Authors
- Formisano, Rita MD
- Zasler, Nathan D. MD
Abstract
Amantadine hydrochloride is one of the most commonly used drugs in the pharmacotherapeutic treatment of disorders of consciousness (DOCs) following traumatic brain injury (TBI). Indeed, its actions as a pro-dopaminergic drug and as an N-methyl-D-aspartate antagonist makes amantadine an interesting candidate to improve consciousness and responsiveness in individuals with DOC, including vegetative state and minimally conscious state. Giacino et al (N Engl J Med. 2012;366(9):819-826) recently reported that amantadine was able to accelerate the functional recovery course of subjects after TBI with DOC, during a 4-week treatment period. Some patients with DOC following severe TBI have been reported to have parkinsonian symptoms. Severe TBI and posttraumatic parkinsonism may share a common midbrain network dysfunction. In fact, both vegetative state and minimally conscious state following severe TBI can include features of akinetic mutism and parkinsonism. Responsiveness to pro-dopaminergic agents in some patients and to deep brain stimulation in others, might depend, respectively, on the integrity, or lack thereof, of the dopaminergic postsynaptic receptors. We are of the strong opinion that more attention should be given to parkinsonian findings in persons with DOC after severe TBI and would advocate for multicenter, randomized, controlled trials to assess risk factors for parkinsonism following severe TBI.
Article Content
AMANTADINE HYDROCHLORIDE is one of the most commonly used drugs in the pharmacotherapy of prolonged disorders of consciousness (DOCs).1 Indeed, its actions as a pro-dopaminergic drug and as an N-methyl-D-aspartate antagonist makes amantadine an interesting candidate to improve consciousness and responsiveness in individuals in vegetative state (VS) and minimally conscious state (MCS).2 Previous small randomized trials demonstrated amantadine efficacy in neurobehavioral recovery of individuals with traumatic brain injury (TBI) and diffuse axonal injury, especially in the acute phase of recovery.3,4 Giacino et al5 recently reported that amantadine treatment was able to accelerate functional recovery of subjects in VS and MCS after TBI during a 4-week treatment period, with slowing of the rate of improvement during the 2 weeks following drug discontinuation.
In this landmark multicenter study, no concurrent effort was made to describe of the presence of parkinsonian features in the study cohort; yet, not uncommonly, patients after severe TBI may show a transient or persistent parkinsonism consisting of rigidity, akinesia, and parkinsonian posturing associated with hypomimia, nonextinguishable glabellar tap reflex, dysarthria, seborrhea, and hypersalivation.6,7
Patients with DOC following severe TBI, especially when there is significant traumatic axonal injury, have been reported to have parkinsonian signs and symptoms.8-13 Parkinsonian signs may also be due to focal lesions in the cerebral white matter involving the caudate nucleus and putamen,14 as well as the substantia nigra.15 Animal studies have shown that even after moderate TBI, diffuse brain injury can result in substantia nigra neurovascular pathology that can be associated with neuroinflammation, as well as dopamine dysregulation.16 Traumatic brain injury has also been shown in rat models to have the potential to induce a progressive degeneration of nigrostriatal dopaminergic neurons.17 Research examining TBI as a risk factor for parkinsonism and Parkinson's disease is certainly not new.18
More recent literature has also examined the association between TBI and parkinsonism, as well as the relationship between neurotoxic agents and enhanced risks for parkinsonism associated with TBI.17,19-22
Studies comparing patients with idiopathic Parkinson's disease and those with posttraumatic parkinsonism have shown that in the latter population, parkinsonian signs and symptoms are due to lesions in the extrapyramidal pathways and not due to a systematic depletion of dopamine.23 Deep brain stimulation (DBS), which is also a therapeutic approach in Parkinson's disease, has been shown to improve the arousal regulation of functionally connected but inconsistently active cerebral networks, present in some patients in MCS24 but not in patients in VS.25
In a patient, described by Schiff et al,25 who remained in MCS for 6 years following TBI, bilateral thalamic DBS produced improvements in intelligible verbalization and functional limb control. On the basis of the clinical description of this case, we suspect that the patient had features of akinetic mutism. Akinetic mutism, first described as secondary to diencephalic lesions, consists of severe quadriparesis, mutism, akinesia, visual fixation, and pursuit.26 It is a rare condition that has been described as a subcategory of MCS.27 Complete or nearly complete loss of spontaneity and initiative, resulting in reduction of action, ideation, speech, and emotion, are hallmarks of akinetic mutism.28 Patients with akinetic mutism may sporadically follow commands and tend to have a prolonged response latency. Thus, akinetic mutism may persist after the recovery of consciousness with substantive parkinsonian features.29
Parkinsonian features may improve after L-Dopa treatment along with different degrees of recovery of consciousness, especially if the drug is used early in recovery.30 Amantadine and other dopamine agonists have been shown to also have some efficacy in improving parkinsonian features and recovery of consciousness after TBI.31-34 Some authors have questioned the efficacy and safety of dopamine agonist use in critically ill patients after TBI31; although, the clinical use of these drugs in neurorehabilitation is well accepted on the basis of numerous positive published studies, consensus opinion, and current practice trends.3,5,35,36,37
Motor slowness in subjects with severe TBI and clinical features of parkinsonism have been shown to be associated with changes of specific anticipatory-evoked potentials and other selective deficits in motor preparation9,10 similar to the alterations found in38,39 patients with Parkinson's disease, indicating diminished preparatory activity in the supplementary motor area. In patients with Parkinson's disease, the reduction of the anticipatory-evoked potentials component of the movement-related cortical potentials is thought to result from inadequate basal ganglia activation of the supplementary motor area.37
In patients with severe TBI, reduced supplementary motor area activity has been associated with lesions in several important areas of the extrapyramidal pathway, such as the frontal lobe, basal ganglia, and brainstem.9 In most of these patients, there was evidence of traumatic axonal injury that did not necessarily involve the rostral brainstem. During the early phase of DOC recovery, survivors of severe TBI with cerebral magnetic resonance imaging (MRI) features of traumatic axonal injury may show extrapyramidal signs40 similar to those observed in multi-infarct parkinsonism.41
As a cautionary note, not all patients with posttraumatic parkinsonism respond to L-Dopa or pro-dopaminergic treatment, as in other secondary parkinsonisms7,41; however, the reasons for this lack of more global response are unclear at this time. Posttraumatic parkinsonism seems to share specific neurophysiological patterns with Parkinson's disease, such as blink reflex habituation changes.42 Matsuda et al43 described 3 patients in VS after TBI with parkinsonian features such as rigidity and hypokinesia who improved following L-Dopa treatment while recovering from prolonged DOC. According to Jellinger,7 the clinical features of posttraumatic parkinsonism often resemble those of postencephalitic parkinsonism, both showing signs of akinesia, rigidity, hypomimia, as well as optomotor and autonomic dysfunction and rarely tremor. Indeed, both the lesion pattern and the therapeutic efficacy of long-term pro-dopaminergic treatment suggest dysfunction within the nigrostriatal dopaminergic system.
Since severe brain injury and posttraumatic parkinsonism may share a common midbrain network dysfunction, VS, MCS, akinetic mutism, and parkinsonism might represent a recovery continuum after severe TBI.29 Responsiveness to pro-dopaminergic agents such as amantadine or L-Dopa in some patients and to DBS in others25 might depend, respectively, on the integrity, or lack thereof, of the dopaminergic postsynaptic43,44,45 receptors. Thus, it is our position that more attention should be given to parkinsonian clinical and neuropathological findings in this population.
In addition, posttraumatic parkinsonian-type impairment responsiveness to therapeutic interventions such as pro-dopaminergic drugs and DBS must be assessed through randomized, controlled, multicenter clinical studies in persons with DOC, as well as compared with the efficacy of these interventions in patients without parkinsonian features. Within that context, population stratification for parkinsonian signs and/or symptoms after severe TBI will also change clinical practice, if appropriate characterization of motor findings in TBI studies will confirm a significant incidence of these features as next step. In this case, a clinical trial on whether a pro-dopaminergic drug such as amantadine is able to accelerate functional recovery in all patients with DOC or only in those with akinetic mutism or parkinsonian signs is warranted.
REFERENCES
1. Whyte J, Katz D, Long D, et al. Predictors of outcome in prolonged posttraumatic disorders of consciousness and assessment of medication effects: a multicenter study. Arch Phys Med Rehabil. 2005;86(3):453-462. [Context Link]
2. Peeters M, Page G, Maloteaux JM, Hermans E. Hypersensitivity of dopamine transmission in the rat striatum after treatment with the NMDA receptor antagonist amantadine. Brain Res. 2002;949(1/2):32-41. [Context Link]
3. Meythaler JM, Brunner RC, Johnson A, Novack TA. Amantadine to improve neurorecovery in traumatic brain injury-associated diffuse axonal injury: a pilot double-blind randomized trial. J Head Trauma Rehabil. 2002;17(4):300-313. [Context Link]
4. Schneider WN, Drew-Cates J, Wong TM, Dombovy ML. Cognitive and behavioural efficacy of amantadine in acute traumatic brain injury: an initial double-blind placebo-controlled study. Brain Inj. 1999;13(11):863-872. [Context Link]
5. Giacino JT, Whyte J, Bagiella E, et al. Placebo-controlled trial of amantadine for severe traumatic brain injury. N Engl J Med. 2012;366(9):819-826. [Context Link]
6. Gerstenbrand F. Das Traumatische Apallische Syndrom. Wien, Austria, and New York, NY: Springer, Verlag; 1967. [Context Link]
7. Jellinger KA. Parkinsonism and persistent vegetative state after head injury. J Neurol Neurosurg Psychiatry. 2004;75:1082-1083. [Context Link]
8. Formisano R, Matteis M, Bivona U, Ciurli P, Zafonte R. ICU discharge criteria and rehabilitation potential for severe brain injury patients. In: Gabrielli A, Laylon AJ, Civetta MYu Taylor & Kirby, eds. Critical Care. 4th ed. London, England: Lippincott Williams & Wilkins; 2009:2254-2265. [Context Link]
9. Di Russo F, Incoccia C, Formisano R, Sabatini U, Zoccolotti P. Abnormal motor preparation in severe traumatic brain injury with good recovery. J Neurotrauma. 2005;22:297-312. [Context Link]
10. Incoccia C, Formisano R, Muscato P, Reali G, Zoccolotti P. Reaction and movement times in individuals with chronic traumatic brain injury with good motor recovery. Cortex. 2004;40:111-115. [Context Link]
11. Bazarian JJ, Cernak I, Noble-Haeusslein L, Potolicchio S, Temkin N. Long-term neurologic outcomes after traumatic brain injury. J Head Trauma Rehabil. 2009;24(6):439-451. [Context Link]
12. Nayernouri T. Post-traumatic parkinsonism. Surg Neurol. 1985;24:263-264. [Context Link]
13. Lees AJ. Trauma and Parkinson disease. Rev Neurol (Paris). 1997;153:541546. [Context Link]
14. Davie CA, Pirtosek Z, Barker GJ, Kingsley DP, Miller PH, Lees AJ. Magnetic resonance spectroscopic study of parkinsonism related to boxing. J Neurol Neurosurg Psychiatry. 1995;58(6):688-691. [Context Link]
15. Morsier G. Parkinsonism consecutif une lesion traumatique du nojau rouge et du locus niger. Psychiat Neurol. 1960;139:60-64. [Context Link]
16. Van Bregt DR, Thomas TC, Hinzman JM, et al. Substantia nigra vulnerability after a single moderate diffuse brain injury in the rat. Exp Neurol. 2012;234(1):8-19. [Context Link]
17. Hutson CB, Lazo CR, Mortazavi F, Giza CC, Hovda D, Chesselet MF. Traumatic brain injury in adult rats causes progressive nigrostriatal dopaminergic cell loss and enhanced vulnerability to the pesticide paraquat. J Neurotr. 2011;28:1783-1801. [Context Link]
18. Grimberg L. Paralysis agitans and trauma. J Nerv Ment Dis. 1934;79:14-42. [Context Link]
19. Lee PC, Bordelon Y, Ritz B. Traumatic brain injury, paraquat exposure, and their relationship to Parkinson's disease. Neurology. 2012;79(20):2061-2066. [Context Link]
20. Jackson-Lewis V, Blesa J, Przedborski S. Animal models of Parkinson's disease. Parkinsonism Relat Disord. 2012;18(suppl 1):183-185. [Context Link]
21. Kokjohn TA, Maarouf CL, Daugs ID, et al. Neurochemical profile of dementia pugilistica. J Neurotrauma. 2013;30(11):981-997. [Context Link]
22. Krauss JK, Jankovic J. Movement disorders after traumatic brain injury. In: Zasler ND, Katz D, Zafonte R, eds. Brain Injury Medicine: Principles and Practice. 2nd ed. New York, NY: Demos Publishers; 2013:670-671. [Context Link]
23. Peppe A, Stanzione P, Pierantozzi M, et al. Does pattern electroretinogram spatial tuning alteration in Parkinson's disease depend on motor disturbances or retinal dopaminergic loss? Electroencephalogr Clin Neurophysiol. 1998;106:374-382. [Context Link]
24. Giacino J, Ashwal S, Childs N, et al. The minimally conscious state: definition and diagnostic criteria. Neurology. 2002;58:349-353. [Context Link]
25. Schiff ND, Giacino JT, Kalmar K, et al. Behavioural improvements with thalamic stimulation after severe traumatic brain injury. Nature. 2007;448:600-603. [Context Link]
26. Royal College of Physicians Working Group. The Permanent Vegetative State. Vol 30. London, England: JR College Physicians; 1996:119-121. [Context Link]
27. American Congress of Rehabilitation Medicine. Recommendations for use of uniform nomenclature pertinent to patients with severe alterations of consciousness. Arch Phys Med Rehabil. 1995;76(2):205-209. [Context Link]
28. Giacino J. Disorders of consciousness: differential diagnosis and neuropathologic features. Semin Neurol. 1997;17(2):105-111. [Context Link]
29. Formisano R, D'Ippolito M, Risetti M, et al. Vegetative state, minimally conscious state, akinetic mutism and Parkinsonism as a continuum of recovery from disorders of consciousness: an exploratory and preliminary study. Funct Neurol. 2011;26(1):15-24. [Context Link]
30. Haig AJ, Ruess JM. Recovery from vegetative state of six months duration associated with Sinemet (L-Dopa/carbidopa). Arch Phys Med Rehabil. 1990;71(13):1081-1083. [Context Link]
31. Kraus MF, Maki PM. Effect of amantadine hydrochloride on symptoms of frontal lobe dysfunction in brain injury: case studies and review. Neuropsychiatry Clin Neurosci. 1997;9(2):222-230. [Context Link]
32. Krimchansky BZ, Keren O, Sazbon L, Groswasser Z. Differential time and related appearance of signs, indicating improvement in the state of consciousness in vegetative state traumatic brain injury (VS-TBI) patients after initiation of dopamine treatment. Brain Inj. 2004;18(11):1099-1105. [Context Link]
33. Orient-Lopez F, Terre-Boliart R, Bernabeu-Guitart M, Ramon-Rona S, Perez-Miras A. The usefulness of dopaminergic drugs in traumatic brain injury. Rev Neurol. 2002;35(4):362-366. [Context Link]
34. Hughes S, Colantonio A, Santaguida PL, Paton T. Amantadine to enhance readiness for rehabilitation following severe traumatic brain injury. Brain Inj. 2005;19(14):1197-1206. [Context Link]
35. Frenette AJ, Kanji S, Rees L, et al. Efficacy and safety of dopamine agonists in traumatic brain injury: a systematic review of randomized controlled trials. J Neurotrauma. 2012;29(1):1-18. [Context Link]
36. Bales JW, Wagner AK, Kline AE, Dixon CE. Persistent cognitive dysfunction after traumatic brain injury: a dopamine hypotheses. Neurosci Biobehav Rev. 2009;33(7):871-1003. [Context Link]
37. Wheaton P, Mathias JL, Vink R. Impact of pharmacological treatments on cognitive and behavioral outcome in the post-acute stages of adult traumatic brain injury: a meta-analysis. J Clin Psychopharm. 2011;31(6):745-757. [Context Link]
38. Dick JP, Rothwell JC, Day BL, et al. The Bereitschafts potential is abnormal in Parkinson's disease. Brain. 1989;112:233-244. [Context Link]
39. Filipovi SR, Covickovi-Sterni N, Radovi VM, Dragasevi N, Stojanovi-Svetel M, Kosti VS. Correlation between Bereitschafts potential and reaction time measurements in patients with Parkinson's disease. Measuring the impaired supplementary motor area function? J Neurol Sci. 1997;147(2):177-183. [Context Link]
40. Tomaiuolo F, Carlesimo GA, Di Paola M, et al. Gross morphology and morphometric sequelae in the hippocampus, fornix, and corpus callosum of patients with severe non-missile traumatic brain injury without macroscopically detectable lesions: a t1 weighted MRI study. J Neurol Neurosurg Psychiatry. 2004;75(9):1314-1322. [Context Link]
41. Fujimoto K. Vascular parkinsonism. J Neurol. 2006;253(3):16-21. [Context Link]
42. Formisano R, Cicinelli P, Buzzi MG, et al. Blink reflex changes in parkinsonism following severe traumatic brain injury correlates with diffuse axonal injury. Med Sci Monit. 2009;15(3):101-106. [Context Link]
43. Matsuda W, Matsumura A, Komatsu Y, Yanaka K, Nose T. Awakenings from persistent vegetative state: report of three cases with parkinsonism and brain stem lesions on MRI. J Neurol Neurosurg Psychiatry. 2003;74:1571-1573. [Context Link]
44. Formisano R, Zafonte R, Hayes R. Vegetative state, minimally conscious state and Parkinson-like syndrome as a recovery continuum. The Neurotrauma Letter. 2008;(02). http://www.internationalbrain.org/articles/vegetative-state-minimally-conscious-. Accessed October 9, 2013. [Context Link]
45. Schiff ND. Central thalamic deep-brain stimulation in the severely injured brain: rationale and proposed mechanisms of action. Ann N Y Acad Sci. 2009;1157:10116. [Context Link]
disorders of consciousness; dopamine; parkinsonism; traumatic brain injury