Coma Arousal Therapy
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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
- 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
- 12. Prognosis of VS The Multi-Society Task Force on PVS. N Engl J Med 1994;330:1572–79.Dhaval Shukla, IFNR2016
- 13. Prognosis of VS in TBI The Multi-Society Task Force on PVS. N Engl J Med 1994;330:1572–79.Dhaval Shukla, IFNR2016
- 14. Mechanism of Recovery from Coma Schiff ND. Handbook of Clinical Neurology 2013;116:295-306. TMS/ DCS Dhaval Shukla, IFNR2016
- 15. Wake up Pills
- 16. Pharmacological Modulation • Dopaminergic • Levodopa • Apomorphine • Bromocriptine • Amantadine • Monoaminergic drugs • Amitriptyline • Sertraline • Methylphenidate • GABAergic • Zolpidem • Intrathecal baclofen • Antiepileptic drugs • Lamotrigine Ciurleo R, et al. Drugs 2013;73:1849–1862.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
- 24. Sensory Stimulation [SS] 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
- 26. ss Mandeep, et al. IJNT 2013;10:13-18.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
- 29. Median Nerve Stimulation [MNS]
- 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
- 34. Spinal Cord Stimulation [SCS] Dorsal epidural or subdural electrode at C2 – C4 level
- 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
- 36. Transcranial electrical or magnetic stimulation 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
- 40. Deep Brain Stimulation [DBS] Cossu G. BJNS 2014;28:187-98.Dhaval Shukla, IFNR2016 Mesencephalic reticular formation (nucleus cuneiformis) Thalamic nucleus (centrum medianum – parafascicularis complex)
- 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
Editor's Notes
- 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