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Syncope: facts and fiction
Medical Hypotheses (2004) 63, 394–401
http://intl.elsevierhealth.com/journals/mehy
Syncope: facts and fiction Niko Zurak, Ervina Bilic* Department of Neurology, Clinical Hospital Centre Zagreb, Kispaticeva 12, 10 000 Zagreb,Croatia Received 11 February 2004; accepted 15 February 2004
Summary According to the current state-of-art on the brainstem functional anatomy and reticular formation, authors believe that nucleus tractus solitarii (NTS) is the neural structure, which meets all the conditions of the hypothetical syncope generating, reflex centre. The afferent branch of this reflex arc represents information from different visceral sources including the brain itself. The efferent branch of this reflex arc is reticular activating system (RAS). The executive mechanism of syncope is deactivation of RAS done with the active engagement of NTS through solitarioreticular pathway (SRT) and parabrachial nuclear complex (PBC). The biological purpose of syncope would be resetting of the NTS in case of an unbearable vegetative input, which is code for triggering the mechanism described. c 2004 Elsevier Ltd. All rights reserved.
Introduction Syncope is usually defined as a sudden and brief loss of consciousness associated with a loss of postural tone, from which recovery is spontaneous [1–5]. The pathophysiology of all forms of syncope is considered as a sudden decrease in or brief cessation of cerebral blood flow [2,6,7]. Comparison of the early definitions of syncope and of considerations about its pathophysiology (e.g., [1]) with the current ones appears to yield no major differences or advances. Interestingly enough, not even such a high consensus on the syncope pathophysiology has produced a logical conclusion based on this premise, that syncope is a transient ischaemic cerebral attack [7,8].
*
Corresponding author. Tel.: + 385-1-37-35-090/91-577-27-25 fax: +385-1-242-1846. E-mail address: [email protected] (E. Bilic).
Syncope has an enormous medical, social and economic impact on the general population. Approximately, one million patients are evaluated for syncope annually in the USA. It has been estimated that syncope evaluation accounts for 3–5% of emergency department visits and 1–6% of hospital admissions. In addition, about 3–5% of healthy blood donors experience fainting during the puncture manipulation [6]. A history of an isolated episode of syncope will be found in as many as 25% of healthy young adults, especially in settings that precipitate fear, disgust or anxiety, and if not repeated it does not warrant further work-up [6,9]. Has the issue of syncope pathogenesis really been definitely solved and the existence of transient cerebral circulation catastrophe demonstrated? We believe that there also exists an alternative solution of the syncope pathophysiology, based on the clinical experience with its paroxysmal onset and short duration. The reflex structure of this paroxysmal event, from a diversity of afferences to a stereotypic efference with clinical equivalence of the loss of consciousness,
0306-9877/$ - see front matter c 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.mehy.2004.02.045
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points to specificities of the mode of central nervous system functioning. Many years ago, William Gowers stressed the pathogenesis of syncope. In his monograph from 1907, entitled “The Borderland of Epilepsy”; he attempts to explain fainting episodes, vertigo, migraine and ‘vagal attacks’ by their relationship to epilepsy fit [10]. A crucial question is where the reflex centre or the governing neural structure from which different afferences can trigger the loss of consciousness is. According to the current state-of-the-art on the brainstem functional anatomy and reticular formation, we believe that nucleus tractus solitarii (NTS) is the neural structure, which meets all the conditions of the hypothetical syncope generating, reflex centre. In the literature, this nucleus is occasionally referred to as a reflex centre in the pathophysiology of syncope induced by baroreceptor afference [11,12]
Functional neuroanatomy of nucleus tractus solitarii Nucleus tractus solitarii NTS is situated in medulla oblongata as a long cylindrical pairly structure extending throughout its length, from the obex to the pontomedullary junction. It is the principal nucleus of reception of general and special visceral afferents. Visceral afferents are conveyed to the NTS by branches of cranial nerves VII (facial), IX (glossopharyngeal) and X (vagus) [13–16]. NTS is bordered ventromedially by the dorsal motor nucleus (DMX) of the vagus (the general visceral efferent cell column of the basal plate). The NTS and DMX are related ventrolaterally to a diagonal laminated strip of reticular formation called lateral tegmental field (LTF). At medial and caudal medullary levels, the NTS is bordered dorsally by the area postrema, a highly vascularized circumventricular organ located outside the bloodbrain barrier. NTS is separated from the dorsal column nuclei (gracilis and cuneatus) by the nucleus of tractus parasolitarius (NPS), which is a cerebellar relay nucleus. At the level of the obex, the caudal bilaterally symmetrical extensions of the NTS merge on both sides of the midline and form a bridge known as commissural nucleus [13,15] (Figs. 1–3). NTS and the adjacent DMX within the spinal cord and brainstem localized substantia intermedia
Figure 1 Afferents to the NTS. DMX, dorsal motor nucleus of nervi vagi; FLD, fasciculus longitudinalis dorsalis; LC, locus coeruleus; NTS, nucleus tractus solitarii; PBC, parabrachial nucleus complex; PG, periaqueductal gray; SG, substantia gelatinosa; SIC, substantia intermedia centralis.
Figure 2 Brain afferents to the NTS. CL, caudal level of NTS; DSN, dorsal subnuclei of NTS; IL, intermediate level of NTS; LSN, lateral subnuclei of NTS; MR, midline region of NTS; VP, ventral parts of NTS.
centralis (SIC), the parabrachial nuclear complex (PBC) and the periaqueductal gray (PG) constitute a chain of centres interconnected by the fasciculus €tz (FLD) (Fig. 3) [17]. longitudinalis dorsalis of Schu Rostrally, this chain of centres is connected with the hypothalamus by way of the fasciculus longitudinalis dorsalis and median forebrain bundle (fasciculus telencephalicus medialis) [17].
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Zurak and Bilic functional organization. One type may be organ specific and represented by a precise viscerotopic organization of projections to NTS subnuclei that are devoted to processing organ specific modalities. The second mode of organization may be integrative whereby afferents from different organs or different receptors within the same organ converge within the solitary complex [15]. The connections between this nucleus and visceral organs are bilateral, to that in the vegetative control of visceral organs this complex nucleus modulates and adapts their function in the most optimal way. This is accomplished by the rich network of internuncial neurones [15].
Brain as a source of afferents
Figure 3 The hypothetic executive way of syncope mechanism. CN, comissural nucleus; DMX, dorsal motor nucleus of nervi vagi; MINT, midline and intralaminar thalamic nuclei; NPS, nucleus parasolitarius; NTS, nucleus tractus solitarii; RAS, reticular activating system; PBC, parabrachial nucleus complex; SRT, solitarioreticular tract; TS, tractus solitarius.
It is very important to stress that, in the NTS perikarya and its fibres and ending complex, practically all neurotransmitters and neuromodulators of the central nervous system have been found: angiotensin II, dynorphin, enkephalin, endorphin, c-MSH, a-MSH, ACTH, vasopressin, oxytocin, TSH, somatostatin, LHRH, CRF, neurotensin, CCK, VIP, substance P, glycine, glutamate, aspartate, GABA, histamine, serotonin, epinephrine, norepinephrine, dopamine and acetylcholine [17,18].
Afferents to the nucleus tractus solitarii As mentioned above, NTS is the principal site of termination of afferent fibres from the viscera (cardiovascular, respiratory, gastrointestinal, urogenital and nociceptive system) and arterial chemo- and baroreceptors [13–15,19] (Fig. 1). In addition, NTS is innervated by neurones arising from the fastigial nucleus, PBC, C1 adrenergic neurones, locus coeruleus (LC) and cerebral cortex. Different visceral afferents within the NTS appear to be organized topographically. The central branches of different visceral afferents enter the medulla oblongata and form the tractus solitarius [14,15]. The distribution of visceral afferents within the NTS appears to reflect two types of structural and
Bilateral connections between the brain and NTS have an important role in maintaining appropriate internal milieu of vegetative functions (Fig. 2). The insular cortex is influenced by visceral as well as limbic afferents, which are segregated along different longitudinally organized cortical strips [20]. This structural arrangement probably reflects a neural substrate through which telencephalic afferents can enter the generation of an organized adaptive behavioural pattern. The outputs of the insular cortex and amygdala, by virtue of their intimate connections, probably superimpose a hierarchical control over emotional expressions. The pathways mediating autonomic responses from both nuclei appear to constitute a functionally integrated system extending from the cortical mantle via NTS to the spinal cord [20]. The cerebral cortex projection to the NTS requires an obligatory synapse in the lower brainstem (PBC, LC and nucleus raphe dorsalis) or subcortical forebrain [15]. Cortical afferents to the NTS project to dorsal and lateral subnuclei and along the midline region largely avoided by the subcortical afferents, terminating within so-called barrel fields (cylindrical columns) [15] (Fig. 2). Subcortical afferents have relatively dense projections to ventral parts of the NTS surrounding DMX [15] (Fig. 2). Forebrain afferents including hypothalamic region project to the intermediate and caudal levels of NTS [15] (Fig. 2).
Efferents from NTS Efferent connections of NTS with peripheral sources of its afferent information represent the ex-
Syncope: facts and fiction ecutive part of its reflex functioning. The main part of NTS efferences are grouped into the solitarioreticular and solitariospinal pathways [21,15]. For the purpose of this presentation, most important are the efferent connections of NTS with reticular formation realized through the solitarioreticular tract (SRT). The executive part responsible for clinical presentation of syncope event is probably the part of reticular formation known as the reticular activating system (RAS) [22]. The SRT contains axons which leave NTS and traverse through the LTF (Fig. 3). This region of LTF was long recognized as part of the reticular matrix [22]. The organizational patterns of cell bodies and afferent processes in the LTF are likely to dictate the direction of information flow along the reflex arcs through the segmental cylindrical systematized afferents and probably establish a moduletype organizational pattern similar to the architecture of the cerebral cortex [15]. The NTS subnuclei surrounding the solitary tract and cell columns in the ventrolateral medulla, which relay the solitarioreticular signals, project to the PBC [15] (Fig. 3). PBC is one of several major brainstem relays of panmodal sensory information to the forebrain. Parabrachial output neurones directly access the cerebral cortex and visceral information is conveyed by the NTS indirectly, by topographically organized solitariofugal pathways to the PBC and ventral sensory thalamus [15]. Parabrachial pathways ascending by the dorsal tegmental bundle to the thalamus and through collateral branches to the hypothalamus constitute a critical component of the RAS [15] (Fig. 3). NTS neurones also give rise to efferent projections to the LC, C1 neurones and dorsal medullary reticular formation [15]. Experimental studies suggest that neurones of the NTS may tonically regulate regional cerebral blood flow (rCBF) throughout the brain influencing cerebrovascular autoregulation [13,23–25].
NTS as a reflex centre It is thought that overlap between different firstorder visceral afferents ending in NTS may be involved in the co-ordination and patterning of synergistic movements among oropharyngeal, oesophageal and abdominal smooth muscles and glands engaged in feeding, swallowing and digestion, and those involved in cardiorespiratory control. Intranuclear pathways are thought to mediate local reflex integration between different sensory modalities [15].
397 All components of visceral reflex arcs in the lower brainstem, including neurones involved in the tonic and reflex control of the autonomic outflow, feedback to the NTS. These circuits comprise the servomechanisms (self-correcting error-control systems) of the lower brainstem, and are designed to co-ordinate changes in reflex excitability of the primary sensory controller (NTS) with the constellations of skeletomotor and visceromotor reflex adjustment to signals continually generated by the internal and external milieu (e.g., exercise, pain and the expression of distinct behaviours). The smooth performance of such goal directed reflexes is servoregulated by sequential transfer of afferents to the NTS from collaterals of intermediary neurones organized along its efferent transsegmental fibre tract. These include propriobulbar interneurones within lateral reticular formation, A5 (caudolateral part of the pontine tegmentum), C1 (ventrolateral myelencephalon) and non-catecholaminergic reticulospinal projection neurones [15,17]. All the mentioned structures make closed multiple feedback control circuits, the insufficiency of which demands NTS resetting with clinical presentation of a syncope.
NTS and sleep-wake mechanisms Sustaining input to the cerebral cortex from the brainstem reticular formation is required for maintenance of consciousness. The portion of the reticular formation that provides this input is known as RAS. The RAS receives collaterals from virtually all sensory pathways (NTS–SRT and others) and projects to the midline and intralaminar nuclei of the thalamus (MITN), which in turn project diffusely to widespread cortical areas [22,26]. At this point it is necessary to focus attention on the sleep, which is a physiologic reversible state of unconsciousness [26]. The mechanisms of sleep might be expected to have a bearing on the mechanisms of consciousness in general. It is well known that active mechanisms play a major role and that specific neural structures can induce sleep by inhibiting the RAS [22,26]. A related view is that the function of sleep amounts to adaptive non-responding, meaning that it prevents activity (e.g., foraging) when it would be dangerous or inefficient, and it blocks harmful reactions that might occur in an animal merely resting but aware of ongoing events [22]. Jouvet stated many years ago: “We must assume that our brain, like our kidneys and heart but unlike our muscular system, does not rest
398 during sleep. On the contrary, it undergoes an active reorganization rather than a real inhibition, and so sleep seems to be an active phenomenon” [27]. Several lines of evidence indicate that the NTS is involved in sleep generation [26]. Distension of the carotid, a powerful stimulus for the NTS region, induces behavioural sleep. Low frequency stimulation of the vago-aortic nerve or of the NTS also produces slow waves on EEG (experimental data). Inactivation of the lower brainstem regions, including the NTS, produces a profound arousal (experimental data) [26]. This action of NTS is realized through the part of SRT that terminates in LTF and especially PBC (Fig. 3). Parabrachial pathways access more widespread areas of the cortex by way of ascending projections through the MITN (Fig. 3). These projection fields include parts of the centromedian–paraparafascicular complex that have long been known to participate in cortical EEG desynchronization and behavioural arousal, as part of RAS [26,28]. Stimulation of the MITN at low frequencies produces sleep and synchronization of EEG, so this part of the thalamus is considered to be a sort of final switching mechanism into which other sleepinducing mechanisms funnel [26]. The integrity of each of these structures is essential in maintaining consciousness and such regions have been implicated in the mechanisms generating states of arousal and wakefulness. It seems that PBC has a crucial role in RAS deactivation, which is the starting point of so-called non-rapid eye movement (NREM) sleep [15].
Neural hypothesis Syncope is a neurally mediated reflex loss of consciousness. The afferent branch of this reflex arc represents information from different visceral sources including the brain itself (Figs. 1 and 2). The reflex centre is NTS in the medulla oblongata. The efferent branch of this reflex arc is RAS. The executive mechanism of syncope is deactivation of RAS done with the active engagement of NTS through SRT and PBC (Fig. 3). The loss of consciousness during the syncope is an analogue to deep sleep. The biological purpose of syncope would be resetting of the NTS in case of an unbearable vegetative input, which is a code for triggering the mechanism described. In conclusion, syncope is an active neural event.
Zurak and Bilic
Discussion According to causation, syncopes are usually classified into two major groups, cardiac and non-cardiac. Examples of cardiac syncope are the cases of heart rhythm disturbances or structural abnormalities of the heart. Neurally mediated syncope (NMS), also known as vasovagal and neurocardiogenic syncope, common or emotional fainting, or reflex syncope, is most common in the non-cardiac group [2]. The term vasovagal has a widespread use today in medicine practice. Its origin can be attributed to Sir William R. Gowers, a renowned 19th-century neurologist [10,29]. Vasovagal syncope accounts for some 40% of all syncopal events [6]. Patients with vasovagal syncope often have a long history of fainting, commonly associated with emotional or painful stimuli. This form of syncope may be precipitated by the sight or loss of blood, or by physical or emotional stress. It is characteristically preceded by symptoms of autonomic hyperactivity such as a dim vision, giddiness, yawning, sweating and nausea. Hysterical fainting is often associated with paresthesias of the hands or face, hyperventilation, dyspnea, chest pain, and feeling of acute anxiety [6]. The NMS group includes situational syncope triggered by cough, micturition, defecation, diving, sneezing and swallowing and carotid sinus syncope (shaving syncope). Other non-cardiac types of syncope include those occurring in psychiatric and neurological diseases, orthostatic hypotension and drug induced syncope [2]. According to Petch, simple faint can be distinguished from syncope by the presence of the following features: upright posture, an emotional or painful stimulus, gradual rather than sudden fading of consciousness, sweating, nausea, pallor, other manifestations of autonomic activity, and rapid recovery course. Simple faints tend to occur and recur in young people [30]. We believe that differences between fainting and syncope are gradual in intensity, the process being basically identical. The loss of consciousness is a common denominator of all forms of syncope. It is usually explained by a transient cerebral haemodynamic catastrophe with consequential brain anoxia. However, it should be noted that such a mechanism has never been demonstrated. The prejudice is related to blood pressure decrease, which is a frequent finding in syncope [31–33]. As early as 1911, Thomas Lewis concluded: “. . . that the fall of blood pressure during syncope is not
Syncope: facts and fiction attributable to fall of ventricular rate, it is an added phenomenon” [10]. Brain is an organ characterized by high perfusion and oxygenation redundancy, supplied with efficient vasomotor autoregulation intended just for the episodes of systemic pressure decline [34–36]. The specificities of extrinsic and intrinsic neural vasomotor autoregulation of the brain supplemental to the myogenic and metabolic aspects of autoregulation common to all organs have recently been highlighted [15,23,37]. Besides NTS, elements of the complex system of intrinsic neural control of the cerebral circulation include C1 area of the rostral ventrolateral medulla, dorsal medullary reticular formation, fastigial nucleus, LC, PBC, centromedian–parafascicular complex of the thalamus, parts of the basal forebrain, and in the cerebral cortex specialized cortical neurones [25,24]. To these, the following classical constituents of extrinsic neural control should be added: sympathicus with the neurotransmitters norepinephrine and epinephrine, and non-adrenergic markers such as neuropeptide Y and 5-HT, parasympathetic influences through acetylcholine, VIP, peptide histidine isoleucine (methionine), and trigeminovascular system with the transmitters substance P, neurokinin A (NKA), CGRP and CCK [25]. Therefore, an indirect harmful effect of blood pressure decrease on cerebral perfusion can only occur in case of total insufficiency of the intrinsic and extrinsic neurogenic cerebral vasomotor autoregulation which, by the same reasoning, should precede or at least concur with the pressure decline. Thus, in the genesis of syncope, the systemic pressure decrease is not its cause but a symptom of NTS insufficiency if preceding it, whereas in case of fainting it is additionally associated with the component of physiological pressure decline characteristic of deep sleep phase [31]. In syncope, the loss of consciousness is usually as quick as lightning, which especially holds for psychogenic syncope, thus offering an additional case against the concept of generalized cerebral hypoxia as the cause of the loss of consciousness, knowing that the brain can normally function for several minutes in anoxic conditions. Accordingly, the precipitating factors causing syncope should first induce total functional failure of all the mentioned resources of extrinsic and intrinsic cerebral autoregulation to cause a haemodynamic cerebral catastrophe with consequential loss of consciousness. It appears quite inconceivable that, for example, a mere sight of blood could result in such a consequence. On the other hand, such a
399 vulnerable cerebral vasomotor autoregulation would sooner or later certainly lead to a perspective of serious organic cerebral pathology. However, clinical practice is in sharp contrast to such a presumption. Syncope is as a rule a benign, shortterm, reversible loss of consciousness without any sequels [4,38]. In our opinion, all syncope cases are caused by a neural reflex mechanism, either as pure functional disturbances (vasovagal, psychogenic) or associated with organic diseases of visceral organs. Organic diseases of visceral organs induce syncope in the same way as functional impairments. The same reflex mechanism is triggered via vegetative afferences by a strong peripheral visceral input caused by organic disease. Although the cardiac causes of syncope have been shown to be associated with an increased mortality and risk of sudden death, recent evidence show that the underlying heart disease, irrespective of the syncope, is a factor associated with an increased risk of death [39]. Although syncope is a common clinical occurrence, the susceptibility to syncope shows considerable interindividual variation. In some individuals it occurs quite frequently, in some rarely, and there are cases of its occurrence once in lifetime [38]. This holds for both the healthy population and patients with different organic pathology of visceral organs, irrespective of the disease severity. The physiologic ‘loss of consciousness’ during sleep and loss of consciousness during grand mal epileptic seizure are the processes that are completely unrelated to cerebral blood hypoperfusion. In our attempts to explain the genesis of syncopal loss of consciousness, we made use of the indisputable neuroanatomical and neurophysiological determinants of the position and function of NTS, and its neural system specific reactive stereotypic response to functional and organic disturbances from the territory of its input (afferences). Isolated presyncopal state, which might be a parallel to epileptic seizure aura, is quite commonly encountered in clinical practice. This implies that in these cases, NTS has completely and without resetting managed to master the control, synthesis and modulation of the vegetative nervous system signals. The differential diagnosis between epileptic seizures and syncope, including the level of intermediary phenomena is frequently a subject of discussion [3,5,8,9,40,41]. Syncope as a paroxysmal phenomenon, as well as prodromes or presyncopal symptomatology, makes us take into consideration the mechanism of the loss of consciousness other than ischemic.
400 The syncopal loss of consciousness is probably a paroxysmal onset of deep narcotic sleep with the function of NTS resetting. In the so-called convulsant variant of syncope, strong myoclonisms associated with falling asleep are most probably involved. Hypnic myoclonias are not pathological events, although they tend to occur more frequently in association with stress or with unusual or irregular sleep schedules [42]. In this way the reflex arc, which we believe to be active in the syncope of whatever genesis, has been closed. The reflex centre of this actually neurogenic process is NTS, a nucleus deserving to be called ‘visceral brainstem’. The complex information pattern from visceral organs or brain leads to strong stereotypic efferent response with a consequential brief loss of consciousness. The effector organ is RAS, which is paroxysmally inactivated by NTS via PBC (Fig. 3). In physiological conditions, this inactivation is the introduction to sleep. Even our civilian experience indicates that entering sleep may in some individuals be so abrupt as to allow us to consider it approximating syncope according to its time sequence and dynamics. The paroxysmal onset of sleep in case of syncope points to the involvement of a more direct solitarioreticular pathway (SRT via PBC and RAS) (Fig. 3). Forebrain structures, including suprachiasmatic nucleus (SCN) of the anterior hypothalamic region, are more engaged in the genesis of physiological sleep-wake cycle as a biorhythmic event [43]. Vegetative phenomena in the so-called precollapse stage are indicative of insufficiency of NTS as a reflex centre for the control and modulation of the overall vegetative input. According to analogy with computer functioning, the critical value of this disbalance is the code for NTS resetting. This is most simply accomplished by deleting all actual vegetative information by abrupt switching to deep narcotic sleep. The strongest evidence for a successful NTS resetting process is disappearance of vegetative symptoms present during the presyncopal period, which as a rule occurs upon awakening from the syncopal state [1,38]. It is hard to state whether brief deep sleep or loss of consciousness in the syncope has the characteristics of NREM or rapid eye movement (REM) sleep. The very short duration of the event precludes any definite differentiation. We believe that both of these options are probable. It is known that in physiological sleep, the mechanisms of NREM phase are activated first, whereas in narcolepsy REM phase is being entered straight off [26]. “Choose something in common and you will find little is known about it”, it was Sir Henry Head’s advice to the then young Russel Brain in the 1920s
Zurak and Bilic [44]. We think that the meaning of this aphorism fully applies to the case of syncope.
Acknowledgements The authors are grateful to Silvio Basic MD for technical assistance.
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Syncope: facts and fiction Niko Zurak, Ervina Bilic* Department of Neurology, Clinical Hospital Centre Zagreb, Kispaticeva 12, 10 000 Zagreb,Croatia Received 11 February 2004; accepted 15 February 2004
Summary According to the current state-of-art on the brainstem functional anatomy and reticular formation, authors believe that nucleus tractus solitarii (NTS) is the neural structure, which meets all the conditions of the hypothetical syncope generating, reflex centre. The afferent branch of this reflex arc represents information from different visceral sources including the brain itself. The efferent branch of this reflex arc is reticular activating system (RAS). The executive mechanism of syncope is deactivation of RAS done with the active engagement of NTS through solitarioreticular pathway (SRT) and parabrachial nuclear complex (PBC). The biological purpose of syncope would be resetting of the NTS in case of an unbearable vegetative input, which is code for triggering the mechanism described. c 2004 Elsevier Ltd. All rights reserved.
Introduction Syncope is usually defined as a sudden and brief loss of consciousness associated with a loss of postural tone, from which recovery is spontaneous [1–5]. The pathophysiology of all forms of syncope is considered as a sudden decrease in or brief cessation of cerebral blood flow [2,6,7]. Comparison of the early definitions of syncope and of considerations about its pathophysiology (e.g., [1]) with the current ones appears to yield no major differences or advances. Interestingly enough, not even such a high consensus on the syncope pathophysiology has produced a logical conclusion based on this premise, that syncope is a transient ischaemic cerebral attack [7,8].
*
Corresponding author. Tel.: + 385-1-37-35-090/91-577-27-25 fax: +385-1-242-1846. E-mail address: [email protected] (E. Bilic).
Syncope has an enormous medical, social and economic impact on the general population. Approximately, one million patients are evaluated for syncope annually in the USA. It has been estimated that syncope evaluation accounts for 3–5% of emergency department visits and 1–6% of hospital admissions. In addition, about 3–5% of healthy blood donors experience fainting during the puncture manipulation [6]. A history of an isolated episode of syncope will be found in as many as 25% of healthy young adults, especially in settings that precipitate fear, disgust or anxiety, and if not repeated it does not warrant further work-up [6,9]. Has the issue of syncope pathogenesis really been definitely solved and the existence of transient cerebral circulation catastrophe demonstrated? We believe that there also exists an alternative solution of the syncope pathophysiology, based on the clinical experience with its paroxysmal onset and short duration. The reflex structure of this paroxysmal event, from a diversity of afferences to a stereotypic efference with clinical equivalence of the loss of consciousness,
0306-9877/$ - see front matter c 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.mehy.2004.02.045
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points to specificities of the mode of central nervous system functioning. Many years ago, William Gowers stressed the pathogenesis of syncope. In his monograph from 1907, entitled “The Borderland of Epilepsy”; he attempts to explain fainting episodes, vertigo, migraine and ‘vagal attacks’ by their relationship to epilepsy fit [10]. A crucial question is where the reflex centre or the governing neural structure from which different afferences can trigger the loss of consciousness is. According to the current state-of-the-art on the brainstem functional anatomy and reticular formation, we believe that nucleus tractus solitarii (NTS) is the neural structure, which meets all the conditions of the hypothetical syncope generating, reflex centre. In the literature, this nucleus is occasionally referred to as a reflex centre in the pathophysiology of syncope induced by baroreceptor afference [11,12]
Functional neuroanatomy of nucleus tractus solitarii Nucleus tractus solitarii NTS is situated in medulla oblongata as a long cylindrical pairly structure extending throughout its length, from the obex to the pontomedullary junction. It is the principal nucleus of reception of general and special visceral afferents. Visceral afferents are conveyed to the NTS by branches of cranial nerves VII (facial), IX (glossopharyngeal) and X (vagus) [13–16]. NTS is bordered ventromedially by the dorsal motor nucleus (DMX) of the vagus (the general visceral efferent cell column of the basal plate). The NTS and DMX are related ventrolaterally to a diagonal laminated strip of reticular formation called lateral tegmental field (LTF). At medial and caudal medullary levels, the NTS is bordered dorsally by the area postrema, a highly vascularized circumventricular organ located outside the bloodbrain barrier. NTS is separated from the dorsal column nuclei (gracilis and cuneatus) by the nucleus of tractus parasolitarius (NPS), which is a cerebellar relay nucleus. At the level of the obex, the caudal bilaterally symmetrical extensions of the NTS merge on both sides of the midline and form a bridge known as commissural nucleus [13,15] (Figs. 1–3). NTS and the adjacent DMX within the spinal cord and brainstem localized substantia intermedia
Figure 1 Afferents to the NTS. DMX, dorsal motor nucleus of nervi vagi; FLD, fasciculus longitudinalis dorsalis; LC, locus coeruleus; NTS, nucleus tractus solitarii; PBC, parabrachial nucleus complex; PG, periaqueductal gray; SG, substantia gelatinosa; SIC, substantia intermedia centralis.
Figure 2 Brain afferents to the NTS. CL, caudal level of NTS; DSN, dorsal subnuclei of NTS; IL, intermediate level of NTS; LSN, lateral subnuclei of NTS; MR, midline region of NTS; VP, ventral parts of NTS.
centralis (SIC), the parabrachial nuclear complex (PBC) and the periaqueductal gray (PG) constitute a chain of centres interconnected by the fasciculus €tz (FLD) (Fig. 3) [17]. longitudinalis dorsalis of Schu Rostrally, this chain of centres is connected with the hypothalamus by way of the fasciculus longitudinalis dorsalis and median forebrain bundle (fasciculus telencephalicus medialis) [17].
396
Zurak and Bilic functional organization. One type may be organ specific and represented by a precise viscerotopic organization of projections to NTS subnuclei that are devoted to processing organ specific modalities. The second mode of organization may be integrative whereby afferents from different organs or different receptors within the same organ converge within the solitary complex [15]. The connections between this nucleus and visceral organs are bilateral, to that in the vegetative control of visceral organs this complex nucleus modulates and adapts their function in the most optimal way. This is accomplished by the rich network of internuncial neurones [15].
Brain as a source of afferents
Figure 3 The hypothetic executive way of syncope mechanism. CN, comissural nucleus; DMX, dorsal motor nucleus of nervi vagi; MINT, midline and intralaminar thalamic nuclei; NPS, nucleus parasolitarius; NTS, nucleus tractus solitarii; RAS, reticular activating system; PBC, parabrachial nucleus complex; SRT, solitarioreticular tract; TS, tractus solitarius.
It is very important to stress that, in the NTS perikarya and its fibres and ending complex, practically all neurotransmitters and neuromodulators of the central nervous system have been found: angiotensin II, dynorphin, enkephalin, endorphin, c-MSH, a-MSH, ACTH, vasopressin, oxytocin, TSH, somatostatin, LHRH, CRF, neurotensin, CCK, VIP, substance P, glycine, glutamate, aspartate, GABA, histamine, serotonin, epinephrine, norepinephrine, dopamine and acetylcholine [17,18].
Afferents to the nucleus tractus solitarii As mentioned above, NTS is the principal site of termination of afferent fibres from the viscera (cardiovascular, respiratory, gastrointestinal, urogenital and nociceptive system) and arterial chemo- and baroreceptors [13–15,19] (Fig. 1). In addition, NTS is innervated by neurones arising from the fastigial nucleus, PBC, C1 adrenergic neurones, locus coeruleus (LC) and cerebral cortex. Different visceral afferents within the NTS appear to be organized topographically. The central branches of different visceral afferents enter the medulla oblongata and form the tractus solitarius [14,15]. The distribution of visceral afferents within the NTS appears to reflect two types of structural and
Bilateral connections between the brain and NTS have an important role in maintaining appropriate internal milieu of vegetative functions (Fig. 2). The insular cortex is influenced by visceral as well as limbic afferents, which are segregated along different longitudinally organized cortical strips [20]. This structural arrangement probably reflects a neural substrate through which telencephalic afferents can enter the generation of an organized adaptive behavioural pattern. The outputs of the insular cortex and amygdala, by virtue of their intimate connections, probably superimpose a hierarchical control over emotional expressions. The pathways mediating autonomic responses from both nuclei appear to constitute a functionally integrated system extending from the cortical mantle via NTS to the spinal cord [20]. The cerebral cortex projection to the NTS requires an obligatory synapse in the lower brainstem (PBC, LC and nucleus raphe dorsalis) or subcortical forebrain [15]. Cortical afferents to the NTS project to dorsal and lateral subnuclei and along the midline region largely avoided by the subcortical afferents, terminating within so-called barrel fields (cylindrical columns) [15] (Fig. 2). Subcortical afferents have relatively dense projections to ventral parts of the NTS surrounding DMX [15] (Fig. 2). Forebrain afferents including hypothalamic region project to the intermediate and caudal levels of NTS [15] (Fig. 2).
Efferents from NTS Efferent connections of NTS with peripheral sources of its afferent information represent the ex-
Syncope: facts and fiction ecutive part of its reflex functioning. The main part of NTS efferences are grouped into the solitarioreticular and solitariospinal pathways [21,15]. For the purpose of this presentation, most important are the efferent connections of NTS with reticular formation realized through the solitarioreticular tract (SRT). The executive part responsible for clinical presentation of syncope event is probably the part of reticular formation known as the reticular activating system (RAS) [22]. The SRT contains axons which leave NTS and traverse through the LTF (Fig. 3). This region of LTF was long recognized as part of the reticular matrix [22]. The organizational patterns of cell bodies and afferent processes in the LTF are likely to dictate the direction of information flow along the reflex arcs through the segmental cylindrical systematized afferents and probably establish a moduletype organizational pattern similar to the architecture of the cerebral cortex [15]. The NTS subnuclei surrounding the solitary tract and cell columns in the ventrolateral medulla, which relay the solitarioreticular signals, project to the PBC [15] (Fig. 3). PBC is one of several major brainstem relays of panmodal sensory information to the forebrain. Parabrachial output neurones directly access the cerebral cortex and visceral information is conveyed by the NTS indirectly, by topographically organized solitariofugal pathways to the PBC and ventral sensory thalamus [15]. Parabrachial pathways ascending by the dorsal tegmental bundle to the thalamus and through collateral branches to the hypothalamus constitute a critical component of the RAS [15] (Fig. 3). NTS neurones also give rise to efferent projections to the LC, C1 neurones and dorsal medullary reticular formation [15]. Experimental studies suggest that neurones of the NTS may tonically regulate regional cerebral blood flow (rCBF) throughout the brain influencing cerebrovascular autoregulation [13,23–25].
NTS as a reflex centre It is thought that overlap between different firstorder visceral afferents ending in NTS may be involved in the co-ordination and patterning of synergistic movements among oropharyngeal, oesophageal and abdominal smooth muscles and glands engaged in feeding, swallowing and digestion, and those involved in cardiorespiratory control. Intranuclear pathways are thought to mediate local reflex integration between different sensory modalities [15].
397 All components of visceral reflex arcs in the lower brainstem, including neurones involved in the tonic and reflex control of the autonomic outflow, feedback to the NTS. These circuits comprise the servomechanisms (self-correcting error-control systems) of the lower brainstem, and are designed to co-ordinate changes in reflex excitability of the primary sensory controller (NTS) with the constellations of skeletomotor and visceromotor reflex adjustment to signals continually generated by the internal and external milieu (e.g., exercise, pain and the expression of distinct behaviours). The smooth performance of such goal directed reflexes is servoregulated by sequential transfer of afferents to the NTS from collaterals of intermediary neurones organized along its efferent transsegmental fibre tract. These include propriobulbar interneurones within lateral reticular formation, A5 (caudolateral part of the pontine tegmentum), C1 (ventrolateral myelencephalon) and non-catecholaminergic reticulospinal projection neurones [15,17]. All the mentioned structures make closed multiple feedback control circuits, the insufficiency of which demands NTS resetting with clinical presentation of a syncope.
NTS and sleep-wake mechanisms Sustaining input to the cerebral cortex from the brainstem reticular formation is required for maintenance of consciousness. The portion of the reticular formation that provides this input is known as RAS. The RAS receives collaterals from virtually all sensory pathways (NTS–SRT and others) and projects to the midline and intralaminar nuclei of the thalamus (MITN), which in turn project diffusely to widespread cortical areas [22,26]. At this point it is necessary to focus attention on the sleep, which is a physiologic reversible state of unconsciousness [26]. The mechanisms of sleep might be expected to have a bearing on the mechanisms of consciousness in general. It is well known that active mechanisms play a major role and that specific neural structures can induce sleep by inhibiting the RAS [22,26]. A related view is that the function of sleep amounts to adaptive non-responding, meaning that it prevents activity (e.g., foraging) when it would be dangerous or inefficient, and it blocks harmful reactions that might occur in an animal merely resting but aware of ongoing events [22]. Jouvet stated many years ago: “We must assume that our brain, like our kidneys and heart but unlike our muscular system, does not rest
398 during sleep. On the contrary, it undergoes an active reorganization rather than a real inhibition, and so sleep seems to be an active phenomenon” [27]. Several lines of evidence indicate that the NTS is involved in sleep generation [26]. Distension of the carotid, a powerful stimulus for the NTS region, induces behavioural sleep. Low frequency stimulation of the vago-aortic nerve or of the NTS also produces slow waves on EEG (experimental data). Inactivation of the lower brainstem regions, including the NTS, produces a profound arousal (experimental data) [26]. This action of NTS is realized through the part of SRT that terminates in LTF and especially PBC (Fig. 3). Parabrachial pathways access more widespread areas of the cortex by way of ascending projections through the MITN (Fig. 3). These projection fields include parts of the centromedian–paraparafascicular complex that have long been known to participate in cortical EEG desynchronization and behavioural arousal, as part of RAS [26,28]. Stimulation of the MITN at low frequencies produces sleep and synchronization of EEG, so this part of the thalamus is considered to be a sort of final switching mechanism into which other sleepinducing mechanisms funnel [26]. The integrity of each of these structures is essential in maintaining consciousness and such regions have been implicated in the mechanisms generating states of arousal and wakefulness. It seems that PBC has a crucial role in RAS deactivation, which is the starting point of so-called non-rapid eye movement (NREM) sleep [15].
Neural hypothesis Syncope is a neurally mediated reflex loss of consciousness. The afferent branch of this reflex arc represents information from different visceral sources including the brain itself (Figs. 1 and 2). The reflex centre is NTS in the medulla oblongata. The efferent branch of this reflex arc is RAS. The executive mechanism of syncope is deactivation of RAS done with the active engagement of NTS through SRT and PBC (Fig. 3). The loss of consciousness during the syncope is an analogue to deep sleep. The biological purpose of syncope would be resetting of the NTS in case of an unbearable vegetative input, which is a code for triggering the mechanism described. In conclusion, syncope is an active neural event.
Zurak and Bilic
Discussion According to causation, syncopes are usually classified into two major groups, cardiac and non-cardiac. Examples of cardiac syncope are the cases of heart rhythm disturbances or structural abnormalities of the heart. Neurally mediated syncope (NMS), also known as vasovagal and neurocardiogenic syncope, common or emotional fainting, or reflex syncope, is most common in the non-cardiac group [2]. The term vasovagal has a widespread use today in medicine practice. Its origin can be attributed to Sir William R. Gowers, a renowned 19th-century neurologist [10,29]. Vasovagal syncope accounts for some 40% of all syncopal events [6]. Patients with vasovagal syncope often have a long history of fainting, commonly associated with emotional or painful stimuli. This form of syncope may be precipitated by the sight or loss of blood, or by physical or emotional stress. It is characteristically preceded by symptoms of autonomic hyperactivity such as a dim vision, giddiness, yawning, sweating and nausea. Hysterical fainting is often associated with paresthesias of the hands or face, hyperventilation, dyspnea, chest pain, and feeling of acute anxiety [6]. The NMS group includes situational syncope triggered by cough, micturition, defecation, diving, sneezing and swallowing and carotid sinus syncope (shaving syncope). Other non-cardiac types of syncope include those occurring in psychiatric and neurological diseases, orthostatic hypotension and drug induced syncope [2]. According to Petch, simple faint can be distinguished from syncope by the presence of the following features: upright posture, an emotional or painful stimulus, gradual rather than sudden fading of consciousness, sweating, nausea, pallor, other manifestations of autonomic activity, and rapid recovery course. Simple faints tend to occur and recur in young people [30]. We believe that differences between fainting and syncope are gradual in intensity, the process being basically identical. The loss of consciousness is a common denominator of all forms of syncope. It is usually explained by a transient cerebral haemodynamic catastrophe with consequential brain anoxia. However, it should be noted that such a mechanism has never been demonstrated. The prejudice is related to blood pressure decrease, which is a frequent finding in syncope [31–33]. As early as 1911, Thomas Lewis concluded: “. . . that the fall of blood pressure during syncope is not
Syncope: facts and fiction attributable to fall of ventricular rate, it is an added phenomenon” [10]. Brain is an organ characterized by high perfusion and oxygenation redundancy, supplied with efficient vasomotor autoregulation intended just for the episodes of systemic pressure decline [34–36]. The specificities of extrinsic and intrinsic neural vasomotor autoregulation of the brain supplemental to the myogenic and metabolic aspects of autoregulation common to all organs have recently been highlighted [15,23,37]. Besides NTS, elements of the complex system of intrinsic neural control of the cerebral circulation include C1 area of the rostral ventrolateral medulla, dorsal medullary reticular formation, fastigial nucleus, LC, PBC, centromedian–parafascicular complex of the thalamus, parts of the basal forebrain, and in the cerebral cortex specialized cortical neurones [25,24]. To these, the following classical constituents of extrinsic neural control should be added: sympathicus with the neurotransmitters norepinephrine and epinephrine, and non-adrenergic markers such as neuropeptide Y and 5-HT, parasympathetic influences through acetylcholine, VIP, peptide histidine isoleucine (methionine), and trigeminovascular system with the transmitters substance P, neurokinin A (NKA), CGRP and CCK [25]. Therefore, an indirect harmful effect of blood pressure decrease on cerebral perfusion can only occur in case of total insufficiency of the intrinsic and extrinsic neurogenic cerebral vasomotor autoregulation which, by the same reasoning, should precede or at least concur with the pressure decline. Thus, in the genesis of syncope, the systemic pressure decrease is not its cause but a symptom of NTS insufficiency if preceding it, whereas in case of fainting it is additionally associated with the component of physiological pressure decline characteristic of deep sleep phase [31]. In syncope, the loss of consciousness is usually as quick as lightning, which especially holds for psychogenic syncope, thus offering an additional case against the concept of generalized cerebral hypoxia as the cause of the loss of consciousness, knowing that the brain can normally function for several minutes in anoxic conditions. Accordingly, the precipitating factors causing syncope should first induce total functional failure of all the mentioned resources of extrinsic and intrinsic cerebral autoregulation to cause a haemodynamic cerebral catastrophe with consequential loss of consciousness. It appears quite inconceivable that, for example, a mere sight of blood could result in such a consequence. On the other hand, such a
399 vulnerable cerebral vasomotor autoregulation would sooner or later certainly lead to a perspective of serious organic cerebral pathology. However, clinical practice is in sharp contrast to such a presumption. Syncope is as a rule a benign, shortterm, reversible loss of consciousness without any sequels [4,38]. In our opinion, all syncope cases are caused by a neural reflex mechanism, either as pure functional disturbances (vasovagal, psychogenic) or associated with organic diseases of visceral organs. Organic diseases of visceral organs induce syncope in the same way as functional impairments. The same reflex mechanism is triggered via vegetative afferences by a strong peripheral visceral input caused by organic disease. Although the cardiac causes of syncope have been shown to be associated with an increased mortality and risk of sudden death, recent evidence show that the underlying heart disease, irrespective of the syncope, is a factor associated with an increased risk of death [39]. Although syncope is a common clinical occurrence, the susceptibility to syncope shows considerable interindividual variation. In some individuals it occurs quite frequently, in some rarely, and there are cases of its occurrence once in lifetime [38]. This holds for both the healthy population and patients with different organic pathology of visceral organs, irrespective of the disease severity. The physiologic ‘loss of consciousness’ during sleep and loss of consciousness during grand mal epileptic seizure are the processes that are completely unrelated to cerebral blood hypoperfusion. In our attempts to explain the genesis of syncopal loss of consciousness, we made use of the indisputable neuroanatomical and neurophysiological determinants of the position and function of NTS, and its neural system specific reactive stereotypic response to functional and organic disturbances from the territory of its input (afferences). Isolated presyncopal state, which might be a parallel to epileptic seizure aura, is quite commonly encountered in clinical practice. This implies that in these cases, NTS has completely and without resetting managed to master the control, synthesis and modulation of the vegetative nervous system signals. The differential diagnosis between epileptic seizures and syncope, including the level of intermediary phenomena is frequently a subject of discussion [3,5,8,9,40,41]. Syncope as a paroxysmal phenomenon, as well as prodromes or presyncopal symptomatology, makes us take into consideration the mechanism of the loss of consciousness other than ischemic.
400 The syncopal loss of consciousness is probably a paroxysmal onset of deep narcotic sleep with the function of NTS resetting. In the so-called convulsant variant of syncope, strong myoclonisms associated with falling asleep are most probably involved. Hypnic myoclonias are not pathological events, although they tend to occur more frequently in association with stress or with unusual or irregular sleep schedules [42]. In this way the reflex arc, which we believe to be active in the syncope of whatever genesis, has been closed. The reflex centre of this actually neurogenic process is NTS, a nucleus deserving to be called ‘visceral brainstem’. The complex information pattern from visceral organs or brain leads to strong stereotypic efferent response with a consequential brief loss of consciousness. The effector organ is RAS, which is paroxysmally inactivated by NTS via PBC (Fig. 3). In physiological conditions, this inactivation is the introduction to sleep. Even our civilian experience indicates that entering sleep may in some individuals be so abrupt as to allow us to consider it approximating syncope according to its time sequence and dynamics. The paroxysmal onset of sleep in case of syncope points to the involvement of a more direct solitarioreticular pathway (SRT via PBC and RAS) (Fig. 3). Forebrain structures, including suprachiasmatic nucleus (SCN) of the anterior hypothalamic region, are more engaged in the genesis of physiological sleep-wake cycle as a biorhythmic event [43]. Vegetative phenomena in the so-called precollapse stage are indicative of insufficiency of NTS as a reflex centre for the control and modulation of the overall vegetative input. According to analogy with computer functioning, the critical value of this disbalance is the code for NTS resetting. This is most simply accomplished by deleting all actual vegetative information by abrupt switching to deep narcotic sleep. The strongest evidence for a successful NTS resetting process is disappearance of vegetative symptoms present during the presyncopal period, which as a rule occurs upon awakening from the syncopal state [1,38]. It is hard to state whether brief deep sleep or loss of consciousness in the syncope has the characteristics of NREM or rapid eye movement (REM) sleep. The very short duration of the event precludes any definite differentiation. We believe that both of these options are probable. It is known that in physiological sleep, the mechanisms of NREM phase are activated first, whereas in narcolepsy REM phase is being entered straight off [26]. “Choose something in common and you will find little is known about it”, it was Sir Henry Head’s advice to the then young Russel Brain in the 1920s
Zurak and Bilic [44]. We think that the meaning of this aphorism fully applies to the case of syncope.
Acknowledgements The authors are grateful to Silvio Basic MD for technical assistance.
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