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Watershed infarcts in the fetal and neonatal brainstem. An aetiology of central hypoventilation, dysphagia, Möbius syndrome and micrognathia

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Abstract

Watershed zone infarcts of the human cerebral cortex at the overlapping junctions of the anterior and middle cerebral arterial territories are well known. Another watershed zone exists in the brainstem tegmentum, between the terminal perfusion zones of the paramedian penetrating and long circumferential arteries, which are paired segmental vessels arising from the basilar artery. The vertebrobasilar circulation achieves its mature configuration and caudorostral flow by 9 weeks gestation. Systemic hypotension and other conditions of reduced basilar perfusion in the fetus, either early or late in gestation, may result in symmetrical longitudinal columns of infarction in the midbrain and tegmentum of the pons and medulla oblongata and laminar necrosis of the midbrain tectum. Within this zone are cranial nerve nuclei III–XII, the nucleus and tractus solitarius or central pneumotaxic center, as well as the nucleus ambiguus and other somatic motor nuclei that subserve muscles of swallowing, mastication and tongue movement. Watershed infarcts in the human fetal and neonatal brainstem are clinically expressed as multiple cranial neuropathies, failure of central respiratory drive and apnea, dysphagia and aspiration, Möbius syndrome and Pierre Robin sequence. MRI is sometimes helpful, but most of the involved neuroanatomical structures are beneath the resolution of present imaging techniques, and the diagnosis during life depends upon clinical neurological examination of the neonate, sometimes supported by evoked potential studies. Postmortem examination confirms the diagnosis and dates the lesions, but also contributes to better understand transient or persistent vascular insufficiencies in the fetal and neonatal brainstem.

Introduction

What is a watershed?

Watershed: Strathcluony…is a very high inland tract, being the Water-shed of the country between the two seas. Prize Ess. Highland Society of Scotland II. 1803.

Watershed: The College, a small stream which flows at a moderate declivity from the eastern Water-shed of the Cheviot Hills,… Lyell, Principles of Geology, Vol. I, 1830, p. 175.

Watershed: The line of Water-shed which divides the inland streams from those on the coast has a height of 3000 feet. Charles Darwin, Voy. Nat. xix, 1845.

Watershed (German, Wassersheide): a region or area bounded peripherally by a water parting and draining ultimately to a particular watercourse or body of water; the catchment area of drainage basin from which the waters of a stream or stream systems drain. Webster's third New International Dictionary, Unabridged, Springfield, MA, G and C Merriam. 1961, p. 2594.

Watershed: a line of separation between waters flowing to different rivers, basins or seas. (Water+shed, ridge of high ground, after German Wassersheide). Oxford English Dictionary, 2nd ed., Oxford, UK 2003, p. 1633.

The term ‘watershed’ was originally used in agricultural and Earth sciences. It denotes a strip of land lying midway between two more or less parallel streams and receiving water from both. It is both protected and at the same time vulnerable. It is protected from a sudden reduction of flow of water from one of the streams, for example damming by beavers, because it can rely upon its other source of water. It is vulnerable to simultaneously decreased flow in both streams, as in drought, because it is the last land to receive water from either stream and the first to become parched, leading to death of vegetation.

Watershed: territory at the distal extent of any major arterial supply, and particularly the region at the junction between the terminal branches of major cerebral arteries. Blackinston's Gould Medical Dictionary, 4th ed. NY: McGraw-Hill. 1979, p. 1477.

Watershed: an area where the peripheries of two vascular beds meet, particularly in the brain; small anatomoses link the adjoining beds. Dorland's Illustrated Medical Dictionary, 29th ed. Philadelphia: WB Saunders; 2000, p. 1982.

Watershed: the area of marginal blood flow at the extreme periphery of a vascular bed. Stedman's Medical Dictionary, 27th ed. Philadelphia: Lippincott Williams and Wilkins; 2000, p. 1983.

Watershed has been extrapolated from agriculture to medicine by analogy, referring to tissue receiving a double blood supply, particularly in the brain. The classical, best-known watershed zones in the brain are the overlapping territories between the anterior and middle cerebral arteries, and between the middle and posterior cerebral arteries. If one of the two major vessels becomes occluded by thrombus or embolus, the watershed zone has another source of blood to enable the tissue to remain viable. If blood flow is diminished in both vessels at the same time, as in the case of systemic hypotension, it becomes the most vulnerable region to infarction. Watershed zone impacts in the cerebral cortex occur at all ages, including the fetus and newborn (Fig. 1).

The tegmentum of the brainstem is another watershed zone, but it is not as well recognized that in the fetus and neonate who has suffered systemic hypotension or a severe ischemic/hypoxic insult, this area also may become infarcted symmetrically. Most modern textbooks of neuropathology, both general and pediatric, fail to mention tegmental infarcts or address the topic only briefly and incompletely as occasional infarcts of the inferior colliculus or near the floor of the fourth ventricle.1., 2., 3., 4., 5. Some papers and textbooks do discuss these neonatal lesions, but the information seems to have poor dissemination.6., 7., 8., 9. Because of a number of essential structures, such as cranial nerve nuclei and intrinsic tracts, such infarcts have important chronic, and potentially life-threatening, clinical consequences.

To understand the tegmental watershed zones, one must appreciate the vascular supply and details of circulation within the brainstem. The basilar artery is the sole source of blood to the pons and medulla oblongata. Embryologically, the basilar artery arises from a pair of vessels, the parallel longitudinal neural arteries, which then undergo a true fusion. Initially, the basilar is fed from the internal carotid artery through a paired series of transitory fetal communicators, the trigeminal, otic and hypoglossal arteries, hence the direction of blood flow in the basilar artery initially is rostrocaudal. This flow changes to the mature caudorostral direction by subsequent formation of the vertebral arteries, accompanied by atresia and disappearance of the series of fetal carotid–basilar communicators and the development of the posterior cerebral arteries by bifurcation at the top of the basilar artery (Fig. 2). Other smaller and less constant transitory embryonic vessels anastomosing the carotid and early basilar arteries include the proatlantal artery, the most rostral in a series of eight segmental cervical arteries, and the stapedial artery.

From the embryonic basilar artery arise segmental pairs of vessels to the brainstem as trios of paired arteries: the paramedian penetrating artery, the short circumferential artery and the long circumferential artery (Fig. 3). These segmental vessels develop at 8–9 weeks gestation.

The watershed zone in the brainstem is between the territories supplied by the paramedian penetrating and long circumferential arteries, as shown in Fig. 3. These vessels are symmetrically paired and occur segmentally in a series of about 25–30 sets. Because these vessels all arise from the same basilar artery beginning at about 8 weeks gestation, watershed zone infarcts in the tegmentum are usually bilateral and symmetrical, and occur as longitudinal columns deep in the floor of the fourth ventricle. The zone spares the paramedian and lateral regions of the tegmentum and also spares the narrow band of immediate subependymal parenchyma. The mature pattern of circulation of the brainstem develops at between 6 and 9 weeks gestation (Figure 2, Figure 3), hence already is well established in human fetuses long before midgestation and is the expected circulation in all premature infants of viable age.

Fetuses are vulnerable to tegmental watershed infarcts at any time in the late first, second and third trimesters. The most frequent condition that results in such anatomically restricted infarcts is systemic hypotension.

The tegmentum is the dorsal half of the pons and medulla oblongata, extending dorsally to the ependymal floor of the fourth ventricle. Within this longitudinal zone lie most of the cranial nerve nuclei, both motor and sensory (IV–XII), many longitudinal tracts, both ascending and descending, the reticular formation and columns of mixed neurons and longitudinal axons, including the nucleus and tractus solitarius and the nucleus ambiguus (Fig. 3).10., 11. The watershed zone of the tegmentum does not include the entire tegmentum, but is the large central area. Excluded are the paramedian and most lateral regions and a narrow band of subependymal tissue.

The nucleus and tractus (or fasciculus) solitarius is the neuroanatomical correlate of the physiological ‘pneumotaxic center’, the central respiratory center.10 Afferent axons carry impulses from the chemoreceptors, such as the carotid body, from the lungs and from stretch receptors (muscle spindles) in the respiratory muscles. Other visceral afferents and axons from other cranial nerve nuclei also contribute.12 These axons descend in the tractus solitarius where they synapse with scattered neurons within the tract (nucleus of the tractus solitarius) and similar neurons forming small aggregates adjacent to this tract (nucleus parasolitarius). Other axons of solitarius neurons synapse in the nearby nucleus ambiguus upon motor neurons to esophageal and pharyngeal muscles.13., 14. The axons of these postsynaptic neurons then descend further where they contact motor neurons of the spinal accessory nucleus (to innervate the sternocleidomastoid, an accessory respiratory muscle) and continue descending into the cervical and thoracic spinal cord to synapse with neurons of the phrenic nerve (C4, to the diaphragm) and of the intercostal muscles (T2–T8).10., 15. Ischemia or infarction of the nucleus and tractus solitarius bilaterally in the neonate has profound effects, expressed clinically as apnea and central respiratory insufficiency or failure. In adults, focal neoplastic metastases to the nucleus solitarius also result in central respiratory failure.16

Immaturity of the nucleus solitarius without infarction is often offered as a neurological explanation of the apnea of prematurity, but the physiological basis for this assertion is speculative. Ischemic impairment of the nucleus solitarius, from decreased basilar artery perfusion that does not progress to frank infarction or neuronal loss, is another hypothetical basis.

The nucleus ambiguus, so named in the 19th century because of rather poorly defined boundaries with histological stains, is the somatic efferent nucleus of the vagus and innervates striated muscle of the pharynx and larynx, hence is essential for the swallowing mechanism. Ischemia or infarction of this nucleus bilaterally results in dysphagia and may cause bilateral paralysis of muscles innervating the vocal cords, leading to asphyxiation due to airway obstruction at the entrance of the trachea.

The reticular formation is one of the earliest brainstem structures to evolve, both phylogenetically and ontogenetically.17 Much of it lies within the tegmentum. The reticular formation has complex afferent and efferent connections, the latter including bulbospinal pathways that decussate and descend. It is important to vasomotor control and, in its more rostral regions, forms the reticular activating system to maintain consciousness and sleep cycles. Despite its sometimes nebulous anatomical boundaries with standard histological stains, the reticular formation is actually a well defined complex that includes many specifically named nuclei, including the locus coeruleus and raphé nuclei, and is heterogeneous in that many various parts utilize different neurotransmitters, including serotonin, monoamines, acetylcholine and GABA.

Cranial nerve nuclei of the trigeminal, abducens, facial, acoustic, vagal, spinal accessory and hypoglossal nerves are located within or at the margins of the tegmental watershed zone and are thus vulnerable to ischemia or infarction. This involvement is variable, depending upon which parts of the watershed zone are most involved, and the clinical expression depends upon anatomical distribution and also the timing of infarction in fetal life that may affect secondary growth of non-neural structures such as the jaw. The involvement of cranial nerve nuclei in tegmental watershed infarcts thus explain many cases of Möbius syndrome, Pierre Robin sequence and denervation of the tongue that may be confused clinically with spinal muscular atrophy (see below).

Section snippets

Examples of tegmental watershed infarcts

Severe global hypoxic/ischemic encephalopathy affecting structures supplied by the internal carotid, as well as the basilar, arterial circulations. In severe cases of fetal and neonatal hypoxic/ischemic encephalopathy, tegmental infarction may be present but, rather than restricted to an isolated basilar arterial watershed distribution, extensive infarcts also are found in territories of the internal carotid circulation, within the cerebral cortex and deep subcortical telecephalic and

Non-syndromic findings

The most common are also the most serious and potentially life-threatening clinical manifestations in infants born with tegmental watershed infarcts from late fetal life: difficulties with (1) regulation of central respiratory drive and (2) deglutition, presenting as apnea and central respiratory failure not of pulmonary aetiology, and dysphagia with risk of aspiration. These symptoms are due to involvement of the nucleus and tractus solitarius and the nucleus ambiguus, as described above. The

Differential diagnosis

A strong history of fetal distress, abruptio placentae or severe perinatal asphyxia are strong evidence supporting this diagnosis. If such a history is not documented, other differential diagnoses of the principal symptoms and signs of central respiratory insufficiency, dysphagia and cranial neuropathies referable to the brainstem must be considered. Posterior fossa malformations that may result in at least some of these findings include Chiari I malformation, Dandy–Walker malformation, Joubert

Clinical examination and laboratory investigations

The diagnosis of tegmental watershed infarction of the brainstem depends largely upon clinical neurological examination of the neonate. A critical exploration of cranial nerve functions, assessment of the gag reflex and swallowing function, including radiographic studies of deglutition, definition of the type of respiratory failure, and assessment of size and mobility of the mandible are essential.

Imaging studies usually are not diagnostic of the microscopic tegmental lesions because these

Acknowledgements

I would like, most sincerely, to thank Professors E.C. Alvord Jr, John H. Menkes and Laura Flores-Sarnat for their valuable suggestions at various stages in the preparation of this manuscript.

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