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Coma Arousal Therapy

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Coma Arousal Therapy for Traumatic Brain Injury

Dhaval ShuklaAddl. Professor of NeurosurgeryNIMHANS, Bangalore.

Dhaval Shukla, IFNR2016Conflicts of Interest: None

Outcome after TBI

Dhaval Shukla, IFNR2016Gosseries O, et al. States of Consciousness 2011;29-55.

ComaUnresponsiveEyes closedNo sign of wakefulness1/3rd die within one monthResolves within 24 weeks in survivorsDhaval Shukla, IFNR2016Shukla D, et al. Clin Neuropathol. 2007;26:197-209.

Coma is a state of pathologic unconsciousness in which theeyes remain closed and the patient cannot be aroused (16).It is most often the result of severe, diffuse bihemisphericlesions of the cortex or underlying white matter; bilateralthalamic damage; or paramedian tegmental lesions. The clinicalcriteria for diagnosing coma were described by Plum andPosner in 1982 (16) and remain well accepted. The definingfeature of coma is the complete loss of spontaneous or stimulus-induced arousal. The eyes remain continuously closeddespite the application of noxious stimuli and there are nosleep/wake cycles on electroencephalography (EEG). On examination, there is no evidence of purposeful motor activity,no response to command, and no indication of receptive orexpressive language ability. Coma is a self-limiting state thattypically resolves within 24 weeks in those who survivethe initial injury.4

Vegetative State (VS)Unresponsive Wakefulness Syndrome [UWS]No cognitive awareness Transition marked by beginning of spontaneous eye opening Sleepwake cyclesNo evidence of purposeful behavioral responses to visual, auditory, tactile, or noxious stimuliNo language comprehension or expression

Dhaval Shukla, IFNR2016Povlishock JT, et al. J Head Trauma Rehabil. 2005;20:7694.

Minimally Conscious State (MCS)Simple command followingIntelligible verbalizationRecognizable verbal or gestural yes/no responsesResponses triggered by relevant environmental stimuli Touching or holding objects by accommodating to size and shape

Dhaval Shukla, IFNR2016

Minimally conscious state (MCS): inconsistent, simplepurposeful behavior, inconsistent response to commandsbegin; transition can be documented using Coma RecoveryScale-Revised (CRS-R) subscale criteria for MCS (47); oftenmute (Rancho Level III) (acute hospital;Evidence of limited but clearly discernible selfor environmental awareness on a reproducibleor sustained basis, as demonstrated by one ormore of the following behaviors:1. Simple command following2. Gestural or verbal yes/no responses(independent of accuracy)3. Intelligible verbalization4. Purposeful behavior including movements oraffective behaviors in contingent relation torelevant stimuli. Examples include:a. Appropriate smiling or crying to relevantvisual or linguistic stimulib. Response to linguistic content of questionsby vocalization or gesturec. Reaching for objects in appropriate directionand locationd. Touching or holding objects byaccommodating to size and shapee. Sustained visual fixation or tracking asresponse to moving stimuli6

Confusional stateInteractive communication Appropriate object use beginAmnesic (PTA)Severe basic attentional deficitsHypokinetic or agitatedLabile behavior

Dhaval Shukla, IFNR2016Povlishock JT, et al. J Head Trauma Rehabil. 2005;20:7694.

Post-confusional StateResolution of PTACognitive impairments in higher level attention, memory retrieval, and executive functioningDeficits in self-awareness, social awareness, behavioral, and emotional regulationAchieving functional independence in daily self care

Dhaval Shukla, IFNR2016Povlishock JT, et al. J Head Trauma Rehabil. 2005;20:7694.

Social competenceRecovering higher level cognitive abilities Self-awareness, and social skillsDeveloping effective adaptation and compensation for residual problemsResumption of basic household independenceAbility to be left home unsupervised

Dhaval Shukla, IFNR2016Povlishock JT, et al. J Head Trauma Rehabil. 2005;20:7694.

resumption of basic household independence and ability tobe left home unsupervised for the better part of a day;developing independence in community, householdmanagement skills, and later returning to academic orvocational pursuits; recovering higher level cognitive abilities(divided attention, cognitive speed, executive functioning),self-awareness, and social skills; developing effectiveadaptation and compensation for residual problems (RanchoLevel VII and VIII) (outpatient community reentry programs,community-based servicesvocational, special education,supported living services, mental health services)9

Assessment of Disorder of Consciousness (DOC)Brainstem integrity and other subcortical evaluation

2. Cortical functioninga. Observation of spontaneous activityb. Responses to stimulation or environmentGiacio JT, et al. Brain Injury Medicine 2013;518-535.Dhaval Shukla, IFNR2016

1. Brainstem integrity and other subcortical evaluation Pupillary response, blink reflex to visual threat Ocular movements, gaze deviations Oculovestibular reflexes (oculocephalic [dolls eyes] maneuvers,calorics) Corneal response Gag reflex Breathing pattern Decerebrate postures Other posturing, reflexes, and tone2. Cortical functioninga. Observation of spontaneous activity Purposeful, complex movements (involving cortically mediatedisolated motor control) vs posturing (decorticate ordecerebrate) or reflex or stereotyped, patterned (subcorticallymediated) movements Spontaneous vocalizations or verbalizations Eye movements (signs of fixation or tracking vs nonspecificroving or no movement)b. Responses to stimulation or environment Tracking or fixation to stimuli (try salient stimuli such asfamiliar pictures, faces, mirror) Verbal stimulation (e.g., patients name, commands, socialgreetings):Begin with simple commands sampling a variety of areasunder different neural control, favoring those areas of potentiallypreserved movement. Eye commandse.g., look up, blink twice Limb commandse.g., make a fist, show two fingers,raise your arm Oral commandse.g., open mouth, stick outtongue Axial or whole body commandse.g., turn yourhead, lean forward Ask patient to stop moving or hold still to distinguishfrom spontaneous repetitive movements. Noxious stimulation Look for localization or purposeful defensive maneuversvs reflexive or generalized, stereotyped movements orfacial expressions. Response in contingent relationship to environment orother stimuli Look for intentional reach for or manipulation of objectson or around the patient (e.g., pulling at tubes, clothing,items placed in the hand) Look for changes in facial expression contingent onstimuli 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 actingmedications, concurrent illness, subclinical seizures, undetectedpain) The potential influence of aphasia, apraxia, and otherhigher cortical disorders that may affect the ability to respondto commands


Dhaval Shukla, IFNR2016

Prognosis of VS

The Multi-Society Task Force on PVS. N Engl J Med 1994;330:157279.Dhaval Shukla, IFNR2016

Prognosis of VS in TBI

The Multi-Society Task Force on PVS. N Engl J Med 1994;330:157279.Dhaval Shukla, IFNR2016

Mechanism of Recovery from Coma

Schiff ND. Handbook of Clinical Neurology 2013;116:295-306.TMS/ DCSss

Dhaval Shukla, IFNR2016

Mesocircuit model placing central thalamic deep brain stimulation (CT-DBS) in the context of mechanisms underlyingspontaneous and medication-induced recovery of consciousness. A mesocircuit model organizing mechanisms underlyingrecovery of consciousness after severe brain injury. Diffuse disfacilitation across frontal, cortical, and striatal neurons broad arisesfrom severe structural brain injury. In particular, reduction of thalamocortical and thalamostriatal outflow following deafferentationand 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 (Grillneret al., 2005). Loss of active inhibition from the striatum allows neurons of the globus pallidus internus (GPi) to fire tonically andprovide active inhibition to their synaptic targets, including relay neurons of the already strongly disfacilitated central thalamus andpossibly also the projection neurons of the pedunculopontine nucleus (PPN) (Williams et al., 2009). Amantadine, L-dopa, andzolpidem 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 andthalamostriatal outflow will depolarize neocortical neurons and facilitate long-range corticocortical, corticothalamic, and corticostriataloutflow. CT-DBS can be considered as a final common pathway aggregating these effects and partially remediating theeffects of strong deafferentation of these neurons in all severe brain injuries. (Reproduced from Schiff, 2012, with permission ofWileyBlackwell.)such as the frontal lobe, striatum, and thalamus are particularlyvulnerable to dysfunction following multi-focalbrain injuries that produce deafferentation or neuronal cellloss [10]. Hypoactivity within the frontal lobe and striatumleads to a lack of disinhibition on the central thalamus fromthe MSN leading to shutdown of the forebrain and resultantdecreased levels of consciousness. Activation of the MSNdisinhibits the central thalamus and reestablishes forebrainactivity.14

Wake up Pills

Pharmacological ModulationDopaminergic LevodopaApomorphineBromocriptineAmantadine

Monoaminergic drugsAmitriptylineSertralineMethylphenidate

GABAergicZolpidemIntrathecal baclofen

Antiepileptic drugsLamotrigine

Ciurleo R, et al. Drugs 2013;73:18491862.Dhaval Shukla, IFNR2016

Placebo-Controlled Trial of Amantadinefor Severe Traumatic Brain Injury

Pre-synaptic stageinhibits the re-uptake of dopaminePostsynapticallydensifies dopamine receptors and modifies their conformation184 patients in VS/ MCS4 - 16 weeks after TBIAmantadine or placebo for 4 weeks 100 400 mg twice dailyFollowed for 2 weeks after discontinuation of treatment

Giacino JT, et al. N Engl J Med 2012;366:819-26. Dhaval Shukla, IFNR2016


Placebo-Controlled Trial of Amantadinefor Severe Traumatic Brain Injury

Giacino JT, et al. N Engl J Med 2012;366:819-26. Dhaval Shukla, IFNR2016

Mean Disability Rating Scale (DRS) Scores during the 6-WeekAssessmentPeriod, According to Study Group.DRS scores range from 0 to 29; lower scores indicate less severe functionaldisability (see Fig. S7 in the Supplementary Appendix for the DRS syllabus).DRS scores improved significantly faster in the amantadine group than inthe placebo group during the 4-week treatment interval. During the washoutinterval (weeks 5 and 6), the rate of recovery was significantly slower in theamantadine group, and mean DRS scores were18

Placebo-Controlled Trial of Amantadinefor Severe Traumatic Brain InjuryGiacino JT, et al. N Engl J Med 2012;366:819-26.

Dhaval Shukla, IFNR2016

DRS scores are represented as follows: moderatelysevere-to-severe disability (range, 7 to 13), severe-toextremely-severe disability (range, 14 to 21), and vegetativestate to extreme vegetative state (range, 22 to 29).DRS score ranges were slightly modified from the originalversion of the DRS16 to allow disability outcomeratings to be directly compared with those reported byGiacino and Kalmar in 1997.6 After 4 weeks of treatment,the proportion of patients with DRS scores falling inthe category for vegetative state to extreme vegetativestate was higher in the placebo group. Conversely, theproportion of patients with scores in the category formoderately-severe-to-severe disability (i.e., least unfavorable)was greater in the amantadine group. Atweek 4, there were no patients with DRS scores between0 and 6 (indicating no-to-moderate disability).19

Placebo-Controlled Trial of Amantadinefor Severe Traumatic Brain InjuryGiacino JT, et al. N Engl J Med 2012;366:819-26.

Dhaval Shukla, IFNR2016

Frequency of Recovery of Key Behavioral Benchmarks on the Coma Recovery ScaleRevised (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 receivedamantadine had a higher rate of recovery across all six behaviors. After washout, at week 6, behavioral recovery remained more favorablein the amantadine group across five of the six behaviors monitored.20

Placebo-Controlled Trial of Amantadinefor 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

ZolpidemOmega-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 hypoactiveRelease of tonic inhibition of the central thalamus in the setting of a significant reduction in background excitatory neurotransmission within the mesocircuitMSN are uniquely vulnerable to cellular dysfunction after hypoxiaReported successes with zolpidem have been after hypoxic-ischemic injuriesTucker C, et al. Neurocrit Care 2016;Dhaval Shukla, IFNR2016

The paradoxical effects couldpossibly be due to the reversal of a diaschisis phenomenonor modulation of subcortical pathways in the frontal cortexleading to disinhibition and thalamocortical overactivity.22

ZolpidemIncreased arousal within 1 h of zolpidem 5 -20 mgEffect lasts 34 hFollowed by somnolenceZolpidem is not effective in all patients with impaired consciousnessMore effective in hypoxia induced coma and in MCS33.7 % probable, 4.8% definite respondersIncreased movement and interaction communicationUse should be considered on a case-by-case basisWhyte J, et al. Am J Phys Med Rehabil. 2014;93:101-113. Dhaval Shukla, IFNR2016

Sensory Stimulation [SS]

Dhaval Shukla, IFNR2016

ssSS is the most widely studied rehabilitative treatmentUnimodal/ multimodal Environmental deprivationImpairments of intellectual and perceptual processes

Arousal could be hasten by applying multisensory stimulation in the acute phase of severe TBIReduce coma duration or to improve functional outcomes

Lombardi FFL, Cochrane Database Syst. Rev. 2012; CD001427.Dhaval Shukla, IFNR2016


Mandeep, et al. IJNT 2013;10:13-18.

Dhaval Shukla, IFNR2016

ssContradictory results on the outcomes of clinical relevance 50% of patients have a spontaneous arousal after the acute eventDifficulty of delivering SS in ICUThere is no reliable evidence to support, or rule out, the effectiveness of SS in patients in comaSS 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

LimitationsPreserved islands of high-order cognitive processing not engagedHabituationAttentional sources not capturedPossible covert answers not advocated

Newer ApproachesComplex stimulation including structured and meaningful stimuliNo repetitive and frequent stimulationAppropriate intensity stimulation, occasionally interspersed with high intensity stimulationIntegrated and simultaneous multisensory stimulationEmotional stimulationAutobiographical stimulationRequests for exhibiting behavioural responses or performing actionsNaturalistic and dynamic actions in real or virtualcontextssLombardi FFL, Cochrane Database Syst. Rev. 2012; CD001427.Dhaval Shukla, IFNR2016

Median Nerve Stimulation [MNS]

Median Nerve Stimulation [MNS]Large cortical representationSpinorecticular component of median nerve pathwayActivates projections between thalamus and cortexPossibly silent or injured synapses are transformed into functional ones by neruotrophic factorsIncreased cerebral blood flow and enhancement of neurotransmitter metabolismNeuroendocrine system

Lei J, et al. J Neurotrauma 2015;32:158489.Dhaval Shukla, IFNR2016

MNS - study437 comatose2 weeks after injuryElectrical neuromuscular stimulatorTrains of asymmetric biphasic pluses at an amplitude of 1020 mampsPulse width of 300microsecs at 40Hz for 20sec/min8 h per day for 2 weeksNo unique complications associated with MNSLei J, et al. J Neurotrauma 2015;32:158489.Dhaval Shukla, IFNR2016

MNS - study

Lei J, et al. J Neurotrauma 2015;32:158489.Dhaval Shukla, IFNR2016

MNS - studyLei J, et al. J Neurotrauma 2015;32:158489.Dhaval Shukla, IFNR2016

Spinal Cord Stimulation [SCS]

Dorsal epidural or subdural electrode at C2 C4 level

Dorsal Column Stimulation [SCS]Low electrical currents applied with dorsal epidural or subdural electrode at C2 C4 levelMight hasten arousalIncrease cerebral blood flowImprove EEGRaise dopamine and noradrenaline levelsLower serotonin in CSF214 cases, VS (stationary for atleast 3 months)Clinical improvement in 54% (TBI cases 75%) Interval from SCS to improvement - 6 months to 5 yearsPredictors of improvementYoung ageShorter coma durationAbsence of low-density areas in brainstem or thalamusAbsence of cerebral atrophyCBF > 20mL/100g/minKanno T, et al. Neuromodulation. 2009;12:33-8.Dhaval Shukla, IFNR2016

Transcranial electrical or magnetic stimulation

Dhaval Shukla, IFNR2016

Transcranial electrical or magnetic stimulationRepetitive delivery of electrical stimuli to the brain through the intact scalpChanges in brain activity that last more than the stimulation periodChanges in synaptic plasticity Influence various aspects of brain functioningSite of action could be distant from the site of stimulation Target area prefrontal cortex, that could stimulate awarenessSide effects: sensation of tingling (76%), itching (68%), slight burning (54%), or mild pain (25%)Cossu G. BJNS 2014;28:187-98.Dhaval Shukla, IFNR2016

Transcranial Direct Current Stimulation [tDCS]Double-blind sham-controlled crossover designAtleast 1 week after brain injury in VS or MCSLeft DLPF cortex (F3) for 20 minutesAssessment with CRS-R and GOSEResponders were defined as those patients who presented a sign of consciousnesscommand followingvisual pursuitrecognition, manipulation, localization, or functional use of objectsorientation to painintentional or functional communicationThibaut A, et al. Neurology 2014;82:111218.Dhaval Shukla, IFNR2016

tDCSPatients in MCS showed significant treatment effect (p = 0.003) as measured by CRS-R total scores

Responders43% patients in MCS 8% patients in VS/UWS

Outcome did not differ between tDCS responders and nonresponders

Thibaut A, et al. Neurology 2014;82:111218.Dhaval Shukla, IFNR2016

Deep Brain Stimulation [DBS]

Cossu G. BJNS 2014;28:187-98.Dhaval Shukla, IFNR2016Mesencephalic reticular formation (nucleus cuneiformis)Thalamic nucleus (centrum medianum parafascicularis complex)

Deep Brain Stimulation [DBS]Compensate a chronic underactivation of potential networks and promote the arousal

Review of Prospective cohort studiesTotal 60 patients50% respondersEEG, BSR, SEP, SSEP, CBF, CMRO2Behavioural arousal responses

Cossu G. BJNS 2014;28:187-98.Dhaval Shukla, IFNR2016

ACP vs. Standard Care

DeFina PA, et al. Restor Neurol Neurosci. 2010;28:769-80.Advanced/ Multimodal Care ProtocolDhaval Shukla, IFNR2016

Ongoing StudiesA 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 ConsciousnessInterventionPolypharmacyMNSNutraceuticalComa, vegetative state, or minimally conscious stateOutcomeTolerance to treatmentNumber and Frequency of side effects/ Adverse eventsCRS-R/ DRS/ FIM/ GCS/ GOS-E/ O-LOG/https://clinicaltrials.gov/ct2/show/NCT02696512Dhaval Shukla, IFNR2016

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 productsMNSNutraceuticalAcidophilus, Alpha-Lipoic Acid, Acetyl L-CarnitineStandard of Care treatmentAge 18 years to 65 yearsGCS 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 protocol43

Recommendations4-6 weeks after TBIPharmacological agentsMNSSS

Months after TBIDCSDBSDhaval Shukla, IFNR2016Cossu G. BJNS 2014;28:187-98.

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 docDhaval Shukla, IFNR2016Giacio JT, et al. Brain Injury Medicine 2013;518-535.

Recommendations for Future StudiesRecruitmentAtleast 2 weeks after injuryMatching controlsAdmission characteristicsClinicalAgeGCSMotor ScorePupillary reactionHypoxiaHypotensionImagingCT scan Classification of TBITraumatic SAHBlood investigationGlucoseHbAt time of starting coma arousal therapyClinical diagnosis as per defined criteria (VS, MCS)Coma Recovery Scale-RevisedDisability Rating Scale

Dhaval Shukla, IFNR2016

Recommendations for Future Studies - Outcome Assessment

Beyond 12 months postinjuryClinical and FunctionalComa Recovery Scale-RevisedDisability Rating ScaleGOSENeuroimagingStructural studies DTI, Cortical VolumetryCerebral blood flow and metabolism studiesfMRI - Resting state and Mental imagery tasksElectrophysiologicalQuantitative EEG (qEEG)Evoked Potentials (EPs)Event Related Potentials (ERP)

Dhaval Shukla, IFNR2016

Thank You


% our cases progressing86% (N=14)78% (N=18)100% (N=7)100% (N=2)

% of cases progressing in literature52%* (N=434)15%* (N=169)50%* (N=30)0%* (N=10)

Chi-Square Results2 (1) = 6.16, p = .01.2 (1) = 39.09, p < .0012 (1) = 5.89, p = .022 (1) = 12.00, p = .001.