Neurocrit Care (2008) 8:293–300
DOI 10.1007/s12028-007-9021-3
REVIEW ARTICLE
A Critical Review of the Pathophysiology of Dysautonomia
Following Traumatic Brain Injury
Ian J. Baguley Æ Roxana E. Heriseanu Æ
Ian D. Cameron Æ Melissa T. Nott Æ Shameran Slewa-Younan
Published online: 30 October 2007
Ó Humana Press Inc. 2007
Abstract The management of Dysautonomia following
severe traumatic brain injury (TBI) remains problematic,
primarily due to an inadequate understanding of the path-
ophysiology of the condition. While the original theories
inferred an epileptogenic source, there is greater support
for disconnection theories in the literature. Disconnection
theories suggest that Dysautonomia follows the release of
one or more excitatory centres from higher centre control.
Conventional disconnection theories suggest excitatory
centre/s located in the upper brainstem and diencephalon
drive paroxysms. Another disconnection theory, the
Excitatory:Inhibitory Ratio (EIR) Model, suggests the
causative brainstem/diencephalic centres are inhibitory in
nature, with damage releasing excitatory spinal cord pro-
cesses. Review of the available data suggests that
Dysautonomia follows structural and/or functional (for
example raised intracerebral pressure or neurotransmitter
blockade) abnormalities, with the tendency to develop
Dysautonomic paroxysms being more closely associated
with mesencephalic rather than diencephalic damage.
Many reports suggest that paroxysmal episodes can be
triggered by environmental events and minimised by var-
ious but predictable neurotransmitter effects. This article
presents a critical review of the competing theories against
the available observational, clinical and neurotransmitter
evidence. Following this process, it is suggested that the
I. J. Baguley (&)
R. E. Heriseanu
M. T. Nott

S. Slewa-Younan
Brain Injury Rehabilitation Service, Westmead Hospital,
Westmead, PO Box 533, Wentworthville, NSW 2145, Australia
e-mail: ianb@biru.wsahs.nsw.gov.au
I. D. Cameron
S. Slewa-Younan
Rehabilitation Studies Unit, Faculty of Medicine, University of
Sydney, Sydney, Australia
EIR Model more readily explains pathophysiological and
treatment data compared to conventional disconnection
models. In particular, the EIR Model provides an explan-
atory model that encompasses other acute autonomic
emergency syndromes, accommodates ‘triggering’ of par-
oxysms and provides a rationale for all known medication
effects.
Keywords Traumatic brain injury
Dysautonomia

ANS
Overactivity
Pathophysiology
Review
Introduction
Patients with Dysautonomia following severe traumatic
brain injury (TBI) display dramatic paroxysmal autonomic
nervous system (ANS) and muscle overactivity [1]. The
natural history of the syndrome suggests it consists of three
phases, the second of which commences with the with-
drawal of sedation [1] and bears a striking resemblance to a
range of other acute ANS overactivity syndromes, such as
Neuroleptic Malignant Syndrome (NMS) and Serotonin
Syndrome (SS), which have recognised mortality rates and
are treated as medical emergencies [2]. In keeping with
this, there are good reasons, though largely anecdotal, to
believe that untreated Dysautonomia increases morbidity
through prolonged hyperthermia, excessive catabolism,
high catecholamine levels and spasticity/dystonia [1, 3–5].
However, despite a growing awareness of the syndrome, it
remains under-recognised and lacks an adequate literature
base to guide treatment.
One of the difficulties experienced in advancing the
knowledge base for Dysautonomia treatment has been the
limited understanding of its pathophysiology. To date, two
main hypotheses have been put forward inferring either an
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epileptogenic cause or some form of cerebral/brainstem
disconnection syndrome. While seizure activity was first
put forward to explain the syndrome [6], a subsequent
review of the case suggested that some paroxysms were
related to acutely increased intracerebral pressure (ICP)
[7]. Furthermore, multiple attempts to either identify or
treat epilepsy in Dysautonomic patients have produced
negative results [8–15]. This is not to say that epilepsy
cannot alter ANS function. Metz et al. reported a patient
with high catecholamines, elevated heart rate and blood
pressure (but without sweating, cognitive changes or pos-
turing) whose clinical features were extinguished with
carbamazepine [16]. Therefore, while it is not possible to
completely exclude an epileptogenic aetiology for all cases
of Dysautonomia [17], disconnection syndromes represent
a simpler and more probable explanation.
Disconnection syndromes following severe TBI have
generally been attributed to structural damage, with most
authors hypothesising a loss of normal autonomic regula-
tory control mechanisms. The postulated sites of
dysfunction range from the upper brainstem and dien-
cephalon through to the anterior hypothalamus and/or other
cortical and subcortical centres [5, 8, 9, 11, 13, 15, 18–24].
Recently, the Excitatory:Inhibitory Ratio (EIR) Model [2]
was proposed as an alternative disconnection theory, where
paroxysms are driven by abnormal processing of afferent
stimuli within the spinal cord. Following a review of the
various disconnection theories, several converging lines of
evidence for and against each theory/model are discussed.
Disconnection Theories
In 1987, Bullard postulated the syndrome represented ‘‘a
release phenomenon at the level of the upper brainstem and
diencephalon secondary to loss of cortical/subcortical
control’’ [21, p. 611]. The association of severe paroxysmal
activity with decerebrate posturing was taken to imply a
functional mesencephalic lesion. Subsequent authors have
reiterated this diencephalon-upper brainstem release con-
cept [8, 9, 13, 25] although Pranzatelli et al. noted it was
generally not possible to localise a single discrete lesion
between these structures [9]. Kishner et al. proposed fur-
ther details of the cortical (orbitofrontal, anterior temporal,
insular) and subcortical (amygdala, periaqueductal grey,
nucleus of the tractus solitarius, cerebellar uvula and ver-
mis) regions involved in modulating hypothalamic control
of ANS functions [5]. Boeve et al. proposed disruption of
autonomic relay systems from anterior hypothalamic or
medullary lesions resulting in activation or disinhibition of
central sympathoexcitatory regions in combination with an
adrenal stress response [11]. Other authors have also sug-
gested anterior hypothalamic or medullary lesions as the
Neurocrit Care (2008) 8:293–300
primary area of damage associated with disconnection
theories of Dysautonomia [22, 23, 26].
These structural disconnection theories of Dysautono-
mia suggest damage to extensive and variable areas of the
brain ranging from the cerebral cortex down through the
diencephalon to the upper brainstem and medulla. Complex
mixtures of focal injury and diffuse axonal injury (DAI) are
typical in TBI [27], making such diverse injury patterns
possible in Dysautonomic subjects. These disconnection
theories are similar (hereafter termed the conventional
disconnection theories) in suggesting that one or more
separate sympathoexcitatory centres in the hypothalamus
and brainstem actively drive paroxysms once ‘released’
from higher control. There are two potential difficulties
with this proposition that need to be considered. Firstly, for
the unidentified sympathoexcitatory centres to drive dy-
sautonomic paroxysms, the extent of damage caudal to this
excitatory centre should be minimal, as such damage would
have the capacity to prevent overactivity. Secondly, the
theories as presented do not make testable hypotheses to
assist researchers in moving the field forward.
Extending these propositions, the EIR Model [2] starts
with the observation that Dysautonomia is one of a number
of overlapping acute emergency autonomic overactivity
syndromes. These syndromes include NMS, SS [28],
Dysautonomia, Parkinsonian-Hyperpyrexia Syndrome
(PHS) [29], intrathecal baclofen withdrawal, Autonomic
Dysreflexia, Malignant Catatonia [30], Malignant Hyper-
thermia [31], Stiff Man Syndrome and Irukandji Syndrome.
The EIR Model combines these syndromes under one
common mechanism by inferring a diencephalic/brainstem
inhibitory centre that normally controls afferent stimulus
processing in the spinal cord. In this model, the tendency
towards developing paroxysmal overactivity is termed the
allodynic tendency [2]. By definition, allodynia refers to a
central sensitisation process occurring within the dorsal
horn of the spinal cord in which non-painful stimuli
become perceived as nociceptive [32]. In the EIR Model,
the allodynic tendency is normally controlled by tonic
inhibitory drive from diencephalic centre/s, and any pattern
of damage through or distal to the inhibitory centre or
centres releases control of this process. The widespread
development of allodynia causes an apparent over-reaction
to what would normally be perceived as minor stimuli,
complicated by structural or functional links with the
sympathetic neurons of intermediolateral grey matter of
spinal cord. Summation of sufficient now-nociceptive
afferent stimuli then drives a positive feedback loop that
produces the sympathetic overactivity of Dysautonomia.
One advantage of the EIR Model is that it provides testable
hypotheses across the full range of acute autonomic syn-
dromes. Of most relevance to this review, the theory
proposes that treatment efficacy will be greatest for
Neurocrit Care (2008) 8:293–300
medications that directly decrease the spinal allodynic
tendency or increase brainstem inhibition.
Disconnection Theories and Observational Data
Despite good inferential reasons to support disconnection
hypotheses, there is limited direct pathophysiological evi-
dence. Only a few Dysautonomia studies report autopsy
data, not all TBI-related. All Dysautonomic subjects in
Strich’s case series [33] exhibited spastic quadriparesis
antemortem and at autopsy showed severe DAI, thalamic
and brainstem damage with normal looking hypothalami.
Bhigjee et al. reported a case with an intra-aqueductal
abscess with normal cortical and sub-cortical structures
other than reduced periventricular white matter [14]. Pen-
field’s original case report revealed a third ventricle
cholesteotoma and a normal hypothalamus at post-mortem
[6]. These findings do not provide a simple or direct answer
regarding the various theories, other than suggesting that
structural hypothalamic lesions are not necessary to pro-
duce Dysautonomia.
More evidence has emerged from CT correlates of
Dysautonomia, with studies identifying severe DAI [1, 11,
12, 34], and/or brainstem injury [1, 20]. These observations
support the association of Dysautonomia with more severe
injury. As the severity of DAI increases, damage penetrates
from subcortical white matter and the corpus callosum into
deeper white matter tracts [27]. In severe DAI, axonal
damage can extend into the pontine-mesencephalic junc-
tion adjacent to the superior cerebellar peduncles [35].
However, these CT findings are not universal, with Fer-
nandez-Ortega et al. suggesting focal lesions were more
prevalent than DAI in their case series [36]. It is worth
noting that the sensitivity and specificity of CT scans are
poor in these anatomical locations, inferring that all these
findings may incorporate a degree of type II error.
A complete analysis of structural disconnection theories
must also account for injury patterns seen in other acute
neurological events associated with Dysautonomia. These
include spontaneous subarachnoid or intracerebral bleeds
[8, 19, 37, 38], pressure from tumours [3, 6, 8, 9, 39–41],
intra-aqueductal abscess [14], hydrocephalus [8, 38, 42]
(occasionally in survivors of severe TBI) [12, 43] and from
cerebral hypoxia in the absence of other trauma [9, 10, 21,
25, 33, 44, 45]. Similar short-lived ANS changes are also
seen in electroconvulsive therapy [46]. Interestingly, in
some of these situations, the condition was reversible upon
removal of the precipitating event, for example, reducing
intracerebral pressure [6, 42].
This latter finding suggests that structural damage may
be a pre-requisite for dysautonomic paroxysms but is not a
sufficient explanation by itself. The observation that
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paroxysms require both structural damage and a functional
‘trigger’ to occur is consistent with other studies. Physio-
logically, the co-existence of ANS paroxysms with
decerebrate posturing implies the presence of brainstem
lesions [21]. In a study examining paroxysmal decerebrate
rigidity, Klug et al. recorded ICP and vegetative signs in 25
patients (15 with severe TBI, 10 with acute cerebrovascular
lesions) [19]. During paroxysms, their analysis revealed a
relationship between muscle overactivity and increased
vegetative signs dependent on compression of the mesen-
cephalon. While their study showed reproducible ICP
effects, other studies have noted both increases and
decreases in ICP around the onset of paroxysms [8, 11]. In
another study, virtually all patients with muscle rigidity
had a breakdown of ANS function, with elevated cardiac
and respiratory rate, blood pressure, hyperthermia and
sweating [47]. More recently, Dysautonomic subjects were
found to have prolonged uncoupling of heart rate from
heart rate variability (HRV) parameters compared to non-
Dysautonomic severe TBI survivors and healthy controls
[24]. This finding suggested that a dysfunction of the
medullary heart rate control centres persisted for more than
12 months post-injury. This greatly exceeds the duration of
observable ANS overactivity (average 2.5 months post-
injury) in an earlier case series of 35 Dysautonomic sub-
jects [1].
Just as importantly, numerous authors have reported an
association between the onset of dysautonomic paroxysms
and various afferent stimuli, both noxious and non-noxious.
Such stimuli have included pain, endotracheal suctioning,
passive movements such as turning, bathing and muscle
stretching [1, 4, 11, 14, 15, 20, 34, 45, 48, 49], constipation
or a kinked catheter [20], emotional stimuli [14], as well as
environmental stimuli such as loud noises [50]. This over-
reactivity to minor stimuli is mirrored in the response
patterns of several acute autonomic overlap conditions, the
most obvious of which is autonomic dysreflexia [2].
‘Triggering’ of dysautonomic paroxysms has not been
factored into the conventional disconnection theories and
as such they do not adequately predict nor explain this
phenomenon. However, as the EIR Model proposes spinal
cord over-reactivity in response to ordinarily benign stim-
uli, this ‘triggering’ is fundamental to explaining
Dysautonomia.
In summary, the combined anatomical and physiological
evidence suggests that Dysautonomic paroxysms are more
consistently associated with mesencephalic rather than
diencephalic lesions, while HRV data suggests functional
deficits around the medulla. Conventional disconnection
theories conceptualise paroxysms being driven by sym-
pathoexcitatory centre/s. Being excitatory, the centre and
its efferent pathways must be intact. The simplest and most
reliable way to achieve this is for the centre to be located
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caudally to the lesion or lesions. However, the anatomical/
physiological evidence would suggest the highest level for
this excitatory centre would be the mesencephalon (or
possibly the medulla). Furthermore, the stimulus data
suggest that this proposed excitatory centre would need to
receive summated afferent information from both central
and peripheral sources. While these concepts are not taken
into account with the conventional theories, the EIR Model
accommodates these findings by proposing an inhibitory
centre rostral to the mesencephalon. In the absence of
inhibition, each additional afferent stimulus increases the
spinal allodynic tendency and therefore potentiates parox-
ysmal activity. Furthermore, the clear association between
paroxysms and various stimuli (as detailed above) suggests
a functional, and hence potentially reversible or manage-
able component to paroxysms. Consequently, the inducible
nature of paroxysms also suggests a rationale for the
mechanism of action of pharmaceutical interventions
which will be discussed in the next section.
Observations Regarding Neurotransmitter Effects
Typically, the neurotransmitters involved in the aetiology
of Dysautonomia have been inferred from observations of
treatment response. On this basis, Rossitch and Bullard
initially suggested that opiate and dopaminergic pathways
were involved [8]. Conversely, Lemke asserted that the
‘‘goal of therapy is to dampen sympathetic outflow or act
to enhance the parasympathetic system’’ [4, p. 7]. In a
review of published pharmacological treatments identified
prior to 2004, the best available evidence for managing
Dysautonomia was intravenous morphine, benzodiaze-
pines, propranolol, bromocriptine and intrathecal baclofen
(ITB) [49]. More recently, gabapentin has also been
identified as a promising agent [15]. While none of these
assertions have been tested in rigorous experiments, evi-
dence for each medication group will be discussed,
especially as it pertains to insights into the pathophysi-
ology of Dysautonomia.
Morphine controls pain and modifies the extremes of
both the ANS changes and dystonic posturing [49] while
suppressing sympathetic outflow [18]. In some dysauto-
nomic subjects, morphine eliminated all episodes [11],
requiring doses up to 20 mg intravenously [8]. In another
study, morphine settled both hyperdynamic cardiac func-
tion and posturing in severe TBI patients [47]. Morphine
appears to act in a dose-dependent fashion, with smaller
doses producing reduced benefit [15].
Dopaminergic agents have been reported to be variably
effective in reducing Dysautonomic paroxysms. Rossitch
reported that bromocriptine decreased temperature and
sweating in three patients, while paroxysms ceased entirely
Neurocrit Care (2008) 8:293–300
in another patient [8]. Russo and O’Flaherty [48] and
Thorley et al. [13] published single case reports of post-
TBI Dysautonomia with positive responses to bromocrip-
tine, while Scott et al. reported greater treatment success
with carbidopa/levodopa [3]. However, other cases report
that bromocriptine failed to produce an observable effect
[9, 10, 15, 24].
There is evidence for increased sympathetic hormone
levels in Dysautonomia [18, 20]. Both alpha agonists and
betablockers have been utilised as treatments, with the two
most common agents being clonidine and propanolol.
Clonidine, an alpha2 adrenoceptor agonist, should be
effective through actions at several of the centres involved
in conventional disconnection theories. Clonidine acts both
centrally (blocking stimulatory adrenergic influences of the
hypothalamus and rostral ventrolateral medulla and acti-
vating a sympathoinhibitory brainstem centre) as well as
peripherally [16]. In a study of seven cases of severe TBI,
clonidine reduced plasma catecholamines and decreased
heart rate without decreasing cerebral blood flow [51].
Despite this, studies show limited evidence for its efficacy
in Dysautonomia. In one study, clonidine controlled blood
pressure but did not obviously affect either the number of
Dysautonomic episodes or the subject’s temperature [48].
In another study, clonidine reduced resting heart rate in two
Dysautonomic patients but did not influence paroxysmal
over-responsiveness to afferent stimuli [52].
Betablockers are sometimes promoted as a preferred
treatment for Dysautonomia [53] as they reduce the
severity of paroxysms [9, 11, 12, 20, 26, 47]. In uncom-
plicated TBI, propanolol decreases circulating
catecholamines [54], and reduces both cardiac work [55,
56] and catabolic drive [18, 57]. It is therefore unsurprising
that beta-blockers minimise the sympathetic overactivity of
dysautonomic paroxysms. Do et al. [12] reported a single
case study where metoprolol (a selective b1 blocker) was
ineffective while labetalol (an a1 and b1 & 2 blocker)
controlled symptoms. They concluded that all three actions
are required, although the number of cases reporting the
efficacy of propanolol argues against the need for a1
activity. In addition, propanolol penetrates the blood brain
barrier and blocks 5HT1A receptors [58], suggesting two
other potential mechanisms for its reported effectiveness in
Dysautonomia.
The GABA B agonist baclofen is administered intra-
thecally for patients with severe spasticity where other
treatment options have failed [59]. ITB acts on inhibitory
interneurons in the spinal cord, avoiding the cerebral
effects seen with oral administration [60]. ITB has been
reported to control ‘sympathetic storm’ phenomena in two
separate case series [34, 38]. Cuny et al. reported ITB
treatment in four Dysautonomic patients, finding that par-
oxysms ceased and recovery improved with relatively low
Neurocrit Care (2008) 8:293–300
doses (100–200 mcg/day) [34]. Becker et al. successfully
treated four Dysautonomic patients with ITB after
exhausting conventional options, with symptoms improv-
ing immediately in three patients [38]. Becker noted that,
despite the positive response, the anatomical and pharma-
cological basis of ITB’s effect was not fully understood. Of
interest, acute ITB withdrawal can exacerbate Dysautono-
mia [34] or produce a condition identical to Dysautonomia
in previously non-dysautonomic individuals [61].
Gabapentin has recently been reported to minimise
Dysautonomic paroxysms. In a case series of six Dysau-
tonomic subjects unresponsive to bromocriptine and
metoprolol, gabapentin appeared to reduce the number and
severity of paroxysms and allowed an overall reduction in
other medications, including ITB, without a recurrence of
symptoms [15]. While gabapentin was initially developed
as an anticonvulsant, its main clinical role is neuropathic
pain treatment via action at the alpha2delta subunit of
voltage-dependent calcium channels in the dorsal horn of
the spinal cord [62–64]. Consequently, gabapentin has the
potential to directly modify Dysautonomia at either a
cerebral or spinal level.
While these data are anecdotal in nature, the relative
efficacy of medications for Dysautonomia implies a
framework for the pathways controlling paroxysmal over-
activity. Given that several of the medications act at both
cerebral and spinal cord levels (morphine, sympathetic
agents, gabapentin), this limits their ability to help differ-
entiate between disconnection theories. However, as the
dominant action of dopaminergic agonists/antagonists is
cerebral whereas ITB acts on the spinal cord, these medi-
cations may provide an opportunity to evaluate the
different disconnection theories.
It has been postulated that the bromocriptine’s variable
efficacy in Dysautonomia management may be explained
by variable patterns of damage resulting from TBI [2]. In
Dysautonomia, bromocriptine is presumed to act at the
hypothalamus and corpus striatum [48] and, under the
disconnection theories, to have an inhibitory effect on
sympathoexcitatory structures. Individuals with damage
denervating this centre rostrally but with intact distal
pathways could potentially respond to the medication.
However, damage through or caudal to this centre would
prevent any inhibitory action on excitatory structures.
While this is possible in both the conventional and EIR
theories, it represents a more complex scenario under
conventional theories. In this case, both the sympathoex-
citatory and inhibitory centres need to be intact and have
functional connecting pathways. To be consistent with the
pathoanatomical data, the sympathoexcitatory centre/s are
most likely to be located below the mesencephalon. The
presumed hypothalamic inhibitory centre now needs intact
pathways running both rostrally and caudally through the
297
mesencephalon (the area implicated to have maximal
damage). This limitation is less evident in the EIR Model,
where the inhibitory pathway only needs connections with
the dorsal horn of the spinal cord.
The role of dopamine in this context brings back the
concept of the acute autonomic overlap syndromes, par-
ticularly the aetiology of NMS (which is entirely
neurotransmitter driven) and PHS (combining dopaminer-
gic neuron loss, dopamine blockade and over-
responsiveness to afferent stimuli) [65–67]. There are
multiple case reports suggestive of post-TBI NMS [13, 43,
68–70]. Furthermore, in simplistic terms, serotonin and
dopamine have a reciprocal relationship in the central
nervous system [58, 71], thereby suggesting that serotonin
excess can mimic dopamine depletion [58]. This concept
effectively ties SS, NMS, PHS and Dysautonomia together
into a similar entity within the EIR Model. Interestingly,
the cases of post-TBI NMS following minor dopamine
blockade suggest that the combination of subclinical
structural damage and relative dopamine blockade can
produce the complete syndrome [24]. The acute autonomic
overlap conditions reinforce the likelihood that neuro-
transmitter abnormalities act in synergy with structural
damage [2, 24].
The difference between disconnection models is more
obvious when considering ITB. In contrast to dopaminergic
agents, ITB is believed to have negligible cerebral activity,
instead working at a spinal cord level. While this obser-
vation does not invalidate conventional disconnection
models, they neither predict nor provide a rationale for this
effect. In contrast, the EIR Model accommodates the
known anti-nociceptive effects and site of action of ITB,
provides a mechanism for ITB’s previously unexplained
efficacy in Dysautonomia and suggests an explanation
for the overlap between Dysautonomia and ITB
withdrawal [2].
While gabapentin is active at both cerebral and spinal
levels, circumstantial evidence suggests the spinal effect
may be of greater importance in Dysautonomia. To achieve
efficacy, gabapentin would need to inhibit activity at the
excitatory centre, wherever it is located. This requires
gabapentin to have brainstem or cerebral activity in con-
ventional models. Gabapentin could be acting as an
anticonvulsant, however, no other anticonvulsant has
shown efficacy in Dysautonomia management. If gaba-
pentin has a separate cerebral effect, there is no clear
indication what this mechanism may be. Under the EIR
Model, gabapentin does not require intact cerebral path-
ways to work, as the effect can be explained solely by the
drug’s well-documented inhibitory action within the dorsal
horn of the spinal cord. Finally, a spinal mechanism of
action readily explains the observed synergistic effects of
gabapentin and ITB [15].
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Combining the Evidence
The limited understanding of the pathophysiology of
Dysautonomia represents one of the barriers to developing
a rational protocol for management of the condition. Of the
two main proposed aetiologies, there is a predominance of
evidence for disconnection rather than epileptogenic the-
ories. All of the disconnection theories suggest a release
phenomenon, where an excitatory centre or centres
becomes overactive and drives paroxysmal overactivity.
Conventional theories presume the excitatory centre/s
coordinate the generalised sympathetic overactivity from a
location somewhere between the upper brainstem and
hypothalamus. In contrast, the EIR Model proposes that the
causative diencephalic centre/s are inhibitory in nature, and
that the ‘released’ excitatory centre is located along the
length of the dorsal horn of the spinal cord. The EIR model,
however, does not preclude sympathoexcitatory centres
below the mesencephalon from exacerbating efferent
spinal overactivity.
Evidence from Dysautonomia literature and a variety of
other conditions suggests that disconnection syndromes can
result from structural and/or functional disconnection.
Structural damage incorporates the highly variable focal
and diffuse injury patterns seen in TBI, but also the quite
different lesions observed in other acquired brain injuries
producing the syndrome. In turn, functional disconnection
may follow temporary exacerbations of structural change
(such as raised ICP) or neurotransmitter abnormalities.
Dysautonomia follows numerous acute neurological events
and displays significant clinical similarities to a range of
other acute autonomic overactivity syndromes. The con-
ventional disconnection theory can accommodate the
development of symptoms in the former group but cannot
be expanded to incorporate all of the overlap conditions. In
contrast, the EIR Model provides a single rationale for all
of these syndromes. Most of the pathoanatomical and
physiological data suggest an association between parox-
ysms and mesencephalic/brainstem abnormalities. This is
supported by autopsy and CT evidence of brainstem injury
and severe DAI. The existence of lesions at and below the
mesencephalon pose difficulties in applying conventional
models, as these models require intact and functioning
excitatory centre/s, often postulated to be diencephalic.
Conversely, the EIR Model proposes an inhibitory centre
or centres above this level, allowing a much wider range of
injury patterns to produce the syndrome. Finally, the EIR
Model predicts the association between paroxysms and
afferent stimuli, observations that are not readily explained
within conventional disconnection theories.
The documented association of paroxysms with envi-
ronmental triggers supports treatment models that aim to
minimise [49] or pre-treat [4] noxious afferent stimuli. A
Neurocrit Care (2008) 8:293–300
variety of medications acting at cerebral and/or spinal
levels are effective in reducing clinical aspects of the
syndrome. The EIR Model provides a readily applicable
rationale for the activity of each of the reported medica-
tions. Specifically, the model suggests that medications that
reduce the allodynic tendency (decreasing over-reactivity
to afferent stimuli) produce a better response than those
treating efferent pathways. This suggests that sympathetic
agents may be treating the symptom rather than the disease.
[2] This contention is supported by preliminary clonidine
data [48, 52] but has not been formally evaluated for be-
tablockers. Conventional disconnection theories can
incorporate most of the observed medication effects with-
out significant modification, but only once further
assumptions are made. In particular, conventional theories
do not provide a rationale explaining how spinally active
ITB produces its effect.
Conclusion of Mechanisms and Future Research
In summary, there is little evidence to support the epilep-
togenic theory of Dysautonomia.
Of the two main disconnection theories, the EIR Model
more easily incorporates the available evidence when
compared to the conventional disconnection theories, with
the most significant difference deriving from evidence of
lesion location. Conventional disconnection theories
require an upper brainstem/diencephalic excitatory centre
or centres to remain undamaged and the caudal pathways to
be intact to be able to effect the proposed mechanism of
action. However, evidence suggesting an association
between mesencephalic and brainstem damage and parox-
ysmal overactivity reduces the probability that such
pathways would be intact. In contrast, the causative
brainstem/diencephalic centre is inhibitory in the EIR
Model, meaning that the pattern of damage does not need
to leave any particular structure or pathway intact within
this region. Other advantages of EIR model include, firstly,
its ability to explain the association of paroxysms with
over-reactivity towards normally non-noxious afferent
stimuli. Secondly, it provides a rationale to explain the
observed efficacy of ITB and gabapentin in Dysautonomia.
Finally, the EIR Model provides a relatively simple, inte-
grative framework that combines the pathogenesis of
Dysautonomia with a range of other acute autonomic
overactivity syndromes. While it remains possible to
modify the conventional disconnection syndromes to take
these factors into account, this increases the complexity of
the model and infers additional pathways.
There remains a significant amount of basic research
that needs to be undertaken regarding the pathogenesis of
Dysautonomia and its management. The principal barrier
Neurocrit Care (2008) 8:293–300
remains the lack of robust investigatory tools to quantify
treatment effects. Such tools would have the capacity to
advance the field beyond the current level of anecdotal
evidence. Having the capacity to critically assess quanti-
tative data against a theoretical framework (as discussed in
this article) would represent a major advance for Dysau-
tonomia research.
Acknowledgement This work resulted, in part, from a project
funded by the Motor Accidents Authority of New South Wales,
Australia.
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