Presentation during IFNR 2016.
Brief description with available evidence on various coma arousal therapy with an illustrative study for each therapy and recommendation for future.
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Coma Arousal Therapy
1.
2. Coma Arousal Therapy for
Traumatic Brain Injury
Dhaval Shukla
Addl. Professor of Neurosurgery
NIMHANS, Bangalore.
Dhaval Shukla, IFNR2016 Conflicts of Interest: None
3. Outcome after TBI
Dhaval Shukla, IFNR2016 Gosseries O, et al. States of Consciousness 2011;29-55.
4. Coma
• Unresponsive
• Eyes closed
• No sign of wakefulness
• 1/3rd die within one
month
• Resolves within 2–4 weeks
in survivors
Dhaval Shukla, IFNR2016 Shukla D, et al. Clin Neuropathol. 2007;26:197-209.
5. Vegetative State (VS)
• Unresponsive Wakefulness
Syndrome [UWS]
• No cognitive awareness
• Transition marked by
beginning of spontaneous
eye opening
• Sleep–wake cycles
• No evidence of purposeful
behavioral responses to
visual, auditory, tactile, or
noxious stimuli
• No language
comprehension or
expression
Dhaval Shukla, IFNR2016 Povlishock JT, et al. J Head Trauma Rehabil. 2005;20:76–94.
6. Minimally Conscious State (MCS)
• Simple command following
• Intelligible verbalization
• Recognizable verbal or gestural
‘‘yes/no’’ responses
• Responses triggered by
relevant environmental stimuli
• Touching or holding objects by
accommodating to size and
shape
Dhaval Shukla, IFNR2016
7. Confusional state
• Interactive communication
• Appropriate object use
begin
• Amnesic (PTA)
• Severe basic attentional
deficits
• Hypokinetic or agitated
• Labile behavior
Dhaval Shukla, IFNR2016 Povlishock JT, et al. J Head Trauma Rehabil. 2005;20:76–94.
8. Post-confusional State
• Resolution of PTA
• Cognitive impairments in
higher level attention,
memory retrieval, and
executive functioning
• Deficits in self-awareness,
social awareness,
behavioral, and emotional
regulation
• Achieving functional
independence in daily self
care
Dhaval Shukla, IFNR2016 Povlishock JT, et al. J Head Trauma Rehabil. 2005;20:76–94.
9. Social competence
• Recovering higher level
cognitive abilities
• Self-awareness, and social
skills
• Developing effective
adaptation and
compensation for residual
problems
• Resumption of basic
household independence
• Ability to be left home
unsupervised
Dhaval Shukla, IFNR2016 Povlishock JT, et al. J Head Trauma Rehabil. 2005;20:76–94.
10. Assessment of Disorder of
Consciousness (DOC)
1. Brainstem integrity and other subcortical
evaluation
2. Cortical functioning
a. Observation of spontaneous activity
b. Responses to stimulation or environment
Giacio JT, et al. Brain Injury Medicine 2013;518-535.Dhaval Shukla, IFNR2016
17. Placebo-Controlled Trial of Amantadine
for Severe Traumatic Brain Injury
• Pre-synaptic stage
• inhibits the re-uptake of dopamine
• Postsynaptically
• densifies dopamine receptors and modifies their conformation
• 184 patients in VS/ MCS
• 4 - 16 weeks after TBI
• Amantadine or placebo for 4 weeks
• 100 – 400 mg twice daily
• Followed for 2 weeks after discontinuation of treatment
Giacino JT, et al. N Engl J Med 2012;366:819-26.Dhaval Shukla, IFNR2016
18. Placebo-Controlled Trial of Amantadine
for Severe Traumatic Brain Injury
Giacino JT, et al. N Engl J Med 2012;366:819-26.Dhaval Shukla, IFNR2016
19. Placebo-Controlled Trial of Amantadine
for Severe Traumatic Brain Injury
Giacino JT, et al. N Engl J Med 2012;366:819-26.Dhaval Shukla, IFNR2016
20. Placebo-Controlled Trial of Amantadine
for Severe Traumatic Brain Injury
Giacino JT, et al. N Engl J Med 2012;366:819-26.Dhaval Shukla, IFNR2016
21. Placebo-Controlled Trial of Amantadine
for Severe Traumatic Brain Injury
• Amantadine is effective in accelerating the pace of
recovery during acute rehabilitation in patients
with DOC.
• Exposure to amantadine is associated with more
rapid emergence of cognitively mediated behaviors
that serve as the foundation for functional
independence.
• Whether amantadine improves the long-term
outcome or simply accelerates recovery en route to
an equivalent level of function remains unknown.
Giacino JT, et al. N Engl J Med 2012;366:819-26.Dhaval Shukla, IFNR2016
22. Zolpidem
• Omega-1 subunit of the GABA alpha receptors situated
in globus pallidus interna (GPi)
• Replace the normal disinhibitory process between the
anterior forebrain medium spiny neurons (MSN) and
Gpi causing increased activation of areas that were
previously hypoactive
• Release of tonic inhibition of the central thalamus in
the setting of a significant reduction in background
excitatory neurotransmission within the mesocircuit
• MSN are uniquely vulnerable to cellular dysfunction
after hypoxia
• Reported successes with zolpidem have been after hypoxic-
ischemic injuries
Tucker C, et al. Neurocrit Care 2016;Dhaval Shukla, IFNR2016
23. Zolpidem
• Increased arousal within 1 h of zolpidem 5 -20 mg
• Effect lasts 3–4 h
• Followed by somnolence
• Zolpidem is not effective in all patients with
impaired consciousness
• More effective in hypoxia induced coma and in MCS
• 33.7 % probable, 4.8% definite responders
• Increased movement and interaction communication
• Use should be considered on a case-by-case basis
Whyte J, et al. Am J Phys Med Rehabil. 2014;93:101-113.Dhaval Shukla, IFNR2016
25. ss
• SS is the most widely studied rehabilitative
treatment
• Unimodal/ multimodal
• Environmental deprivation
• Impairments of intellectual and perceptual processes
• Arousal could be hasten by applying multisensory
stimulation in the acute phase of severe TBI
• Reduce coma duration or to improve functional
outcomes
Lombardi FFL, Cochrane Database Syst. Rev. 2012; CD001427.Dhaval Shukla, IFNR2016
27. ss
• Contradictory results on the outcomes of clinical
relevance
• 50% of patients have a spontaneous arousal after
the acute event
• Difficulty of delivering SS in ICU
• There is no reliable evidence to support, or rule
out, the effectiveness of SS in patients in coma
• SS is a low invasive, not-dangerous, inexpensive,
and simple to apply methodology, and for these
reasons, it remains a potentially attractive
rehabilitative method
Lombardi FFL, Cochrane Database Syst. Rev. 2012; CD001427.Dhaval Shukla, IFNR2016
28. Limitations
• Preserved islands of high-order
cognitive processing not engaged
• Habituation
• Attentional sources not captured
• Possible covert answers not
advocated
Newer Approaches
• Complex stimulation including
structured and meaningful stimuli
• No repetitive and frequent stimulation
• Appropriate intensity stimulation,
occasionally interspersed with high
intensity stimulation
• Integrated and simultaneous
multisensory stimulation
• Emotional stimulation
• Autobiographical stimulation
• Requests for exhibiting behavioural
responses or performing actions
• Naturalistic and dynamic actions in
real or virtualcontext
ss
Lombardi FFL, Cochrane Database Syst. Rev. 2012; CD001427.Dhaval Shukla, IFNR2016
30. Median Nerve Stimulation [MNS]
• Large cortical representation
• Spinorecticular component of median nerve
pathway
• Activates projections between thalamus and cortex
• Possibly silent or injured synapses are transformed
into functional ones by neruotrophic factors
• Increased cerebral blood flow and enhancement of
neurotransmitter metabolism
• Neuroendocrine system
Lei J, et al. J Neurotrauma 2015;32:1584–89.Dhaval Shukla, IFNR2016
31. MNS - study
• 437 comatose
• 2 weeks after injury
• Electrical neuromuscular stimulator
• Trains of asymmetric biphasic pluses at an amplitude of
10–20 mamps
• Pulse width of 300microsecs at 40Hz for 20sec/min
• 8 h per day for 2 weeks
• No unique complications associated with MNS
Lei J, et al. J Neurotrauma 2015;32:1584–89.Dhaval Shukla, IFNR2016
32. MNS - study
Lei J, et al. J Neurotrauma 2015;32:1584–89.Dhaval Shukla, IFNR2016
33. MNS - study
Lei J, et al. J Neurotrauma 2015;32:1584–89.Dhaval Shukla, IFNR2016
35. Dorsal Column Stimulation [SCS]
• Low electrical currents applied with dorsal epidural or
subdural electrode at C2 – C4 level
• Might hasten arousal
• Increase cerebral blood flow
• Improve EEG
• Raise dopamine and noradrenaline levels
• Lower serotonin in CSF
• 214 cases, VS (stationary for atleast 3 months)
• Clinical improvement in 54% (TBI cases 75%)
• Interval from SCS to improvement - 6 months to 5 years
• Predictors of improvement
• Young age
• Shorter coma duration
• Absence of low-density areas in brainstem or thalamus
• Absence of cerebral atrophy
• CBF > 20 mL/100 g/min
Kanno T, et al. Neuromodulation. 2009;12:33-8.Dhaval Shukla, IFNR2016
37. Transcranial electrical or magnetic
stimulation
• Repetitive delivery of electrical stimuli to the brain
through the intact scalp
• Changes in brain activity that last more than the
stimulation period
• Changes in synaptic plasticity
• Influence various aspects of brain functioning
• Site of action could be distant from the site of
stimulation
• Target area – prefrontal cortex, that could stimulate
awareness
• Side effects: sensation of tingling (76%), itching
(68%), slight burning (54%), or mild pain (25%)
Cossu G. BJNS 2014;28:187-98.Dhaval Shukla, IFNR2016
38. Transcranial Direct Current Stimulation
[tDCS]
• Double-blind sham-controlled crossover design
• Atleast 1 week after brain injury in VS or MCS
• Left DLPF cortex (F3) for 20 minutes
• Assessment with CRS-R and GOSE
• Responders were defined as those patients who
presented a sign of consciousness
• command following
• visual pursuit
• recognition, manipulation, localization, or functional use
of objects
• orientation to pain
• intentional or functional communication
Thibaut A, et al. Neurology 2014;82:1112–18.Dhaval Shukla, IFNR2016
39. tDCS
• Patients in MCS showed
significant treatment effect
(p = 0.003) as measured by
CRS-R total scores
• Responders
• 43% patients in MCS
• 8% patients in VS/UWS
• Outcome did not differ
between tDCS responders
and nonresponders
Thibaut A, et al. Neurology 2014;82:1112–18.Dhaval Shukla, IFNR2016
41. Deep Brain Stimulation [DBS]
• Compensate a chronic underactivation of potential
networks and promote the arousal
• Review of Prospective cohort studies
• Total 60 patients
• 50% responders
• EEG, BSR, SEP, SSEP, CBF, CMRO2
• Behavioural arousal responses
Cossu G. BJNS 2014;28:187-98.Dhaval Shukla, IFNR2016
42. VS-TBI VS-NTBI MCS-TBI MCS-NTBI
% our cases
progressing
86% (N=14) 78% (N=18) 100% (N=7) 100% (N=2)
% of cases
progressing in
literature
52%*
(N=434) 15%*
(N=169) 50%*
(N=30) 0%*
(N=10)
Chi-Square Results
2 (1) = 6.16, p =
.01.
2 (1) = 39.09, p <
.001
2 (1) = 5.89, p =
.02
2 (1) = 12.00, p =
.001.
ACP vs. Standard Care
DeFina PA, et al. Restor Neurol Neurosci. 2010;28:769-80.
Advanced/ Multimodal Care Protocol
Dhaval Shukla, IFNR2016
43. Ongoing Studies
• A Phase 1/2,Open-Label Study to Evaluate the Safety and
Efficacy of the International Brain Research Foundation
(IBRF) Disorders of Consciousness Advanced
Care/MultiModal Care Protocol in Patients With Severe
Disorders of Consciousness
• Intervention
• Polypharmacy
• MNS
• Nutraceutical
• Coma, vegetative state, or minimally conscious state
• Outcome
• Tolerance to treatment
• Number and Frequency of side effects/ Adverse events
• CRS-R/ DRS/ FIM/ GCS/ GOS-E/ O-LOG/
https://clinicaltrials.gov/ct2/show/NCT02696512Dhaval Shukla, IFNR2016
44. Recommendations
• 4-6 weeks after TBI
• Pharmacological agents
• MNS
• SS
• Months after TBI
• DCS
• DBS
Dhaval Shukla, IFNR2016 Cossu G. BJNS 2014;28:187-98.
45. Recommendations for Future Studies
(a) clarifying the natural history of recovery from UWS
and MCS
(b) identifying predictors of recovery of consciousness
and function
(c) elucidating the pathophysiology underlying specific
DOC
(d) developing treatments capable of altering outcome in
patients with doc
Dhaval Shukla, IFNR2016 Giacio JT, et al. Brain Injury Medicine 2013;518-535.
46. Recommendations for Future Studies
• Recruitment
• Atleast 2 weeks after injury
• Matching controls
• Admission characteristics
• Clinical
• Age
• GCS
• Motor Score
• Pupillary reaction
• Hypoxia
• Hypotension
• Imaging
• CT scan Classification of TBI
• Traumatic SAH
• Blood investigation
• Glucose
• Hb
• At time of starting coma arousal therapy
• Clinical diagnosis as per defined criteria (VS, MCS)
• Coma Recovery Scale-Revised
• Disability Rating Scale
Dhaval Shukla, IFNR2016
47. Recommendations for Future Studies -
Outcome Assessment
• Beyond 12 months postinjury
• Clinical and Functional
• Coma Recovery Scale-Revised
• Disability Rating Scale
• GOSE
• Neuroimaging
• Structural studies – DTI, Cortical Volumetry
• Cerebral blood flow and metabolism studies
• fMRI - Resting state and Mental imagery tasks
• Electrophysiological
• Quantitative EEG (qEEG)
• Evoked Potentials (EPs)
• Event Related Potentials (ERP)
Dhaval Shukla, IFNR2016
Notas del editor
Coma is a state of pathologic unconsciousness in which the
eyes remain closed and the patient cannot be aroused (16).
It is most often the result of severe, diffuse bihemispheric
lesions of the cortex or underlying white matter; bilateral
thalamic damage; or paramedian tegmental lesions. The clinical
criteria for diagnosing coma were described by Plum and
Posner in 1982 (16) and remain well accepted. The defining
feature of coma is the complete loss of spontaneous or stimulus-
induced arousal. The eyes remain continuously closed
despite the application of noxious stimuli and there are no
sleep/wake cycles on electroencephalography (EEG). On examination, there is no evidence of purposeful motor activity,
no response to command, and no indication of receptive or
expressive language ability. Coma is a self-limiting state that
typically resolves within 2–4 weeks in those who survive
the initial injury.
Minimally conscious state (MCS): inconsistent, simple
purposeful behavior, inconsistent response to commands
begin; transition can be documented using Coma Recovery
Scale-Revised (CRS-R) subscale criteria for MCS (47); often
mute (Rancho Level III) (acute hospital;
Evidence of limited but clearly discernible self
or environmental awareness on a reproducible
or sustained basis, as demonstrated by one or
more of the following behaviors:
1. Simple command following
2. Gestural or verbal ‘‘yes/no’’ responses
(independent of accuracy)
3. Intelligible verbalization
4. Purposeful behavior including movements or
affective behaviors in contingent relation to
relevant stimuli. Examples include:
a. Appropriate smiling or crying to relevant
visual or linguistic stimuli
b. Response to linguistic content of questions
by vocalization or gesture
c. Reaching for objects in appropriate direction
and location
d. Touching or holding objects by
accommodating to size and shape
e. Sustained visual fixation or tracking as
response to moving stimuli
resumption of basic household independence and ability to
be left home unsupervised for the better part of a day;
developing independence in community, household
management skills, and later returning to academic or
vocational pursuits; recovering higher level cognitive abilities
(divided attention, cognitive speed, executive functioning),
self-awareness, and social skills; developing effective
adaptation and compensation for residual problems (Rancho
Level VII and VIII) (outpatient community reentry programs,
community-based services—vocational, special education,
supported living services, mental health services)
1. Brainstem integrity and other subcortical evaluation
• Pupillary response, blink reflex to visual threat
• Ocular movements, gaze deviations
• Oculovestibular reflexes (oculocephalic [‘‘doll’s eyes’’] maneuvers,
calorics)
• Corneal response
• Gag reflex
• Breathing pattern
• Decerebrate postures
• Other posturing, reflexes, and tone
2. Cortical functioning
a. Observation of spontaneous activity
• Purposeful, complex movements (involving cortically mediated
isolated motor control) vs posturing (decorticate or
decerebrate) or reflex or stereotyped, patterned (subcortically
mediated) movements
• Spontaneous vocalizations or verbalizations
• Eye movements (signs of fixation or tracking vs nonspecific
roving or no movement)
b. Responses to stimulation or environment
• Tracking or fixation to stimuli (try salient stimuli such as
familiar pictures, faces, mirror)
• Verbal stimulation (e.g., patient’s name, commands, social
greetings):
Begin with simple commands sampling a variety of areas
under different neural control, favoring those areas of potentially
preserved movement.
Eye commands—e.g., ‘‘look up,’’ ‘‘blink twice’’
Limb commands—e.g., ‘‘make a fist,’’ ‘‘show two fingers,’’
‘‘raise your arm’’
Oral commands—e.g., ‘‘open mouth,’’ ‘‘stick out
tongue’’
Axial or whole body commands—e.g., ‘‘turn your
head,’’ ‘‘lean forward’’
Ask patient to ‘‘stop moving’’ or ‘‘hold still’’ to distinguish
from spontaneous repetitive movements.
• Noxious stimulation
Look for localization or purposeful defensive maneuvers
vs reflexive or generalized, stereotyped movements or
facial expressions.
• Response in contingent relationship to environment or
other stimuli
Look for intentional reach for or manipulation of objects
on or around the patient (e.g., pulling at tubes, clothing,
items placed in the hand)
Look for changes in facial expression contingent on
stimuli such as familiar voices, particular conversation,
pictures, music, etc.
Look for attempts at purposeful mobility in bed, chair,
and even ambulation
Gestural behaviors indicating intentive communication
(e.g., yes/no signals)
• Confounding factors affecting arousal (e.g., centrally acting
medications, concurrent illness, subclinical seizures, undetected
pain)
• The potential influence of aphasia, apraxia, and other
higher cortical disorders that may affect the ability to respond
to commands
Mesocircuit model placing central thalamic deep brain stimulation (CT-DBS) in the context of mechanisms underlying
spontaneous and medication-induced recovery of consciousness. A “mesocircuit” model organizing mechanisms underlying
recovery of consciousness after severe brain injury. Diffuse disfacilitation across frontal, cortical, and striatal neurons broad arises
from severe structural brain injury. In particular, reduction of thalamocortical and thalamostriatal outflow following deafferentation
and loss of neurons in central thalamus withdraws important afferent drive to the medium spiny neurons (MSNs) of striatum,
which may then fail to reach firing threshold because of their requirement for high levels of synaptic background activity (Grillner
et al., 2005). Loss of active inhibition from the striatum allows neurons of the globus pallidus internus (GPi) to fire tonically and
provide active inhibition to their synaptic targets, including relay neurons of the already strongly disfacilitated central thalamus and
possibly also the projection neurons of the pedunculopontine nucleus (PPN) (Williams et al., 2009). Amantadine, L-dopa, and
zolpidem may reverse these conditions of marked downregulation of anterior forebrain activity across frontal cortices, striatum,
and central thalamus, acting at different locations with the mesocircuit. Collectively, restoration of thalamocortical and
thalamostriatal outflow will depolarize neocortical neurons and facilitate long-range corticocortical, corticothalamic, and corticostriatal
outflow. CT-DBS can be considered as a final common pathway aggregating these effects and partially remediating the
effects of strong deafferentation of these neurons in all severe brain injuries. (Reproduced from Schiff, 2012, with permission of
Wiley–Blackwell.)
such as the frontal lobe, striatum, and thalamus are particularly
vulnerable to dysfunction following multi-focal
brain injuries that produce deafferentation or neuronal cell
loss [10]. Hypoactivity within the frontal lobe and striatum
leads to a lack of disinhibition on the central thalamus from
the MSN leading to shutdown of the forebrain and resultant
decreased levels of consciousness. Activation of the MSN
disinhibits the central thalamus and reestablishes forebrain
activity.
Mean Disability Rating Scale (DRS) Scores during the 6-Week
Assessment
Period, According to Study Group.
DRS scores range from 0 to 29; lower scores indicate less severe functional
disability (see Fig. S7 in the Supplementary Appendix for the DRS syllabus).
DRS scores improved significantly faster in the amantadine group than in
the placebo group during the 4-week treatment interval. During the washout
interval (weeks 5 and 6), the rate of recovery was significantly slower in the
amantadine group, and mean DRS scores were
DRS scores are represented as follows: moderatelysevere-
to-severe disability (range, 7 to 13), severe-toextremely-
severe disability (range, 14 to 21), and vegetative
state to extreme vegetative state (range, 22 to 29).
DRS score ranges were slightly modified from the original
version of the DRS16 to allow disability outcome
ratings to be directly compared with those reported by
Giacino and Kalmar in 1997.6 After 4 weeks of treatment,
the proportion of patients with DRS scores falling in
the category for vegetative state to extreme vegetative
state was higher in the placebo group. Conversely, the
proportion of patients with scores in the category for
moderately-severe-to-severe disability (i.e., least unfavorable)
was greater in the amantadine group. At
week 4, there were no patients with DRS scores between
0 and 6 (indicating no-to-moderate disability).
Frequency of Recovery of Key Behavioral Benchmarks on the Coma Recovery Scale–Revised (CRS-R).
At baseline (week 0), very few patients in either study group had behaviors associated with normal consciousness. By the end of week 4,
recovery of key behavioral milestones was common in both groups (range, 26 to 44% of all cases). However, patients who received
amantadine had a higher rate of recovery across all six behaviors. After washout, at week 6, behavioral recovery remained more favorable
in the amantadine group across five of the six behaviors monitored.
The paradoxical effects could
possibly be due to the reversal of a diaschisis phenomenon
or modulation of subcortical pathways in the frontal cortex
leading to disinhibition and thalamocortical overactivity.
A Phase 1/2,Open-Label Study to Evaluate the Safety and Efficacy of the International Brain Research Foundation (IBRF) Disorders of Consciousness Advanced Care/MultiModal Care Protocol in Patients With Severe Disorders of ConsciousnessTolerance to treatmentNumber and Frequency of side effectsAdverse eventsCRS-RDRSFIMGCSGOS-EO-LOGPolypharmacy using FDA-approved productsMNSNutraceutical Acidophilus, Alpha-Lipoic Acid, Acetyl L-CarnitineStandard of Care treatmentAge 18 years to ≤ 65 years
GCS rating of 3 to 9 (severe impairment)
acquired brain injuryComa, vegetative state, or minimally conscious statePhilip A DeFinahttps://clinicaltrials.gov/ct2/show/NCT02696512philip defina ACP/MCP protocol