Neuropharmacology In TBI: What We Know & What We Don t

Transcription

1 Neuropharmacology In TBI: What We Know & What We Don t 1

2 Neuropharmacology in TBI: What We Know and What We Don t. Jaime M. Levine, D.O. JFK Johnson Rehab Institute Heidi Fusco, M.D. Rusk Rehabilitation

3 Jaime M. Levine, D.O. Clinical Background and Training Director of Brain Injury Medicine at the Extended Recovery Unit, JFK-Johnson Rehabilitation Institute Former Medical Director of Brain Injury Rehabilitation at Rusk Rehabilitation, NYU- Langone Medical Center Completed Brain Injury Medicine Fellowship at JFK-Johnson Rehab Institute Mentors: Drs. Malone, Greenwald, Flanagan Brain Injury Medicine ABMS Certified 3

4 Agenda/Goals of this lecture Why use neuropharmacology after brain injury Neurotransmitter pathways Rules of neuropharmacology Agents/medications to support Motor recovery Aphasia recovery Healthy sleep Arousal Behavioral Regulation Attention and processing speed Memory Executive function Neglect recovery

5 Agenda/Goals of this lecture continued Review the recent literature regarding the range of recommendations in pharmacological treatments in brain injury, Consolidate recommendations Give examples from our own practices Withdrawing of an Agent Questions

6 Rules of Thumb Healthy brain versus injured brain will impact response to medications Remember, you are in charge! What specifically are you targeting? What is your goal? Start low, go slow Make use of interdisciplinary team Inform team at onset and with dose adjustments A side effect to one patient, is a targeted intervention in another! Limit polypharmacy If fatigue is a side effect, dose at bedtime If patient has pain and depression, select an agent that targets both If orthostasis a side effect, choose an SNRI Dosing subject to change during recovery Consider dosing schedule Varies by setting 6

7 Point A: Impairment due to brain injury (Deficits in ADL s, Ambulation, Communication, Cognition) PT, OT, SLP, Cognitive Therapy Medical stability, secondary prevention Time: Recovery, Plasticity, Healing, Compensation and Learning Point B: Greater independence, Functional Abilities Neuropharmacologic Augmentation?

8 A very brief word on Neurotransmitters Serotonergic Adrenergic Cholinergic Dopaminergic

9 Keep in mind: Different Neurotransmitter pathways travel through the same region in the brain Deficits after brain injury not due to deficiency in one neurotransmitter Clinicians are using neuropharmacology anyway Hammond et al, 2015 Psychotropic Medication Use During Inpatient Rehabilitation for Traumatic Brain Injury Of 2130 patients with TBI in rehab centers 67% received antidepressants 47% received anticonvulsants 33% received anxiolytics 30% received hypnotics 28% received stimulants 25% received antipsychotics 25% received antiparkinson agents

10 Informed Consent Essential With each medication Most often off-label usage Side effects/interactions are real Low potential for harm overall, but must be very cautious Family should be treated as part of the team 10

11 How do we Measure Outcomes? Barthel Index Modified Rankin Scale Fugl-Meyer Assessment of Motor Response After Stroke Agitated Behavioral Scale Rancho Los Amigos Scale JFK-Coma Recovery Scale, Revised Functional Independence Measure (FIM) O-Log GOAT Various Neuropsychology Indices Aphasia Scales Western Aphasia Battery (WAB) Psycholinguistic Assessment of Language Processing in Aphasia (PALPA) 11

12 Best Way to Measure Outcome? Feedback from the interdisciplinary team! Weekly assessment of goals 12

13 Should mention: Much research in Motor and Aphasia recovery is done in stroke and acquired brain injury populations. Growing body of research done in pharmacological augmentation of Motor and Aphasia recovery in the TBI population. 13

14 Agents to Support Motor Recovery: What We Know and What We Don t. 14

15 Agents to Support Motor Recovery SSRI s Fluoxetine Citalopram SNRI s Reboxetine Dopaminergics Levodopa Amphetamine-like compounds Achetylcholinergic Donepezil 15

16 Agents to Support Motor Recovery (SSRI s) What We Know: SSRI s have utility in non-depressed patients with stroke, with good functional results. Depression occurs in about one third of patients with stroke Some antidepressants may act directly on the injured neuronal structures and modulate spontaneous reorganization Question of reopening a window of plasticity FMRI studies have shown improvement in motor cortex after single dose of fluoxetine or paroxetine. (Pariente et al. 2001) Should everyone with an ischemic stroke be on an SSRI? 16

17 Agents to Support Motor Recovery (SSRI s) What We Know: FLAME trial showed that in patients with ischemic stroke and moderate to severe motor deficits, the early prescription of fluoxetine with physical therapy led to enhanced motor recovery after three months. Double-blind, placebo-controlled trial, nine stroke centers with ischemic stroke, hemiplegia/hemiparesis, and Fugl-Meyer motor scale score of 55 or less, years old. Excluded patients with depression Randomly assigned to either fluoxetine (20mg QD) or placebo. All had PT Primary outcome measure was change on FMMS between day 0 and day 90. Results: FMMS score improvement at day 90 was significantly greater in the fluoxetine group. Greater number of functionally independent patients (Modified Rankin Scale 0-2) Less number of depressed patients Side effects: hyponatremia, GI distress didn t stop treatment 17

18 Agents to Support Motor Recovery (SSRI s) What We Know: Patients treated with citalopram for three months post stroke had a better recovery from disability one year after stroke than patients who did not receive antidepressant therapy.* Suggests lasting effect Citalopram can enhance dexterity in chronic stroke patients.** Eight chronic stroke patients (> 6 months) Double-blind, placebo-controlled, single-dose crossover design Motor function assessed: nine-hole-peg-test, hand grip strength Results: Citalopram significantly improved performance on nine hold peg test for paretic hand but not for the unaffected hand. Grip strength remained unchanged *Mikami K, Jorge RE, Adams HP Jr, David PH, Leira EC, Jang M, Robinson RG. Effect of antidepressants on the course of disability following stroke. Am J Geriatr Psychiatry **Zittel S, Weiller C, Liepert J. Citalopram improves dexterity in chronic stroke patients. Neurorehabil Neural Repair. 2008;22:

19 Agents to Support Motor Recovery (SSRI s) What We Don t: Do SSRI s Have a Similarly Beneficial Effect in Patients with Traumatic Brain Injury? Fluoxetine increases hippocampal neurogenesis and induces epigenetic factors but does not improve functional recovery after traumatic brain injury* In rats, 3 days post mod-sev TBI or sham surgery, were given fluoxetine. Looked at gait, spacial learning and memory No differences The treatment effect of motor recovery with fluoxetine persist beyond 90 days? How do these agents behave in a hemorrhagic stroke? The FMRICH study is protocoled and underway. Fluoxetine for motor recovery after acute intracerebral hemorrhage (FMRICH): study protocol for a randomized, double-blind, placebo-controlled, multicenter trial. *Wang Y 1, Neumann M, Hansen K, Hong SM, Kim S, Noble-Haeusslein LJ, Liu J. Fluoxetine increases hippocampal neurogenesis and induces epigenetic factors but does not improve functional recovery after traumatic brain injury. J Neurotrauma Feb;28(2):

20 Agents to Support Motor Recovery (SSRI s) What We Don t: Evidence for platelet dysfunction with SSRI. Need to wait 1-2 weeks post-hemorrhage to use? Why might SSRI s improve motor function? Possible upregulation of brain-derived neurotrophic factor, a protein important during activity-dependent remodeling Improved serotonergic transmission and increased cortical activation Can lesioned-brain plasticity be modulated by medications? And will this improve final functional status of patients? SSRI s are not interchangeable. 20

21 Agents to Support Motor Recovery (SNRI s) What We Know: Reboxetine induced a significant improvement in tapping speed and grip strength in ten patients with chronic stroke. Reboxetine inhibits the reuptake of noradrenaline. 10 chronic stroke patients, double-blind, placebo-controlled crossover trial. Less likelihood of spontaneous recovery due to chronicity. Subjects had impairments in fine motor control and upper extremity paresis. Excluded depressed patients. Received reboxetine 6mg daily or placebo Results: A single dose enhanced hand tapping speed and grip strength of affected hand. No improvement seen in the Nine-Hole-Peg Test Zittel S, Weiller C, Liepert J. Reboxetine improves motor function in chronic stroke: A pilot study. J Neurol. 2007;254:

22 Agents to Support Motor Recovery (SNRI s) What We Don t: Is it easier to modulate simple movement than influence complex motor tasks? What about venlafaxine, or other more commonly used SNRI s? What is the effect for motor recovery following TBI? Why do these agents cause sedation in some patients, but have activating properties in others? 22

23 Agents to Support Motor Recovery (Levodopa) What We Know: Currently there is limited, but overall positive, evidence for supporting or refuting the use of levodopa to support post-stroke motor recovery. Levodopa is a dopamine precursor that is metabolized to dopamine in the brain. I found seven randomized, double-blind, placebo-controlled studies looking at levodopa use in chronic stroke patients: Four studies showed some degree of improvement.* One study showed improvement which was not statistically significant.** Two studies showed no significant difference between levodopa group and control.*** *Scheidtmann et al 2001, Floel et all 2005, Rosser et al 2008, Acler et al 2009 **Sonde et al 2007 ***Lokk et al 2001, Restenmeyer et al

24 Agents to Support Motor Recovery (Levodopa) What We Don t: This agent is still so commonly used! Why is that? The dopamine precursor levodopa was found to increase speed, overall success, and long-term retention of novel word learning in healthy individuals (Knecht et al. 2004) fmri studies where levodopa was onboard showed some increased activation, and also showed better response to transcranial magnetic stimulation. 24

25 Agents to Support Motor Recovery (Amphetamines) What We Know: Currently there is limited evidence for supporting or refuting the use of amphetamines to support post-stroke motor recovery. Found 4 recent studies looking at amphetamines and motor performance following stroke: 1 showed benefit and 3 didn t. Dexamphetamine dosed at 10mg twice weekly for 5 weeks along with PT improved arm motor control. (Schuster et al. 2011) Amphetamine dosed at 10mg twice weekly for 10 sessions with PT showed no additional benefit. (Gladstone, 2005) D-amphetamine dosed at 5mg on day 0 and 4, then 10mg twice weekly for 35 days, with PT showed no additional benefit. (Sprigg et al. 2007) D-amphetamine at 10 doses of 10mg twice weekly showed no significant benefit. (Platz et al. 2005) 25

26 Agents to Support Motor Recovery (Donepezil) What We Know: Donepezil may improve the FIM motor score in elderly cognitively impaired patients post stroke. Dr. Ellen Whyte et al, patients, all over 60 year old 12 week open label trial of : galantamine 24 mg or donepezil 5-10mg Outcome measure: FIM motor and apathy evaluation Results: Donepezil group had 14 point greater boost in FIM motor score Change in apathy associated with FIM gain

27 Agents to Support Motor Recovery Other Agents Being Looked At: Statins Neuroprotection at the acute phase followed by an increase in the cerebral blood flow, leading eventually to improved functional outcome. (Giannopoulos et al. 2012) Phosphodiesterase inhibitors Sildenafil promotes vasodilation, enhances angiogenesis, neurogenesis, and synaptogenesis when initiated at 24h post stroke. (Zhang et al. 2005) Niacin improves functional outcomes in rats post stroke (Chen et al. 2007) Glibenclamide Sulfonylureas may halt oxidative stress and inflammation in the hippocampus after reperfusion (Abdallah et al. 2011). Another study showed retrospectively that patients taking this post stroke had a better neurological outcome (Kunte et al. 2007) 27

28 Agents to Support Motor Recovery, Summary of Take Home Points from the Literature: SSRI s have utility in non-depressed patients with stroke, with good functional results. FLAME trial showed that in patient with ischemic stroke and moderate to severe motor deficits, the early prescription of fluoxetine with physical therapy led to enhanced motor recovery after three months. Patients treated with citalopram for three months post stroke had a better recovery from disability one year after stroke than patients who did not receive antidepressant therapy. Citalopram can enhance dexterity in chronic stroke patients. Donepezil may improve the FIM motor score in elderly cognitively impaired patients post-stroke. Reboxetine induced a significant improvement in tapping speed and grip strength in ten patients with chronic stroke. Currently there is limited evidence for supporting or refuting the use of levodopa to support post-stroke motor recovery. Currently there is limited evidence for supporting or refuting the use of amphetamines to support poststroke motor recovery. Donepezil may improve the FIM motor score in elderly cognitively impaired patients post stroke. 28

29 Agents to Support Motor Recovery Anecdotes from My Practice: Ischemic stroke patients: Without an obvious contraindication, all patients with an ischemic stroke in the acute rehab phase should be on an SSRI! Fluoxetine has the strongest evidence. Start 20mg for motor recovery Increase to 40mg if develop signs of depression No drug holiday continue onwards, with need for follow-up Citalopram has the second strongest evidence Agent of choice in the elderly because well-tolerated Start at 10mg, titrate to 20mg for motor recovery Titrate to 40mg if develop signs of depression No drug holiday continue onwards, with need for follow-up In a patient with hemiplegia, and no improvement on SSRI, often add levodopa 25/100 tab TID, and titrate up to 1.5 or 2 tabs TID Not strong enough evidence to use an SNRI for motor recovery in my opinion TBI patients: Would not offer SSRI first-line to promote motor recovery Would use dopamine promoting agents such as levodopa 29

30 Agents to Support Aphasia Recovery: What We Know and What We Don t. 30

31 Agents to Support Aphasia Recovery Dopaminergic agents Levodopa Bromocriptine Amantadine Cholinergic Donepezil NMDA receptor agonist Memantine 31

32 Agents to Support Aphasia Recovery (Dopaminergics) What We Know: The evidence for the efficacy of dopaminergic agents in aphasia therapy is mixed. Levodopa and bromocriptine are the main agents used, most commonly bromocriptine Observed in the 1970 s that Parkinsonian patients showed improved speech function following levodopa therapy. Gill and Leff (2013) reviewed 15 studies done between 1988 and 2012 that used dopaminergic agents in aphasia. Most studies dosed up to 30mg daily for bromocriptine 7/15 reported a positive effect of dopaminergic therapy 2 were RCT s (Seniow. 2009, Leman et al, 2011) The rest showed no differences 32

33 Agents to Support Aphasia Recovery (Amantadine) What We Know: Amantadine may have a beneficial effect on language performance in patients with aphasia. Amantadine increases the release of dopamine and norepinephrine, has a weak antagonism of NMDA receptor, and has slight anticholinergic effects. Studies done have been small, single case reports. Arciniegas et al. 2004, Barrett and Eslinger

34 Agents to Support Aphasia Recovery (Cholinergics) What We Know: Donepezil has been shown to improve the severity of aphasia and motor aspects of speech in poststroke aphasia. Berthier et al studied 26 patients, RCT, double-blind, for efficacy of donepezil in chronic poststroke aphasia. Dose was 5mg x 4 weeks, then 10mg daily x 12 weeks, then 4 week wash-out = 20 week trial Age < 70 with duration of aphasia > 1 year Results: Donepezil significantly improved the severity of aphasia on the Western Aphasia Battery and the picture naming subtest of the PALPA (Psycholinguistic Assessment of Language Processing in Aphasia). Between-group differences were no longer significant at week 20, so there is no lasting benefit when discontinued. Adverse effects: donepezil group with irritability, seizure, headache, abnormal dreams, insomnia, fatigue 34

35 Agents to Support Aphasia Recovery (NMDA-receptor ag) What We Know: Memantine alone or combined with constraint-induced aphasia therapy in chronic poststroke aphasia patients improved aphasia severity. These effects persisted on long-term follow-up. Theory: Acute stroke causes neuronal and myelin sheath damage in part due to overactivation of NMDA receptors calcium influx excitotoxic cell death. Drugs that modify the NMDA receptor, like memantine, may augment synaptic plasticity in language areas. Randomized, double-blind, placebo-controlled trial of both memantine and CIAT Memantine 20mg daily or placebo x 16 weeks drug + CIAT x 2 weeks drug alone x 2 weeks washout x 4 weeks Results: Memantine group showed significantly better improvement on Western Aphasia Battery compared w/placebo while given and after washout. Combination of memantine and CIAT showed best effect and was long-term Berthier et al

36 Agents to Support Aphasia Recovery What We Don t: Regarding dopaminergic agents: the evidence is mixed, but in terms of cognitive models, at what level are they working? Dopamine is implicated in modulating a whole range of cognitive functions, including reward, attention, memory and problem-solving, so perhaps language recovery is affected through these channels? Regarding donepezil: How does it improve language? May affect neurovascular organization and promote reorganization of cortical networks and blood flow regulation 36

37 Agents to Support Aphasia Recovery, Summary of Take Home Points from the Literature: The evidence for the efficacy of dopaminergic agents in aphasia therapy is mixed. Donepezil has been shown to improve the severity of aphasia and motor aspects of speech in poststroke aphasia. Memantine alone or combined with constraint-induced aphasia therapy in chronic poststroke aphasia patients improved aphasia severity. These effects persisted on longterm follow-up. 37

38 Agents to Support Aphasia Recovery Anecdotes from My Practice: Donepezil has mixed evidence but I use it anyway. Start at 5mg for 5-6 days, then increase to 10mg. Avoid drug holiday because effect is only seen while taking the drug. Side effects: mild sedation and GI effects Reach same ceiling, but reach it faster, so get more out of acute rehab experience. May be sedating in some, and cause agitation/aggression in others Don t have much experience with memantine because there s only one good study, but due to good side effect profile would consider its use. Effective in elderly demented patients to control agitation, can be sedating 38

39 Agents to Support Better Sleep: What We Know and What We Don t. 39

40 Agents to Support Healthy Sleep Melatonin Ramelteon Amitryptiline Trazodone 40

41 Agent to Support Healthy Sleep (Melatonin) What We Know: Melatonin has value for sleep disorders following head injury. Consensus is that about 30% of patients following head injury have insomnia. Little published on its use in TBI One case report of a 15-year old girl with head trauma who developed a delayed sleep phase syndrome. (Nagtegaal, J.E. 1997) Physiological markers monitored: Sleep-wake rhythm, plasma melatonin, body temp, wrist activity All markers returned to normal after treatment with 5mg melatonin A few studies on melatonin in neurologically impaired children with neutral to favorable results. Ramelteon is a pharmaceutical grade analogue of melatonin Jorge et al,

42 Agent to Support Healthy Sleep (Melatonin and Amitriptyline) What We Know: Melatonin has value for sleep disorders following head injury. Kemp et al. did a randomized double-blind controlled cross-over trial with melatonin (5mg) or amitriptyline (25mg). Minimum 6 months post-tbi y/o Sleep variables measured: 1. Alertness 2. Duration 3. Quality 4. Latency Also measured neuropsychological functioning and mood Results: Melatonin: improved daytime alertness Amitriptyline: improved sleep duration and shortened latency Most patients were unimpaired on neuropsychological tests of attention and speed of processing No changes in cognitive performance or mood No adverse drug effects 42

43 Agent to Support Healthy Sleep (Trazodone) What We Think We Know: Trazodone is a multifunctional drug that helps patients with TBI sleep. Mechanism of action is unique: has dose-dependent actions Hypnotic actions at low doses due to blockade of: 5-HT2A receptors H1 histamine receptors Alpha1 adrenergic receptors Higher doses block the serotonin transporter (SERT) and have antidepressant properties (Stahl, 2009) 43

44 Agents to Support Healthy Sleep Take Home Points From the Literature: Melatonin has value for sleep disorders following head injury. Trazodone is a multifunctional drug that helps patients with TBI sleep. 44

45 Agents to Support Healthy Sleep Anecdotes from My Practice: Ramelteon at 4mg dosing is great to have onboard. Few to no contraindications Viewed as a supplement not drug to some Trazodone mg QHS Caution in young men Avoid with other serotonergics, especially at higher doses Antidepressant effect at higher doses Mirtazapine 7.5mg, may increase to 15mg Antidepressant effects Good results Can increase appetite Neurontin Back-load dosing Instead of 300mg Q8, can give 300mg QAM and 600mg QHS Benzodiazepines, Z drugs, are never my top choice Baclofen for nighttime spasms Back-load dosing Tizanidine similarly 45

46 Agents to Support Arousal: What We Know and What We Don t. 46

47 Agent to Improve Arousal Sedative/hypnotic Zolpidem Dopaminergics: Amantadine Bromocriptine Stimulants Methylphenidate Modafinil 47

48 Agents to Improve Arousal (Zolpidem) What we Know: A very small number of patients with disorders of conscious are responders to zolpidem, and it is not possible to distinguish responders in advance. Zolpidem has been reported to cause temporary recovery of consciousness in VS and MCS patients. (Whyte et al, 2014) 84 participants Traumatic and non-traumatic DOC of at least 4 month duration Results: 4 definite responders were identified No features were predictive of response Indicators included: Increased movement, social interaction, command following, functional object use Response lasted 1-2 hours 48

49 Agents to Improve Arousal (Dopaminergics) What we Know: Amantadine is the agent of choice for treating profound hypoarousal following TBI, especially when a patient has a disorder of consciousness. Giacino et al enrolled 184 patients in the vegetative or minimally conscious states following TBI Patients currently receiving inpatient rehab 4-16 weeks post-tbi Randomized, placebo-controlled 4 week treatment period, 2 week washout period Used Disability Rating Scale Results: The amantadine group had faster recovery during the treatment phase Recovery slowed during the washout phase for the amantadine group End points were equal No significant adverse events 49

50 Agents to Improve Arousal (Mixed Neurostimulants) What we Know: Amantadine and/or methylphenidate may improve emergence from coma in hypoxic ischemic encephalopathy resulting from cardiac arrest. Retrospective cohort study from Patients received either amantadine, methylphenidate, or both. Outcome measures were: Primary Outcome: Command following Secondary Outcomes: Survival to hospital discharge, cerebral performance category, modified Rankin scale Results: Patients receiving neurostimulants trended toward improved rate of command following, as well as improvements on the secondary outcome measures 50

51 Agents to Improve Arousal What we Don t: What is the mechanism of action behind these agents improving consciousness? How can we identify zolpidem responders in advance? 51

52 Agents to Improve Arousal Take Home Points From the Literature: Amantadine is the agent of choice for treating profound hypoarousal following TBI, especially when a patient has a disorder of consciousness. Amantadine and/or methylphenidate may improve emergence from coma in hypoxic ischemic encephalopathy resulting from cardiac arrest. A very small number of patients with disorders of conscious are responders to zolpidem, and it is not possible to distinguish responders in advance. 52

53 Agents to Improve Arousal Anecdotes from My Practice: Vitamin A Methylphenidate Have not integrated zolpidem because I cannot identify responders in advance For milder injuries Provigil as a general wakefulness-promoting agent Preferred in the elderly over methylphenidate Start test dose of 50mg at 7am, then increase slowly to max of 100mg at 7am and noon Can linger, so eliminate afternoon dose if trouble sleeping Methylphenidate if attention also an issue Comorbid depression Activating antidepressants, such as venlafaxine Start 25mg daily, then increase to 150mg total daily dose Can also support blood pressure if orthostasis an issue 53

54 Withdrawing of Agent Standard of practice is to disentangle natural recovery from medication effect. Role of drug holiday Anyone on a neurostimulant deserves a drug holiday to see if natural recovery caught up or not. Acute rehab phase is a good time because have feedback from interdisciplinary team Mostly for short-acting meds Caveat is donepezil: if patient is on the agent and is making gains in language function, usually just continue through acute rehab phase Evidence of no sustained effect Always better to be on fewer meds When in doubt, stop it! 54

55 Thank you! 55

56 Summary of Take Home Points (1/7) SSRI s have utility in non-depressed patients with stroke, with good functional results. FLAME trial showed that in patient with ischemic stroke and moderate to severe motor deficits, the early prescription of fluoxetine with physical therapy led to enhanced motor recovery after three months. Patients treated with citalopram for three months post stroke had a better recovery from disability one year after stroke than patients who did not receive antidepressant therapy. Citalopram can enhance dexterity in chronic stroke patients. Donepezil may improve the FIM motor score in elderly cognitively impaired patients post stroke. Reboxetine induced a significant improvement in tapping speed and grip strength in ten patients with chronic stroke. Currently there is limited evidence for supporting or refuting the use of levodopa to support post-stroke motor recovery. Currently there is limited evidence for supporting or refuting the use of amphetamines to support post-stroke motor recovery.

57 Summary of Take Home Points (2/7) The evidence for the efficacy of dopaminergic agents in aphasia therapy is mixed. Donepezil has been shown to improve the severity of aphasia and motor aspects of speech in poststroke aphasia. Memantine alone or combined with constraint-induced aphasia therapy in chronic poststroke aphasia patients improved aphasia severity. These effects persisted on long-term follow-up. Melatonin has value for sleep disorders following head injury. Trazodone is a multifunctional drug that helps patients with TBI sleep. Amantadine is the agent of choice for treating profound hypoarousal following TBI, especially when a patient has a disorder of consciousness. Amantadine and/or methylphenidate may improve emergence from coma in hypoxic ischemic encephalopathy resulting from cardiac arrest. A very small number of patients with disorders of conscious are responders to zolpidem, and it is not possible to distinguish responders in advance.

58 Now introducing... Heidi Fusco, MD Clinical Instructor of Rehabilitation Medicine at Rusk Rehabilitation Hospital Care provided at acute, subacute, consultation and outpatient practice Training TBI Fellowship at Rusk w/mentors: Drs. Flanagan, Levine, and Im. PM&R Residency at Spaulding w/mentors: Drs. Chae, Giap and Herman ABMS certified in Brain Injury Medicine