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Therapeutic options to enhance coma arousal after traumatic brain injury: State
of the art of current treatments to improve coma recovery

Article  in  British Journal of Neurosurgery · October 2013

DOI: 10.3109/02688697.2013.841845 · Source: PubMed

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© 2013 The Neurosurgical Foundation
ISSN: 0268-8697 print / ISSN 1360-046X online
DOI: 10.3109/02688697.2013.841845

REVIEW ARTICLE

Therapeutic options to enhance coma arousal after traumatic

brain injury: State of the art of current treatments to improve
coma recovery
Giulia Cossu

Azienda Ospedaliera Universitaria San Luigi Gonzaga, Orbassano, Turin, Italy

Br J Neurosurg Downloaded from informahealthcare.com by 83.228.195.212 on 10/10/13

However, there is preserved capacity for spontaneous or

Abstract
stimulus-induced arousal, evidenced by sleep–wake cycles.3
Traumatic brain injury is a leading cause of death and disability.
Furthermore, there is a subgroup of patients with severe
Optimizing the recovery from coma is a priority in seeking
alterations in consciousness who do not meet diagnostic
to improve patients’ functional outcomes. Standards of care
criteria for coma or the VS. These patients are characterized
have not been established: pharmacological interventions,
by a partial preservation of conscious self- or environmen-
right median nerve and sensory stimulation, dorsal column
tal awareness, and their condition is classified as minimally
stimulation (DCS), deep brain stimulation, transcranial
conscious state (MSC). Patients may evolve to a MSC from
magnetic stimulation, hyperbaric oxygen therapy and cell
coma or VS after acute brain injury.4
transplantation have all been utilized with contrasting results.
For personal use only.

The importance of an accurate diagnosis is strictly related

The aim of this review is to clarify the indications for the
various techniques and to guide the clinical practice towards
an earlier coma arousal. A systematic bibliographic search
was undertaken using the principal search engines (Pubmed,
Embase, Ovid and Cochrane databases) to locate the most
pertinent studies. Traumatic injury is a highly individualized
process, and subsequent impairments are dependent on
multiple factors: this heterogeneity influences and determines
therapeutic responses to the various interventions.
Keywords: coma arousal; neurorehabilitation; post-traumatic
coma; severe head injury; traumatic brain injury (TBI)
Introduction
Traumatic brain injury (TBI) is a leading cause of death
and disability in young people, whilst more recently an
increased incidence had been reported after traffic or sport-
ing accidents.1
Coma and vegetative state (VS) follow TBI in about one
out of eight patients with an important social and economi-
cal impact.
Patients in coma present a complete unresponsiveness of
the arousal system with no spontaneous eye opening and are
unable to be awakened by application of vigorous sensory
stimulation.2
VS is characterized by the complete absence of
behavioural evidence for self- or environmental awareness.
to prognostic implications.5 About half of people in coma
because of TBI will wake within a year of the accident and
speeding recovery is a priority to improve their functional
outcomes and prognosis.6
Classically the recovery is categorized into two groups: the
normal-to-recover group who wake from coma and recover
the most important functional and cognitive properties
during the first 6 months post-injury and the slow-to-recover
group who remain in coma for a longer period before
eventually improving.7
Standards of care to stimulate coma arousal and to guide
rehabilitative treatment have not been established. Phar-
macological interventions, right median nerve stimulation
(RMNS), sensory stimulation (SS), dorsal column stimula-
tion (DCS), transcranial magnetic stimulation (TMS), deep
brain stimulation (DBS), hyperbaric oxygen (HBO) therapy
and cell transplantation (CT) have all been utilized to better
achieve rehabilitation goals.
Materials and methods
Data search and study selection
A preliminary search on the main search engines (Pubmed,
Embase, Ovid and Cochrane databases) was performed to
identify therapeutic options commonly adopted to stimu-
late coma arousal after a severe TBI, and a systematic bib-
liographic investigation was carried out to find the more

Correspondence: Giulia Cossu, MD, Azienda Ospedaliera Universitaria San Luigi Gonzaga, 10043 Orbassano, Turin, Italy. Tel: ⫹ 393292238990/
⫹ 41798228687. E-mail: giulia.css@gmail.com
Received for publication 19 May 2012; accepted 2 September 2013

1
 2 G. Cossu
pertinent papers. No limits of language or date of publication
(until September 2011) were posed, and any study design
was accepted. The key words were “therapy” combined
with “post traumatic coma”, “coma arousal”, “head injury” or
“brain injury” and the names of each therapeutic interven-
tion. On Pubmed, a search was carried out using Mesh terms
(Coma and Post Head Injury); the related articles function
was used to broaden the search, and articles identified
in review papers or in reference lists but not included in
the original search were also considered. All abstracts and
citations scanned were reviewed.
The studies considered have at least one severe post-
traumatic patient in the sample population and should
evaluate each therapeutic intervention with specific out-
comes. No limits were established for time from injury to
initiation of treatment. Included articles were evaluated for
the following: study design, sample size, type of treatment
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and outcome measures. All articles not specifically regard-
ing therapeutic options to enhance arousal or recovery from
post-traumatic coma were excluded.
The work was set up according to the rules of a classic
review, and interventions were evaluated individually in dif-
ferent sections.
Outcomes and results
For personal use only.
Pharmacological treatments
There is a growing interest towards the field of “rehabilita-
tion pharmacology”,8 and investigations are focussed on
the disruption of the normal functioning of dopaminergic
and glutamatergic systems. During the first hours after
head trauma, dopamine levels are reduced in the cerebral
spinal fluid9 with a possible association with a delayed
arousal and cognitive deficits.10 Drugs acting on the dop-
aminergic system are thought to stimulate the reticular
activating arousal centre to improve wakefulness and
attention by enhancing dopamine release or by blocking
its re-uptake.11
Glutamate, because of its excitatory activity, could theo-
retically promote recovery after TBI, but elevated levels were
measured immediately after head trauma12: toxic effects
could derive from the activation of N-methyl-D-aspartate
Table I. Summary of papers about amantadine.
Study Number of patients Design
Hughes S [15] 123 Retrospective Amantadine 100–200
cohort study
Saniova B [16] 74 Retrospective Amantadine 200 mg
cohort study
Meythaler JM [9] 35 Double-blind Amantadine 200 mg
cross-over design
(randomly
assigned)
Patrick PD [17] 10 Prospective, Amantadine vs
double-blind
randomized trial
RLA, Rancho los Amigos Scale; GCS, Glasgow Coma Scale; MMSE, Mini Mental State Examination; DRS, Disability Rating Scale; GOS, Glasgow Outcome Scale;
GOAT, Galveston Orientation and Amnesia Test; FIM-Cog, Functional Independence Measure; CNCS, Coma Near Coma Scale; WNSSP, Western NeuroSensory
Stimulation Profile.
(NMDA) receptors, and drugs blocking this pathway seem
to protect from neurotoxicity in animal models.13,14
Amantadine
After TBI frontal lobes appear to be particularly vulner-
able and dopamine plays a significant role in this area: an
enhancement in arousal could derive from a treatment with
amantadine, an adamantine derivative with dopaminergic
effects. Pre-synaptically, it facilitates dopamine release
from central neurons and delays its reuptake, whilst
post-synaptically it increases the number of receptors or
changes their conformation in an agonistic manner. This
drug has also the potential to restore the balance between
glutamatergic and dopaminergic neurotransmitter sys-
tems via its antagonism of NMDA receptors, thus reducing
glutamate-induced excitotoxicity.
In literature, three studies refer to the use of amantadine
to enhance coma recovery after head injury in an adult pop-
ulation and one trial was conducted in a children population
(Table I).
In a cohort study, Hughes et al.15 evaluated 123 patients
with severe TBI in coma: 28 cases treated with amantadine
100 or 200 mg BID and 95 controls. Amantadine was pre-
scribed 6 weeks post injury. Clinical improvements tended
to occur within 1 week after initiation but the OR comparing
the odds of coma arousal in the treatment group versus the
control group was 1.42 (with 95% CI: 0.607 and 3.325).
Saniova et al.16 conducted a retrospective study in a cohort
of 74 patients with severe TBI (GCS score ⬍ 8) comparing
changes in Glasgow Coma Scale (GCS) scores and mortal-
ity in 41 patients receiving amantadine 200 mg BID from
the 3rd day post injury versus 33 controls. At baseline, GCS
scores were similar in the two treatment groups but those in
the amantadine group increased significantly (mean GCS
score of 10 in the treated group versus a mean GCS score of
6 observed in the placebo group; p ⬍ 0.0001). The mortality
rates were 6% for the amantadine group and 51% in the con-
trol group (p ⬍ 0.001).
Meythaler JM et al.9 conducted a double-blind, random-
ized, placebo-controlled, crossover clinical trial with 35
subjects with TBI and GCS scores less or equal to 10 within
the first 24 h after admission. They were enrolled to receive
Intervention Results Outcome measures
46.4% patients emerged from Arousal from coma
mg BID versus coma after treatment vs. (RLA)
standard treatment 37.9% controls; p ⫽ 0.42 and
OR ⫽ 1.42
Improvement in GCS scores GCS score and
BID vs standard (p ⬍ 0.0001) and reduced mortality rates
therapy mortality (p ⬍ 0.001) after
amantadine
More rapid improvement MMSE, DRS, GOS,
vs placebo with amantadine but no GOAT,FIM-Cog
differences at 6-month
evaluation.
Significant improvements in RLA, CNCS, WNSSP,
pramipexolo all outcome measures versus DRS
baseline

amantadine 200 mg or placebo for 6 weeks each (12 weeks
total) as soon as possible after injury (between 4 days and
6 weeks) following randomization. Both groups improved
more rapidly (significant improvement in the MMSE, DRS,
GOS and FIM-Cog) when treated with amantadine regard-
less of when a patient started the therapy in the first 3 months
after injury, but at the 6-month re-evaluation, there were no
differences in outcome measures.
The paediatric study conducted by Patrick et al.17 in a
children population was an 8-week, prospective double-
blind, randomized trial which enrolled ten children with
TBI sustained at least 1 month previously and remaining in
a low-response state (Rancho Los Amigos Scale [RLA],ⱕ 3).
Patients received pramipexole or amantadine. RLA levels
improved significantly on medication (p ⬍ 0.05), and scores
improved significantly from baseline on the Coma Near
Coma Scale, Western NeuroSensory Stimulation Profile,
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and Disability Rating Scale (p ⬍ 0.005) with no difference
in efficacy between the two dopamine agonists.
Selection and treatment biases in Hughes’s study15 ren-
dered the groups not comparable, and it failed to establish a
relationship between the effect of amantadine in promoting
recovery of consciousness. In fact amantadine treatment was
initiated in patients remaining at the trauma centre and with
a longer time coma. Important predictors of arousal were:
age ⬍ 40; low GCS score and short-latency somatosensory
For personal use only.
evoked potential (SSEP). Once these variables were con-
trolled for, amantadine did not significantly contribute to
improve the prognosis. In the same way, physician-related
selection bias and the retrospective design are limitations of
Saniova’s study.16 In Meythaler’s trial,9 amantadine seems to
improve the rate of recovery but not the ultimate outcome
and the window of timing for amantadine administration
after TBI is too wide. Furthermore, authors do not analyse
direct effects of amantadine in coma arousal, but consider
the measures of disability recovery exclusively.
Patrick’s clinical trial17 supports the benefit of aman-
tadine or pramipexole in the restoration of functional
arousal, awareness, and communication among chil-
dren with a significant brain injury. The sample size was
small but sufficient to show an improvement in mental
status, and the efficacy appeared to be more prominent in
recent TBI.
Amantadine is a safe and inexpensive therapeutic option
that could be beneficial in the acute setting, but its efficacy
in promoting neurological recovery following severe TBI
remains to be established. The studies found in the literature
reported several limitations, and the results are often not
comparable: drug regimen, timing of administration and
different outcome measures can influence the finding of a
treatment benefit.
Table II. Summary of papers about bromocriptine.
Study Number of patients Design
Passler MA [18] 5 Retrospective review
of clinical cases
VS, Vegetative state; MCS, minimally conscious state; DRS, Disability Rating Scale; FIM, Functional Independence Measure; CRS, Coma Recovery Scale; BRISC, Barry
Rehabilitation Inpatient Screening of Cognition.
Current treatments optimizing coma recovery 3
Bromocriptine
Bromocriptine is an ergot-derived agonist of the dopamine
receptor D2 and in minor manner D1. Reviewing the litera-
ture, two articles refer to the efficacy of bromocriptine in the
period post-TBI but only one was useful in evaluating efficacy
of bromocriptine in promoting coma arousal (Table II).
One retrospective review of five consecutive patients in a
VS following TBI tried to assess the effects of bromocriptine
administration in the acute setting (average of 40 days post-
TBI)18: the combination of a multidisciplinary rehabilitation
programme and bromocriptine administration seemed to
enhance functional recovery. The patients showed improve-
ments in their level of cognitive and physical functioning
(rated by the DRS) within the first 4 weeks of treatment
(starting dose of 1.25 mg of bromocriptine BID with a titra-
tion up to 2.5 mg BID for at least 4 weeks) switching from a
VS into an MSC.
A larger population and a comparison of bromocriptine
effects with other interventions, with a double-blind design
study, could help to discover the real benefit deriving from
this dopamine agonist.
Methylphenidate
Methylphenidate is a neuroprotective drug structurally
related to amphetamines and a weak stimulant of CNS with
pronounced effects on mental activities. It promotes the
release of stored dopamine and norepinephrine from pre-
synaptic vesicles, and blocks the return of catecholamines
into pre-synaptic nerve ending.19 Methylphenidate has
shown some benefits in late psychosocial problems in TBI
patients, and its effect on arousal and consciousness has
been also demonstrated in the subacute phase after trauma.
In the literatures, there were different articles with reference
to methylphenidate administration but only one was related
to the aim of this review (Table III).
A prospective randomized double-blind clinical trial20
included 40 patients with severe TBI (GCS score, between
5 and 8) and 40 patients with moderate TBI (GCS score,
between 9 and 12) who were randomly divided: the treat-
ment group received methylphenidate 0.3 mg/kg BID by
the second day of admission until the time of discharge,
and the control group received a placebo. Methylphenidate
was associated with reductions in ICU and hospital length
of stay by 23% in severe TBI patients (p ⫽ 0.06 for ICU and
p ⫽ 0.029 for hospital stay time). The major limitations of this
trial were the indirect measurements of clinical outcomes
and the marginal statistical significance. Larger, prospective,
double-blind, placebo-controlled trials are needed to clarify
methylphenidate usefulness.
Among the possibilities here presented, a greater reli-
ability may be assigned to amantadine but the efficacy of
Treatment Results Outcome measures
Bromocriptine in combination Switch from a VS into DRS, FIM, CRS, BRISC.
with multidisciplinary a MCS
rehabilitation interventions
 4 G. Cossu

Table III. Summary of papers about methylphenidate.

Studio Number of patients
Moein H [20] 40 patients with severe
TBI ⫹ 40 patients
with moderate TBI
ICU, Intensive care unit.
Design Treatment Results Outcome measures
Perspective randomized Methylphenidate 0.3 Reductions in ICU and ICU and hospital stay
double-blind trial mg/kg BID versus hospital stay by 23%
placebo in severe TBI

neuroprotective drugs in acute head injury remains unclear.
This has encouraged the scientific world to search for new
non-pharmacologic approaches to promote brain functions
recovery.
Median nerve stimulation
Electrical currents (electrical stimulation [ES]) applied
through peripheral nerves may reach central areas.21 The
right median nerve is easily accessible and is chosen as a
gate to activate the brainstem and the cerebrum because of
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from coma an average of 2 days earlier than the control group
(9.5 days vs. 11.5 days, respectively, p ⫽ 0.31). At 3 months
post-injury, no group difference was found in GOS, although
the ES group had improved functions over controls mea-
sured by the Functional Independence Measure/Functional
Assessment Measure (FIM/FAM; mean of 114 in the treated
group versus 64.5 in the control group; not significant).
The review redacted by Cooper EB et al.24 summarizes
the previously shown studies21,23: outcomes evaluated were
the number of days in coma, days spent in ICU and days of

its spinoreticular component that synapses with neurons
of the ascending reticular activating system: its stimula-
tion is today considered among the modalities to facilitate
arousal.22 The RMNS has also been related to a significant
increase in cerebral blood flow and to improvements in
electroencephalogram.21,22 From a literature search emerged
four interesting articles about median nerve stimulation and
coma arousal (Table IV).
Cooper et al.21 presented the early outcomes of 25 patients
For personal use only.
endotracheal intubation. An earlier awakening was observed
in treated patients, and a predictable sequence of events
indicating a positive outcome was identified in involuntary
contractions of the median-innervated muscles of the hand.
RMNS emerged as an easy technique, cost-effective and with
a safety profile: it may facilitate an earlier awakening with a
higher final level of rehabilitation and may be beneficial to
longer-term outcomes following severe TBI.23
In the prospective study conducted by Liu JT et al.,25 six

with closed head injuries treated with RMNS, and the results
of a double-blind perspective cohort pilot project which fol-
lowed a sample of 6 comatose patients whether receiving
RMNS or not . Patients included had a persistent GCS score
inferior or equal to 8, and the treatment was started within 1
week from admission. The treatment group recovered more
quickly, performed better on GCS score, had a shorter ICU
stay (an average of nine days less in the ICU), and showed
better GOS at one month with no evidence of side effects
derived from the ES.
The double-blind randomized controlled trial conducted
by Peri CV et al.23 followed 6 patients treated with RMNS
and 4 controls. The groups were comparable for sociodemo-
graphic features, and GCS and ES started with a mean of 62 h
post-injury. Time out of coma was the first outcome measure
taken (GCS score ⱖ 9) and the ES treatment group emerged
patients in coma with heterogeneous aetiology (2 cases with
TBI) were enrolled for RMNS. Four of six patients recovered
consciousness within 35 days and younger patients (⬍ 40
years old) performed better. However, the different coma
aetiology strongly influenced the time of arousal and the
responsiveness to the treatment.
Statistical power was limited in these small studies: a
multicentre trial would be necessary to collect data to deter-
mine whether RMNS results in a true earlier awakening in
traumatic patients.
SS
SS is the most widely studied rehabilitative treatment
for patients with disorders of consciousness. Patients in
coma should not experience a condition of environmental
deprivation resulting in impairments of intellectual and

Table IV. Summary of papers about RMNS.

Study Number of patients Design Treatment Results Outcome measures
Cooper JB [21] 6 Prospective cohort, RMNS versus standard Treatment group showed GCS score, ICU stay,
double-blind study rehabilitation earlier arousal, better GOS at 1-month
functional and cognitive
outcomes
Peri CV [23] 10 Double-blind RMNS versus standard No significant difference in Number of days
randomized rehabilitation outcomes. Treated group in coma, GOS
controlled trial awake earlier from coma and FIM/FAM at
(p ⫽ 0.31) and improved 3-months
outcome in FIM/FAM but
not in GOS at 3-months.
Cooper EB [24] Review RMNS versus standard Treatment group showed Number of days in
rehabilitation earlier arousal, better coma, ICU stay
functional and cognitive and endotracheal
outcomes intubation
Liu JT [25] 6 Prospective cohort RMNS 4 of 6 patients recovered from CBF, number of days
study coma within 35 days in coma
RMNS, Right median nerve stimulation; ICU, intensive care unit; GCS, Glasgow Coma Scale; GOS, Glasgow Outcome Scale; FIM/FAM, Functional Independence
Measure/Functional Assessment Measure; CBF, cerebral blood flow.
 Current treatments optimizing coma recovery 5

perceptual processes. Different kinds of SS (unimodal SS,
multimodal SS and sensory regulation) are thought to
reduce coma duration or to improve functional outcomes.1
The review of Lombardi FFL et al.6 searched to assess the
effectiveness of SS programmes in patients in coma or VS
considering only RCT or CCT comparing SS programmes
with standard rehabilitation. For the purpose of this review
were considered two of the three articles belonging to
Lombardi’s review and three other studies (Table V).
Johnson’s study26 investigated the efficacy of multisen-
sory stimulation (acoustic, tactile, olfactory, gustatory and
proprioceptive stimulation) in patients with severe TBI. This
randomized controlled trial included 14 male TBI patients
with GCS ⱕ 8. Seven patients were allocated to the active
intervention group with therapeutic sessions of 20 min daily,
and seven patients received the usual care during their ICU
permanence (admission within 24 h post injury). There was
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levels were registered with a permanent effect achieved after
the stimulation programme was applied for more than one
month.
The study conducted by Gruener et al.29 focussed on
16 patients suffering from severe brain injury and in coma
from at least 48 h. GCS scores at baseline were between 3
and 9, and the stimulation therapy was administered daily
in two units of 1 h in a dynamic manner for a mean period
of time of 10 days (range, 1–30 days). Significant changes
were identified in VS parameters (heart and respiratory fre-
quencies) in deep comatose patients (GCS score of 3 or 4),
whilst standardized behavioural assessment turned out to be
particularly useful with medium coma (GCS score of 5 or 6).
In both cases, the most important changes were found after
tactile and acoustic stimulations. Fourteen patients were
re-assessed 2 years later with variable outcomes: their GOS
was variable between 2 and 5.

not a significant difference in outcomes between the two
groups (evaluated daily as: GCS score, state of ventilation,
spontaneous eye movements, oculocephalic (OC) response
and oculovestibular (OV) response).
Mitchell’s study27 was conducted on twelve severely head-
injured patients to whom was administered a programme of
vigorous SS by relatives (60 min), one or two times a day, for
6 days a week for a maximum of four weeks, compared with
a matched control group. The total duration of coma was
For personal use only.
The study carried out by Davis et al.30 examines the effi-
cacy of a structured auditory SS programme (SSP) in nine
male patients with severe TBI, while three patients with simi-
lar characteristics were used as controls. The programme
started 3 days after injury and lasted for 7 days. In the inter-
vention group, a non-significant improvement was noted in
evaluating GCS and RLA scores when compared with base-
line levels; DRS and SSAM were significantly improved at the
discharge period (p ⬍ 0.01).

significantly shorter in the treatment group (22 days versus
27 days; p ⬍ 0.05), and coma lightened more rapidly in the
experimental group.
In the study conducted by Oh and Seo28, there was a
single experimental group (seven patients enrolled within 3
months from the traumatic event, with a GCS score between
3 and 10, following an interrupted time series design).
Subjects enrolled were TBI patients who received twice a
multisensory stimulation programme lasting 4 weeks with a
recession period of 4 weeks. Responsiveness was evaluated
using GCS score: significant improvements in consciousness
From these studies, there seems to be no valid evidence
to determine whether SS benefits traumatic patients. In
Johnson’s study,26 no statistically significant differences
were found in outcome measures between the two treat-
ment groups; in Mitchell’s study,27 arousal could be hasten
by applying multisensory stimulation in the acute phase of
severe TBI, but there are no details about the criteria who
guided in the administration of different patterns of SS and
authors just considered the length of coma as outcome
measure. According to Oh’s study,28 an early application of
a SS programme lasting at least 1 month is crucial to achieve

Table V. Summary of papers about SS.

Study Number of patients Design Treatment Results Outcome measures
Johnson DA [26] 14 Prospective Multisensory stimulation No significant treatment GCS score, state of
randomised versus standard effects ventilation, eye
controlled trial rehabilitation movements, OC/OV
response
Mitchell S [27] 24 Controlled clinical trial Multisensory stimulation Earlier awakening from Duration of coma
versus standard coma in treated group
rehabilitation (p ⬍ 0.05)
Oh H [28] 7 Single experimental Multisensory stimulation Improvement in GCS GCS score
group with an program score after the SS
interrupted time
series design
Gruener ML [29] 16 Prospective cohort Multimodal onset Significant changes in Vegetative parameters
study stimulation therapy vegetative parameters and behavioural
and in behavioural assessment
assessment after the
stimulation
Davis AE [30] 12 Prospective cohort Auditory SS program No significant difference GCS score, RLA, SSAM,
versus standard in GCS scores but DRS
rehabilitation better outcome
measured as SSAM
and DRS in treated
patients
GCS, Glasgow Coma Scale; OC, oculocefalic; OV, oculovestibular response; RLA, Rancho Los Amigos Scale; SSAM, Sensory Stimulation Assessment Measure; DRS,
Disability Rating Scale.
 6 G. Cossu
a permanent improvement of the consciousness level; the
generalization of these data may be limited because of the
lack of a control group and the lack of sensibility of GCS score
in the early recovery phase. In Gruener’s study,29 signifi-
cant changes were identified in the VS parameters or in the
behavioural assessments of patients after tactile or acoustic
stimulation and from Davis’s study30 emerged that an early
and repeated exposure to SSP may promote arousal.
The analysed studies provide contradictory results on the
outcomes of clinical relevance although the lack of observed
side effects makes the SS to be easily considered in early
stages after trauma.
DCS
DCS consists of low electrical currents applied with an
epidural or subdural electrode at C2–C4 level: this proce-
dure might hasten arousal, increase cerebral blood flow,
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improve EEG, raise dopamine and noradrenaline levels,
and lower serotonin in the cerebrospinal fluid (CSF).31
In literature, two interesting articles were analysing the
relationship between the use of DCS and post-traumatic
coma arousal (Table VI).
Kanno and coll.31 first described DCS in patients in
persistent VS (stationary from at least 3 months): according
to a study of 42 cases of post-traumatic and post-stroke veg-
etative patients treated with DCS, authors reported a clinical
For personal use only.
improvement in 42.9% of patients. Most of patients with a
better prognosis were young, and their CT scan did not show
low-density areas in cortex, brainstem or thalamus. The neu-
rostimulation seemed to increase cerebral blood flow and to
enhance catecholamine’s metabolism in CNS; furthermore,
DCS was related to EEG improvements in patients in persis-
tent VS. The interval from the start of DCS therapy to the first
sign of improvement can be very variable (from 6 months to
5 years).32
In the study conducted by Oyama et al.33 (only the abstract
is available in English), DCS was performed in ten patients in
coma with heterogeneous aetiology (two cases of TBI) and
unresponsive to the conventional rehabilitative treatments.
The effectiveness was assessed using a standard scoring
system which consisted of state scale and reaction scale
(PVS scale, developed by the Japanese Society for Treatment
of Coma). The scores improved in four patients with sig-
nificant results in spontaneous movement of the oral cavity
and changes of expression, concern about circumstances,
voluntary purposeful movement, and coherent verbalization
2 weeks after the stimulation.
Very few data were available about the practice of DCS.
These Japanese trials reported improvements in the field
of basic social interaction with better outcomes in younger
Table VI. Summary of papers about DCS.
Study Number of patients Design
Kanno T [31] 42 Prospective cohort study
Oyama H [33] 10 Prospective cohort study
DCS, column stimulation; CBF, cerebral blood flow; CA, catecholamine; CSF, cerebrospinal fluid; EEG, electroencephalogram; PVS scores, State Scale and Reaction
Scale, Japanese Society for Treatment of Coma.
cases (age, ⬍ 40 years), in shorter coma and in cases without
a thalamic damage or cerebral atrophy. The coma aetiology
affects the response to the treatment: traumatic brain-injured
patients improved their outcomes in 75% of the cases, while
cases due to vascular or hypoxic injury rarely responded.31
At the moment, the evidence supporting DCS is too weak
and larger trials are compulsory to consider this as a helpful
treatment option.
Transcranial electrical or electromagnetic stimulation
The transcranial electrical or magnetic stimulation (TMS) is
a method of delivering electrical stimuli to the brain through
the intact scalp. TMS can be delivered in single pulses or in
trains of several pulses: repetitive TMS (rTMS) could induce
changes in brain activity that last more than the stimulation
period and could implicate changes in synaptic plasticity.34
With the variation in stimulation parameters, TMS would be
able to influence various aspects of brain functioning35 and
the site of action could be distant from the site of stimulation36:
it may be important to target cortical areas, such as the pre-
frontal cortex, that could stimulate awareness (Table VII).
The study conducted by Sharova et al.37 enrolled six
patients with chronic post-traumatic unconscious state
(from 1.5 to 5.5 months post injury): after a protocol of fron-
tal transcranial electrical stimulation, five patients showed
an appearance of emotional reactions (changes in facial
expressions, minimal mimicry or vocalization) and fixation
of gaze, and four patients recovered a verbal contact with
major clinical effects observed 10–14 days after stimulation.
A 6-week case report conducted by Pape et al.39 deliv-
ered a rTMS protocol to a 26-year-old man with severe TBI
in VS from 10 months. Stimulation with paired-pulse trains
was directed over the right dorsolateral pre-frontal cortex
during thirty sessions provided 5 days a week for 6 weeks:
action potentials could be relayed from this site to the
brainstem, and it could provide activating impulses to the
cortex. A trend towards significant (p ⬍ 0.066) neurobe-
havioral gains, reported on the Disorders of Consciousness
Scale, was temporally related to rTMS with a progression
from a vegetative status to a MSC. According to these
findings, continued stimulations could induce further
neurobehavioral progression.
rTMS merits further investigation as therapeutic interven-
tion in patients with disorder of consciousness after severe
TBI: at the moment, the potential implications are not known
and the evidence for its usefulness remains too weak.
DBS
DBS is a well-recognized treatment for tremor control
in Parkinson’s disease and has been used to facilitate
Treatment Results Outcome measure
DCS 43% patients showed clinical CBF, CA levels in CSF, EEG,
improvements awakening from coma
DCS 4 patients significantly PVS scores
improved
 Current treatments optimizing coma recovery 7

Table VII. Summary of papers about transcranial electrical or electromagnetic stimulation.

Study Number of patients Design Treatment Results Outcome measures
Sharova EV [37] 6 Prospective cohort study Transcranial electrical 5 of 6 patients Clinical observations (emotional
stimulation improved reactions and fixation of gaze)
Pape TLB [38] 1 Case report rTMS Recovery from VS Clinical observations,
to MCS neurobehavioral assessments
rated on the Disorders of
Consciousness Scale
rTMS, Repetitive transcranial magnetic stimulation; VS, vegetative state; MCS, minimally conscious state.

recovery of consciousness in patients in VS and MSC: elec-
trodes placed in brain stem or diencephalic structures by
stereotactic surgery deliver pulses of electrical activity to
activate the reticular system.1 Thus, an external stimulation
may compensate a chronic underactivation of potential
networks and promote the arousal.
In literature four studies reported clinical experiences
(Table VIII):
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VS showed a longer latency of N20 in SEP or SSEP while the
EEG revealed a desynchronization pattern, findings not
reported in the non-responsive cases.
In Yamamoto’s study,40 21 cases of a persistent VS caused
by various kinds of brain damage (9 cases of traumatic injury)
were evaluated neurologically and electrophysiologically
at 3 months after the traumatic event and were treated by
DBS. The electrodes were placed in the mesencephalic

Tsubokawa et al.39 showed eight cases of persistent VS
(from over 6 months) treated by DBS localized at the mes-
encephalic reticular formation (nucleus cuneiformis in two
cases) and at the non-specific thalamic nucleus (centrum
medianum–parafascicularis complex or CM–pf complex in
six cases) for more than 6 months. Four cases had a severe
traumatic injury, three cases had a cerebrovascular acci-
dent, and one suffered from anoxia. The stimulation was
applied for 30 min every 2 h in the daytime: three patients
For personal use only.
reticular formation (two cases) and in the CM–pf complex
(19 cases) and received DBS mainly between 3 and 6 months
after injury. The follow-up lasted 10 years. Eight patients
became able to obey verbal commands, but they remained
in a bedridden state except for one case that reached a higher
level of autonomy. These successful eight cases revealed a
desynchronization on continuous EEG frequency analysis
and the Vth wave of the BSR and N20 of the SEP were recorded
with a prolonged latency. Responsive cases had a prolonged

became able to communicate adequately and one other
patient recovered very close to this state; also the EEG and
the behavioural arousal responses were improved, with an
increased in CBF and cerebral O2 consumption. Although
the arousal response appeared immediately after commenc-
ing stimulation, for the Authors it would be necessary, at
least, to continue the stimulation for four months, in order
to evaluate the stimulating effect to emerge from persis-
tent VS. Neurophysiologic evaluation with simultaneous
recordings of continuous EEG, auditory brainstem response
(BSR), somatosensory evoked potential (SEP) and SSEP was
performed. The three cases that emerged from a persistent
survival in comparison to the non-responsive patients (mean
of 6 years versus 3 years). Furthermore, Yamamoto reported
his experience in DBS therapy with a direct stimulation of
CM–pf complex applied in five patients in MCS: four patients
recovered most of their functional skills and emerged from
the bedridden state.
In Cohadon’s article,41 25 cases of post-traumatic VS
persisting from three months were submitted to DBS:
electrodes were implanted in the CM–pf complex with
bipolar stimulation provided for 12 h daily for 2 months.
In 13 cases, a definite improvement was obtained with
the recovery of some degree of consciousness and

Table VIII. Summary of papers about deep brain stimulation.

Study Number of patients Design Treatment Results Outcome measures
Tsubokawa T [39] 8 Prospective cohort study DBS 4 of 8 patients recovered Neurological grading of the persistent
from VS to adequate vegetative state (Nikon University),
oral communication EEG, BSR, SEP, SSEP, behavioural
arousal responses, CBF; cerebral O2
consumption
Yamamoto T [40] 21 in VS and Prospective cohort study DBS 8 of 21 patients in VS EEG, BSR, SEP, SSEP, behavioural
5 in MCS became able to obey arousal responses and mean
verbal commands survival time
4 of 5 patients in MCS
emerged from the
bedridden state
Cohadon F [41] 25 Prospective cohort study DBS 13 of 25 patients Behavioural arousal responses
recovered some degree
of consciousness and
social relationship
Schiff ND [42] 1 6-month double-blind DBS Behavioural Cognitively mediating behaviours
alternating crossover improvements related (JFK Coma Recovery Scale
study to the DBS application revised or CRS-R), object naming,
functional limb control and oral
feeding
DBS, Deep brain stimulation; VS, vegetative state; EEG, electroencephalogram; BSR, auditory brainstem response; SEP, somatosensory evoked potentials; SSEP, short-
latency somatosensory evoked potential; CBF, cerebral blood flow; MCS, minimally conscious state.
 8 G. Cossu
interpersonal relationship after 1–3 weeks from the begin-
ning, but all patients remained severely disabled.
Schiff and coll42 reported a case of significant behavioural
improvements (measured through the JKF Coma Recovery
Scale – Revised or CRS-R) during a double-blind alternating
crossover trial conducted in a post-traumatic MCS case last-
ing 6 years. The results were recorded over a 6-month bilat-
eral DBS of the central thalamus, with the electrodes posi-
tioned in the central lateral nucleus, paralaminar regions of
the median dorsalis, and the posterior-medial aspect of the
CM–pf complex.
This study opens the possibility to successfully apply DBS
in particular cases of patients with disorders of conscious-
ness persistent for more than 6 months.
DBS is an intervention of promising efficacy: it could
lead to emergence from a persistent VS or from a MSC, but
the candidate should be adequately selected on the basis of
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neuroradiological and neurophysiological criteria,39 and a
precise previous definition of patient’s disorder of conscious-
ness is important when evaluating the effects of DBS therapy.
This treatment could accelerate recovery and improve the
final level of performance,43 but the generalization of these
small studies is problematic.
Hyperbaric oxygen administration
Hyperbaric oxygen (HBO) administration consists in
For personal use only.
administration of pure oxygen at a pressure greater than that
of the atmosphere: this process could accelerate neurologic
recovery after spinal cord injury by reversing hypoxia and
reducing oedema. In the literature, there is no agreement
towards the efficacy of HBO in improving the outcome of
brain injury,43,44 but experimental studies investigating the
effects of HBO in damaged brains stated that the treatment
inhibits neuronal death and improves aerobic metabo-
lism in brain injury, accelerating the resolution of clinical
symptoms.45
One of the largest positive study was the trial conducted
by Shi XY et al.45 which enrolled a cohort of 320 patients with
brain injury randomized to HBO therapy or medications. The
outcomes were evaluated clinically and with a SPECT before
and after the treatments: HBO therapy was related to a sig-
nificant improvement in symptoms, control of epilepsy, and
resolution of hydrocephalus (p ⬍ 0.01).
On the contrary, a review on the argument showed no
effect or harm from hyperbaric oxygen when used to treat
traumatic brain injuries or strokes.43 HBO remains an inter-
vention of unproven efficacy and further investigations
will be necessary to define its potential role in severe head
trauma.
Table IX. Summary of papers about CT.
Study Number of patients Design
Seledtsov VI [46] 38 cases and 38 Controlled,
controls retrospective cohort
trial
Seledtsov VI [47] 25 Cases and 25 Controlled,
matched controls retrospective cohort
trial
CT, Cell transplantation; GOS, Glasgow Outcome Scale; MRI, magnetic resonance imaging.
CT
Cells belonging to nervous and haematopoietic foetal
tissues might promote recovery of consciousness in severely
head-injured patients through the release of neural media-
tors or the direct substitution of damaged tissues.46 They are
isolated from human foetuses (gestational age, 16–22 weeks)
after spontaneous or therapeutic abortion, are prepared as
cell suspension, and are grafted subarachnoidally via lumbar
puncture. In the literature two articles fit the search criteria
(Table IX).
Seledtsov VI et al.46 summarizes the results of a con-
trolled, retrospective clinical investigation of 38 severely
head-injured patients with a GCS score of ⬍ 8. CT was
undertaken 5–8 weeks after the injury, and the control
group was composed by 38 matched patients. In 33 treated
patients, the signs of awakening (opening eyes and perfor-
mance of simple tasks) occurred at 3–7 days post-grafting
with a restoration of main psychical functions at 15–20 days.
Other three cell-grafted patients showed awakening; they
were cell-grafted once again with a further improvement.
The mortality rate in the trial and control group was 5%
(two cases) and 45% (17 cases), respectively, and a favour-
able GOS was noted in 33 (87%) cell-grafted and only in 15
(39%) control patients at 18–24 months post-injury. Statisti-
cal analysis revealed that CT treatment generally improved
the outcomes by 2.5-fold without serious complications
from the procedure.
Another retrospective clinical study47 conducted to
evaluate the efficiency of cell therapy in severely brain-
injured patients, enrolled 25 cases (8 women and 17 men)
with a GCS score between 3 and 5 points and in coma from
5 to 8 weeks and a matched control group. The mortality in
the treatment group was 8% versus 56% in the control group,
and satisfactory results of transplantation were recorded in
80% cases: treated patients awoke on days 3–5 after CT with
a recovery of the main mental functions 15–20 days after
transplantation. After 1–1.5 years, atrophic changes (MRI)
virtually regressed in patients with good or satisfactory
results.
According to the studies here reported, CT may promote
wakening consciousness and neurological rehabilitation
during the acute period in severe brain injury but further
research are needed to assess its real efficacy.
Discussion
The therapeutic options illustrated in this review are
several and promising: they should be actually applied only
in experimental contexts and the results should be accu-
Treatment Results Outcome measures
CT versus Earlier arousal from coma in Mortality, number of
rehabilitation the treated group, better days in coma, GOS
therapy GOS
CT versus Earlier arousal from coma in Mortality, number
rehabilitation the treated group, better of days in coma,
therapy functional outcomes GOS, MRI at 1 year
 Current treatments optimizing coma recovery 9

rately monitored in clinical trials. A schematization of their
possible applications is showed in Fig. 1.
In rehabilitation setting, the first important step is the
correct assessment of patients’ clinical status, incorporating
neuroradiological data with neurophysiologic and behav-
ioural analyses.
Dopamine agents and neuroprotective drugs could have
a role in promoting arousal in an acute setting: by stimu-
lating dopamine pathways and by restoring glutamate bal-
ance, they could enhance an earlier recovery and a more
rapid improvement in patients in persistent low-response
conditions and in the paediatric population, with minimal
side effects.
In the studies concerned, the pharmacologic approaches
have been introduced in patients in coma within 6 weeks
from the traumatic event, and it seems reasonable that
if no measured improvement within the first 4 weeks
(for Methylphenidate and Bromocriptine) or 6 weeks
(Amantadine) of treatment is observed, alternative inter-
ventions should be considered.
Among the non-pharmacologic treatments, the median
nerve stimulation and the SS are between the most famous

Within 4–6 weeks 3–6 months from Beyond 6 months

from TBI TBI from TBI
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Pharmacoological agents: DBS

DBS
- More evidence for amantadine use - Patients not responding to
- It could be considered as
pharamcological treatments,
- To start within the first weeks from RMNS or SS therapeutic option after
traumatic event 6 months in MCS
- Previous distinction between
- To continue maximum for 4–6 weeks VS and MCS: MCS is more
patients with a significant
preservation of frontal
- Possible to combine with RMNS and SS likely to show improvements
networks or in well-
- Patients selection with EEG,
selected VS cases
For personal use only.

BSR, SEP, SSEP and

neuroradiological studies3
RMNS - Correct localization of
electrodes in central thalamus
- Within weeks from ICU admission
- Pts selection1
- Posssible to combine with pharmacological
treatment and SS
- Positive prognostic factor: involuntary
contractions of median inervated muscles
of the hand

Alternative treatments:
SS - DCS: unclear efficacy, patients not responsive to
- Within weeks from traumatic event other treatments, previous neuroraradiological
- Pts selection2 patients' selection4 necessary
- Possibility to combine SS with the previous - rTMS or transcranial electrical stimulation: very
options weak evidence, clinical implication not clear,
probably of prognostic importance

Alternative treatments:
- HBO: unclear efficay
- CT: promising, tested within 5–8 weeks from injury,
ethical problems

Fig. 1. Clinical application of the different therapeutic options to enhance coma arousal. Step I: Correct assessment of patients’ clinical status,
incorporating neuroradiological data with neurophysiologic and behavioural analyses. Step II: Start the treatment. Traumatic brain injury
(TBI); right median nerve stimulation (RMNS); sensory stimulation (SS); intensive care unit (ICU); hyperbaric oxygen (HBO) therapy; cell
transplantation (CT); deep brain stimulation (DBS); vegetative state (VS); minimally conscious state (MCS); dorsal column stimulation (DCS);
and repetitive transcranial magnetic stimulation (rTMS).1Patients’ selection for RMNS: patients with severe cardiac arrhythmias, implanted
defibrillators, pacemakers, uncontrolled seizures, cervical spinal cord or brachial plexus injury, large intracranial hematomas, gunshot wound
to the head, right median nerve injury, or positive pregnancy may not get benefit of this technique16. 2Patients’ selection for SS: only patients
clinically stable, with a normal intracranial pressure, without a mechanical ventilation and without sedation could get benefit of this technique29.
3Responsive cases presented a desynchronization on continuous EEG frequency analysis and the Vth wave of the BSR and N of the SEP were
20
recorded with a prolonged latency39,40. 4Better prognosis in young patients and with a computer tomography (CT) without low-density areas in
cortex, brainstem or thalamus . 31
 10 G. Cossu
rehabilitative options to restore cerebral functions in uncon-
scious patients.
RMNS is an easy technique, with a safety profile and cost–
effective, and it seems to be followed by an earlier arousal
and better cognitive outcomes. Also, this technique finds
an application in the acute care setting and it could be
conceived as an alternative or in association with the
pharmacological treatment or other SS. The important
point is the patient’s selection: patients with severe cardiac
arrhythmias, implanted defibrillators, pacemakers, uncon-
trolled seizures, cervical spinal cord or brachial plexus injury,
large intracranial haematomas, gunshot wound to the head,
right median nerve injury, or positive pregnancy may not get
benefit of this technique.21
The SS aims to avoid a condition of environmental depri-
vation: more consistent results are observed with an early
application (the maximal delay reported in the literature is
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after 3 months from head injury) and apparently with pro-
longed stimulation. Also in this case the accurate selection
of the patients is crucial.29 One proposal in a clinical setting
could be the association of SS with other techniques, consid-
ered the lack of side effects.
In treated patients, a positive trend towards recovery of
consciousness was observed and the treatment could be
considered a helpful tool if a definite therapeutic protocol
would be established.
For personal use only.
Very few data are available about the DCS and the results
are still inconsistent. This minimally invasive neurosurgi-
cal technique has been first described in Japanese patients
in vegetative status (stationary for at least 3 months)31: the
neurostimulation seems to improve vegetative and biologi-
cal parameters, but its clinical application in post-traumatic
coma patients is not defined. A pre-procedural neuroradio-
logical imaging excluding a diencephalic damage or a cere-
bral atrophy is mandatory. More precise indications over
patient selection are necessary to promote the use of this
technique.
Transcranial electrical or magnetic stimulation is based
on the hypothesis that an external non-invasive conditioning
can influence synaptic plasticity and probably consciousness
recovery. The potential implications of this technique are not
fully understood but the lack of response to rTMS could be
considered as a negative prognostic factor for recovering
from coma. We have at the moment very few information at
disposition, and the identification of target zones remains a
major problem.
In patients not responding to pharmacologic treat-
ments, RMNS or SS, more aggressive techniques should be
attempted, above all in younger patients (⬍ 40 years) and
in patients with an altered state of consciousness persis-
tent from 3 months. The probability of spontaneous arousal
decreases quickly from this period of time, and at 6 months
a post-traumatic VS is considered persistent (PVS). The
most promising technique in these situations is the DBS.
The neurostimulation field is an area of growing
investigations, and DBS can be effective in helping patients
to emerge from reduced consciousness conditions. A pre-
cise differentiation between the VS and a MSC is a funda-
mental step: patients most likely to show improvements are
those with relatively preserved areas of essential cortical
networks (above all within the anterior forebrain) and a pri-
mary damage in arousal centres (more typical for MCS than
for VS).42 Patients in VS present often a thalamic neuronal
death, while in MCS patients a predominant loss of synaptic
connections has been recorded. Furthermore, an accurate
pre-treatment selection of candidates through neurological
and electrophysiological studies (BSR; SEP; SSEP; continu-
ous EEG) and neuroradiological investigation (functional
MRI, PET) should be performed: responsive cases according
to Tsubokawa39 and Yamamoto40 presented a desynchroni-
zation on continuous EEG frequency analysis, and the Vth
wave of the BSR and N20 of the SEP were recorded with a
prolonged latency.
An important point is the correct localization of elec-
trodes in central thalamus: neurons belonging to this area
are selectively vulnerable to dysfunction following severe
brain injury, and they play a role in forebrain arousal path-
ways (mesocircuit model).48 Recently, a particular attention
is directed to the central lateral intralaminar nucleus and
adjacent paralaminar components of the central thalamus
(rich in calbindin staining neurons that strongly project to
the supragranular cortical regions).42
Clinical application of DBS therapy for patients in MCS
is strongly promising to achieve improvement in functional
executive skills and to emerge from the bedridden state,40,42
while for patients in VS the results interpretation is the object
of debate. The absence of response to DBS could be consid-
ered as a negative prognostic factor to predict the irrevers-
ibility of a post-traumatic VS.
Most of patients recruited in the trials here analysed
received DBS therapy within 3–6 months after injury,39,40,41
but positive responses might be observed also after this
period, above all in MCS cases with a consistent preservation
of cerebral integrative networks.42
It would be of extremely importance to carry out a blinded
study in an homogenous cohort to determine the real impact
of DBS on behavioural assessments in severely brain-injured
patients.
Two alternative approaches poorly described in lit-
erature are the hyperbaric oxygen administration and CT
technique. The efficacy of hyperbaric oxygen administration
remains unproved, while patients treated with CT seemed to
show an improvement in arousal and rehabilitation results.
This last technique merits further researches to assess its
efficacy.
Conclusions
TBI is an highly individualized process and the subsequent
impairments are dependent on multiple factors as neu-
rotransmitter disturbance, lesion site, comorbidity and injury
severity. This heterogeneity obviously influences therapeutic
responses to any given intervention.
The most promising treatments in the acute phase are
the amantadine administration, together with the median
nerve electrical stimulation and the SS, whilst in disorders
of consciousness persistent from three months or longer, the
most affordable technique seems to be the DBS.

The selected articles had limitations due to the limited
number of cases analysed in each study, the diversity in
coma length and coma severity, the heterogeneity of out-
come measures and the different timing of intervention and
of follow-up.
A need remains for well-designed, multicentred and
sufficiently powered trials enrolling specific subtypes
of brain trauma to help the clinicians in the everyday
clinical practice and to offer the patient the best treatment
protocol.
Acknowledgements
I would like to thank Mr. Nigel D. Mendoza for his avail-
ability, for his advices during the revision of the manuscript
and for the moral support he has always shown. I thank also
Dr. Paolo Fornaciari for his trust and his contribution.
Br J Neurosurg Downloaded from informahealthcare.com by 83.228.195.212 on 10/10/13
Declaration of interest: The author reports no compet-
ing financial interests. The author reports no declarations of
interest. The author alone is responsible for the content and
writing of the paper.
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