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Brainstem tegmental necrosis and olivary hypoplasia: Raising awareness of a rare neuropathological correlate of congenital apnea Christos D. Katsetos MD, PhD, FRCPath, Carol E. Anderson MD, Miguel A. Guzman MD, Judy Mae Pascasio MD, Jean-Pierre de Chadarévian MD, FRCPC, Agustin Legido MD, PhD, ΜΒΑ www.elsevier.com/locate/enganabound

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S1071-9091(14)00048-5 http://dx.doi.org/10.1016/j.spen.2014.05.001 YSPEN495

To appear in: Semin Pediatr Neurol

Cite this article as: Christos D. Katsetos MD, PhD, FRCPath, Carol E. Anderson MD, Miguel A. Guzman MD, Judy Mae Pascasio MD, Jean-Pierre de Chadarévian MD, FRCPC, Agustin Legido MD, PhD, ΜΒΑ, Brainstem tegmental necrosis and olivary hypoplasia: Raising awareness of a rare neuropathological correlate of congenital apnea, Semin Pediatr Neurol , http://dx.doi.org/10.1016/j.spen.2014.05.001 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Katsetos et al.

Brainstem Tegmental Necrosis and Olivary Hypoplasia: Raising Awareness of a Rare Neuropathological Correlate of Congenital Apnea

Christos D. Katsetos, MD, PhD, FRCPath,*, Miguel A. Guzman, MD,

†,§

† ,‡

Carol E. Anderson, MD,*

Judy Mae Pascasio, MD,*,





Jean-Pierre de Chadarévian, MD, FRCPC *, and Agustin Legido, MD, PhD, ΜΒΑ*,







Departments of *Pediatrics, Pathology and Laboratory Medicine, and Neurology, Drexel University College of Medicine, St. Christopher’s Hospital for Children, Philadelphia, PA. §

Current address: Department of Pathology and Laboratory Medicine, Saint Louis

University Medical Center, St. Louis, MO.

Key words: Congenital apnea, brainstem, calcifications, inferior olives, necrosis, tegmentum, polyhydramnios Address reprint requests to Christos D. Katsetos, MD, PhD, FRCPath Section of Neurology St. Christopher’s Hospital for Children 160 East Erie Avenue Philadelphia, PA 19134 E-mail: [email protected]

 

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This case study illustrates an instance of death in an early term female newborn with congenital apnea in the clinical setting of multiple congenital anomalies (retrognathia, posteriorly rotated ears, camptodactyly, and arthrogryposis) and prenatal history of polyhydramnios. Postmortem neuropathologic findings were significant for tegmental necrosis in the caudal pons and medulla characterized by a coalescence of microcalcifications accompanied by neuronal loss, axonal spheroids, gliosis, and a concomitant hypoplasia of the inferior olives. This report raises awareness of the rare lethal entity of brainstem tegmental necrosis and olivary hypoplasia and its nosological relationship to the Möbius syndrome in the context of differential diagnosis of congenital apnea owing to central respiratory dysfunction.

 

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Baby Girl F was born at an outside hospital at 37 4/7 weeks to her 26 year-old G2 P1 mother. Prenatal ultrasound had detected polyhydramnios, a decreased biophysical profile, and distal arthrogryposis. The mother was generally healthy, although she had a history of migraine headaches. There were no reported exposures to medications other than prenatal vitamins. There was no maternal illness. The use of alcohol, tobacco, or recreational drugs was denied. The infant was delivered by spontaneous vaginal delivery, complicated by maternal fever to 101.2 degrees. Apgar scores were 2 at one minute, 4 at five minutes, and 6 at ten minutes. When there were no spontaneous respirations at one minute of age, bag mask ventilation was initiated. Endotracheal intubation was attempted, but was unsuccessful due to the small jaw that did not open widely enough to permit it. The infant’s birth-weight of 2443 grams was between 3rd and 10th percentile for gestational age of 38 weeks. The head circumference of 33 cm was near the 25th percentile for 38 weeks; and the length of 48 cm was also near the 25th percentile for 38 weeks. The infant was transferred on the day of delivery (DOL 1) to a hospital where pediatric otolaryngology service was available. Intubation was difficult, and three chest tubes were required. On physical examination, there were flexion abnormalities of the fingers (camptodactyly), with the index finger most severely affected in addition to fingers 3-5 bilaterally. The big toe was in a flexed position bilaterally. Because of the abnormal flexion of extremities, a clinical diagnosis of arthrogryposis was rendered. There was retrognathia, posteriorly rotated ears, an extranuchal fold, and hypertelorism. Because of the intubation oral examination was not feasible. An echocardiogram showed patent foramen ovale with bidirectional blood flow, as well as a patent ductus arteriosus. The infant was placed onto a head cooling protocol, as well as nitrous oxide for persistent pulmonary hypertension of the newborn. On the second day of life, an electroencephalogram showed seizure activity that correlated with clinical seizures. Pressors had to be increased, and the patient was placed on high frequency oscillator ventilation. On the 6th day of life, the patient had multiple prolonged episodes of bradycardia, hypotension, and hypoxemia. These episodes increased until there was no longer any response to increased fluids, increase in pressors, or positive pressure ventilation. On day of life 7, the patient was pronounced dead.

 

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General Autopsy Findings The body was that of a well-nourished female infant with biometric profile within normal range. Autopsy findings confirmed the clinical findings of multiple congenital anomalies including a patent ductus arteriosus, patent foramen ovale, retrognathia (Fig. 1A), short neck (Fig. 1A), posteriorly rotated ears (Fig. 1B), camptodactyly (Fig. 1C and 1D), and dorsiflexed toes, bilaterally (1E). Additional autopsy findings included medial hypertrophy of pulmonary arteriolar walls (Heath Edward grade I), diffuse alveolar damage with hyaline membrane formation, and acute bronchitis with incipient aspiration pneumonia. Skeletal muscle from the diaphragm and appendicular musculature showed no evidence of neurogenic atrophy or a myopathic process. Postmortem Neuropathological Findings Gross examination of the formalin-fixed central nervous system (CNS) specimen included serial coronal sections of the cerebrum, parasagittal sections of the cerebellum, and axial sections of the midbrain, brainstem, and spinal cord. For microscopic evaluation, a total of 26 brain tissue blocks representative of diverse anatomical areas were submitted for histological processing and paraffin embedding. Histological sections were stained with hematoxylin and eosin (H&E). Kluver-Barrera stain (luxol fast blue counterstained with cresyl violet) was used on selected paraffin sections from the brainstem for the evaluation of myelin changes and neuronal changes. Immunohistochemistry was performed using a polymer detection system (in an automated immunostainer) on serially cut, immediately adjacent histological sections from brainstem paraffin blocks using a mouse monoclonal antibody to CD68 (clone KP1; Dako, Carpinteria, CA) and rabbit polyclonal antibody to glial fibrillary acidic protein (GFAP) (Dako). CNS pathological findings at autopsy are summarized as follows: The brain weight was within normal range for gestational age. Cranial dura, including falx cerebri and tentorium cerebelli, and brain venous sinuses were grossly unremarkable. There was no evidence of intracranial hemorrhage. The cerebral hemispheres were symmetric and showed a developmentally unremarkable gyral pattern, compatible with estimated gestational age. Gross examination of the cerebrum, both on external examination and on serial rostrocaudal coronal sections, revealed no evidence of overt malformations, or of encephaloclastic and/or  

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destructive lesions. There was mild dilatation of the lateral and third ventricles without evidence of hydrocephalus. The corpus callosum was present, albeit mildly thinned at all levels. Septum pellucidum and fornices were grossly unremarkable. There was no evidence of intraventricular hemorrhage or germinal matrix hemorrhage. Two supratentorial focal ischemic lesions were identified: (a) A small subacute right parietal infarct with features of early liquefactive necrosis conforming to the cortical border zone of the anterior and middle cerebral arteries and (b) a single microscopic focus of recent periventricular leukomalacia (PVL) characterized by features of coagulative necrosis involving the deep periventricular white matter adjacent to the right atrium (not shown). Small blood vessels and capillaries within the bed of the parietal infarct showed microthrombi. In addition to the single focus of PVL, there was moderate, nondescript diffuse gliosis of the telencephalic white matter without evidence of amphophilic globules or calcifications. The remainder of the cerebral cortex and hemispheric white matter showed no evidence of ischemic or hemorrhagic stroke. There was no evidence of a diffuse cortical hypoxic-ischemic damage (laminar or pseudolaminar necrosis) in the context of perinatal global anoxic-ischemic encephalopathy. There was also absence of pyogenic inflammation in the context of septic infarction or purulent leptomeningitis. Mesolimbic structures (amygdala, hippocampus, subiculum, and parahippocamal gyrus), the fusiform gyrus and lateral temporal neocortex, the basal ganglia and diencephalic structures (hypothalamic, thalamic and subthalamic nuclei) were all grossly and histologically unremarkable. Similarly, horizontal sections of the mesencephalon were grossly and histologically unremarkable. Axial sections of the brainstem showed no grossly overt abnormalities. The fourth ventricle was patent and only modestly dilated. However, microscopic evaluation of the caudal pons and medulla revealed multifocal, coalescent microcalcifications accompanied by variously prominent loss of neurons and dense gliosis of the tegmentum (Figs. 2-4). No viral inclusions or foci of liquefactive necrosis or cystic encephalomalacia were identified. At the level of the caudal pons multiple foci of mineralization were detected in the vicinities of the abducens (cranial nerve VI) and medial vestibular nuclei, prepositus hypoglossal nucleus, medial longitudinal fasciculus, the root of cranial nerve VI, and the pontine reticular formation, extending into portions of the raphé nuclei. There was engorgement of blood vessels and perivascular dilatations/retractions in the gliotic parenchyma of the tegmentum (Fig. 2). The basis pontis was devoid of destructive lesions and for the most part, showed no overt  

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developmental abnormalities (Fig. 2). At the level of the medulla the aforementioned changes affected the hypoglossal (cranial nerve XII) nucleus and vagal (cranial nerve X) nuclei and the dorsal respiratory group, in the dorsomedial region of the medulla, composed of cells in the solitary tract nucleus, encroaching into portions of the medial longitudinal fasciculus, raphé nuclei and reticular formation (Fig. 3). There was also concomitant hypoplasia of the inferior olivary nuclei and presence of heterotopic olivary tissue in the tegmentum (Fig. 3). Dystrophic calcifications, neuronal loss, and gliosis were demonstrated on close-up microscopic views (Fig. 4A-4C). Evidence of axonal damage in the form of axonal spheroids (retraction bulbs) was also demonstrated within a milieu of calcifications and gliosis (Fig. 4B). A heterotopic ependymal tubule was noted in the vicinity of tegmental gliosis (Fig. 4C). The destructive tegmental changes notwithstanding, there was preservation of populations of tegmental neurons (Fig. 4D). The pyramids were symmetric and moderately gliotic. There was hyperplasia of the arcuate nuclei (not shown). A meningeal glioneuronal heterotopia was also identified focally (not shown). There was no evidence of syringobulbia or ventral pontine necrosis in the context of ponto-subicular necrosis. Immunohistochemical staining for GFAP highlighted dense fibrillary immunoreactivity in areas of tegmental gliosis and variable immunostaining in the rest of the parenchyma (not shown). No CD68-immunolabeled macrophages in the context of liquefactive necrosis or a demyelinating process were identified (not shown). Anatomically, the cerebellum was developmentally unremarkable both on external examination and upon parasagittal sectioning. No cystic midline abnormality was present. Microscopically, the cerebellar cortical architecture was appropriate for developmental age. Hypoxic-ischemic Purkinje cell changes were not observed. A rare heterotopic cluster of Purkinje-like cells was noted in the white matter interdigitating in the cerebellar folia adjacent to the internal granule layer (not shown). This was an incidental and nonspecific finding. There was diffuse moderate to prominent cerebellar white matter gliosis extending to the neuropil of the dentate nucleus. The spinal cord was unremarkable on external examination and upon serial axial sectioning. No neural tube defects were identified. There was no evidence of hydromyelia, hematomyelia, diastematomyelia, syrinx, or duplication of the cord. Microscopically, anterior horn motor neurons and ventral spinal roots, posterior horn neurons, white matter funiculi (anterior, lateral, and posterior columns), and ventral and dorsal spinal roots were all intact.  

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Discussion  This case illustrates an instance of death in a 7-day-old female full term infant who presented with an unexplained neonatal apnea. The decedent had multiple congenital anomalies including retrognathia, short neck, posteriorly rotated ears, and flexion deformities of the limbs, notably camptodactyly and dorsiflexed toes akin to arthrogryposis. Delivery was vaginal and uneventful but there was a well-documented prenatal history of polyhydramnios. Neonatal history was significant for a hypoxic-ischemic episode incurred during intubation immediately following childbirth. Since then, the patient remained ventilator-dependent, developed non-sustained generalized tonic-clonic seizures, and subsequently bacterial sepsis. Eventually, patient succumbed to intractable respiratory failure. Postmortem neuropathological findings were significant for the discovery of neuronal loss, gliosis and calcifications involving the tegmental regions of the caudal pons and medulla consistent with the diagnosis of brainstem tegmental necrosis and olivary hypoplasia, a rare lethal clinicopathologic entity associated with congenital apnea.1-3 The condition was originally reported in three male infants1, 2 but was subsequently reported in a female patient.3 Here we report, the second such case to our knowledge, in a female newborn raising awareness about this distinctive nosological entity when evaluating an infant with unexplained congenital apnea accompanied by facial and limb abnormalities in the setting of a prenatal history of polyhydramnios. The brainstem findings in the present case closely resemble those previously described in the benchmark publications by Kinney and co-workers1 by Cortez and Kinney.2 The originally reported cases were male, with normal karyotypes, dysmorphic features (cleft palate, micrognathia), and talipes equinovarus/bilateral clubfeet.2 Interestingly, as in the present case, evidence of retrognathia and posteriorly rotated ears was also described in one of the originally reported cases.1, 2 A subsequent case with similar findings was reported in a female newborn.3 A common feature of all previously published cases was perinatal history of polyhydramnios.2 A hallmark autopsy finding accounting for the pathogenesis of congenital apnea in the present case is the histologic demonstration of tegmental mineralizations and severe gliosis in the caudal pons and medulla associated with abnormalities of the hypoglossal and dorsal vagal nuclei, the nucleus and fasciculus of the solitary tract and the inferior olives.1-3 Prominent gliosis and calcifications of the pontine and medullary tegmentum, coupled with neuronal loss of selected tegmental nuclei, may correlate with the decedent’s congenital apnea, providing a  

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plausible explanation for the decedent’s hypoxic-ischemic episodes and ventilator dependency. The rarity of this entity notwithstanding, there seems to be significant nosological overlap with similar pathological lesions described under different nomenclature in past decades. An example of a related, albeit more extensive selective brain stem damage in the clinical setting of polyhydramnios was reported in a 2,600 g term infant who never breathed spontaneously and who died at 36 hours of life.4 Similar findings, with extensive pontine and medullary tegmental involvement have also been described in the context of Möbius syndrome.5-8 The clinical phenotype of Möbius syndrome may result from a variety of pathologic processes. Although pathological changes observed in cranial nerve nuclei are most often viewed as developmental malformations (aplasia or dysplasia), the presence of mineralized necrotic foci in multiple brainstem nuclei has led to the postulation that prenatal destructive (encephalomalacic) lesions may constitute the pathological basis for some cases of congenital Möbius syndrome.5 In a rigorous clinico-pathological study Mito and colleagues elucidated neuropathologic correlates of central respiratory dysfunction in 7 infants, ranging in from newborn to 2 years of age, who had primary respiratory problems unrelated to increased intracranial pressure and fatal outcomes.9 Five of seven infants were male. A spectrum of neuropathological findings was unraveled in the brainstem including developmental abnormalities in the context of aplasia of cranial nerves VI and VII, neuronal heterotopia and migration failure of the inferior olivary nuclei, abnormalities of cranial nerves X and XII, tegmental microcalcifications and gliosis, as well as vascular/ ischemic damage.9 Collectively, the postmortem neuropathological findings in the present case point to a remote intrauterine (prenatal) insult selectively affecting the brainstem tegmentum at the levels of caudal pons and medulla including respiration-related centers. Importantly, the timing of the tegmental lesions differs from the small subacute cortical infarct in the right parietal border zone and the recent right parietal PVL also discovered at autopsy. In contrast to the tegmental lesions the origin of which is prenatal, the focal supratentorial lesions are attributed to postnatal episodes of hypotension leading to focal hypoxic-ischemic brain injury in cortical and subcortical watershed distributions. The pathogenesis of brainstem tegmental necrosis and olivary hypoplasia is unknown. The relationship of tegmental calcifications either to prenatal hypoxic-ischemic damage (infarction) or intrauterine infection is also unclear.9 Based on previous neuropathological studies  

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describing this pattern of tegmental injury under different terminology, it appears that the underpinning pathogenesis may be multifactorial comprising developmental and vascular etiologies.5, 6, 9 Selective symmetrical necroses of many tegmental brain stem nuclei including motor cranial nerve nuclei can occur in the context of severe hypoxic-ischemic CNS damage following prolonged hypotensive episodes and/or cardiac arrest, known under the terms "hypotensive brain stem necrosis"10 or "cardiac arrest encephalopathy".11 Conversely, the remarkable restriction of the lesions to the medulla and caudal pons suggests the possibility of a genetic defect in the segmentation and formation of rhombomeres during brainstem development.2 Abnormalities in the organization of the inferior olivary and arcuate nuclei revealed in this and previous studies lend credence to the existence of dual developmental and metachronous destructive mechanisms in-utero.1, 2 Given the dearth of neuroimaging, and neuropathological correlations, the extent to which these tegmental brainstem lesions can be detected in life by conventional neuroimaging is unknown. However, a previous study performed in a similar case has demonstrated --by noncontrast axial CT-- evidence of tegmental hyperdensity consistent with calcification at the level of the caudal brainstem correlating with histological documentation of mineralizations of the hypoglossal nucleus and dorsal motor nucleus of the vagus nerve confirmed at postmortem examination.3 Small tegmental calcifications detectable by CT have also been described in the context of Möbius syndrome.7 The causes of congenital (neonatal) apnea are diverse and include CNS, respiratory, infectious, gastrointestinal, metabolic (hypoglycemia, hypocalcemia, hyperammonemia, increase of organic acids, hypothermia), cardiovascular, hematological, and other miscellaneous etiologies.3 A CNS etiology warrants consideration in the differential diagnosis of unexplained respiratory dysfunction in infants (Table 1). The latter may encompass a range of structural brainstem abnormalities, including developmental malformations and/or destructive/necrotizing lesions affecting specific components of the brainstem, particularly the tegmental region. Diffusion-weighted MR imaging (DWI) studies have shown persistent hyperintense signals in the pontine and mesencephalic tegmenta of children with mitochondrial cytopathies.12 Brainstem involvement in Leigh disease is one of the causes of central respiratory dysfunction in infants.13, 14

In the absence of anatomically defined correlates of central congenital apnea, the diagnosis of

congenital central hypoventilation syndrome (CCHS) should be entertained.15 The latter is a  

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diagnosis of exclusion requiring molecular genetic confirmation of PHOX2B gene mutation status.15 In summary, this case study illustrates salient neuropathological findings of brainstem tegmental necrosis and olivary hypoplasia and raises diagnostic awareness of this rare disorder and its relationship to congenital Möbius syndrome. The report underscores the need for rigorous autopsy-based studies aimed at a better understanding and elucidation of the divergent pathological substrates of CNS-related congenital apnea that may be useful in prospective neuroimaging studies. Brainstem tegmental necrosis (with calcifications) and olivary hypoplasia is a rare nosologic entity that warrants consideration in the differential diagnosis of congenital (neonatal) apnea owing to central respiratory dysfunction. Acknowledgements The support of the St. Christopher’s Foundation for Children for the coverage of the production cost of this publication is gratefully acknowledged. References 1. Kinney HC1, Filiano JJ, Brazy JE, Burger PC, Sidman RL: Congenital apnea with medullary and olivary hypoplasia: a pathologic study with computer reconstructions. Clin Neuropathol 8:163-173, 1989 2. Cortez S, Kinney HS: Brainstem tegmental necrosis and olivary hypoplasia: a lethal entity associated with congenital apnea. J Neuropathol Exp Neurol 55:841-849, 1996 3. Moya MP, Delong GR, Barboriak D, Cummings TJ: A lethal association of congenital apnea with brainstem tegmental necrosis. Pediatr Neurol 30:219-221, 2004 4. Rorke LB: Pathology of Perinatal Brain Injury. Raven Press: New York. 1982, pp. 121125 5. Thakkar N, O'Neil W, Duvally J, Liu C, Ambler M: Möbius syndrome due to brain stem tegmental necrosis. Arch Neurol 34:124-126, 1977 6. TowfighiJ, MarksK, PalmerE, VannucciR: Mobius syndrome. Neuropathologic observations Acta Neuropathol (Berl) 48:117, 1979

 

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7. Igarashi M, Rose DF, Storgion SA: Moebius syndrome and central respiratory dysfunction. Pediatr Neurol 16:237-240, 1997 8. Lammens M, Moerman Ph, Fryns JP, et al. Neuropathological findings in Moebius syndrome. Clin Genet 54:136-141, 1998 9. Mito T, Becker LE, Takashima S: Neuropathology of central respiratory dysfunction in infancy. Pediatr Neurosurg 17:80-87, 1991/1992 10. Gilles FH: Hypotensive brain stem necrosis. Selective symmetrical necrosis of tegmental neuronal aggregates following cardiac arrest. Arch Pathol 88:32-41, 1969 11. Janzer RC, Friede RL: Hypotensive brain stem necrosis or cardiac arrest encephalopathy? Acta Neuropathol 50:53-56, 1980 12. Sakai Y, Kira R, Torisu H, Ihara K, Yoshiura T, Hara T: Persistent diffusion abnormalities in the brain stem of three children with mitochondrial diseases. AJNR Am J Neuroradiol 27:1924-1926, 2006 13. Huntsman RJ, Sinclair DB, Bhargava R, Chan A: Atypical presentations of Leigh syndrome: a case series and review. Pediatr Neurol 32:334-340, 2005 14. Saito Y: Reflections on the brainstem dysfunction in neurologically disabled children. Brain Dev 31:529-536, 2009 15. Little R: A 2-year old with no ventilator requirement but who cannot be extubated. Semin Pediatr Neurol 15:157-159, 2008

 

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Table 1 Central nervous system (CNS) etiologies of congenital apnea* ___________________________________________________ Prematurity • Intraventricular hemorrhage Drugs Seizures Hypoxic-ischemic injury Brainstem infarction Brain herniation Neuromuscular disorders • Congenital muscular dystrophy • Fukuyama congenital muscular dystrophy (FCMD) • X-linked myotubular (centronuclear) myopathy • Nemaline myopathy • Congenital myotonic dystrophy • Congenital myasthenic syndrome with episodic apnea (formerly known as familial infantile myasthenia gravis) Mitochondrial disorders • Leigh syndrome CNS anomalies • Chiari II Malformations • Pontocerebellar hypoplasias Brainstem tegmental necrosis and olivary hypoplasia/Möbius syndrome Congenital Central Hypoventilation Syndrome (CCHS) (PHOX2B gene mutations) ___________________________________________________ *Modified after reference 3

 

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Figure Legends Figure 1: A: Decedent’s face frontal view demonstrating micrognathia/retrognathia, short neck, depressed nasal ridge, and mild hypertelorism. B: Lateral view showing retrognathia, posteriorly rotated ears and short neck. C: Flexion deformities, camptodactyly (fixed flexion deformity of the proximal interphalangeal joints)(arrow) and arthrogryposis. D: Close-up view of camptodactyly. E: Close-up view depicting dorsiflexion of toes. Figure 2: A: Panoramic view of an axial section of the caudal pons illustrating multiple foci of mineralization (arrows) in the vicinities of the abducens and medial vestibular nuclei, nucleus prepositus hypoglossal, medial longitudinal fasciculus, the root of cranial nerve VI, and pontine reticular formation, extending to portions of the raphé nuclei. The basis pontis shows no overt abnormalities. B: Close-up view of the tegmental microcalcifications (arrows) in a milieu of dense gliosis and neuronal loss. There is dilatation and acute engorgement of perforating blood vessels accompanied by perivascular clear spaces (prominent Virchow-Robin spaces) secondary to parenchymal glial scarring. Hematoxylin and eosin stain. Figure 3: Panoramic view of an axial section of the open medulla illustrating multiple foci of mineralization (closed arrows) in the dorsomedial region involving the hypoglossal nucleus, vagal nuclei and the dorsal respiratory group (solitary tract nucleus), encroaching into the vicinities of the medial longitudinal fasciculus, raphé nuclei and reticular formation. The open arrow points to a small depression on the floor of the fourth ventricle corresponding to a slightly accentuated posterior median sulcus. There is disorganization and hypoplasia of the inferior olivary nuclei (IO) and presence of heterotopic olivary tissue in the tegmentum (asterisk). Hematoxylin and eosin stain. Figure 4: Close-up microscopic views of the lesions in the medullary tegmentum illustrating dystrophic calcifications, neuronal loss, and gliosis (A-C). Panel B depicts large round eosinophilic profiles consistent with axonal spheroids (retraction bulbs)(arrows) adjacent to parenchymal calcifications and gliosis. Panel C depicts a heterotopic ependymal tubule in a milieu of tegmental gliosis with a microcalcification. Panel D illustrates preservation of populations of tegmental neurons. Hematoxylin and eosin stain.  

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Brainstem tegmental necrosis and olivary hypoplasia: raising awareness of a rare neuropathologic correlate of congenital apnea.

This case study describes an instance of death in an early term female newborn with congenital apnea in the clinical setting of multiple congenital an...
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