91

Pathophysiology of Acute Coma and Disorders of

Consciousness: Considerations for Diagnosis and
Management
Bethany M. McClenathan, MD1 Nitish V. Thakor, PhD2 Robert E. Hoesch, MD, PhD1

1 Department of Neurology, Neurocritical Care, University of Utah, Salt Address for correspondence Robert Hoesch, MD, PhD, University of
Lake City, Utah Utah, Department of Neurology, 50 N. Medical Dr., Salt Lake City, UT
2 Department of Biomedical Engineering, Johns Hopkins School of 84132 (e-mail: [email protected]).
Medicine, Baltimore, Maryland

Semin Neurol 2013;33:91109.

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Abstract Disorders of consciousness are due to failure of the arousal system. In this review, the
Keywords authors introduce the spectrum of disorders of consciousness and describe the
coma structures, projections, and neurotransmitters involved in the generation and mainte-
consciousness nance of arousal. Next, they discuss the neurologic diseases frequently associated with
vegetative state arousal failure. Evaluation of patients with disorders of arousal is summarized, including
minimally conscious the neurologic exam, electrophysiological studies, biochemical testing, and imaging
state modalities. Finally, they review treatment options, including therapeutic hypothermia,
arousal medications, and deep brain and spinal cord stimulation.
cardiac arrest
ischemic stroke
traumatic brain injury
therapeutic
hypothermia
subarachnoid
hemorrhage
intracranial
hemorrhage

Consciousness was dened by Plum and Posner1 as the state persistent vegetative state is dened by a vegetative state
of full awareness of the self and ones relationship to the lasting at least 30 days,1 with some authors extending the
environment; it is composed of arousal and content. Arousal period to 3 months3 for nontraumatic brain injury and one
is controlled by the reticular activating system and other year for traumatic brain injury.3 For both the minimally
cortical structures, whereas content or awareness depends on conscious state and the vegetative state, arousal may be
cortical and subcortical function.2 Disorders of consciousness retained, but content of consciousnessawarenessis se-
include coma, the minimally conscious state, the vegetative verely damaged. Evolving nomenclature refers to the vegeta-
state, hypersomnia, abulia, akinetic mutism, and brain death. tive state as unresponsive wakefulness syndrome.4 The
Coma is dened as a state of complete unresponsiveness to minimally conscious state and vegetative state result from
both external and internal stimuli.1 The minimally conscious severe bilateral cortical damage or bilateral damage to corti-
state is primarily a disorder of awareness characterized by a cal connectivity.1 Hypersomnia is excessive sleeping or fa-
decreased level of consciousness with some preserved aware- tigue during the daytime, and can be primary, idiopathic, or
ness of self or environment.1 The vegetative state occurs when due to an underlying metabolic or structural etiology.5 Abulia
a comatose patient has periods of arousal with eye opening, is a decrease in initiative along with apathy; it can be seen in
but with profound disruption in or absent awareness.1 A frontal lobe damage. It can progress into akinetic mutism,

Issue Theme Acute Coma and Disorders Copyright 2013 by Thieme Medical DOI http://dx.doi.org/
of Consciousness; Guest Editors, Hans A. Publishers, Inc., 333 Seventh Avenue, 10.1055/s-0033-1348964.
Pttgen, MD, and Romergryko G. New York, NY 10001, USA. ISSN 0271-8235.
Geocadin, MD Tel: +1(212) 584-4662.
92 Pathophysiology of Acute Coma and Disorders of Consciousness McClenathan et al.

which occurs when a patient does not move or speak.1 Brain disorders of consciousness. The neurologic viability of ICU
death is the cessation of all central neurologic function and is and brain-injury survivors depends on the ability to wake up
the equivalent of somatic death. By denition, both arousal and regain awareness. We will rst review the anatomy and
and awareness are irreversibly lost when brain death occurs.1 physiology of arousal with a strong focus on the interconnec-
In this review, we will focus on the anatomy and physiology of tions of all of the structures involved in arousal. Specic
arousal and the pathophysiology of coma, the minimally neurologic processes that can result in alterations of con-
conscious state, and the vegetative state, with an emphasis sciousness are then discussed with a focus on the exact
on etiology, evaluation, and evolving treatments in particular etiology of disorders of consciousness for each disease state.
neurologic diseases. Hypersomnia, abulia, akinetic mutism, Finally, we will discuss diagnosis and management of patients
and brain death will not be directly addressed in this review. with disorders of consciousness.
However, the anatomy and physiology of normal sleep and
the pathophysiology of hypersomnia are used as models to
Anatomy and Physiology of Arousal
understand the pathophysiology of coma and other disorders
of consciousness. Arousal is possible due to the complex interplay among

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Disorders of consciousness are prevalent in the neurologic multiple cortical, subcortical, and deep structures, and is
and neurosurgical population, especially in traumatic brain inuenced by a myriad of different excitatory and inhibitory
injury (TBI), acute ischemic stroke (AIS), intracerebral hem- neurotransmitters. In general, the cortex and cortical inter-
orrhage (ICH), subarachnoid hemorrhage (SAH), and global connections are responsible for the content of consciousness
cerebral ischemia following cardiac arrest. For example, there or awareness. The cortex, though vital for consciousness, is
are
1.7 million TBIs each year in the United States. Although thought to contain no inherent activating system and relies

80% of patients with TBI are able to be discharged from the on multiple subcortical systems for activation. Therefore,
emergency department, 52,000 die and 275,000 require these subcortical systems activate the cortex, permitting
hospitalization;6 20% of patients present with moderate to awareness; this process is referred to as arousal. These
severe impairment in consciousness.7 Acute ischemic stroke subcortical structures include the reticular activating system
affects
800,000 Americans each year,8 and many suffer from with its individual components, other brainstem nuclei, the
decreased level of consciousness with brainstem, thalamic, or thalamus, the basal forebrain, and the hypothalamus. Each of
large hemispheric infarction. Disorders of consciousness oc- these structures will be discussed separately below and are
cur acutely in up to 27% of patients with AIS and is associated summarized in Table 1. Furthermore, although the cortex
with increased mortality.9 Intracerebral hemorrhage has an cannot initiate arousal, the role of cortex in the maintenance
approximate annual incidence of 17 to 21 cases per 100,000 of arousal will also be considered.
person-years;10 57% of these patients die within 30 days.11 The reticular activating system has long been known to
Subarachnoid hemorrhage has an incidence of 2 to 16 cases play a key role in arousal. Moruzzi and Magoun rst proposed
per 100,000 person-years;12
17% will have arousal failure on the reticular activating system in 194920 after experiments
presentation.13,14 Globally, there are an estimated 55 out-of- with cat brainstem transection demonstrated unresponsive-
hospital cardiac arrests per 100,000 person-years;15 in the ness when the transection was performed at the level of the
United States, there are
200,000 in-hospital cardiac ar- rostral midbrain, but intact arousal when the transection was
rests16 each year. Most of these patients either die or are performed in the pons and medulla. Subsequently, compo-
neurologically devastated with only
5% having good neuro- nents of the reticular activating system have been identied
logic outcomes with aggressive management.17 More gener- in the brainstem and in multiple ascending and descending
ally,
50% of critically ill patients are comatose and another projections to other parts of the brain. Its components also
15% are delirious or have disorders of consciousness on now are considered to include the midbrain reticular forma-
admission to the intensive care unit (ICU);18 over 80% of tion, mesencephalon, thalamic intralaminar (centromedian)
patients develop a disorder of consciousness characterized by nucleus, dorsal hypothalamus, and the tegmentum.2124
coma or encephalopathy during their ICU admission. Disor- These structures will be addressed within the context of
ders of consciousness in ICU patients are associated with each neuroanatomical structure in subsequent sections.
longer ICU stays and increased risk of mortality.19 Therefore,
disorders of consciousness are important neurologic and Brainstem
critical care problems; effective treatments for disorders of The brainstem contains key structures for arousal, including
consciousness could have enormous impacts on patient out- the reticular formation, raphe nuclei, locus coeruleus, sub-
comes and medical economics. stantia nigra pars compacta, ventral tegmental area, and the
Here we will discuss the challenges of disorders of con- mesopontine tegmentum, which includes the pedunculopon-
sciousness. Patients with decreased levels of arousal require tine tegmental nuclei and the laterodorsal tegmental nuclei.
extensive health care utilization and incur nancial costs and The nuclei extend throughout the brainstem, sending ascend-
emotional challenges on their families. With continued ad- ing and descending signals to inuence arousal. Furthermore,
vancement in specialized intensive care, more patients with the dendrites of these nuclei are optimally positioned within
brain injuries are surviving to discharge. The ability of health the brainstem to detect signals as they pass to and from the
care providers to achieve better mortality for patients means periphery. The dendrites of these neurons form web-like
that physicians are faced with more patients affected by reticula around the passing axons and can detect a wide

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 Pathophysiology of Acute Coma and Disorders of Consciousness McClenathan et al. 93

Table 1 Summary of arousal structures, projection targets, neurotransmitters, and general function

Neuroanatomical Nuclei Neurotransmitter Target Function

structure
Brainstem
Medulla, pons, and Reticular formation GABA PnO (intrinsic Promotes arousal26,27
midbrain action)
Ach PnO (intrinsic Promotes REM sleep26,27
action)
Medulla and caudal Caudal raphe nuclei Serotonin Spinal cord Promotes arousal33
pons
Rostral pons and Rostral (median and Serotonin Cortex, basal fore- Inhibits REM sleep, pro-
midbrain dorsal) raphe nuclei brain, LC, thalamus, motes arousal32,52
hypothalamus, RF,

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PB/PC
GABA Dorsal RN Suppresses arousal during
slow-wave sleep37
Rostral pons LC NE Prefrontal cortex, Promotes arousal22,32,45
VTA
Glutamate LC (intrinsic action) Inhibition and activation of
LC (biphasic)47
Dorsolateral pons PB/PC Glutamate Lateral hypothala- Promotes arousal22,54
mus (suprafornical),
substantia
innominata
Midbrain and pons PPN/LDT Ach PnO Promotes REM sleep26,27,31
Ach Contralateral PPN Modulate PPN thalamic
projections220
Ach SNPC/VTA Modulate DA release23,40
Ach Motor cortex Promotes arousal40,221
Ach PB/PC Enhancement of REM
sleep22,222
Ach, GABA, Thalamus Modulates arousal
glutamate states3941,220
GABA PnO Promotes arousal30
GABA Basal forebrain Inhibits arousal39
Glutamate Basal forebrain Promotes arousal39
Midbrain SNPC Dopamine Dorsal striatum Promotes REM sleep49,50
VTA Dopamine Septal area, nucleus Promotes arousal32,223
accumbens, amyg-
dala, piriform/pre-
frontal/ cingulate/
entorhinal cortices
Diencephalon
Thalamus Specic Glutamate Motor, sensory, vi- Modulates arousal57,224
sual, and auditory
cortices
Reticular nucleus GABA PnO Inhibits REM sleep58
(specic)
Nonspecic Glutamate Diffuse cortical and Modulates arousal59,60,224
subcortical
connections
(Continued)

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94 Pathophysiology of Acute Coma and Disorders of Consciousness McClenathan et al.

Table 1 (Continued)

Neuroanatomical Nuclei Neurotransmitter Target Function

structure
Hypothalamus Posterior Orexin LC Promotes arousal71,72
Orexin PnO Promotes arousal or sleep
(state-dependent)225
Lateral Orexin TMN, dorsal RN, Promotes
LDT, thalamus, bas- arousal35,36,66,75,78,223,226
al forebrain
GABA, melanin-con- LC Promotes sleep66,70,227
centrating hormone
(MCH)
Dorsocaudal GABA Ventral oral pontine Inhibits REM sleep58

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nucleus reticular nucleus
TMN Histamine Diagonal band of Promotes arousal32,73
Broca, VTA SNPC,
PB, cortex
Glutamate TMN Promotes and REM sleep76
Basal forebrain
Diagonal band of Histamine VTA Promotes arousal32,73,80
Broca
Ach cortex Promotes arousal and REM
sleep78,79
Magnocellular pre- Histamine VTA Promotes arousal32,73,80
optic area
Ach Cortex Promotes arousal and REM
sleep78,79
Glutamate Lateral Promotes arousal and REM
hypothalamus sleep228
Substantia Ach Cortex Promotes arousal and REM
innominata sleep22,78,79
Glutamate Lateral Promotes arousal and REM
hypothalamus sleep228
Nucleus basalis of Ach Prefrontal cortex Promotes arousal and REM
Meynert sleep45,78,79
Median septum Ach Cortex Promotes arousal and REM
sleep74,75
Globus pallidus Ach Cortex Promotes arousal and REM
sleep78,79

Abbreviations: Ach, acetylcholine; GABA, gamma-aminobutyric acid; LC, locus coeruleus; LDT, laterodorsal tegmental nucleus; MCH, melanin-
concentrating hormone; NE, norepinephrine; PB, parabrachial nucleus; PC, precoeruleus; PnO, nucleus pontis oralis; PPN, pedunculopontine nucleus;
REM, rapid eye movement; RF, reticular formation; RN, raphe nuclei; SNPC, substantia nigra pars compacta; TMN, tuberomammillary nucleus; VTA,
ventral tegmental area.

variety of external sensory or internal thalamic stimuli that tagonists result in increased REM sleep through blocking the
pass through surrounding structures. Therefore, these retic- inhibitory action of GABA on Ach release. The PnO receives
ular neurons are optimally positioned to respond to both projections from the mesopontine tegmentum Ach receptors,
external and internal signals in the control of arousal.25 which promote REM sleep, while hypothalamic orexinergic
The pontine reticular formation contains the nucleus projections to the PnO maintain wakefulness.31 Thus, the PnO
pontis oralis (PnO), which contains two systems with oppos- of the reticular formation has a strong inuence on normal
ing actions on arousal. The gamma-aminobutyric acid (GABA) awake and sleep patterns through its GABAergic and cholin-
ergic system of the PnO promotes wakefulness by acting on ergic projections; it is also inuenced by projections from
internal GABA receptors within the PnO, inhibiting acetyl- other structures, including the hypothalamus.
choline (Ach) release, and suppression of rapid eye movement The raphe nuclei extend throughout the length of the
(REM) sleep,2630 while the cholinergic system promotes the brainstem near the midline around ventricular structures.
initiation of REM sleep.26,27 Gamma-aminobutyric acid an- The rostral raphe nuclei are responsible for most of the

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 Pathophysiology of Acute Coma and Disorders of Consciousness McClenathan et al. 95

serotonergic output to the cortex, basal forebrain, and deep band of Broca and the preoptic area have projections to the
arousal structures with reciprocal connections, which pro- VTA. Dopaminergic neurons from the SNPC project to the
mote wakefulness and inhibit REM sleep.32 The caudal raphe dorsal striatum.49 Loss of
50% of these dopaminergic neu-
nuclei neurons in the medulla have serotonergic outow to rons results in a decrease in sleep latency and REM sleep.50
the spinal cord.33 Recent studies demonstrate that dorsal The dopaminergic output from the SNPC and the VTA inu-
raphe nuclei neurons are heterogeneous, with various sub- ence sleep architecture. Studies of dopamine-decient knock-
groups ring during different levels of arousal, wakefulness, out mice have demonstrated that a lack of dopamine results in
non-REM sleep, and REM sleep.34 Serotonergic signaling from a semiconscious or awake state with minimal awareness of
the raphe nuclei is inuenced by other neurotransmitters, their surroundings, which reversed with viral rescue.51 Orex-
including excitation via orexin afferents from the hypothala- inergic projections also depolarize LDT nuclei, impacting
mus.35,36 GABAergic inputs from neighboring dorsal raphe arousal states through the enhancement of LDT function.36
nuclei onto serotonergic dorsal raphe nuclei serve to regulate The parabrachial nucleus (PB) and the precoeruleus (PC),
their state-dependent activity and suppress serotonergic located in the dorsolateral pons, are recently recognized
output during slow-wave sleep.37 The effects of the raphe arousal structures. The PB and PC receive serotonergic input

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nuclei on arousal are inuenced by which subgroup of from the dorsal raphe nuclei, which inuences outow
neurons within the raphe nuclei is ring, as well as by signals from the PB and PC to the VTA.52 The PB was originally
intrinsic GABAergic action onto serotonergic neurons and recognized to have visceral and gustatory function,53 but
extrinsic hypothalamic signaling. investigators have now identied arousal functions. The PB
The pedunculopontine nucleus (PPN) and the laterodorsal has excitatory glutamatergic outow to the hypothalamus,
tegmental area (LDT) extend from the caudal midbrain, just which inuences awakening.54 In a cat study of various
below the red nucleus, into the rostral pons to the level of the arousal states, a population of GABAergic neurons in the PB
locus coeruleus.38 The PPN and LDT are the main sources of was found to be active during non-REM sleep.55 The PC also
cholinergic innervation to the brain through diffuse inter- inuences arousal. Electroencephalogram (EEG) tracing stud-
connecting dendrites, and also have GABAergic and gluta- ies of rats have found enhanced neuronal activity within the
matergic output.39 They send diffuse projections to the motor PC and periaqueductal gray, an area of gray matter in the mid-
cortex,40 the thalamus,41 ventral tegmental area (VTA),23 brain tegmentum, during REM sleep and postulate that these
substantia nigra pars compacta (SNPC), and spinal cord.40 areas may serve a REM-on function, while the lateral
The PPN has a signicant role in the regulation of arousal pontine tegmentum serves a REM-off function.56 Animal
increased intracellular calcium/calmodulin-dependent pro- lesional studies revealed the onset of sleep with PB lesions
tein kinase (CaMK) signaling in the PPN results in increased and coma with both PB and PC. Effects on arousal are due to
wakefulness.42 Pedunculopontine nucleus and LDT projec- connections with the substantia innominata, which then acts
tions also modulate thalamic nuclei and dopaminergic neu- upon the cortex.22 The interconnections of the PB and PC with
rons of the VTA.23 other structures important for arousal support their roles in
The locus coeruleus is an excitatory noradrenergic nucleus the arousal system.
in the rostral pons43 in the oor of the fourth ventricle and is
the primary source of norepinephrine to the brain.44 The Thalamus
locus coeruleus has extensive reticular projections to multi- The thalamus is part of the diencephalon and is optimally
ple arousal structures. Noradrenergic neurons in the locus positioned within the arousal system for its multitude of
coeruleus project to the anterior cingulate, medial prefrontal, cortical connections and relay function with deep structures.
and orbitofrontal cortices.45 Hypothalamic orexinergic pro- It has both specic and nonspecic nuclei that have functions
jections to the locus coeruleus trigger the release of small in arousal.57 The specic nuclei have projections to the motor
quantities of glutamate, which aids in the release of norepi- and sensory cortices and are primarily located in the lateral
nephrine.46 The response in the locus coeruleus to glutamate portion of the thalamus; they are directly involved in the
has two phases: Glutamate is initially excitatory to the locus transmission of afferent and efferent stimuli. GABAergic
coeruleus, but it then results in late postactivation inhibition projections from the reticular thalamic nucleus to the PnO
of the LC.47 Locus coeruleus neurons have phasic ring inhibit REM sleep during arousal.58 The nonspecic midline
discharges, which are short 10- to 20-Hz bursts and are nuclei have more diffuse projections to the cortex and have
stimulated by new stimuli, while basal discharges re at roles in sensory functions and cognition. Intralaminar nuclei
0.1 to 5 Hz. These different rates of discharges affect the are nonspecic nuclei with basal ganglia projections and also
perception of different sensory stimuli in the trigeminal have relay functions from deep structures of the reticular
thalamocortical pathways.48 The ability to perceive external activating system to the cortex,59 as well as to multiple
stimuli reects the role of locus coeruleus in arousal; activity subcortical structures.60 The thalamic reticular nucleus re-
in the locus coeruleus results in cortical activation, and hence ceives signals from the rest of the thalamus as well as the
arousal. cortex with reciprocal inhibitory GABAergic projections back
The SNPC and the VTA contain dopaminergic neurons to the thalamus.61
located in the midbrain. Inputs from the motor and sensory The thalamocortical neurons have classically been de-
cortices are excitatory to the SNPC; the VTA receives excit- scribed to have two types of electrical discharges: tonic and
atory signals from the lateral hypothalamus. The diagonal burst. Membrane depolarization results in tonic discharges

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96 Pathophysiology of Acute Coma and Disorders of Consciousness McClenathan et al.

and occurs during wakefulness.57 Membrane hyperpolariza- sleep.76 The TMN and the hypothalamus promote wakeful-
tion results in burst electrical discharges and is associated ness through the actions of histamine and orexin,
with sleep and unresponsiveness.57 A third mode of thala- respectively.
mocortical discharge, termed high-threshold bursting, has
been seen in the lateral geniculate nucleus of the cat and is Basal Forebrain
stimulated by glutamatergic and cholinergic receptor activa- The basal forebrain includes the substantia innominata, the
tion.62 It has a frequency of 3 to 15 Hz, occurs during relative nucleus basalis of Meynert, diagonal band of Broca, magno-
membrane depolarization, and corresponds to relaxed wake- cellular preoptic nucleus, median septum, and the globus
fulness and early sleep.62 The ventral posteromedial (VPM) pallidus.77 Hypothalamic orexinergic neurons project onto
nucleus of the thalamus has cortical projections to the post- cholinergic neurons of the basal forebrain, which activate
central gyrus. Cholinergic inputs to the VPM result in in- cortical and subcortical structures during arousal and REM
creased tonic ring rates and neocortical activation of the sleep.45,78,79 GABAergic basal forebrain neurons are inter-
somatosensory cortex, whereas noradrenergic VPM input spersed with cholinergic neurons and project to the cortex to
results in neocortical deactivation.63 Serotonergic signals aid in cortical deactivation and the promotion of slow-wave

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from the dorsal raphe nuclei result in inhibition of light- sleep.39 The cortical effects of cholinergic projections from
induced slow-bursting activity within the lateral geniculate the basal forebrain are modulated by inputs from deep
nucleus (LGN); the LGN has connections to other thalamic structures involved in arousal.
nuclei involved more directly in arousal.64 The LGN is con-
nected to the suprachiasmatic nucleus, which controls circa- Cortex
dian rhythms. These examples demonstrate that intrinsic The cortex is unable to generate wakefulness due to an
thalamic ring is inuenced by other caudal arousal struc- absence of an intrinsic arousal mechanismsubcortical in-
tures, such as the brainstem, and has a strong inuence on puts to the cortex from deep reticular activating-system
level of arousal. structures, relayed through the thalamus, are required for
arousal. Most of the input signals to the cortex are relayed via
Hypothalamus the thalamus.61 There are also abundant outow signals from
The hypothalamus is a structure essential for sleep and the cortex to deeper structures. Dopaminergic projections
arousal, and orexin (hypocretin), an arousal-promoting pep- from motor and somatosensory cortices target the SNPC80
tidergic hypothalamic neurotransmitter, has been a focus of and the lateral orbitofrontal cortex targets the VTA.80
many studies of arousal and coma in recent years. The In the cortex, there are two primary rates of discharge.
posterior hypothalamus has the most important function in Activated, or desynchronized, discharges are fast and of low
the maintenance of arousal based on cat experiments,65 amplitude, occurring during wakefulness. Synchronized, or
whereas the anterior hypothalamus promotes sleep.65 The deactivated, activity is slow and of a large amplitude.63 This
lateral hypothalamus also has an important function in activity is controlled by the VPM of the thalamus, which is
wakefulness and contains orexin-producing neurons.66 inuenced by the LDT and PPN and the locus coeruleus in the
Orexin is released by the lateral hypothalamus. Orexin re- brainstem. Cholinergic stimulation from the LDT and PPN on
ceptors are located throughout the brain, but are more the VPM results in increased VPM ring and cortical desynch-
densely distributed in the pons, medulla, thalamus, and ronization, whereas noradrenergic outow from the locus
hypothalamus.67 Intermingled within the lateral hypothala- coeruleus onto the VPM results in suppression of VPM output
mus are sleep-promoting melanin-concentrating hormone- and neocortical synchronization.63 A study in anesthetized
containing neurons68,69 and GABAergic neurons.66,70 Orexin patients of the inuence of anesthesia on the cortex revealed
projections from the hypothalamus stimulate the dorsal a change in the membrane potential during wakefulness with
raphe nuclei, LDT, and locus coeruleus.36,71,72 GABAergic abolishment of synaptic quiescence that had been recorded
projections from the dorsocaudal hypothalamic nucleus to during anesthesia. Blockage of cholinergic input from the
the bilateral ventral oral pontine reticular nucleus inhibit thalamic VPM did not prevent the occurrence of wakeful
REM sleep during arousal.58 Orexinergic, and to a lesser membrane potential patterns; however, blockage of norad-
extent, GABAergic projections reach diffusely throughout renergic input from the locus coeruleus resulted in episodes
the brain to result in arousal. of cortical synaptic quiescence in awake animals.81 Both
The tuberomammillary nucleus (TMN) in the posterior norepinephrine and acetylcholine inuence cortical arousal.
hypothalamus is the only source of histamine in the brain and The default mode network (DMN) is a resting-state net-
projects to multiple cortical and deep arousal structures.73 work of cortical functional connectivity during resting states
Histaminergic neurons have increased ring during wakeful- and quiescence during externally oriented mental tasks,
ness and decreased-to-absent ring while sleeping, most proposed to function as a level of background electrical
likely due to the inuence of GABA;74 orexinergic projections cortical activity and possibly internal thought genera-
from the lateral hypothalamus inuence the TMNs histamin- tion.82,83 Raichle et al rst described the DMN in 2001 based
ergic projections to the PPN and LDT.75 Glutamate is released on brain oxygen-extraction fraction studies on brains in an
from the TMN and then inuences the release of histamine by awake, but resting state.82 The DMN is composed of the
the TMN. Increased glutamate had been detected during both corticocortical connections among the precuneus, posterior
waking and REM sleep when compared with non-REM cingulate cortex (PCC), retrosplenial cortex, the ventral

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 Pathophysiology of Acute Coma and Disorders of Consciousness McClenathan et al. 97

anterior cingulate cortex, the ventromedial prefrontal cortex, which is known to promote cellular damage through dysre-
and the parahippocampalgyrus.8285 The main features of the gulation of calcium, sodium, and potassium.96 Patients with
DMN include functional connectivity and increased metabo- diffuse axonal injury present with a spectrum of symptoms,
lism during rest and deactivation during tasks.82,86 The PCC ranging from mild concussive-type symptoms to coma. Ani-
may have inhibitory actions on structures involved in cogni- mal models of diffuse axonal injury have found that the
tive tasks during rest,83 specically extrastriate visual gyri occurrence of posttraumatic coma depends on the location
and portions of the parietal lobe.84 Increased ventromedial of axonal damage and vector of acceleration causing the
prefrontal cortex activity has reciprocal decreased activity injury. Sagittal acceleration typically results in coma lasting
also in extrastriate visual areas as well as structures involved less than 15 minutes in most cases; oblique acceleration
in attention, including the inferior parietal lobule and several results in coma lasting a few minutes up to 6 hours. Lateral
frontal lobe gyri.84 These areas with corresponding decreased acceleration is associated with a higher percentage of pro-
activity during sleep and rest are termed the anticorrelated longed, persistent coma, and pathologic evidence of axonal
network, and are involved in awareness of internal and damage in the corpus callosum and area around the superior
external stimuli during wakefulness.87 During the progres- cerebellar peduncle a well as the cerebral hemispheres,

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sion from wakefulness through the stages of sleep, the cerebellar white matter, upper brainstem, and centrum semi-
functional connectivity of the components of the DMN grad- ovale.92 More axonal injury, including axonal bulbs and
ually breaks down; the connections are completely disrupted varicose axonal swellings, in the frontal, parietal, and tempo-
during slow-wave sleep.85 Therefore, the DMN appears to be ral lobes as well as the basal ganglia are seen with coronal
an important network with strong inuences on arousal; plane rotation; however, axial plane rotation has signicantly
although the cortex is unable to generate arousal, intrinsic more midbrain and pontine injury, particularly in the dorso-
cortical mechanisms appear to assist in the maintenance of lateral portion of the upper brainstem, and much less in the
arousal through mechanisms such as the DMN. cerebral hemispheres; therefore, it is associated with imme-
diate posttraumatic coma due to severe damage to arousal
structures.95
Pathophysiology of Arousal Failure in
When diffuse axonal injury lesions are located in the
Specic Diseases
brainstem, patients have a worse outcome and less chance
Various neurologic diseases are associated with disorders of of regaining consciousness compared with other common
consciousness, including traumatic brain injury, intracranial lesion locations, such as the corpus callosum.97 Patients with
hemorrhage, subarachnoid hemorrhage, acute ischemic TBI, who underwent magnetic resonance imaging (MRI) at
stroke, and global hypoxic-ischemic injury. Although the the time of their initial injury, were found to have lesions
mechanisms of injury for each of these diseases are varied, involving important arousal structures, including the upper
they each can result in decreased levels of awareness due to pons, midbrain, hypothalamus, basal forebrain, and diffuse
damage of one or more of the key neuroanatomical structures cortical locations. These were associated with worse out-
that are involved in the preservation of consciousness. comes at 1 year, including death, vegetative state, and severe
disability, when compared with patients without lesions in
Traumatic Brain Injury these structures.98 Studies of patients with TBI have detailed
Traumatic brain injury encompasses a wide range of head loss of orexinergic neurons within the lateral hypothalamus
injuries, including mild TBI, also known as a concussion, as on autopsy,99 as well as decreased orexin levels in the CSF,
well as more serious head trauma that can result in death. The correlating with sleepwake disturbances in surviving pa-
term traumatic brain injury includes loss of consciousness tients with TBI.100 Animal studies have shown depressed
with focal injuries, including contusions and hemorrhages, or orexin levels in the hippocampus and hypothalamus after
more global injuries, such as diffuse axonal injury.88 The type impact head injury with loss of normal diurnal variation with
of injury sustained depends on the mechanism of injury. The resulting loss of wakefulness and motor activity.101 The
Glasgow Coma Scale (GCS), used to categorize disorders of occurrence of disorders of consciousness in TBI patients
consciousness, can be used to classify TBI into mild, moderate, depends on a multitude of factors, including the mechanism
and severe injury.89 Mild TBI is correlated to a GCS of 13 to 15 of injury and neuroanatomic location of damage, particularly
and involves brief (< 30 min) loss of consciousness, alteration the upper brainstem, thalamus, and hypothalamus.
of consciousness at the time of injury, or posttraumatic
amnesia of the event lasting less than 24 hours.90 Moderate Intracerebral Hemorrhage
TBI corresponds to a GCS of 9 to 12, whereas TBI with GCS of Most patients with ICH have preserved consciousness at the
less than 9 is classied as severe.91 time of presentation; however, their neurologic status can
Diffuse axonal injury occurs in the setting of acceleration rapidly change. A study of 619 patients presenting to the
deceleration motion, resulting in rotational head motion.92,93 emergency department with ICH found an average GCS on
As the name implies, shearing injury to axons and small arrival of 14, but 22.6% of subjects had a loss of at least 2 GCS
capillaries is widespread, occurring primarily in white-mat- points while still in the emergency department, primarily as a
ter tracts, brainstem, graywhite junctions, and the corpus result of hematoma expansion.102 The clinical outcomes of
callosum.92,94,95 Diffuse axonal injury also results in an over ICH depend on the location of the hemorrhage, with most
200% increase in the amount of extracellular glutamate, studies dividing ICH into either supratentorial or

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98 Pathophysiology of Acute Coma and Disorders of Consciousness McClenathan et al.

infratentorial.11 Many of the essential components of the are periventricular, these pathological changes could produce
reticular activating system are located infratentorially in the persistent damage to the arousal system. Clinically, supra-
brainstem and infratentorial hemorrhages tend to have worse tentorial ICH with hydrocephalus is associated with an in-
outcomes.11 creased risk of death and failure to regain independence.
Primary brainstem hemorrhages have a high incidence of
disorders of consciousness. A study of 212 patients with Subarachnoid Hemorrhage
brainstem ICH found an average GCS on admission of 4; Subarachnoid hemorrhage can be traumatic, spontaneous, or
only 6.1% of patients had a good outcome, while 25.4% had aneurysmal. Disorders of consciousness are frequently pres-
moderate to severe disability, 10.8% were in a vegetative state, ent at the time of patient presentation and GCS scores are
and 57.5% died.103 Ventral hemorrhagesinvolving ventrally used in the initial grading of SAH.115,116 Traumatic SAH is
located arousal structuresare associated with worse out- present in
40% of patients presenting with moderate to
comes compared with dorsal pontine hemorrhages.104 Mas- severe head trauma, and is associated with worse outcome
sive hemorrhages within the pons have even worse and increased risk of death.117 Initial level of consciousness,
outcomes.104 Coma at presentation, hematoma location and extensive SAH, and the presence of IVH are all associated with

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volume, hematoma extension, hydrocephalus, and intraven- poor outcome.118 Of patients with treated poor-grade World
tricular hemorrhage have all been associated with poor out- Federation of Neurological Surgeons Scale aneurysmal sub-
comes.104,105 Unfortunately, most studies do not specify poor arachnoid hemorrhages, which correspond to a GCS from 3 to
outcomes beyond disability and death and do not specify the 12, 53% had a good outcome, while 47% had poor outcome,
cause of death. Many cases of reported deaths may be due to consisting of severe disability, vegetative state, and death.119
withdrawal of care due to a comatose state. At the initial time of bleeding, there is an acute rise in
Supratentorial hemorrhages can also result in disorders of intracranial pressure (ICP), followed by a decrease in cerebral
consciousness. Thalamic bleeds involving either the medial or blood ow and an increase in cerebral blood volume,120
entire thalamus are associated with lower GCS scores and resulting in a transient ischemia that leads to cerebral edema.
more intraventricular hemorrhage (IVH), both of which are In 2004, Kusaka et al developed the term early brain injury
associated with worse outcomes.106,107 A study of 53 patients to refer to the global brain injury that occurs in the rst 72
with thalamic hematomas found good outcome at 3 months hours after SAH.121 Leakiness of the bloodbrain barrier
in 24 patients, poor outcome in 21 patients, and eight patients occurs, resulting in increased brain swelling and ICP eleva-
died; GCS, pupillary asymmetry, and hematoma volume were tion.121 Although the effects of SAH on wakefulness can be
all predictive of poor outcomes.108 Nearly half of supratento- due to direct effects on arousal structures from IVH and
rial lobar hemorrhages present with alterations of arousal, hydrocephalus, other effects result from these global cerebral
and a GCS score less than 13.109 One study that found poor processes.
outcomedened as death, a vegetative state, or dependence Cerebrospinal uid analysis in patients with SAH with
was predicted by hemorrhage volume greater than 40 cm3 secondary hydrocephalus found elevated levels of neurola-
and a GCS of 13 or less.109 This study also found that a GCS of ment heavy chain, a marker of axonal damage, starting
7
less than or equal to 12 in the setting of 6 mm or more midline days after the initial bleed. The degree of elevation correlated
shift at the level of the septum pellucidum was predictive of a both with the GCS score and the WFNS scale.122 A study of
100% chance of vegetative state or death.109 Midline shift orexin levels in the CSF found that patients with high volume
corresponds with degree of mass effect and lateral displace- of SAH or IVH with resulting hydrocephalus have undetect-
ment of structures, which corresponds to compression of able orexin levels when the GCS was less than or equal to 8.
arousal structures within the brainstem, thalamus, and tha- Subarachnoid hemorrhage can cause damage to the hypo-
lamocortical projections. thalamus, and absent production of orexin is a marker of
Intraventricular hemorrhage has been shown to be an hypothalamic injury and is associated with decreased levels
independent predictor of poor outcome after ICH,110112 of consciousness.123 In addition to severe disorders of con-
and occurs most frequently in thalamic and basal ganglia sciousness, survivors of SAH experience problems with
bleeds. Intraventricular hemorrhage may result in obstruc- sleepwake cycles, including trouble initiating and maintain-
tive hydrocephalus due to blockage of normal cerebrospinal ing sleep, as well as daytime fatigue.124
uid ow and reabsorption, causing ventricular system ex- The etiologies of disorders of consciousness in patients
pansion, and compression of the periventricular gray and the with SAH are varied. The changes in cerebral blood ow cause
reticular activating system nuclei located there. Experimental transient ischemia, which then results in changes to the
animal studies have demonstrated gross pathological changes permeability of the bloodbrain barrier and ultimately to
in the brain within 1 to 3 hours of induced hydrocephalus.113 global cerebral edema. Cerebral edema and elevated ICP as a
The rst changes observed were enlargement of the lateral result of obstructive hydrocephalus from IVH also result in
ventricles followed by attening of the cortical surface, then impaired consciousness.
progressive dilation of the entire ventricular system.113 Mi-
croscopic changes also occur, primarily in the periventricular Acute Ischemic Stroke
region, including proliferation of germinal cells, changes in The occurrence of impaired consciousness is uncommon in
the ventricular walls, and uid extravasation into the peri- AIS; however, consciousness can be affected when ischemia
ventricular white matter.114 Because many arousal structures involves certain cerebral structures, particularly those

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 Pathophysiology of Acute Coma and Disorders of Consciousness McClenathan et al. 99

involved in the generation and maintenance of arousal. Large due to alterations in histamine and orexin. Malignant MCA
infarctions with surrounding edema and mass effect can infarctions may result in coma due to the global effects of
result in elevation of ICP or obstructive hydrocephalus. Dis- cerebral edema or mass effect on arousal structures.
orders of consciousness can also occur due to bihemispheric
involvement in ischemic stroke.125 Global Cerebral Ischemia
As previously described, the thalamus and the brainstem Cardiac arrest causes global cerebral ischemia, and successful
have signicant control of arousal. The inuence of thalamic return of spontaneous circulation results in reperfusion
lesions on wakefulness has been well described. A case series injury. Neurons are vulnerable to ischemic injury, and dam-
of patients with paramedian thalamic stroke demonstrated age can be seen after only 2 minutes of lost perfusion.137
hypersomnia with 10 to 20 or more hours of sleep per day.126 Certain cerebral structures are more susceptible to ischemic
Another series of patients with bilateral thalamic infarcts injury, including the CA1 and CA4 regions of the hippocam-
demonstrated multiple alterations of consciousness, includ- pus; pyramidal cells in layers 3, 5, and 6 of the neocortex; the
ing coma at onset, hypersomnia, decreased vigilance, and amygdala; the cerebellar vermis; portions of the caudate
concentration decits; most of these decits were seen in nucleus; and some brainstem nuclei.137140 The reticular

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patients with bilateral paramedian thalamic artery infarc- nucleus, ventroposterior nucleus, the medial geniculate nu-
tion.127 An imaging study of patients with brainstem lesions, cleus, and the intralaminar nuclei of the thalamus are also
primarily due to AIS, but also including hemorrhagic lesions, particularly sensitive to ischemia.137,138 Therefore, several
with resulting coma, found that coma or hypersomnolence important arousal structures are very susceptible to ischemia.
occurred with lesions involving the upper pontine tegmen- The reasons for differing vulnerability are most likely
tum. The length of coma was longest with bilateral and larger multifactorial. A slower rate of phosphorylation of glutamate
lesions.21 channels by CaMK, an enzyme activated after ischemia,
Isolated infarctions of the hypothalamus are quite rare, but occurs in the cortex compared with the striatum, which
case reports describe low CSF concentration of orexin,128 may account for increased cortical sensitivity in ischemia.141
development of narcolepsy, uctuating sleep-wake cycle Other hypotheses include variability of cellular metabolism
with restlessness,129 and the development of amnestic syn- needs or induction of certain enzymes, including heat shock
drome with isolated mammillothalamic tract infarction.130 proteins, c-fos, or c-jun, which increase vulnerability to
Animal models have demonstrated neuroprotective effects of ischemia.139 The initial ischemic insult due to lack of blood
orexin after ischemic stroke, suppression of the development ow and resultant hypoxia trigger the ischemic cascade. The
of postischemic intolerance to glucose,131 and a decrease in supply of adenosine triphosphate is quickly exhausted, which
brain infarct area following ischemia and then reperfusion.132 results in inability to maintain essential sodium and potassi-
Middle cerebral artery (MCA) infarctions can be associated um transmembrane gradients and membrane depolarization.
with signicant cerebral edema resulting in increased risk of Damaged neurons release massive amounts of glutamate,
neurologic deterioration and death and are referred to as which then activate NMDA receptors, resulting in calcium
malignant MCA infarctions. Features associated with fatal inux intracellularly.142 The inux of calcium from the
cerebral edema in malignant MCA strokes include higher extracellular space and release of intracellular calcium stores
National Institutes of Health Stroke Scale scores, decreased results in elevation of intracellular calcium concentra-
level of consciousness, and early nausea and vomiting.133 tion;143,144 as a result, mitochondrial function is impaired,
Cerebral edema may result in transtentorial herniation and/ oxygen free radicals and nitric oxide are produced, and
or compression of the diencephalon by the temporal lobe. A intracellular enzymatic pathways are activated, including
study of malignant MCA infarctions treated with maximal protein kinases B and C, CaMK, mitogen-activated protein
conservative intensive carenonsurgical management kinase (MAPK), and phospholipases A2, C, and D.145,146 A
found an average admission GCS score of 13, with progression recent study demonstrated that glutamate induces increased
to coma within 1 to 2 days. Seventy percent progressed to neuronal gap junction coupling, which is proposed to propa-
brain death.134 The addition of decompressive hemicraniec- gate a death signal from neurons dying in one locus to
tomy to the treatment of malignant MCA infarction has surrounding cells.147 Glutamate also blocks activation of
resulted in a signicant mortality benet with a 50% absolute neuroprotective processes following ischemia, including in-
risk reduction. However, meta-analyses have revealed con- sulin-like growth factor- (IGF-) 1 signaling.148 Transient
icting results regarding the amount of functional benet ischemia also results in activation of astrocytes and microglial
and shift from poor outcome (death, a vegetative state, and cells, which causes worsening of ischemic injury through
severe disability) to good outcome.135,136 Although there production of additional proinammatory cytokines, includ-
appears to be a trend toward benet, the issue of decom- ing tumor necrosis factor- (TNF-) and interleukin- (IL-)
pressive hemicraniectomy is still under investigation. 1.149
Acute ischemic stroke typically presents with preservation Even after the return of spontaneous circulation and
of arousal; however, the presence of impaired consciousness cerebral perfusion, cellular injury and death continue via a
signies the severity of illness. Infarctions involving the process called reperfusion injury.150 Return of blood ow to
thalamus and brainstem have an increased risk of disorders ischemic brain results in the generation of lipid peroxidation,
of consciousness compared with other locations. Hypotha- accumulation of oxygen free radicals, excess intracellular
lamic ischemia is rare in isolation, but exhibits global effects calcium and extracellular glutamate, changes in microglial

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100 Pathophysiology of Acute Coma and Disorders of Consciousness McClenathan et al.

cell morphology, activation of astrocytes and microglia, and cortical response is predictive of death in comatose patients
elevation of interleukins and TNF-, resulting in neuronal after cardiac arrest; delayed N20 responses are associated
apoptosis.151,152 with either death or persistent vegetative state.167 Clinicians
are utilizing biochemical markers including neuron-specic
enolase and the astrocyte/glial protein S100 more frequently
Evaluation and Diagnosis
in the evaluation of patients with disorders of consciousness.
The neurologic exam is the rst step in the acute evaluation of In diffuse axonal injury, elevations of neuron-specic enolase
any patient with an abnormal level of consciousness. One of and S100 within the rst 3 days after injury were associated
the most studied and utilized clinical exams is the GCS, which with poor outcome, including severe disability, a vegetative
was originally published in 1974, and assesses motor and state, and death.168 In cardiac arrest patients, elevations of
verbal function and eye opening.89 The Full Outline of UnRe- neuron-specic enolase are associated with death or vegeta-
sponsiveness (FOUR) score was published in 2005 to address tive state.169 Earlier prediction of outcome by utilizing these
some of the shortcomings of the GCS, including inability to tools could prevent prolonged aggressive care for patients
assess verbal function in intubated patients and lack of with poor outcomes, including coma, vegetative state, and

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brainstem testing. The FOUR score tests eye, motor, brain- minimally conscious state.
stem, and respiratory patterns; lower scores are more predic- Imaging modalities under investigation in patients with
tive of mortality than the lowest GCS score.153 Despite this, disorders of consciousness include MRI, functional MRI (fMRI),
the FOUR score has yet to be universally adopted. and single-photon emission computed tomography (SPECT).
The ocular and motor exams are the most predictive of Clinical studies have shown patterns of MRI signal changes that
long-term neurologic outcome. The eye exam appears to have were predictive of outcome after cardiac arrest. Abnormalities
the best predictive value. Absence of pupillary light reexes is on MRI were most prevalent in the cortex of the parietal,
predictive of poor outcome in nontraumatic coma, including temporal, and occipital lobesespecially at watershed areas
coma after cardiac arrest.154,155 However, the timing of and basal ganglia, particularly the putamen.170 In regards to
pupillary assessment is important, especially because of the outcome, an increased volume of restricted diffusion and
implementation of therapeutic hypothermia after cardiac increased involvement of the cortical gray matter, thalamus,
arrest. In cardiac arrest patients, unreactive pupils on arrival caudate, and putamen on MRI were associated with a higher
were not predictive of survival rates, but absent pupillary likelihood of coma.170 Diffusion tensor imaging (DTI) shows
reactivity or absent corneal responses at 72 hours were the integrity of connecting white matter tracts, and damage to
predictive of death.156 A study of cold caloric vestibulo-ocular these tracts, as is found in diffuse axonal injury, is associated
response testing in vegetative-state patients demonstrated with nonrecovery.171 Disruption in the connectivity of the
100% sensitivity and 92% specicity of the fast-phase compo- DMN has been described in patients with disorders of con-
nent for predicting recovery of consciousness.157 The cortex sciousness, including coma, persistent vegetative state, mini-
controls the fast phase, and its presence demonstrates the mally conscious state, and TBI on fMRI.86,172176 An fMRI study
integrity of cortical projections. Oculocephalic testing is less compared activity of the DMN in subjects with different levels
predictive.158 The motor examination also has predictive of consciousness as a result of trauma or hypoxic injury.
value. A study of postcardiac arrest patients demonstrated Deactivation of the DMN within the medial parietal and medial
extensor or absent motor response to noxious stimuli on frontal lobes was diminished in minimally conscious subjects
day 3 was associated with a 93% risk of death.159 In aneurys- and absent in vegetative state subjects, compared with healthy
mal SAH patients, higher motor exam scoring on the GCS at controls.86 A functional connectivity study of the DMN after
admission as well as spontaneous eye opening during hospi- TBI demonstrated increased level of activation within the
talization are predictive of a favorable 1-year outcome.160 DMN, which correlated with difculty with sustained atten-
Ischemia affects the electrophysiology of the brain. Electro- tion.174 Damage to connecting white matter tracts within the
encephalogram reactivity correlates with different arousal DMN results in structural and functional disconnection and
stages, and assists with prognostication in coma. Unfavorable decreased ability to deactivate.174 An fMRI study of 13 coma-
EEG patterns, including burst suppression, generalized or tose patients after cardiac arrest found DMN activity in two
periodic epileptiform discharges, absence of EEG activity, as patients who regained consciousness, but no activity in 11
well as alpha or theta coma are associated with poor outcomes patients in an irreversible coma.176 Imaging of the DMN may
after cardiac arrest.161,162 Better prognosis occurs in EEGs with yield more information about the odds of the recovery of
continuous background electrical activity.163,164 After cardiac consciousness in comatose patients. Global connectivity on
arrest, good neurologic recovery in patients with a burst fMRI is higher in patients in the minimally conscious state
suppression EEG pattern is extremely rare.164,165 Burst sup- compared with the vegetative state.177 An fMRI study found
pression results from a loss of cortical inhibition from the
10% of patients with disorders of consciousness could mod-
thalamus. As the level of coma deepens, the inhibitory function ulate their brain activity by performing specic mental imag-
of the basal forebrain on the hippocampus decreases, resulting ery in response to yesno questions, which could establish a
in generation of delta ripples or oscillations of CA3 pyramidal means of communication for these patients, without any other
cells within the hippocampus.166 clinical evidence of awareness.178 The SPECT images demon-
Somatosensory evoked potentials measure the N20 corti- strate the distribution of cerebral blood ow, which is a
cal response to stimulation of the median nerve. Absent N20 surrogate marker for cerebral metabolism. Post-TBI patients

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 Pathophysiology of Acute Coma and Disorders of Consciousness McClenathan et al. 101

Table 2 Summary of current treatment options in disorders of consciousness

Treatment modality Mechanism of action Location of action

Temperature regulation
Therapeutic hypothermia Inhibition of inammatory cascades, Global, but especially temperature-
decreased metabolic demands, sensitive areas, including parts of the
reversal of ischemic damage, de- cortex, thalamus, and
creases oxygen free radicals hippocampus180185
Medications
Amantadine Inhibits NMDA receptors, dopamine Nigrostriatal, mesolimbic, and
agonist frontostriatal pathways197,198
Methylphenidate Cortical activation via dopamine and Prefrontal, frontal, posterior
NE cingulate; retrosplenial, inferior pari-
etal, temporal, and occipital cortices;

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precuneus201,203
Modanil/armodanil Inhibits dopamine and NE transport; Hypothalamus, TMN, thalamocortical
activates dopamine, glutamate, se- connections197200
rotonin, and histamine release; GABA
and orexin effects; thalamocortical
coupling
Zolpidem Sedative hypnotic, GABA agonist Damaged neural tissue201204
IT Baclofen GABA agonist Spinal cord-cortical vs. thalamocorti-
cal circuitry208211
Electrical stimulation
Deep brain stimulation Increases cortical desynchronization, Thalamus or reticular
blood ow, metabolism formation219,220
Epidural spinal cord stimulation Increased cerebral blood ow, perfu- Cervical spinal cord223,224
sion, and metabolism; decreased ox-
ygen free radicals; increased
dopamine and NE216,217

Abbreviations: GABA, gamma-aminobutyric acid; IT, intrathecal; NMDA, N-Methyl-D-aspartic acid; NE, norepinephrine; TMN, tuberomammillary
nucleus.

in a persistent vegetative state undergoing SPECT had a 100% state, and vegetative state. Therapeutic hypothermia for
chance of favorable outcome with normal cerebral blood ow. neuroprotection, arousal-promoting medications, and deep
However, approximately two-thirds of patients with periven- brain and cervical cord electrical stimulation will be dis-
tricular/frontotemporal hypoperfusion and nearly 90% of those cussed and are summarized in Table 2.
with global and pericontusional hypoperfusion had unfavor- Over the last 10 years, therapeutic hypothermia has
able outcome.179 emerged as the standard of postcardiac resuscitation care.
The assessment of patients with disorders of conscious- Furthermore, therapeutic hypothermia is the only successful
ness is multimodal. The neurologic exam, including coma post-ischemic neuroprotective therapy, despite years of neu-
grading scores, remains the cornerstone in the evaluation of rologic research on countless candidate therapies. Therapeu-
comatose patients. However, additional information can be tic hypothermia slows all enzymatic processes, which results
gained through the use of additional tools. Somatosensory overall in decreased inammation and apoptosis.180 It also
evoked potentials demonstrate the integrity of connections decreases cerebral metabolic demands for oxygen and glu-
between deep structures and the cortex. Advanced imaging cose, which causes a net decrease in adenosine triphosphate
studies reveal both structural and functional connectivity utilization compared with production.181 Therapeutic hypo-
within the brain. Nonetheless, establishment of these modal- thermia reverses some of the damaging consequences of the
ities to predict outcome in coma will require additional study. initial ischemic injury, including reducing extracellular glu-
tamate, thereby decreasing intracellular calcium and its
effects.182,183 Hypothermia also results in a decrease of
Emerging Therapies for Disorders of
oxygen free radicals, inactivation of caspases, and decreased
Consciousness
bloodbrain barrier permeability.184 Hypothermia results in
Knowledge of the structures and interconnections required attenuated stress response within particularly temperature-
for arousal, as well as the mechanisms for arousal failure in sensitive areas, including portions of the cortex, thalamus,
the evaluation of patients with disorders of consciousness, are and hippocampusall structures involved in the generation
keys to understanding patients in coma, minimally conscious and maintenance of arousal.185

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102 Pathophysiology of Acute Coma and Disorders of Consciousness McClenathan et al.

A Cochrane Review of high-quality studies of therapeutic and inuences on GABAergic and orexinergic pathways.197
hypothermia after cardiac arrest found improved cerebral Modanil acts on orexinergic neurons within the hypothala-
performance and increased chance of survival after hospital mus to initiate histamine release by the TMN.198 It also
discharge in patients treated with therapeutic hypothermia promotes thalamocortical coupling.199 Arousal-promoting
compared with standard intensive care.186 The 2010 Ameri- effects could be postulated from several of these sites of
can Heart Association Advance Cardiovascular Life Support action. Although these drugs have not been investigated
placed increased emphasis on postcardiac arrest care, recom- prospectively in patients with disorders of consciousness,
mending therapeutic hypothermia following ventricular - case reports suggest benet.200
brillation arrest, and consideration of hypothermia after Zolpidem is an imidazopyridine nonbenzodiazepine seda-
arrest from other arrhythmias.187 Therapeutic hypothermia tive-hypnotic and GABA agonist,201 originally developed as a
is also being investigated in other disease processes, including sleep aid, which has been investigated as a possible treatment
TBI and AIS.188,189 Although there is still a high likelihood of for disorders of consciousness. Several case reports describe
death and disability following cardiac arrest, therapeutic an improvement in level of consciousness and arousal in
hypothermia is now a standard part of postcardiac arrest patients who are in coma, persistent vegetative state, or

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care to improve neurologic outcome via survival of neurons minimally conscious state,201204 ranging from the develop-
within arousal structures. ment of spontaneous eye opening to purposeful speech. These
Medications that have been studied in patients in a coma, benecial effects were transient in all patients. Imaging
vegetative state, and minimally conscious state are numerous. studies demonstrated generalized cortical activation, im-
Amantadine, one of the most extensively studied drugs in provement of cerebral perfusion in areas of brain injury,
disorders of consciousness, is an amino adamantine, and was and reversal of cerebellar diaschisis on SPECT.202,205 Reacti-
rst used in inuenza treatment and then for the treatment of vation of injured neural tissue is proposed to be due to
Parkinson disease. It inhibits glutamatergic NMDA receptor agonistic effects on GABA receptors within damaged areas
channels, stabilizes the channel in a closed state,190 and is a by zolpidem.201 Two placebo-controlled studies of the use of
dopamine agonist. Amantadine is postulated to act on dopa- zolpidem in patients in a persistent vegetative state have been
mine-dependent areas involved in arousal and attention, published. One study of adults in a vegetative state found
including the nigrostriatal, mesolimbic, and frontostriatal improvement from the vegetative state to the minimally
pathways.191 A recent study of amantadine in patients in the conscious state in one out of 15 patients with zolpidem
persistent vegetative state or the minimally conscious state administration.206 A study of three children with persistent
after TBI demonstrated that administration of amantadine vegetative state did not show any benet.207 Although zolpi-
between 4 and 16 weeks after injury was associated with dem may not improve the majority of patients with disorders
faster rates of improvement compared with placebo. Im- of consciousness, there appears to be a subset of patients that
provement included following commands; object use; and could potentially benet. Larger-scale randomized placebo-
speech, including saying yes or no; these gains in function were controlled studies need to be performed to investigate (1) the
lost after the drug was discontinued. Another amino adaman- mechanism by which zolpidem results in arousal, and (2)
tine, memantine, has not been prospectively studied in dis- which patients may benet before conclusions about the role
orders of consciousness. However, a rat study demonstrated a of zolpidem in disorders of consciousness can be reached.
similar ability to promote wakefulness after sleep deprivation Baclofen is a GABA agonist used in the treatment of
compared with methylphenidate.192 Memantine is also neuro- spasticity as a result of central nervous system injury. The
protective against glutamate-induced excitotoxicity.193 occurrence of spasticity is common in patients with brain
Methylphenidate is a stimulant that activates noradrener- injury and disorders of consciousness; some of these patients
gic and dopaminergic systems within the prefrontal cor- have been treated with intrathecal baclofen. Case reports of
tex.194 Studies of methylphenidate have focused on the improvement in levels of consciousness after intrathecal
treatment of attention problems after TBI in patients who baclofen in patients with persistent vegetative state reveal
are awake and aware. There are limited case reports regarding a range of improvement from return of spontaneous eye
its use in coma, and a meta-analysis of these case reports did opening (improvement to minimally conscious state) to
not show a benet.195 In severe TBI, methylphenidate is spontaneous motor movement, following commands, and
associated with a decreased length of ICU and hospital spontaneous speech.208211 The authors of a ve-patient
stay.196 An imaging study of glucose metabolism in patients case series postulated that intrathecal baclofen improves
with impaired consciousness demonstrated an elevation in levels of arousal by one of two possible mechanisms: (1)
metabolic activity within the precuneus, and posterior cin- the GABAergic action of baclofen modulates gating of signals
gulate, retrosplenial, and inferior parietal cortices, as well as from the spinal cord to the cortex, resulting in increased
frontal, temporal, and occipital gyri after administration of cortical awareness of self and stimuli perhaps by blocking
methylphenidate. These patients also demonstrated an im- sensory overload; or (2) benecial effects within the brain,
provement in GCS scores.196 including improved stability and coherence of thalamocort-
Modanil and armodanil are stimulants with diffuse ical circuits, improving circadian rhythms and sleepwake-
pharmacological effects, including inhibition of dopaminergic cycle regularity through GABAergic action on glutamate
and noradrenergic transporters; activation of dopaminergic, receptors, and increased alertness through serotoninergic
glutamatergic, serotonergic, and histaminergic release;197 actions.208 No randomized placebo-controlled studies have

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 Pathophysiology of Acute Coma and Disorders of Consciousness McClenathan et al. 103

been published at this time on the use of intrathecal baclofen from these deep arousal structures. Multiple neurotransmit-
in patients with disorders of consciousness. ters, including serotonin, GABA, Ach, glutamate, dopamine,
Deep brain stimulation (DBS) of thalamic nuclei and the histamine, and orexin, act on receptors of interconnected
mesencephalic reticular formation has also been investigated arousal structures to inuence arousal. Understanding the
in patients in the persistent vegetative state or the minimally interplay of arousal structures and their neurotransmitters is
conscious state. Early case series demonstrated emergence essential to understanding the mechanisms of arousal failure
from vegetative state, EEG arousal responses, and increased in neurologic disorders with disorders of consciousness.
global cerebral blood ow and metabolism after DBS implan- Treatment options for disorders of consciousness are an
tation.212 A study of 21 patients in a vegetative state treated exciting area of research and successful implementation
with DBS revealed emergence from vegetative state to com- would have an enormous clinical impact. Several treatments
mand-following in eight patients. Furthermore, EEG record- have promising trials and/or case reports of improving levels
ings showed desynchronization, which corresponds with of consciousness in patients in the minimally conscious state,
wakefulness.213 Patient failure to respond to DBS in the the vegetative state, or coma. Particularly compelling are the
vegetative state or the minimally conscious state may indicate medications amantadine and zolpidem, and the use of elec-

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irreversibility of their condition.214 The challenge of studying trical stimulation, such as DBS. Understanding the mecha-
DBS in these patients includes the issue that some of these nisms of arousal failure and the mechanism of action of
patients would be predicted to regain consciousness and various treatment options will give clinicians the ability to
arousal in the periods during which they were studied, which target patients who could improve from treatment with one
may confound some of the positive results seen. Interestingly, therapy, or even a combination of therapies. Due to the
an improved level of arousal with DBS has also been described diverse pathophysiologic changes resulting in disorders of
up to 6 years after the initial injury.215 Deep brain stimulation consciousness, treatment may require individualized medical
requires more investigation, and further studies into the care, such as medication choice, precise neuroanatomical
mechanisms of disorders of consciousness will guide future location of a deep brain stimulator, and the frequency of
DBS research, including DBS localization and electrical stim- brain stimulation. Tailored treatment of disorders of con-
ulation programming. sciousness could have major societal impact, including im-
Epidural electrical spinal cord stimulation has also been proved utilization of health care resources and decreased
investigated, primarily in patients in the minimally conscious emotional and nancial burden on families of patients with
state. Electrical stimulation is applied intermittently to the disorders of consciousness. Such tailored treatment may be
cervical spine, resulting in muscle twitches of the upper possible through the clinicians improved understanding of
extremities. Spinal cord stimulation activates cerebral glu- arousal structures, their neurotransmitters, connections, and
cose metabolism, which results in an increase in global mechanisms of failure.
cerebral blood ow and perfusion;216 dopamine and norepi-
nephrine increases and decreased levels of oxygen free
radicals also occur.217 The mechanism by which spinal cord
stimulation causes these changes is not known.218 A study of References
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