Luca Filippi* MD; Ludovica Palermo MD; Marco Pezzati MD; Carlo Dani MD, Neonatal Intensive Care Unit, Department of Critical Care Medicine; Maria Matteini MD, Nuclear Medicine Unit; M Teresa De Cristofaro MD, Department of Clinical Physiopathology; Firmino F Rubaltelli MD, Neonatal Intensive Care Unit, Department of Critical Care Medicine, University Careggi Hospital, Florence, Italy.
Case report
Paradoxical embolism in a preterm infant
*Correspondence to first author at Neonatal Intensive Care Unit, Department of Critical Care Medicine, University Careggi Hospital, viale Morgagni, 85 I-50134 Florence, Italy. E-mail:
[email protected]
Cerebral paradoxical embolism has not until now been described as a cause of cryptogenic stroke in newborn infants. A male infant was born at 27 weeks 2 days’ gestational age by emergency Caesarean section in a twin pregnancy because of intrauterine growth retardation and absence of diastolic flow in the twin. His birthweight was 950g (50th centile). Apgar scores were 7 and 8 at 1 and 5 minutes respectively. At 17 days of life he showed sudden respiratory distress and signs of encephalopathy. Presence of deep venous thrombosis, patent foramen ovale (PFO), and clinical progression suggested paradoxical embolism which were confirmed by neuroradiological findings. The high incidence of PFO and central venous catheter-related deep venous thrombosis in newborn infants suggest that paradoxical embolism is probably a more common complication than has been thought.
See end of paper for list of abbreviations.
Patent foramen ovale (PFO) is a potential cause of ischemic stroke due to paradoxical embolism, especially in younger patients. The mechanism is in the passage of venous thrombi through the patent foramen into the systemic circulation, causing cerebral embolism (Mas et al. 2001, Lamy et al. 2002). Clinical descriptions of paradoxical embolism are anecdotal in neonates and have never been associated with cerebral stroke (Tillet et al. 2001). We report a preterm infant who showed sudden respiratory distress and cerebral injury at 17 days of life. Presence of deep venous thrombosis, PFO, and clinical progression suggested the hypothesis of paradoxical embolism. Case report A male was born at 27 weeks 2 days’ gestational age in a twin pregnancy by emergency Caesarean section because of intrauterine growth retardation and absence of diastolic flow in the twin. His birthweight was 950g (50th centile); Apgar scores were 7 and 8 at 1 and 5 minutes respectively. The twin died of sepsis at 10 days of life. On arrival at the neonatal intensive care unit, mild respiratory distress syndrome required administration of two doses of surfactant as well as nasal continuous positive airway pressure with fraction of inspired oxygen between 25 and 35% for 7 days. At 24 hours of life, coagulopathy was treated with plasma and antithrombin III infusions. Cardiac ultrasonography showed PFO and patent ductus arteriosus that was treated successfully with ibuprofen. Cerebral ultrasonography showed mild bilateral periventricular hyperechogenicity and blood within lateral ventricles, without ventricular dilatation (grade II intraventricular hemorrhage). At 10 days of life partial enteral feeding was tolerated and ‘kangaroo care’ began without oxygen supplementation. A central venous catheter was inserted into the left long saphenous vein to
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ensure parenteral feeding supplementation. At 17 days of life the infant, after a brief crying spell, showed sudden respiratory distress, gasped, and had respiratory arrest; blood gas analysis showed mixed acidosis (pH 7.09, partial pressure of CO2 70.1mmHg; partial pressure of oxygen, 53.2mmHg; HCO3 15.2mmol/L; base excess 10.2mmol/L); chest X-ray was normal. The infant was immediately intubated, resuscitated, and treated with antibiotics. After a few hours, severe generalized hypotonia, absent spontaneous respiratory drive, and tonic–clonic seizures were observed; the child was then treated with phenobarbital and diazepam. Laboratory examinations showed high values of fibrinogen (1.196g/dL) and d-dimers (187µg/dL), while clinical examination showed oedema, swelling, and blue–purple discolouration of the left leg, consistent with deep venous thrombosis. The central venous catheter was obstructed and was removed and treatment with tissue plasminogen activator started. The following morning ultrasounds showed the non-compressibility of the saphenous vein lumen, and alteration of Doppler flow in the left iliac vein, confirming the diagnosis of thrombosis. Three days later chest X-ray showed multiple irregular bilateral densities. Cerebrospinal fluid (CSF) examination, metabolic evaluation (redox status, ammonium, plasma, and CSF amino acid analysis, urinary organic acid, and plasma very long chain fatty acid profiles), and electromyography were normal. Cerebral diffusion-weighted magnetic resonance (MR)
R
L
Figure 1: Axial cerebral diffusion-weighted MR imaging demonstrates at 23 days of life focal areas of hyperintensity in left subinsular area, left basal ganglia and internal capsule. Bilateral intraventricular clots are evident. Relative proton MR spectroscopy profile shown at bottom. Cho, choline; Cr, creatinine; NAA, N-acetyl-aspartate.
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imaging at 23 days of life showed focal areas of increased signal intensity in the periventricular white matter, mainly in the left subinsular area, left basal ganglia, and left internal capsule. In these areas proton MR spectroscopic imaging detected a rise in lactate, a drop in N-acetyl-aspartate (NAA), a decrease in NAA/choline, and an increase in choline/creatinine ratios (Fig. 1). Cerebral single photon emission computed tomography (SPECT) with technetium-99m-L,L-ethyl cysteinate dimer (99mTc-ECD) showed focal regions of reduced brain perfusion in the left insulo-striatal and left temporal areas. Over the following days we observed progressive improvement of muscle tone and of reactivity even though flaccidity of the right arm remained. At 20 days, electroencephalogram (EEG) showed paroxysmal abnormalities of the waveform in the left hemisphere, but at 40 days it was normal. The infant was extubated at 37 days of life. At the time of discharge (77 days of life) neurological evaluation confirmed the presence of paresis of the right arm; physiotherapy commenced, the infant was successfully bottle fed, smiled at parents, and had an excellent level of alertness. At 4 months of age (corrected for gestational age) positron emission tomography (PET) with 18F-labelled 2-deoxy-2-fluoro-d-glucose (FDG) showed a symmetric and homogeneous distribution and uptake of the tracer in the cortex, basal ganglia, and cerebellar hemispheres. At 6 months of (corrected) age, head circumference was 43.5cm (50th centile). The paresis was limited to the distal areas of the right arm, with reduced motor ability of the hand and wrist, although arm function was satisfactory; he could grasp an object with the right hand. His clinical condition was excellent. He was able to keep his head erect and steady and could change the orientation of his entire body to reach out towards a desired object. He could be pulled from a sitting to a standing position and could support his weight on extended legs. His parents refused permission to screen him in a specialized coagulation unit for potentially inherited or acquired causes of thrombophilia. Discussion Paradoxical embolism through PFO has been increasingly implicated in the aetiology of cerebral ischemia, particularly in younger patients with cryptogenic stroke (Mas et al. 2001, Lamy et al. 2002). In individuals with atrial or ventricular septal defects, emboli arising in the systemic venous system may pass across the cardiac defect and enter the arterial circulation. The most common intracardiac defect associated with paradoxical embolism is PFO (Connuck et al. 2002). The motion of the fossa ovale membrane may promote paradoxical shunting by enhancing the preferential orientation of the flow from the inferior vena cava toward the foramen ovale (De Castro et al. 2000). The association between PFO and cryptogenic stroke has repeatedly been demonstrated in clinical studies (De Castro et al. 2000, Mas et al. 2001, Lamy et al. 2002). Arterial embolus may present with ischemic extremities, cerebral infarction, abdominal or flank pain, and sometimes it is associated with pulmonary embolism. Recent studies also suggest that attacks of migraine with aura may be due to paradoxical embolism (Sztajzel et al. 2002). The diagnosis of paradoxical embolism is often difficult to establish and requires the presence of arterial embolism, simultaneous venous thrombosis, or pulmonary embolism, abnormal intracardiac communication, and right-to-left shunt. Paradoxical embolism has rarely been reported in newborn
infants (Tillett et al. 2001), but until now it was never identified as a cause of cerebral stroke. Stroke has been associated with catheterization in neonates in several reports, associated mostly with temporal artery catheters (Bull et al. 1980). An association between stroke and umbilical vein catheterization (Ruff et al. 1979) or aortic thrombosis originating within the patent ductus arteriosus has been reported (Knowlson et al. 1978). Among the neonates with cerebral infarction the most common association (28% of cases) was pulmonary hypertension (Govaert et al. 2000). These reports suggest a potential pathogenic role of the right-to-left shunt, as occurs in paradoxical embolism. In our patient, the abrupt onset of clinical deterioration, the sudden respiratory distress with normal radiological appearance of chest, and the presence of deep venous thrombosis led to a suspicion of paradoxical embolism. In the following days, the appearance of multiple bilateral densities at chest X-ray was compatible with pulmonary embolism. The hypothesis of cerebral ischemic stroke due to paradoxical embolism was then reinforced by the presence of PFO and by clinical progression (decreased consciousness at onset, rapid improvement of muscle tone, improvement in reactivity, EEG findings, and the presence of right-arm paresis). Neuroradiological evaluation can enhance the diagnostic process: in our patient MR imaging findings suggested focal injury of the left basal ganglia and internal capsule. We performed cerebral diffusionweighted MR imaging because in newborn infants it allows earlier and more accurate delineation of the extent of cerebral damage rather than the conventional MR imaging (Robertson et al. 1999). There was a strong correlation between brain proton MR spectroscopic imaging (evidence of cerebral ischemic injury on the basis of increased levels of lactate and decrease in NAA; Groenendaal et al. 1995) and SPECT findings (reduced regional cerebral perfusion; Masdeu et al. 1995). PET is a useful complementary examination because, measuring local cerebral metabolic rate for glucose, it is able to show functional deficits after stroke even in morphologically intact brain regions, information not obtainable with either MR imaging or spectroscopy (Karbe et al. 1995). In our patient at 4 months of age we found no signs of hypometabolism (decrease of cerebral metabolic rates for glucose), which are typical of cerebral areas directly damaged by ischemic insult (Kuhl et al. 1980), nor loci of relatively higher FDG uptake, which can be seen in children with a congenital hemiplegia. (Vandemeeren et al. 2002). This finding suggests that the cerebral damage had been restricted, ischemic rather than necrotic, and had nearly resolved (Govaert et al. 2000). The basal ganglia and thalamus are, of course, particularly susceptible to hypoxic–ischemic damage in preterm infants. We took into consideration the possibility that the pulmonary embolism could have caused hypoxic–ischemic damage, even though asphyxia is a rare cause of cerebral infarction (Govaert et al. 2000). The immediate resuscitation, the persistence of normal values of oxygenation, and the clinical progression (normal head circumference, absence of bilateral dyskinesia, progressive reduction of the paresis, excellent neurodevelopment) make this an unlikely hypothesis. We cannot exclude the fact that both the arterial stroke and the deep venous thrombosis are due to an underlying thrombotic disorder. Prothrombotic disorders are relatively common in neonates with a history of neonatal stroke (Golomb 2003). In a multicenter case control study a significant proportion
(68.1%) of term neonates with symptomatic ischemic stroke had evidence of prothrombotic disorders increased Lipoprotein (a) level, the factor V G1691A mutation; the prothrombin G20210A variant; the methylenetetrahydrofolate reductase T677T genotype; protein C, protein S or antithrombin deficiencies; and acquired anticardiolipin antibodies (Gunther et al. 2000). The parents, who considered that the presence of a central venous catheter was the most important trigger for development of venous thromboembolic disease, refused our proposal to screen for potentially inherited or acquired causes of thrombophilia. In conclusion, individuals with PFO are at a higher risk of stroke (Lamy et al. 2002), but paediatricians and neonatologists often think, wrongly, that embolism is exclusively an adult disease. The incidence of PFO in healthy term newborn infants is more than 60% in the first hours of life and about 55% at 2 to 6 months of age (Connuck et al. 2002). Thrombotic complications have been observed in 20 to 25% of newborn infants requiring the use of central venous catheters (Salonvaara et al. 1999). The high incidence of PFO and central venous catheter-related deep venous thrombosis in newborn infants suggest that paradoxical embolism is probably a more common complication than has been thought. DOI: 10.1017/S0012162204001203 Accepted for publication 11th February 2004.
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List of abbreviations CSF EEG FDG MR NAA PET PFO SPECT
Cerebrospinal fluid Electroencephalogram 2-deoxy-2-fluoro-d-glucose Magnetic resonance N-acetyl-aspartate Positron emission tomography Patent foramen ovale Single photon emission computed tomography
The Faculty of Biology and Medicine of the University of Lausanne invites applications for a position at the Department of Pediatrics and Pediatric Surgery of the University Medical Centre (CHUV) :
Full or Associate Professor and Head of the Neuropediatric Unit Candidates should : • be certified in general pediatrics, with specialisation in neuropediatrics • have international reputation with competences at professorial level • have solid clinical experience and be able to organize the activities of the Unit in the field of general neuropediatrics • have a pre- and postgraduate teaching record • have an original research program which would allow collaboration with already existing research networks • have experience in the management of clinical and research activities • be able to work in French or to develop that capacity within one year. The duties are available on the website at the address www.unil.ch/fbm/page2295_fr.html. For further information, please contact Prof. S. Clarke (
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European Academy of Childhood Disability The 16th EACD meeting will be held in Edinburgh from 7-9th October 2004, with satellite meetings on 6th October. Assembly Rooms, George Street, Edinburgh, Scotland Satellite Sessions: There will be two pre-conference sessions running in parallel in the afternoon of Wednesday 6th October in the Assembly Rooms, Edinburgh. Full programme and booking details are available on the conference web-site www.EACD2004.com Session 1 – Innovation in Diagnosis and and Intervention for Autism and Related Disorders
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Congenital Muscular Dystrophies: A Clinical Approach to Molecular Diagnosis
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Assessment/Investigations of Children with Autism
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