Sudden Infant Death With Area Postrema Lesion Likely Due to Wrong Use of Insecticide Anna M. Lavezzi, MDa, Achille Cappiello, CDb, Veronica Termopoli, CDb, Emanuela Bonoldi, MDc, Luigi Matturri, MDa

We report a noteworthy case of a 7-month-old infant who suddenly and abstract unexpectedly died during her sleep. After a complete postmortem examination, review of the clinical history, and detailed death scene investigation, the death remained unexplained, leading to a diagnosis of sudden infant death syndrome. However, an extensive review of the neuropathology revealed a severe a“Lino Rossi” Research Center for the Study and Prevention of Unexpected Perinatal Death and SIDS, Department of alteration in the area postrema (a highly vascular structure lying at the base of Biomedical, Surgical, and Dental Sciences, University of the outside of the -brain barrier). The alteration was Milan, Milan, Italy; bLC-MS Laboratory, DiSTeVA, University of Urbino, Urbino, Italy; and cInstitute of Anatomic Pathology, likely due to massive and repeated to a common household insecticide in the last Hospital of Lecco, Lecco, Italy few weeks of life. These results provide an explanation for this sudden infant death, allowing a differential diagnosis from sudden infant death syndrome. Dr Lavezzi performed the histopathological examination, planned the study, analyzed all the findings in collaborative discussion with Dr Matturri, and wrote the manuscript; Drs Cappiello Theareapostrema(AP)isasmall sepsis, pneumonia, or myocarditis, was and Termopoli designed and performed the protuberance on the midline of the dorsal highlighted. Other causes of death, such chemical characterization of pesticides in the brain surface of the at the as dehydration, a fluid and electrolyte sample; Dr Bonoldi carried out the autopsy and the clinical-anamnestic study; and all authors approved base of the fourth ventricle. This structure imbalance, congenital lesions, inborn the final manuscript as submitted. is one of the most highly vascularized metabolic disorders, and carbon monoxide Ethical approval was granted by the Italian Health parts of the , with unique asphyxia, were ruled out. A review of Ministry in accordance with Italian law 31/2006. access to the circulation due to the the clinical history, death scene Parents of the infant provided informed consent for presence of fenestrated .1,2 The investigation, and circumstances of death both anatomopathologic and toxicologic analyses, AP vascularization is typical of that of the were negative. Then, given the absence of under protocols approved by the “Lino Rossi” circumventricular organs, whose vessels any useful information for a diagnostic Research Center Institutional Review Board of Milan University. are devoid of the blood-brain barrier, thus approach, an initial diagnosis of sudden enabling blood-borne substances to arrive infant death syndrome (SIDS) was made. www.pediatrics.org/cgi/doi/10.1542/peds.2015-0425 3,4 DOI: directly in the brain parenchyma. The However, a careful examination of the 10.1542/peds.2015-0425 AP also includes numerous catechol- brainstem performed at the “Lino Accepted for publication Jun 19, 2015 aminergic neurons that can select Rossi” Research Center of Milan Address correspondence to Anna M. Lavezzi, MD, molecules entering from the blood as University (Italy), according to Italian “Lino Rossi” Research Center for the Study and fl well as from the cerebrospinal uid, law 31/2006 “Regulations for Prevention of Unexpected Perinatal Death and SIDS, Department of Biomedical, Surgical, and Dental thereby preventing the diffusion of Diagnostic Post Mortem Investigation noxious agents.5,6 Here we present Sciences, University of Milan, Via della Commenda in Victims of Sudden Infant Death 19, 20122 Milan, Italy. E-mail: [email protected] a noteworthy case of sudden infant Syndrome (SIDS) and Sudden death with a severe lesion of the AP PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, Intrauterine Unexpected Death 1098-4275). likely due to excessive absorption of an Syndrome (SIUDS)”* and following insecticide for domestic use. fi Copyright © 2015 by the American Academy of speci c guidelines (available at: Pediatrics CASE PRESENTATION FINANCIAL DISCLOSURE: The authors have indicated *Italian law 31/2006 decrees that all infants who they have no financial relationships relevant to this A 7-month-old female infant suddenly suddenly died in Italian regions within the first year article to disclose. of age of suspected SIDS must undergo an in-depth and unexpectedly died during sleep. FUNDING: No external funding. anatomopathologic examination of the autonomic After a complete autopsy, no macro- , particularly of the brainstem, POTENTIAL CONFLICT OF INTEREST: The authors have scopic or microscopic evidence of signif- where the main neuronal centers controlling the indicated they have no potential conflicts of interest icant diseases, including meningitis, vital functions are located. to disclose.

Downloaded from www.aappublications.org/news by guest on September 28, 2021 PEDIATRICS Volume 136, number 4, October 2015 CASE REPORT http://users.unimi.it/centrolinorossi/ en/guidelines.html) disclosed, in histologic sections from the inferior base of the fourth ventricle, the total absence of the AP. Several of these sections, treated with the TUNEL (terminal deoxynucleotidyl transferase dUTP nick end labeling) immunohistochemical procedure to identify apoptotic cells, revealed the presence of positive neurons along the free border of this region. Figure 1 shows the injured AP FIGURE 1 compared with that in an age-matched . A, Coronal section through the caudal medulla oblongata showing the ripped AP in the case presented (see arrows); the inset highlights several apoptotic neurons in the eroded region. B, Normal control subject who died of congenital AP in an age-matched control case. A and B, Klüver-Barrera stain. Inset, TUNEL (terminal deoxy- heart disease. This alteration was not nucleotidyl transferase dUTP nick end labeling) method. Original magnification 310 (A, B), 3100 (inset). interpreted as being due to delayed development (ie, hypoplasia or National Institute of Standards and brainstem in a 7-month-old infant agenesis) because the medullary Technologies electronic library who suddenly died during sleep; the surface in this area appeared ripped (http://webbook.nist.gov/chemistry/), death was initially diagnosed as SIDS. and eroded, with diffuse apoptotic and has acaricide properties. SIDS represents the leading cause of neurons and deprived of the usual thin According to the reports by her postneonatal death in the developed layer of flattened ependymal cells, all parents, which were collected world and is defined as the sudden, findings suggestive of the direct action according to routine investigative unexpected death of an infant ,1 of a harmful agent. No other alteration procedure in cases of sudden infant year of age that remains unexplained of the was death by the medical staff, the infant after a thorough investigation, observed. was healthy until the day she suddenly including performance of a complete “ As required by the protocol of the Lino and unexpectedly died. autopsy and review of the ” Rossi Research Center, a fresh sample However, our remarkable findings made circumstances of death and the of cerebral cortex, before brain it necessary to inquire more closely into clinical history.8 The onset of the fatal fi xation, was sent to the Liquid the circumstances in which the death episode mostly occurs during sleep, Chromatography-Mass Spectometry occurred. In particular, the presence of leading to the assumption that (LC-MS) Laboratory of the University of intense signal corresponding to DBNP a subset of infants with SIDS have Urbino (Italy) for toxicologic on the toxicology screen prompted us to a dysfunctional maturation of investigation of environmental risk inquire further about exposures to neuronal centers involved in factors (eg, cigarette smoke, drugs, environmental contaminants around breathing control.9 alcohol, air pollution, pesticides), which thetimeofdeath.Fromthismore In this case we observed a ripped and was performed according to the in-depth investigation, we learned some 7 eroded surface at the level of the AP, method proposed by Cappiello et al. additional information from the doctor an alteration that we have never Examination of the total ion who had examined the infant at death. previously seen in our large series of chromatogram, in full-scan mode to The doctor reported that the father SIDS neuropathology investigations search for nontargeted compounds during the last 2 weeks of life had (available at: http://users.unimi.it/ with a mass ranging from 50 to 550 u., sprayed large doses of insecticide centrolinorossi/en/publications. revealed in this case several matrix around the infant because of flies in the html), even in a specific study focused peaks. Most of them were fatty acids house. This information had not on this structure.10 and endogenous matrix components, previously been reported to forensic butoneofthepeakswithastrong investigators and helped explain the The AP is a medullary formation mass range was related to the high levels of this toxin found during devoid of the blood-brain barrier and, presence of 2,6-ditert-butyl-4- the toxicology screen. as such, enables blood-borne nitrophenol (DBNP) (Fig 2). This is substances to arrive directly in the DISCUSSION a toxic contaminant, detected for the brain.3,4 However, the AP neurons first time in a US navy submarine and We report here an unusual alteration function as chemosensors, preventing identified by comparison with the of the AP that was discovered at the transit of harmful agents.6 For reference spectra reported in the histologic examination of the many years, the AP has been

Downloaded from www.aappublications.org/news by guest on September 28, 2021 e1040 LAVEZZI et al caused by massive absorption of an insecticide. We believe this report to be important because it reveals that only an in-depth histopathologic examination of the brainstem, associated with an accurate, timely survey of the history and the circumstances in which the death occurred, can enable a correct differential diagnosis to be made in a case of sudden infant death and discriminate between a death due to a well-identified cause and SIDS. We underscore the importance of a careful appraisal of the death scene investigation, which should include FIGURE 2 interviews of witnesses and Toxicology. Total ion chromatogram of the cerebral cortex sample in full-scan mode showing several documentation about the residential matrix peaks. The arrow indicates the peak corresponding to DBNP detection. environment. Every reasonable effort should be made in particular to identify considered a trigger presence of this medullary alteration possible exposure of the infant before zone that can induce emetic reflexes alone is sufficient to justify the death to harmful agents and chemical in the presence of noxious chemical infant’s death, thereby excluding the hazards. Furthermore, the medical staff stimulations.11,12 Subsequently, initial SIDS diagnosis. must document the initial factual experimental studies have disclosed In addition, the identification in the information obtained from parents and additional important roles for this fi cerebral cortex sample of the infant of caregivers during the rst minutes structure. In particular, it has been DBNP, an acaricide classified among after their arrival on the death scene. demonstrated that AP neurons “Hazard 6.1 (b)—Substances that are A limitation of this study is its focus on receive peripheral vagal and acutely toxic–fatal”,18 aroused only a single case, so it does not allow baroreceptor afferent projections particular interest considering the generalization of the results to the from the sensory neurons of the high concentration. This finding wider population of a direct correlation stomach, intestines, liver, kidneys, indicates that the infant had absorbed between excessive use of household heart, and other internal organs.13,14 substantial amounts of this toxic insecticides and brain damage. The AP neurons are able to send the However, our report provides insight collected information to important substance before death. Further for further research in this direction. brainstem centers, such as the investigations were then performed ’ nucleus, the dorsal on the infant s conditions of life This case report represents a dire motor vagal nucleus, and the before the death. Basic information warning to the general public of the dorsolateral pontine nuclei, assigned had been revealed by the parents as risks of indiscriminate use of toxic to the control of cardiovascular and soon as the event occurred at home chemical contaminants. In particular, respiratory functions.15,16 Therefore, (ie, the heavy, repeated use of pediatricians and others providing the AP is ideally situated as insecticides around the infant). health care to infants are reminded a fundamental center of However, this specific circumstance about the importance of counseling communication between visceral was not mentioned either by the parents and other caregivers about the functions and neuronal control of mother or father at the later hazards of household chemicals and the vital activities.17 Consequently, interview. Furthermore, it is well importance of reading warning labels. lesions of the AP eliminate the brain’s known that retrospective information modulatory role of the systemic collected from the parents about autonomic state. possible risk factors after a fatal event ABBREVIATIONS are unreliable, probably due to an The erosion of the AP found in the unconscious feeling of guilt.19 AP: area postrema present case resulted in the failure to DBNP: 2,6-ditert-butyl-4- identify toxic substances and to In conclusion, the case presented here nitrophenol prevent their direct access to cannot be diagnosed as SIDS, because SIDS: sudden infant death brainstem centers playing a vital role the peculiar alteration of the AP syndrome in the autonomic central control. The found in the brainstem was very likely

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Downloaded from www.aappublications.org/news by guest on September 28, 2021 Sudden Infant Death With Area Postrema Lesion Likely Due to Wrong Use of Insecticide Anna M. Lavezzi, Achille Cappiello, Veronica Termopoli, Emanuela Bonoldi and Luigi Matturri Pediatrics originally published online September 14, 2015;

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