis,disseminated intravascular coagulation, or hyperviscositydue to immunoglobulin perfusion). Only one other symp-tomatic case of cerebral arterial infarct has been describedin Kawasaki disease since immunoglobulin treatment hasbecome available (Table).12 The authors mentionedimmunoglobulin-linked hyperviscosity, but the child hadalso been diagnosed with chickenpox 3 months previously,which is a well-known risk factor for childhood stroke aswell. The analysis of the arterial ischemic stroke reported inKawasaki disease (Table) shows that these strokes occur indifferent arterial territories.3 Interestingly, although visceral(coronary arteries) and limb Kawasaki vasculitis leads todilatation before stenosis or occlusion occurs, this does notoccur in the cerebral arteries. Only two observations ofintracranial hemorrhage following aneurysm rupture havethus far been described (Table).15,16 Recently, a child withcerebral vasculitis with microhemorrhages was reported.17

Our child exhibited complete occlusion of the left inter-nal carotid artery. No cardioembolic source was discovered.There was no angiographic evidence of carotid dissection,

although the left ptosis (considered a minimal form ofClaude Bernard-Horner syndrome) supported the hypoth-esis of carotid wall thickening. We found no evidenceof longstanding thrombophilia. A final diagnosis of carotidinflammation (Kawasaki carotiditis), complicated bylocal thrombosis and distal embolism favored by acuteprothrombotic conditions was made.

The stroke occurred 11 days after fever onset. In theliterature, stroke onset associated with Kawasaki diseaseranges from 10 to 59 days (Table 1). The child’s hemiplegiawas noticed the morning of the day following immuno-globulin infusion. A rate of 13% of immunoglobulin-relatedthrombotic complications is reported in adult patientswith autoimmune disorders, occurring either during intra-venous immunoglobulin infusion or within the week thatfollows the treatment.18 Arterial complications are themost common and 75% of all thrombotic events occurwithin 24 hours of the immunoglobulin infusion.18-20

Three main theories have been put forward to explainintravenous immunoglobulin-associated thrombosis: (1)increased blood viscosity21 leading to a hypercoagulablestate, (2) procoagulant activity of immunoglobulin, and (3)immunoglobulin-induced arterial vasospasm.19 In ourpatient, hyperviscosity could have been further enhancedbecause of a possible moderate capillary leak with

FIGURE.(A) Axial diffusion-weighted brain images showing an extended cerebral infarct in the left middle cerebral artery territory. (B) Axial image of magneticresonance angiography showing the complete occlusion of the left internal carotid artery (arrow). (C) Upper view of the circle of Willis (magnetic resonanceangiography); arrow indicates the complete occlusion of the left internal carotid artery extending from its origin to the distal middle cerebral artery. (D)View of the cervical arteries (phase contrast images); arrow indicates the complete occlusion of the left internal carotid artery.

I. Sabatier et al. / Pediatric Neurology 49 (2013) 469e473472

functional renal failure and hyponatremia, the red bloodcell transfusion, and albumin perfusion. At the time of thestroke, serum protein was elevated although water intakewas within normal range according to age.

The latest professional guidelines reiterate the impor-tance of administering the optimal therapy (2 g/kg intra-venous immunoglobulin in one administration combinedwith high-dose aspirin: 80-100 mg/kg daily divided intofour doses), as soon as possible after diagnosis.2,22 Oncedefervescence is obtained, the dose of aspirin is thenreduced to a single daily dose of 3-5 mg/kg2. Kawasakidisease is a medical emergency. If administered in the first10 days of illness, this treatment is effective in reducingsystemic inflammation and the occurrence of coronaryaneurysm (from 25% in natural history to 5% in acutelytreated patients).2 It is possible that this treatment alsodecreases the possibility of cerebrovascular complications,which seem to be more frequent in severe and untreatedforms of Kawasaki disease.3 If treatment is delayed pastthe 10th day, it is less effective at preventing coronaryaneurysms. In our patient, the young girl received theappropriate treatment after 10 days of fever because of the

biological signs suggestive of other syndromes that had tobe ruled out.

High doses of intravenous immunoglobulin probablywork via two action mechanisms (at least): (1) decreasingby accelerating their apoptosis the number of circulatingneutrophils that are increased in number during the acutephase of Kawasaki disease and (2) destroying the infectedcells through antibody-dependant cellular cytotoxicity.Delayed administration of intravenous immunoglobulintherapy decreases its effectiveness. In our young patient,this delay may have allowed enough time for alteration ofthe endothelium resulting in a condition that favored thedevelopment of thrombus.

Kawasaki disease is a time-limited acute vasculitis.However, carotid intima-media thickness, a surrogatemarker of atherosclerosis, is associated with systemicarterial stiffness in children several years after diagnosisof Kawasaki disease.23-25 This finding is more frequent inthe group with coronary aneurysms, but can also occur inthe group with normal coronary arteries.23 Ongoing edu-cation on cardiovascular risk factor reduction is certainlyimportant for all children with Kawasaki disease.

I. Sabatier et al. / Pediatric Neurology 49 (2013) 469e473 473

In conclusion, stroke is a rare neurological complicationin Kawasaki disease. Optimal treatment should be per-formed as soon as possible after diagnosis. Evaluation ofhydration status is strongly recommended before intrave-nous immunoglobulin.

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