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Cardiovascular regulation and lesions of the central nervous system.

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NEUROLOGICAL PROGRESS
Cardiovascular Regulation and Lesions
of the Central Nervous System
William T. Talman. MD
The central nervous system has an important role in the second-to-second regulation of cardiac activity and vasomotor
tone. Central lesions that lead to a disturbance in autonomic activity tend to cause electrocardiographic and pathological evidence of myocardial damage, cardiac arrhythmias, and disturbances of arterial blood pressure regulation. To
a great extent such cardiovascular disturbances result from alterations in sympathetic activity. Similar alterations in
sympathetic activity can occur under conditions of emotional stress and precipitate cardiac arrhythmias that can
themselves lead to the syndrome of sudden death. Experimental and clinical evidence suggests that central neural
mechanisms may be involved in this important human syndrome, but no central lesion has yet been identified to
account for it. Recent experimental evidence, derived from hypertension research, suggests that chemical disturbances
in the central nervous system, without accompanying structural lesions, may be found to explain cardiovascular
disturbances such as sudden death and hypertension.
Talman WT: Cardiovascular regulation and lesions of the central nervous system.
Ann Neurol 18:l-12, 1985
It has long been recognized that disorders of the central nervous system (CNS) can alter cardiovascular
function. Recently, in addition, the importance of central mechanisms in normal cardiovascular control has
also become increasingly apparent (see {68, 118, 1441
for reviews).
The CNS, by modulating excitatory and inhibitory
influences on autonomic discharge, can regulate arterial pressure, vasomotor tone, and cardiac output, rate,
rhythm, and metabolism {76]. Its essential role in
maintaining arterial blood pressure through the sympathetic nervous system is accepted (761. On the other
hand, only recently have the neural influences on myocardial metabolism and contractility begun to be
realized (118, 120). These influences may, indeed, be
great enough to override the classic length-tension
mechanisms defined by Starling 1119, 1451.
Neural mechanisms, in general, control the secondto-second modulation of cardiovascular responses to
internal and external environmental stimuli. Integration of these and other visceral-somatic responses occurs within the CNS (1, 761, which then has the capacity to alter cardiovascular activity as a result of or in
anticipation of behavioral events {lo, 21, 36, 45, 46,
72, 82, 1141. In fact, this coupling of cardiovascular
activity to behavior may be one of the principal contributions of the CNS to circulatory control. In addition
to its acute direct modification of cardiovascular activity, the CNS also indirectly affects the circulatory system through its effects on fluid and electrolyte balance.
Clearly, then, disorders of the CNS can potentially
lead to perturbations of cardiovascular control. A full
discussion of the neural influences on cardiac contractility, rhythmicity, and coronary blood flow is beyond
the scope of this review. Instead, the reader is referred
to several excellent reviews (see 142, 1181) regarding
these topics.
This article will review cardiovascular disturbances
resulting from diseases of the CNS and will relate
these disturbances to other cardiovascular disorders
that have often been considered without regard to
CNS influences. For example, a study of the anatomy
and pathophysiology of the cardiac injury and cardiac
arrhythmias following subarachnoid hemorrhage will
provide an interesting perspective on the syndrome of
sudden death.
From the Department of Neurology and Cardiovascular Research
Center, University of Iowa and Veterans Administration Medical
Center, Iowa Ciry, IA 52242.
Received Jan 11, 1985. Accepted for publication Jan 12, 1985
Anatomy of Central Cardiovascular Regulation
Preganglionic sympathetic and parasympathetic neurons are the primary effector units of central cardiovascular regulation [27, 771. Most preganglionic sympathetic neurons are found in the intermediolateral cell
column of the spinal cord (271, but a small percentage
(10%) are found in adjacent spinal structures C27).
The parasympathetic preganglionic neurons involved
in cardiovascular regulation are found largely in the
dorsal motor nucleus of the vagus and nucleus ambip u s , both of which are in the medulla oblongata {27}.
Both the sympathetic and parasympathetic neurons
receive extensive connections from other central neu-
Address reprint requests to Dr Talman,
1
B
A
rons which themselves receive afferents from peripheral mechanoreceptors and chemoreceptors andor
from other central nuclei [27, 861 (Fig 1A). The great
preponderance of afferent fibers from peripheral receptors terminate in another medullary structure, the
nucleus tractus solitarius [ll, 27, 73, 102, 1391. Axonal projections from the nucleus tractus solitarius terminate not only in the dorsal motor nucleus of the
vagus, nucleus ambiguus, and intermediolateral column but also in the serotonergic raphe nuclei and ventrolateral medullary reticular formation (specifically
the C1 adrenergic neurons) [87}. These latter two nuclear regions and the nucleus tractus solitarius provide
the primary suprasegmental connections to the intermediolateral cell column in the spinal cord (Fig 1B) [4,
18, 87, 95, 1261. The intermediolateral cell column
also receives axonal projections from the parabrachial
nucleus, from vasopressinergic and oxytocinergic cells
of the hypothalamus, and from noradrenergic cells of
the A5 group [SS, 131, 1473. The intermediolateral
column does not seem to receive direct projections
from the cerebral cortex 1861. There is an anatomical
framework for cortical influences on sympathetic neurons, however.
Specifically, such influences can occur via the cortical-nucleus tractus solitarius projections { 128, 147) or
by other cortical projections to the limbic system, hypothalamus 11321, and parabrachial nuclei E1291.
These nuclei are reciprocally connected to the nucleus
tractus solitarius as well as to other brainstem nuclei
that project to the spinal cord {20, 27, 65, 1303. The
inputs to the intermediolateral cell column, in addition
to providing a biochemical basis for complex interactions with the sympathetic preganglionic neurons,
also provide an anatomical framework for coupling
2
Annals of Neurology
Vol 18 No 1 July 1985
Fig I . A greatly simplijed representation of central pathways
involved in cardiovascular regulation. The dominant reciprocal
pathways connecting central nuclei which are important in cardiovascular regulation are depicted (A).The nucleus tractutlrs solitarius is the site of termination of afferenthbersfrom carotid sinus and arterial baroreceptors as well as cardiopulmonary
receptors. Carotid sinus fibers originate in the petrosal ganglion
of the glossopbaqngeal nerve while aortic and cardiopulmonary
affetzt fibws originate in the nodose ganglion of the vagus. Cells
within the nucleus tractus solitarius make extensive reciprocal
connections with other suprasegmental nuclei which are also important in cardiovascuLar control, Efferent impulses to the heart
and blood vessels originate in the dorsal motor nucleus ofthe vagus, nucleus ambiguus, and intermediolateral cell column in the
spinal cord (B). The suprasegmental pathways to the preganglionic sympathetic neurons are depicted. The preganglionic fibers
from the intermediolateral column terminate in the stellate ganglion from which postganglionic efferents to the heart and vessels
originate. (Amyg = amygdala; DMV = dorsal motor nucleus
of the vagus; IML = intermediolateral column; LH-PVN =
lateral hypothalamus-paraventricular nucleus; NA = nucleus
ambiguus; NG = nodose ganglion; NTS = nucleus tractus solitarius; PB-KF = parabrachial nucleus-Kolliker-Fuse nucleus;
PG = petroalganglion;RN = rapbe nu&c SG = stehteganglion.l
cardiovascular function to behavior, neuroendocrine
function, and other autonomic activity.
Destructive or excitatory lesions at any level in these
central pathways can produce disturbances of one or all
of the aforementioned aspects of cardiovascular function.
Electrocardiographic Evidence of Myocardial
Ischemia or Injury with Disease of the CNS
The Clinical Phenomenon
Since Byer and colleagues’ t l 7 3 description of electrocardiographic changes occurring in diseases of the
CNS, electrical evidence of myocardial damage occur-
Normal
T Wave Inversion Pattern
ST Depression Pattern
ST Elevation Pattern
U
200 msec
Fig 2. The electrocardiographic changes most frequently described
with subarachnoid hemorrhage.A single cardiac cycle is represented with a hypothetical cardiac rate of 70 beats per minute.
The normal pattern fu@lls the criteria described by Marriott
.194}. Thefigure depicts the typically prolonged QT interval 17)
in each abnormal pattern as well as U waves (upper and lower
right), S T depression and T wave inversion (upper right), T
wave inversion alone (lower left)!and peaked P and T waves
with ST elevation (lower right). The actual electrocardiographic
changes accompanying central lesions may involve any one or
combination of the changes depicted here. Other common electrocardiographicfindings are discussed in the text.
described in patients who have sustained subarachnoid
hemorrhage, intracerebral hemorrhages, ischemic
cerebrovascular insults, and head trauma [ I S , 25, 4 3 ,
53, 55, 60, 61, 67, 81, 84, 101). Less frequently they
have also been found in patients with brain tumors,
meningitis, multiple sclerosis, spinal cord lesions, and
hydrocephalus, and during neurosurgical procedures
involving the forebrain 144, 53, 58, 61, 67, 1011. The
incidence of abnormal electrical phenomena varies
with the central process. For example, electrocardiographic abnormalities have been reported in 60 to
70% of subjects with intracerebral hemorrhage, 15 to
40% of individuals with nonhemorrhagic stroke, and
40 to 70% of subjects with subarachnoid hemorrhage
125, 43, 81, 84). Though the ST-T changes with central disease are typical of those seen in myocardial injury or ischemia 1741, vector cardiography has not suggested such an injury in affected subjects [67}. Despite
this lack of evidence for myocardial injury, the ST
changes are associated with greatly increased mortality
130, 35, 61). In one series, 80% of the patients with
ST depression died after subarachnoid hemorrhage, in
contrast with 33% in patients without ST depression
1611.
Pathophysiological Considerations
ring with disease of the CNS has become a wellrecognized phenomenon 12, 3, 1571. However, the
changes have been appreciated largely by cardiologists
and have rarely been explored in the neurological literature. Their recognition is important to both groups
from a pathophysiological as well as clinical standpoint.
Clinically, recognizing the possibility that a serious (but
remediable) disease of the CNS may masquerade as a
myocardial infarction can lead to earlier and more appropriate diagnosis and to life-saving treatment. Conversely, the high incidence of cardiac disease in patients with strokes 11253 dictates treating patients with
electrocardiographic changes accompanying CNS disease as if they had had a myocardial infarction until
that diagnosis has been excluded. Pathophysiologically
these conditions provide a remarkable glimpse at neurally mediated cardiovascular control.
The electrocardiographic changes reported with disease of the CNS have most commonly included prolonged QT intervals, depressed ST segments, flat or
inverted T waves, and U waves 115, 25, 30, 3 5 , 4 3 , 4 8 ,
5 5 , 60, 61, 67, 1011. Tall peaked T waves, notched T
waves, elevated ST segments, high-amplitude P waves,
Q waves, and increased QRS voltages have also been
described (Fig 2 ) 130, 35, 48, 60, 61). The changes
may evolve for several days after the neurological insult. With the exception of persistent U waves and QT
prolongation, the electrocardiogram usually reverts to
normal within two weeks 115, 431. Various combinations of these electrocardiographic findings have been
For some time there has been controversy concerning
the cause of the electrocardiographic changes. Some
researchers have hypothesized that the changes were
secondary to electrolyte disturbances 115, 611 and
have demonstrated a particularly high incidence of hypokalemia in affected subjects 135, 6lf. Other reports
have demonstrated the same electrocardiographic
changes without accompanying electrolyte or metabolic disturbances 143, 58, 671. Whether the electrocardiographic changes truly reflect myocardial damage
secondary to concomitant ischemic heart disease has
often been the question. Subjects have been described
with the typical electrical changes but with normal cardiac enzymes and normal findings upon postmortem
cardiac examination [35, 1131. In contrast, some investigators have described subendocardial hemorrhages
148, 7 8 ) seen post mortem and have suggested that
these accounted for the electrocardiographic findings
178). Others have not duplicated these findings 11131.
An interesting cardiac pathological picture without
coronary artery disease has been found repeatedly,
however. Specifically, at postmortem examination
some patients with brain lesions have manifested focal
myocytolysis, myofibrillar degeneration, lipofuscin
pigment deposition in myofibrils, and histiocytic
infiltration of the diffuse necrotic areas in the heart
122, 23, 81, 1131. These pathological changes have
occurred independent of any coronary artery disease.
The neurogenic hypothesis for the generation of the
electrocardiographic and morphological changes has
Neurological Progress: Talman: Central Cardiovascular Control
3
been supported by well-controlled experimental studies in which sympathetic and/or vagal tone has been
increased [16, 51, 69, 70, 75, 79, 93, 98, 100, 108,
1621. Specifically, increasing sympathetic activity by
electrical [loo} or mechanical [Sl} stimulation of the
hypothalamus causes myocardial damage as described.
The clinical correlate to this experimental model may
be seen in subjects with tumors of the basal forebrain
and parasellar structures [58]. Mechanical stimulation
of the extensive connections between both areas and
the hypothalamus and brainstem presumably accounts
for the relatively high incidence of abnormal electrocardiograms in subjects with such tumors.
Electrocardiographic changes compatible with ischemia also occur with direct stimulation of the sympathetic system via the stellate ganglia C75, 162) or the
cardiac nerves [79]. In these situations, the neural effects on the electrocardiogram are lateralized E79,
162). Stimulation of the right stellate ganglion produces ST elevation and deep inversion of the T waves
[l62]. Similar T wave inversion occurs with stimulation of the recurrent (right) cardiac nerve [79}. In contrast, stimulation of the left stellate ganglion produces
ST depression and tall peaked T waves with an increased QT interval { 1621. Stimulation of the left ventrolateral cardiac nerve also increases the positive amplitude of the T waves [79}. It is not clear whether
unilateral stimulation at the level of the hypothalamus
stimulates predominantly one side of the cardiac sympathetic pathway; however, a majority of the projections from the hypothalamus to the spinal cord are
known to terminate ipsilaterally 1130). It is likewise
unclear what the pathogenetic mechanism for the sympathetically mediated myocardial damage might be.
Sympathetic stimulation significantly increases myocardial oxygen demand (47, 1401 and produces transient
coronary vasoconstriction [ 1091. Under these circumstances myocardial damage could result during a phase
of relative tissue ischemia.
The following evidence suggests that the catecholamines released with sympathetic stimulation or central lesions may themselves be cardiotoxic. First,
myocardial toxicity occurs when norepinephrine is intravenously infused {133, 1481. Second, there is an
inverse correlation between the clinical outcome of
subjects with central lesions and plasma epinephrine
and norepinephrine levels on admission [9]. Third, in
studies of experimental subarachnoid hemorrhage in
mice, McNair and associates [SS] and Hawkins and
Clower [56} have demonstrated that reserpine pretreatment (which decreases monoaminergic stores)
markedly reduces or abolishes the myocardial damage
attendant to the central lesion. Fourth, after experimentally produced subarachnoid hemorrhage, the development of electrocardiographic changes is associated with an increased concentration of catecholamines
4 Annals of Neurology Vol 18 No I July 1985
in cardiac tissue { 1081. Finally, the most prominent
signs of myocardial damage occur in cells nearest to
intracardiac nerve terminals [48].
Because of conflicting evidence, the role of the parasympathetic nerves in cardiac damage is not as clearly
defined as that of the sympathetic nerves. Hawkins and
Clower 1561 found that blockade of vagal tone with
atropine had little effect on the myocardial damage
following experimental head trauma, but Manning and
colleagues 1931 demonstrated that electrical stimulation of the vagus nerve caused myocardial damage that
could be prevented by pretreatment with atropine. Thus
the influence of altered vagal tone in the development
of myocardial damage must be considered unsettled.
Cardiac Arrhythmias with Disease of the CNS
The Clinical Phenomenon
Although experimental evidence has, for a century,
suggested that the CNS has a role in cardiac dysrhythmias 128, 1351, the relevance of these experimental
data to the clinical situation was first emphasized by
Parizel in 1973 [llO]. His observations of supraventricular tachycardia, ectopic ventricular contractions,
multifocal ventricular tachycardias, ventricular flutter,
and ventricular fibrillation in subjects with subarachnoid hemorrhage [l 101 have been confirmed [25, 35,
40, 49, 111, 1591 and extended to subjects with head
injuries [60], cerebral ischemia [GO], and cerebral
tumors [58], as well as those who have undergone
neurosurgical procedures [58J The cardiac dysrhythmias in these conditions could occur with or without
electrocardiographic signs of myocardial damage. Even
though neural influences may generate the cardiac dysrhythmias, it is possible that the rhythm disturbances
may be secondary to incipient cardiac damage caused
by the neural influences.
The arrhythmias occurring after cerebral damage
may be temporally and pathophysiologically distinguishable 1391. In a study of experimentally produced
subarachnoid hemorrhage, immediate arrhythmias
were related to increases in intracranial pressure and
required intact vagal and sympathetic nerves as well as
an intact spinal cord C391. In some animals ventricular
escape rhythms were associated with vagally mediated
bradycardia, but major ventricular arrhythmias also occurred after vagal nerve transection. In contrast, more
delayed arrhythmias developed 3 to 10 minutes after
the introduction of subarachnoid blood despite vagal
and sympathetic nerve transection. These delayed arrhythmias, which could be blocked by propranolol,
were presumed to be secondary to increased levels of
circulating catecholamines 1111. As they usually followed the development of ST-T changes on the electrocardiogram, it is possible they could have originated
from focal areas of cardiac damage, made more arrhythmogenic by the catecholamines.
The importance of these complicating cardiac arrhythmias to the overall prognosis of subjects with intracranial disease is profound. They presumably are a
major cause of sudden death in patients with subarachnoid hemorrhage, which alone accounts for 4 to 5% of
all nonviolent sudden deaths 11111. One experimental
study in cats with unilateral ischemia in the distribution
of the left middle cerebral artery demonstrated major
arrhythmias in 60% of the animals 1160). Furthermore, 45% of all the animals with arrhythmias died
suddenly from the arrhythmia. In human subjects intracerebral hemorrhages were found in 5 to 8% of the
patients who died suddenly 152, 591. Indeed, the potential for sudden death from cardiac arrhythmias in
patients with cerebral lesions in general and subarachnoid hemorrhages in particular has led some investigators to suggest that the antiarrhythmia treatment in
patients with intracranial hemorrhages should be just
as aggressive as the treatment of subjects with acute
myocardial infarctions 11111. Specifically, atropine or
beta blockers, or both, have been recommended in
subjects with appropriate indications (supraventricular
bradyarrhythmias or tachyarrhythmias, respectively),
and specific antiarrhythmia therapy should be directed
promptly at any other atrial or ventricular arrhythmia
11111.
Neural Mechanisms of Arrhy fhmogenesis
That the arrhythmias are neurogenically mediated (or,
as mentioned previously, related to neurogenic myocardial injury) has been suggested by numerous studies. Under normal physiological situations, stimulation
of cardiac sympathetic nerves accelerates sinoatrial depolarization and thus shortens the cycle length of sinus
nodal firing El611. Under appropriately intense stimulation, therefore, a sinus tachyarrhythmia develops
{SO, 134, 1611. Conversely, vagal stimulation or application of acetylcholine to the sinoatrial nodes slows or
abolishes depolaritation of the sinus node fibers 11611.
This attenuated depolarization and accompanying
shifts in membrane threshold potentials decrease the
sinoatrial nodal rate and lead to sinus bradycardia
~1611.Similar alterations of atrioventricular nodal conduction may occur as well 1801. Essentially, then, neurally mediated bradycardia is vagally induced while
neurally mediated tachycardia is predominantly sympathetically induced 11341. With disturbances in sympathetic and/or vagal tone, as may occur with disease of
the CNS, arrhythmias may develop. The intravenous
infusion of norepinephrine or epinephrine alone can
lead to cardiac arrhythmias and conduction disturbances that in every way resemble those following central stimulation 1831. Conversely, centrally mediated
arrhythmias have been eliminated by interruption of
vagal 11431 or sympathetic activity 1491. In the feline
cerebral ischemia model mentioned in the previous
section, treatment with both atropine and propranolol
was required to stop the life-threatening arrhythmias
ri6o-j.
The effectiveness of propranolol in the above study
should not imply that the sympathetic influences on
the arrhythmias are mediated solely by beta-adrenergic
receptors. Beta blockade with propranolol in one
study had no effect on the multifocal ectopic ventricular contractions and ventricular tachycardias in a
woman who had sustained a subarachnoid hemorrhage
1491. Blockade of her left stellate ganglion with 1%
lidocaine completely abolished the arrhythmias. It is
probable that anesthetic block of the right stellate ganglion would not have been as effective in this patient,
for there is substantial evidence suggesting a greater
arrhythmogenic effect of left versus right cardiac sympathetic activity. In this regard, direct electrical stimulation of the left (but not the right) cardiac sympathetic
nerve produces ventricular and supraventricular arrhythmias 16, 501. Even a relative increase in left cardiac sympathetic activity, as can be produced by cooling or removing of the right stellate ganglion, leads to
similar arrhythmias 11371. Stimulation at the level of
the stellate ganglion decreases the ventricular refractory period 1571. This reduction is seen more with left
stellate stimulation. It is perhaps the decreased refractory period that leads to the increased risk of ventricular fibrillation seen in either perfused or ischemic cardiac muscle 154, 137, 1571.
That supraventricular and ventricular arrhythmias
can be mediated by means of sympathetic activation
from central structures has been amply demonstrated
in the classic literature. Ranson and his colleagues
11211 found, for example, that, with detailed exploration of the hypothalamus with a stimulating electrode,
only sympathetic responses are elicited. In addition,
stimulation of the hypothalamus produces an almost
immediate frequency-dependent increase in sympathetic activity in the inferior cardiac nerve 1115, 1161.
Although some authors have suggested that the cardiac
arrhythmias following hypothalamic stimulation may
be vagally mediated, at least three lines of evidence are
inconsistent with this hypothesis. First, Ranson’s original work demonstrates that only sympathetic activation
follows hypothalamic stimulation 112I}. Second,
Mauck and his colleagues [62, 961 have clearly demonstrated that diencephalic stimulation elicited ventricular arrhythmias that were solely sympathetically
mediated. Finally, in more recent studies, the decreased ventricular fibrillation threshold that followed
hypothalamic stimulation was independent of vagal or
adrenal function but was blocked by beta-adrenergic
antagonists 11561.
Stimulation of higher cerebral structures (amygdala,
hippocampus, anterior cingulate gyms, temporal pole,
and subiculum) can lead to sympathetically mediated
Neurological Progress: Talman: Central Cardiovascular Control 5
atrial and ventricular arrhythmias [5, 29, 1241. The
development of these cardiac arrhythmias does not
seem to rely upon the spread of electrical current to
other areas or upon the induction of seizure activity
1631. Seizures, however, can produce profound
changes in cardiovascular regulation and have the potential for being arrhythmogenic {29, 31, 99, 1551.
Most of the above studies have demonstrated increased sympathetic tone and consequent arrhythmias
secondary to stimulation of central structures. In contrast, lesions of the CNS usually are thought to destroy, rather than stimulate, the involved structures. It
is worth noting, however, that the great preponderance of cases describing centrally mediated cardiac arrhythmias involve lesions that are either hemorrhagic
(particularly subarachnoid hemorrhage) or potentially
focally epileptogenic (trauma, surgery, or tumors).
Either type of lesion could lead to local excitation of
neurons that could themselves increase the activation
of sympathetic preganglionic neurons.
The central mechanisms underlying the arrhythmogenic potential for these lesions are highly complex
and not simple to describe. Neurons lying in close
approximation to each other may have different effects
on sympathetic activity. For example, stimulation of
the A1 and A5 noradrenergic neurons elicits an apparent decrease in sympathetic activity 113, 891, as does
the activation of noradrenergic and adrenergic receptors within the nucleus tractus solitarius 124, 1631. In
contrast, stimulation of the adrenergic cells of the C1
group elicits an apparent increase in sympathetic tone
{127]. The net effect of a global increase in central
catecholamine activity, as occurs after the intravenous
administration of tyrosine [138), is an increase in the
ventricular fibrillation threshold. Thus, it is likely that
central lesions producing arrhythmias, if through central catecholamine mechanisms, do so by effectively
decreasing central noradrenergic and adrenergic receptor stimulation.
Serotonin-containing fibers provide another important input to preganglionic sympathetic neurons 141.
Yet, the relationship of serotonin to the cardiac disturbances under discussion is equally unclear. Increasing
brain serotonin levels may decrease cardiac sympathetic activity IS} and increase the ventricular
fibrillation threshold 1121. However, the mechanism
of serotonin’s action is unknown, for recent studies
have suggested that direct stimulation of serotonergic
neurons in the raphe nucleus increases sympathetic
preganglionic activity p 7 1 .
Relationship of the CNS to the Syndrome
of Sudden Death
It is quite clear from the above review that structural
lesions of the CNS can lead to profound alterations in
cardiac regulation and can result in potentially fatal
6 Annals of Neurology Vol 18 No 1 July 1985
cardiac arrhythmias and sudden death. Although no
structural lesions in the CNS have been found to relate
to the syndrome of sudden death, there has been considerable evidence that suggests a central neural mechanism in the genesis of that syndrome as well. The
mounting evidence has led one noted student of sudden cardiac death, Dr Bernard Lown, to state that “the
focus should be shifted from the heart as target to the
brain as trigger” 1901. Because of the similarity between the cardiac events in sudden death syndrome
and the cardiac events in CNS lesions, a brief review of
the central and sympathetic influences on fatal cardiac
dysrhythmias will be undertaken here.
Current evidence suggests that the sudden death syndrome is the result of a cardiac electrical event rather
than an acute coronary occlusion 191, 1041. That is
not to say that the electrical phenomenon might not
occur in the presence of coronary ischemia. It seems
quite possible, however, that the cardiac event might
be triggered by the autonomic nervous system independent of intrinsic cardiac disease. In fact, ventricular
fibrillation, the presumed cause of most cases of sudden death, can be reproducibly elicited in the normal
as well as the ischemic heart upon stimulation of cardiac sympathetic nerves 190, 137, 1571. The mechanisms by which the sympathetic nerves may be stimulated in general or with sufficient specificity by a
central neural process are not so clear, but stress, and
an individual’s particular response to it through the
CNS, may play a role 185, 901. Indeed, studies have
demonstrated the importance of genetic or developmental factors in the autonomic responses to stressful
stimuli 137, 1361. The nature and degree of stress itself
may be exceedingly important factors in the genesis of
these arrhythmias. Engel [38) has pointed out that
stressful situations in which a subject recognizes a need
for action which would be futile, even if performed,
are the most conducive to sudden death. The observations of an increased incidence of cardiac arrhythmias
and sudden death in subjects exposed to a natural disaster would seem to substantiate this relationship
1154, 1581. Over forty years ago, Cannon C191 reviewed a remarkable syndrome of sudden death attendant to another stressful stimulus, namely a voodoo
spell which was perceived as inescapable. In his review
he detailed the evidence that such a stimulus exacted
its fatal end by intense “sympathoadrenal” activation.
A role for a central neural mechanism in cardiac
sudden death is supported by the following evidence.
First, autonomic activation, particularly if asymmetrically favoring the left side, can lead to ventricular
fibrillation 16, SO, 54, 57, 137, 1571. Second, the ventricular fibrillation threshold in normal, and particularly in ischemic, myocardium is decreased through the
inffuence of sympathetic activation 190, 137, 1571.
Third, the level of autonomic tone is integrally related
to behavioral events that are clearly under central control [lo, 36, 46,82, 1141. Fourth, psychically stressful
stimuli can elicit pathological autonomic discharges
119, 38, 72, 107). Fifth, destruction of the hypothalamus and its descending pathways normalizes the
decreased ventricular fibrillation threshold caused by
stress [142). Sixth, stress, particularly that from which
there is no escape, is associated with ventricular fibrillation and sudden death in experimental animals and
correlates with an increased incidence of sudden death
in human subjects [19, 38, 154, 158).
Disturbances of Blood Pressure Regulation
with Lesions of the CNS
A lesion at any site in the CNS can potentially produce
acute, even fulminant, elevations of arterial blood pressure through direct or remote effects on central structures.
Hypertension
Hypertension has been described as a direct effect of
lesions at several sites in the medulla oblongata and
hypothalamus. In fact, the first demonstration rhat hypertension could be the direct result of a localized
central lesion was made in rats subjected to bilateral
lesions of the nucleus tractus solitarius [32]. Subsequent work has shown that chemical disturbances as
well as lesions of the nucleus tractus solitarius cause
hypertension [l50, 1511. The hypertension secondary
to such disturbances in the nucleus tractus solitarius
results from disinhibition of sympathetic activity and a
consequent profound increase in vasomotor tone and
total peripheral resistance [333. The elevation of arterial pressure may also be related in part to the resulting
significant elevations of plasma vasopressin levels
{146}. If the experimental animal survives the acute
hypertension, it typically manifests extremely labile
blood pressures for the remainder of its life [lOS,
1471. Such hypertension with subsequent lability of
arterial pressure has also been described in human subjects who have sustained ischemic f1031, degenerative
[92}, or destructive 1741 lesions of the nucleus tractus
solitarius.
Ischemia or distortion of the dorsal medulla along
the floor of the fourth ventricle can also lead to
significant hypertension [64}.Experimental evidence
would suggest that this dorsal medullary area is responsible for the classic “Cushing response” (hypertension,
bradycardia, and apnea) 1261 as well as the cerebral
ischemic response that results from rendering the
brainstem acutely ischemic [641. The Cushing response can develop as a result of distortion of this
dorsal medullary area by any proximate or distant lesion. Cushing 1261 himself suggested a medullary site
fa- the generation of the pressor response, but its precise localization to the dorsal medullary reticular for-
mation has only recently been demonstrated in experimental animals [641. Cushing C261 also suggested,
using somewhat teleological reasoning, that the graded
pressor response to increasing intracranial pressure
was a protective mechanism that maintained cerebral
blood flow. The Cushing response does tend to maintain cerebral blood flow in the face of rising intracranial
pressure. However, it seems unlikely that the Cushing
response results from ischemia within the critical area
because: (1) the distorting pressures that elicit the response are within the range of capillary pressure; and
(2) pulsatile distorting pressures are more effective
than tonic pressures in eliciting the response C641.
Although the Cushing response is not seen commonly enough to be considered a sensitive sign of herniation 11171, when it does develop it warrants immediate attention to that life-threatening situation.
Another uncommon but diagnostically troublesome
form of hypertension has also been described in human subjects with tumors within the posterior fossa
141, 122). The tumors, which most often involve the
cerebellum or structures in the cerebellopontine angle,
presumably produce their cardiovascular effect by distorting the brainstem C122f. It is unclear which brainstem structure is being disturbed with the distortion,
but a marked increase in sympathetic activity with increased levels of circulating catecholamines seems to
be the result. Both the sympathetic discharges and the
hypertension may be paroxysmal and thus may clinically and biochemically resemble a pheochromocytoma [41, 122).
Recent experimental studies have identified a new
model of hypertension following lesions of another
medullary region, the area of the A1 noradrenergic
neurons [ 141. The hypertension that develops following the A1 lesion seems to be dependent upon the
release of vasopressin resulting from disturbance of the
Al-hypothalamic pathway 1131. N o human subjects
have yet been described with a lesion confined to the
A1 area; yet the experimental model provides an extraordinary example of a neural lesion producing a hypothalamic hormonal response that leads to systemic
hypertension.
Hypertension as a result of a lesion near the hypothalamus has been described in a human subject
Y112). It is unknown whether the hypertension was
secondary to increased sympathetic activity or secondary to adrenal cortical or adrenal medullary hypersecretion. Experimental hypothalamic lesions have produced hypertensive states that were dependent upon
such adrenal hypersecretion [lob, 1231.
Lesions of forebrain structures other than the hypothalamus rarely produce hypertension as a direct effect of the lesion. Hypertension and marked changes
in cardiovascular regulation can occur if the forebrain
lesions are epileptogenic 131, 99, 1551.
Neurological Progress: Talman: Central Cardiovascular Control
7
The role of lesions of the CNS, if any, in the genesis
of essential hypertension is not established. Some investigators have suggested that distortion of the brainstem by ectatic branches of the basilar artery may cause
essential hypertension [7 11, but no structural central
lesions have yet been found in subjects who had essential hypertension.
Hypotension
Lesions of the CNS can produce hypotension as well
as hypertension. Essentially the CNS lesions that produce shock involve the rostral ventrolateral medulla or
the fiber tracts from that area to the interrnediolateral
cell column in the spinal cord. Lesions of these areas
produce ‘‘spinal’’ levels of blood pressure (mean arterial pressures of less than 50 mrn Hg) and are often
fatal 1127). Although lesions of the C1 rostral ventrolateral medulla have not been specifically described
in human subjects, Plum and Posner [117] described
the course of a woman (Patient 1-2) in whom these
areas were involved by a hemorrhage. During the evolution of her hemorrhage, which ultimately extended
from the pons into the cervical spinal cord, the patient
suffered hypotensive episodes that required pressor
agents to stabilize her blood pressure.
Orthostatic Hypotension
It is unclear whether solitary lesions of the CNS in
human subjects can produce orthostatic hypotension.
Experimental evidence would suggest that truly orthostatic hypotension develops after the formation of
lesions of the vestibular nuclei and fastigial nucleus of
the cerebellum [34]. Examples of this cardiovascular
syndrome in human subjects with lesions of the vestibular and fastigial nuclei were recently reported T661;
however, the lesions involved many other structures.
Thus, the syndrome could not be said to have localizing value. Of course, diffuse degenerative lesions
involving peripheral autonomic nerves as well as central structures (such as in the Shy-Drager syndrome
11411) typically cause orthostatic hypotension. A discussion of such conditions or of the central sites of
action of drugs (such as L-dopa) which cause orthostatic hypotension is beyond the scope of this review
(see El531 for review of orthostatic hypotension).
Experimental evidence suggests that lesions confined to the nucleus tractus solitarius, and thus the
baroreflex arc, do not cause orthostatic hypotension
[34). However, distortion of the nucleus tractus solitarius can lower arterial pressure 1152). Thus, hypotensive episodes may occur in subjects who have
mass lesions compressing the nucleus tractus solitarius,
but these events would not truly represent orthostatic
hypotension. Instead, they may be the result of transient distortions of the brainstem that occur with or
without postural changes.
In addition to their potential for lowering arterial
8 Annals of Neurology
Vol 18 No 1 July 1985
pressure through neural mechanisms, lesions of the
CNS can produce anorexia, adipsia, and vomiting.
Thus, hypovolemia should always be considered and
treated before ascribing orthostatic hypotension to a
solitary central lesion.
Conclusion
Well-defined cardiovascular disturbances, which in
many ways mimic essential hypertension and sudden
death, occur with lesions of the CNS. Yet no structural
central lesions have been recognized to correlate with
either naturally occurring condition. Future studies
may demonstrate that central disturbances at a
neurochemical rather than a structural level may contribute to these and other important cardiovascular
syndromes.
The author is an American Heart Association Established Investigator whose research is supported in part by Veterans Administration Merit Review Tab 18 and N I H RO1 HL32205.
The author acknowledges with deepest appreciation the efforts of
Ms Diana Allen and Ms Jean Hulme in the preparation of this
manuscript and is grateful for the comments provided by Professors
Francois Abboud, Adolph Sahs, and James Corbett. Dr David A.
Ruggiero’s consideration and advice were critically important in preparing the anatomical discussion and figures.
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