Neuropharmacology in TBI - Arousal handouts.pptx

10/18/13 Review of Neuropharmacology in Pediatric Brain Injury Disclosure InformaHon AACPDM 67th Annual MeeHng October 16-­‐19, 2013 Speaker Name: Jilda Vargus-­‐Adams MD MSc Disclosure of Relevant Financial Rela?onships I have the following financial relaHonships to disclose: Grant/Research support from: Cerebral Palsy InternaHonal Research FoundaHon, Ipsen Disclosure of Off-­‐Label and/or inves?ga?ve uses: I will discuss the following off label use and/or invesHgaHonal use in my presentaHon: Virtually every medicaHon discussed in this presentaion including amantadine, carbidopa/levodopa, bromocripHne, methylphenidate, and zolpidem Neuropharmacology for Arousal in Brain Injury •  Disorders of Consciousness –  DescripHons –  Assessments •  Treatment of Disorders of Consciousness –  Environmental and general medical management –  Neuropharmacology •  Dopaminergic agents •  Fish oil •  John Pelegano MD (15 minutes): IntroducHon and iniHal case presentaHons •  2. Jilda Vargus-­‐Adams MD,MSc (30 minutes): Neuropharmacologic agents to increase arousal •  3. Micah Baird MD (30 minutes): Neuropharmacologic agents for agitaHon and improved cogniHon. •  4. Break (10 Minutes) •  5. John Pelegano MD (15 minutes): The unusual story of zolpidem, conclusion of case presentaHons. •  6. Jilda Vargus-­‐Adams MD,MSc (20 minutes): Clinical experiences from the audience, QuesHons & Answers. Neuropharmacology for Arousal in Brain Injury •  With great thanks to Stacy Suskauer MD, pediatric physiatrist and research scienHst at Kennedy Krieger/Johns Hopkins, for sharing slides and advice Severe Disorders of Consciousness •  Severely altered arousal and/or awareness of self and the environment –  Coma –  VegetaHve State –  Minimally Conscious State Consensus definiHons from Aspen Neurobehavioral Workgroup 1 10/18/13 Anatomic structures subserving awareness and arousal Coma (ALL criteria must be met) •  No spontaneous or induced eye opening** •  No command following •  No intelligible speech •  No purposeful movement •  No discrete defensive capacity to localize noxious sHmuli Be: Basal forebrain Hypo: Hypothalamus Thal: Thalamus ARAS: Ascending reHcular acHvaHng system •  Rarely lasts longer than 2-­‐4 weeks ager trauma; evolves to vegetaHve state **Bilateral ptosis can also occur in sejng of cranial nerve injuries** Weiss et al., CriHcal Care, 2007 VegetaHve State (ALL criteria must be met) •  Presence of sleep-­‐wake cycles (periodic eye opening) •  No sustained, reproducible, purposeful, or voluntary behavioral responses to sHmuli •  No evidence of language comprehension •  Bowel and bladder inconHnence •  PreservaHon of autonomic funcHons permits survival with adequate care •  Variable preservaHon of cranial/spinal reflexes Brand new terminology VegetaHve State => “Unresponsive Wakefulness Syndrome” Behaviors Consistent with VegetaHve State** •  Spontaneous movement •  Startle myoclonus •  Smile •  Shed tears •  Moan, grunt, scream ** When inconsistent, nonpurposeful, coordinated only reflexively Prolonged VegetaHve States Current recommendaHon: • 
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Describe as: VegetaHve State + EHology + DuraHon – 
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Eliminate use of “Persistent VegetaHve State” “Permanent VegetaHve State” 2 10/18/13 “Late Awakenings” (never say never) •  Donald Hebert – firefighter “wakes up” and converses with family 10 years ager anoxic BI (atributed to medicaHon cocktail) •  Terry Wallis – “wakes up” and talks, then regains motor funcHon, 19 years ager TBI (atributed to axonal regrowth) Minimally Conscious State •  Behaviors are inconsistent but reproducible or sustained enough to differenHate from reflex •  Clearly discernable evidence of any one of: –  Simple command following –  Gestured or verbal yes/no response –  Intelligible verbalizaHon –  Movements or affecHve behaviors that occur in conHngent relaHon to relevant sHmuli and are not reflexive acHvity Minimally Conscious State: conHngent behavioral responses •  Pursuit eye movement or sustained fixaHon in direct response to moving or salient sHmuli •  Crying, smiling, or laughing in response to emoHonal but not neutral content •  VocalizaHon or gestures in direct response to linguisHc content of comments or quesHons •  Reaching for objects with a clear relaHonship between object locaHon and direcHon of reach •  Touching or holding objects in a manner that accommodates the size and shape of the object More brand new terminology MCS (-­‐) -­‐ Minimal levels of behavioral interacHon characterized by the presence of non-­‐reflex movements such as: (i) orientaHon of noxious sHmuli, (ii) pursuit eye movements that occur appropriately in relaHon to relevant environmental sHmuli. MCS (+) -­‐ Presence of (i) command following, (ii) intelligible verbalizaHon or (iii) gestural or verbal yes/no responses. Emergence from MCS •  Return of reliable and consistent interacHve communicaHon OR funcHonal object use –  CommunicaHon may be through verbalizaHon, wriHng, yes/no signals, or augmentaHve communicaHon device (6/6 correct responses to situaHonal orientaHon quesHons) –  FuncHonal object use: discriminaHon and appropriate use of at least 2 common arHcles (cup, hairbrush, etc.) Bruno et al., J Neurol, 2011
3 10/18/13 Recommenda?ons for Assessment Standardized Evalua?on Tools OpHmize paHent’s arousal/atenHon • 
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Minimize sedaHng medicaHons Provide sufficient sHmulaHon Choose a distracHon-­‐free environment Choose target behavior carefully • 
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Family/therapist input Consider impairments Non-­‐reflexive movements Use broad range of sHmuli/responses •  Evaluate responses to many different sHmuli •  May require training to administer •  JFK Coma Recovery Scale – Revised (CRS-­‐R) •  Rappaport Coma/Near Coma Scale (CNCS) •  Western Neuro Sensory SHmulaHon Profile (WNSSP) • 
Serially re-­‐assess JFK Coma Recovery Scale -­‐ Revised Rappaport Coma/Near Coma Scale •  Command Following •  VocalizaHon •  Motor responses to •  Auditory FuncHon •  Visual FuncHon •  Motor FuncHon – 
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–  FuncHonal object use* •  Oromotor/Verbal FuncHon •  CommunicaHon –  FuncHonal communicaHon* •  Arousal Environmental IntervenHons to OpHmize Responsiveness Contrast of Standardized Scales JFK Coma Recovery Scale (Revised) Rappaport Coma/Near-­‐
Coma Scale •  Motor FuncHon –  Noxious SHmulaHon: • 
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1: No response 2: Abnormal posturing 3: Flexion withdrawal 4: LocalizaHon –  Object InteracHon •  5: ManipulaHon •  6: AutomaHc Motor Response •  7: FuncHonal Use •  Motor Response – 
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Command Following Shoulder tap Nasal swab Nail bed pressure Ear pinch/pull Pain Visual sHmulaHon/threat TacHle sHmulaHon Olfactory sHmulaHon Auditory sHmulaHon • OpHmize sHmulaHon – PosiHon upright – wheelchair or stander • Even beter – get the child out of the wheelchair – Lights on during day – MulH-­‐sensory sHmulaHon, including movement – …but not too much sHmulaHon • OpHmize sleep – Nighjme rouHne – Lights off/noises off at night – May need dayHme naps/rest breaks 4 10/18/13 A structured medical approach to opHmize responsiveness Minimizing SedaHng MedicaHons Seda?ng Medica?ons •  Wean potenHally sedaHng medicaHons –  Tone meds: •  Baclofen •  Tizanidine •  Benzodiazepines –  GI meds •  H2-­‐blockers •  Metoclopromide •  OpHmize night-­‐Hme sleep –  Trazodone –  Melatonin •  Evaluate and opHmize hearing and vision •  Await stabilizaHon of acHve medical issues (?) –  NarcoHcs –  Cardiovascular agents •  Clonidine •  Propranolol •  Consider neurosHmulant trial(s) •  MulHple agents available, with varying levels of evidence –  Amantadine –  Carbidopa/Levodopa –  BromocripHne –  Pramipexole –  Methylphenidate –  Tone meds: •  Dantrolene (? SedaHng) •  Carbidopa/Levodopa •  Botulinum toxin –  GI meds •  PPI •  Erythromycin –  Other pain meds –  Cardiovascular agents •  Alternate anH-­‐hypertensives •  Alternate beta-­‐blockers Amantadine Dopaminergic Agents •  Dopamine deficiency ogen follows TBI Less Seda?ng Alterna?ves •  Pre-­‐synapHc and post-­‐synapHc dopamine agonist •  Used in all states of consciousness following TBI (facilitaHon of arousal from coma through opHmizaHon of atenHon, processing speed for higher-­‐level cogniHve tasks) •  Variability in published reports re: efficacy •  IniHally developed as anH-­‐viral agent, also used in Parkinson’s disease Amantadine: RCT in adults with VS or MCS aPer TBI Giacino et al., NEJM, 2012 Giacino et al., NEJM, 2012 5 10/18/13 Pramipexole Double-­‐blind placebo-­‐controlled cross-­‐over study of amantadine in children with acquired brain injury •  Non-­‐ergoline Dopamine agonist •  Not much published… •  Approved for use in early Parkinson’s disease and restless leg syndrome McMahon, Am J Phys Med Rehab, 2009 31 Carbidopa/Levodopa Double-­‐blind study of Amantadine vs Pramipexole in children with severe TBI (n=10) •  Dopamine precursor classically used in Parkinson’s disease, also used in pediatric movement disorders •  Case study/anecdotal reports of improvements in funcHon for individuals in VS or MCS •  Ogen considered for use in paHents with DOC when there is a co-­‐exisHng movement disorder Patrick et al., JCN, 2006 33 BromocripHne Methylphenidate •  Dopamine agonist – directly binds to dopamine receptors •  Increases extracellular dopamine and norepinephrine •  Possible efficacy for aphasia ager stroke •  Typically used for atenHon, processing speed •  Used in autonomic dysregulaHon (“storming”) ager TBI •  Some evidence that rate, but not overall level, of recovery enhanced in moderate TBI •  Used in malignant hyperthermia •  Also used in Parkinson’s disease • 
(Plenger et al., Archives of PM&R, 1996) •  One report of shorter ICU and hospital stay ager adult severe TBI when started on hospital day #2 • 
(Moein et al., Clinical Neurology & Neurosurgery, 2006) 6 10/18/13 Suggested References Bruno MA, Vanhaudenhuyse A, Thibaut A, Moonen G, Laureys S., From unresponsive wakefulness to minimally conscious PLUS and funcHonal locked-­‐in syndromes: recent advances in our understanding of disorders of consciousness., J Neurol. 2011 Jul; 258(7):1373-­‐84. Giacino JT, Whyte, The VegetaHve and Minimally Conscious States, J Head Trauma Rehabil. 2005 Jan-­‐Feb; 20(1): 30–
50. Giacino JT, Whyte J, Bagiella E, Kalmar K, Childs N, Khademi A, Eifert B, Long D, Katz DI, Cho S, Yablon SA, Luther M, Hammond FM, Nordenbo A, Novak P, Mercer W, Maurer-­‐Karatup P, Sherer M, Placebo-­‐controlled trial of amantadine for severe traumaHc brain injury, N Engl J Med. 2012 Mar 1; 366(9):819-­‐26. Kalmar K, Giacino JT, The JFK Coma Recovery Scale-­‐-­‐Revised, Neuropsychol Rehabil. 2005 Jul-­‐Sep; 15(3-­‐4):454-­‐60. McMahon MA, Vargus-­‐Adams JN, Michaud LJ, Bean J, Effects of amantadine in children with impaired consciousness caused by acquired brain injury: a pilot study, Am J Phys Med Rehabil. 2009 Jul; 88(7):525-­‐32. Patrick PD, Blackman JA, Mabry JL, Buck ML, Gurka MJ, Conaway MR, Dopamine agonist therapy in low-­‐response children following traumaHc brain injury, J Child Neurol. 2006 Oct; 21(10):879-­‐85. Rappaport M, Dougherty AM, KelHng DL, EvaluaHon of coma and vegetaHve states, Arch Phys Med Rehabil. 1992 Jul; 73(7):628-­‐34. With thanks! CincinnaH Children’s Hospital Medical Center QuesHons: jilda.vargus-­‐[email protected] 7