Htr200243

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Copyright c 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins Efficacy of Amantadine Treatment onSymptoms and NeurocognitivePerformance Among AdolescentsFollowing Sports-Related Concussion Cara Camiolo Reddy, MD; Michael Collins, PhD; Mark Lovell, PhD; Anthony P. Kontos, PhD Objective: To evaluate the efficacy of amantadine in the treatment of symptoms and neurocognitive performance
in adolescents following sports-related concussion. Participants: A clinical sample of 25 male (n = 11) and female
(n = 14) adolescent subjects with an age-, sex-, and concussion history–matched group of 25 male (n = 11) and female (n = 14) control subjects. Setting: Outpatient concussion clinic. Intervention: Retrospective, case-control
design. Treatment group consisted of patients treated with 100 mg of amantadine twice daily (200 mg total per
day) following a period of rest. Matched controls were evaluated and treated conservatively without medication
at the same concussion program prior to the start of the current amantadine protocol. Main Outcome Measures:
Immediate Postconcussion Assessment and Cognitive Test computerized neurocognitive test battery and symptom
report. Results: Results support significantly greater improvements from pre- to posttest in reported symptoms,
verbal memory, and reaction time performance for the amantadine group than the matched controls. There were
no significant differences for visual memory or visual motor processing speed. Conclusion: This study provides
empirical support for amantadine as an effective pharmacologic treatment of certain concussion-related cognitive
deficits and symptoms in athletes with protracted recovery of more than 3 weeks. Key words: amantadine, concussion,
postconcussion symptoms
THE pathophysiology of traumatic brain injury lae of TBI. For individuals who have sustained a mild (TBI) has been postulated to involve complex bio- TBI, or concussion, these disruptions clinically manifest chemical cascades leading to dysregulation of ions and in an array of symptoms including physical, cognitive, neurotransmitters, as well as increases in inflammatory emotional, or sleep-related disturbances.2 mediators and free radical production.1 Disruption in Dopamine, in particular, is known to have strong in- the release and uptake of neurotransmitters has been fluences in the frontal lobe and is involved in regulation considered a likely source of the neurocognitive seque- of behavior, executive function, judgment, arousal, andmotor control.3 Medications that antagonize dopamin-ergic pathways (eg, haloperidol, risperidone) have re- Author Affiliations: Departments of Physical Medicine and
sulted in negative consequences for recovery from Rehabilitation (Dr Camiolo Reddy) and Orthopedic Surgery (Drs Camiolo TBI.4,5 Conversely, medications that improve dopamin- Reddy, Collins, Lovell, and Kontos), University of Pittsburgh MedicalCenter, Pittsburgh, Pennsylvania. ergic transmission (eg, bromocriptine, methylphenidate)have led to improvements in functional outcomes in The authors thank Rosanna Sabini, DO, and Maria Twichell, MD, Depart-ment of Physical Medicine and Rehabilitation, University of Pittsburgh, for animal models.6,7 Limited but growing evidence sug- gests that dopaminergic neurostimulants may facilitate Drs Camiolo Reddy and Kontos had full access to all of the data in the study recovery and quality of life for persons with brain injury; and take responsibility for the integrity of the data and the accuracy of the data however, no studies to date have addressed the effects of neurostimulants on athletes following concussion.
Michael W. Collins, PhD and Mark R. Lovell, PhD, are stockholders in Amantadine is a dopaminergic agent that presy- ImPACT Applications, Inc, the company that develops and sells ImPACT naptically facilitates the release of dopamine and in- software. None of the other authors have any financial or other conflicts ofinterests to disclose. hibits reuptake, thereby increasing the concentrationof dopamine in the synaptic cleft. Amantadine also Corresponding Author: Cara Camiolo Reddy, MD, Department of Physical
Medicine and Rehabilitation, University of Pittsburgh Medical Center, 1400
has a direct postsynaptic effect on dopamine recep- Locust St D-G103, Pittsburgh, PA 15219 tors that increases density and/or alters their config- uration. In addition, amantadine is a noncompetitive Copyright 2012 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Copyright c Wolters Kluwer Health | Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
N-methyl-D-aspartate antagonist that may afford neuro- treatment group would (1) report a significantly greater protective effects through inhibition at excitatory gluta- decrease in symptoms from pre- to posttest and (2) score significantly better on neurocognitive tests from pre- to For several decades, amantadine has been used as an posttest than age-, sex-, and concussion history–matched antiviral agent and was subsequently found to be effec- controls. The researchers expected that participants in tive in the treatment of Parkinson disease.8 Preliminary the control group would also improve over time, al- research and anecdotal evidence regarding the use of though not as much as those in the treatment group.
amantadine for the treatment of neurocognitive deficitsresulting from TBI has been promising, and, as such, amantadine is often used off label for persons with mild, moderate, and severe TBI. Recognized as a safeand well-tolerated medication, the potential adverse ef- The retrospective case-control, pre-/posttest design fects of amantadine include gastrointestinal upset, in- used in this study was approved by the institutional somnia, vivid dreams, anorexia, irritability, agitation, review board of the University of Pittsburgh.
livedo reticularis, and peripheral edema. These adverseeffects are dose dependent and reversible. Reported ad- Participants
ministration of amantadine for the treatment of TBI has A clinical sample of 25 adolescents (11 male, 14 fe- ranged from 50 to 400 mg daily in divided doses, with male participants) evaluated and treated at the UPMC a favorable onset of action of approximately 48 to 72 Sports Medicine Concussion Program constituted the hours.9 In several case studies and retrospective reviews, “treatment” participants. They were given 100 mg of researchers have reported that amantadine improved amantadine twice daily at breakfast and lunch (200 mg cognitive function including attention, concentration, total per day) for an average of 3 to 4 weeks after fail- processing time, psychomotor speed, sequencing, agita- ing to recover following a period of rest of approxi- tion, impulsivity, perseveration, vocalizations, fatigue, mately 21 days. An age-, sex-, and concussion history– initiation, participation in therapy, and response to com- matched group of 25 adolescents evaluated and treated mands and sensory stimulation.10–17 One small placebo- conservatively (ie, rest) without medication at the same controlled double-blind crossover study reported no sta- clinical concussion program prior to the start of the tistical effect of amantadine on cognitive function in current amantadine protocol was selected as controls.
persons with TBI.18 In contrast, another study using These individuals did not receive any confounding phar- a similar design and sample reported consistent trends macologic treatments, and all nonpharmacologic treat- toward more rapid functional improvement after aman- ment (ie, education) was consistent between groups.
tadine administration as measured by the Disability Rat- Inclusion criteria for all were (1) 13 to 19 years of ing Scale, Glasgow Outcome Scale, and Functional In- age and (2) a diagnosis of current symptomatic sports- related concussion. Exclusion criteria were (1) history To date, there have been no published empirical re- of migraines, headaches, neurologic disorder, sleep dis- ports on the use of amantadine in the treatment of order, or attention-deficit disorder and/or attention- symptoms and cognitive deficits in athletes following deficit/hyperactivity disorder; (2) diagnosis of major psy- concussion. Moreover, in previous literature on the use chiatric disorder; (3) current, or history of, substance of amantadine in TBI, most participants were adults, abuse; (4) contraindications for treatment with amanta- with varying time periods between injury and therapeu- dine; or (5) concurrent pharmacologic treatment involv- tic intervention and heterogeneity in mechanism and ing medications with known central nervous system or severity of injury. Therefore, the purpose of the current symptom-modifying effects. The average age was 15.54 study was to examine changes in symptoms and neu- (SD = 1.42) years. Demographic and testing informa- rocognitive performance from pre- to posttreatment in tion for the treatment and control groups is provided in a sample of adolescent athletes following concussion.
Table 1. There were no significant group differences on The treatment group received 100 mg of amantadine twice daily (200 mg per day) and was compared with agroup of untreated, age-, sex-, and concussion history– Outcome measures
matched controls. Given the reported neurocognitivebenefits of amantadine for patients with TBI, the re- All participants completed the Immediate Postcon- searchers hypothesized that amantadine would be effi- cussion Assessment and Cognitive Test (ImPACT) com- cacious in the treatment of postconcussive symptoms puterized neurocognitive test battery and symptom re- and cognitive deficits in individuals who have not spon- port. The ImPACT comprises a series of 6 modules taneously recovered within 3 weeks from injury. Specifi- that yield 4 composite scores: verbal memory (% cor- cally, the researchers hypothesized that the amantadine rect), visual memory (% correct), visual processing speed Copyright 2012 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
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Amantadine Efficacy in Sports-Related Concussion Among Adolescents Summary of demographic and test variables for the amantadine (n = 25) treatment and matched control (n = 25) subjects and results of independent sample t tests Amantadine group
Control group
(higher number = better performance), and reaction for medical evaluation and treatment when their symp- time (in seconds, lower number = better performance).
toms from concussion have not abated within 21 to The ImPACT also contains a 22-item self-report symp- 30 days postinjury. Pharmacologic treatments are intro- tom inventory that includes items for problems such as duced if the athlete has not shown significant signs of headache, dizziness, memory problems, difficulty con- recovery within this 3- to 4-week period following in- centrating, anxiety, depression, and sleep. The concus- jury, as research from our group indicates that 80% of sion symptom inventory uses a 7-point Likert-type scale athletes recover spontaneously within this time.28 in which 0 is a complete absence of symptoms and 6 Those in the treatment group were given 100 mg of is the most severe.19–21 The ImPACT and symptom re- amantadine twice daily for 3 to 4 weeks. None discon- port have been reported to be both valid and reliable in tinued the medication because of adverse effects. Those in the control group were not given medication, as theywere admitted to the clinic prior to the implementa- Procedures
tion of the current medication protocols. Those in bothgroups were tested again using the ImPACT and the All individuals selected for the study sustained a symptom report at approximately 40 to 50 days postin- sports-related concussion and were referred for evalu- ation to the UPMC Sports Medicine Concussion Pro-gram by an emergency department, high school ath- Data analysis
letic trainer, or physician. As most were injured whileplaying organized sports, concussions were diagnosed Repeated-measures analyses of covariance (covaried initially by certified athletic trainers and/or team physi- for concussion history) with Bonferroni corrections were cians present on the sidelines. The basis for diagnosis used to compare the pre- and posttest ImPACT (ie, ver- was presentation of 1 or more of the following signs bal and visual memory, visual processing speed, reaction or symptoms after a direct or indirect impact to the time) and symptom scores of the amantadine treatment head: (1) any noticeable change in mental status; (2) loss group with the matched controls. All statistical tests were of consciousness, disorientation, posttraumatic amnesia, performed using Statistical Package for the Social Sci- or retrograde amnesia; or (3) any self-reported symp- ences (SPSS: IBM) version 18. A significance level of P toms (eg, headache, dizziness, balance dysfunction, vi- < .05 was used for all statistical tests.
sual blurring, diplopia) that appeared following a direct or indirect impact to the head. For individuals who werenot injured while playing organized sports, concussions A series of repeated-measures analyses of covariance were diagnosed by emergency or family medical person- (covaried for concussion history at a value of 0.68) sup- nel and subsequently referred to the clinic for evaluation ported significant within-subject effects for time across and treatment. All initial diagnoses were confirmed by all ImPACT neurocognitive composite scores and re- clinical personnel (ie, neuropsychologists or physicians) ported symptoms (Table 2). Specifically, participants in using the aforementioned description.
both groups reported a decrease in symptoms and an Following injury, all participants completed a clinical increase in verbal and visual memory, visual processing neuropsychological interview that included self-report speed, and reaction time scores from pre- to posttest.
and information from their parents. At that time, they There were 3 significant between-group differences at also completed the pretest ImPACT battery and symp- the pretest: (1) verbal memory (F1,47 = 7.90, P = .007), tom report (see Table 1 for average times from injury to with the amantadine group (M = 72.52, SD = 20.76) pre- and posttests). It is standard protocol at the UPMC scoring significantly lower than the controls (M = 84.92, Sports Medicine Concussion Program to refer patients SD = 7.57); (2) visual memory (F1,47 = 4.43, P = .04), Copyright 2012 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
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Summary of within-subject effects for time (pre- to posttest) across symptoms and ImPACT composite scores (N = 50) Posttest
with the amantadine group (M = 61.92, SD = 16.37) proved (ie, decreased in time [in seconds]) from pre- scoring significantly lower than the controls (M = 70.08, to posttest, improvement of the treatment group was SD = 9.14); and (3) total symptoms (F1, 47 = 6.67, significantly larger than that of the control group.
P = .01), with the amantadine group (M = 37.08,SD = 20.81) scoring significantly higher than the con- DISCUSSION
trols (M = 23.00, SD = 18.60). There were no significantbetween-group differences at the pretest for processing Estimates indicate that several million sports- and speed (P = .18) or reaction time (P = .13). The time recreation-related concussions occur annually in the interval between pre- and posttest was 22.8 days (SD = United States,29 with a majority of patients recovering 26.40) for the amantadine group and 20.2 days (SD = spontaneously within the first 1 to 3 weeks postin- 30.91) for the control group (t = 0.32, P = 0.75).
jury. Unfortunately, for many individuals, symptoms As is evident in Table 3, 3 significant interactions be- including headaches, dizziness, fogginess, difficulty tween time (pre- and posttests) and group (treatment and concentrating, sensitivity to light and noise, irritabil- controls) were supported for symptoms, verbal mem- ity, and sleep dysregulation persist beyond the first ory, and reaction time. The interaction between time month after injury. These symptoms can be signifi- and group on symptoms is represented in Figure 1. Al- cantly disabling, often resulting in an inability to attend though symptoms of both groups decreased from pre- school, complete academic work, participate in sporting to posttest, decrease of the treatment group was larger and extracurricular activities, and interact socially with than that of the control group. The interaction between time and group on verbal memory is represented in In this study, we retrospectively evaluated a group Figure 2. Again, although verbal memory performance of patients treated with amantadine alone and them of both groups increased from pre- to posttest, increase compared with an age-, sex-, and concussion history– of the treatment group was significantly larger than that matched group of patients who went through the con- of the control group. The interaction between time and cussion program prior to the initiation of medication group on reaction time is represented in Figure 3. Again, protocols. The control group did not receive any phar- although reaction time performance of both groups im- macologic treatment, and neither group received any Summary of results from the repeated-measures analyses of covariance for the amantadine (n = 25) treatment and matched control (n = 25) subjects Amantadine group
Control group
Pre, M (SD)
Post, M (SD)
Pre, M (SD)
Post, M (SD)
Wilk λ
η2
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Amantadine Efficacy in Sports-Related Concussion Among Adolescents Figure 3. Reaction time covariate appearing in the model is
evaluated at the following value: concussion history = 0.68.
Figure 1. Symptom covariate appearing in the model is eval-
uated at the following value: concussion history = 0.68.
tive processing and functional improvement when usedin the treatment of TBI. This is the first study to assess concurrent pharmacologic treatment with known cen- the use of this medication in the treatment of student tral nervous system or symptom-modifying effects, in- athletes following mild TBI or concussion. These re- cluding medications to treat headaches, sleep, or mood.
sults highlight one possible treatment for the patients As expected, both groups had significant within-subject with prolonged recovery from concussion, but the au- improvements as noted by a decrease in reported symp- thors recognize and assert that this medication may not toms and improvements in verbal and visual memory, be the treatment of choice for all patients with postcon- visual processing speed, and reaction time from pre- to cussive symptoms. Individualized concussion treatment posttest. This indicates natural recovery from concussive requires in-depth interview to evaluate the symptoms injury, which is expected to occur over time; however, and to tailor a management plan based upon each indi- for those in the amantadine treatment group, the im- provements in reported symptoms, verbal memory, and The current study was limited by several factors. Most reaction time were significantly greater than those found notably, the sample size was small due to the need to in their matched controls, suggesting efficacy for aman- limit the subject pools to patients taking amantadine tadine in the treatment of these symptoms.
only (treatment group) or no medications at all (matched These results corroborate prior case reports and anec- controls); potential participants were excluded from dotal evidence that amantadine positively affects cogni- both groups if they had been prescribed any other inter-ventions such as sleep aids, pain relievers, or headachemedications. Nonetheless, the small sample size couldhave resulted in nonrepresentative groups and spuriousfindings. However, the groups were matched on knownfactors that influence concussion outcomes includingage, sex, and concussion history. Although both groupsreceived education as part of our standard managementprotocols, we were unable to control for adherence torest in the amantadine and control groups; however,there is no reason to suggest that either group wouldhave been more or less likely to adhere appropriately.
The case-control research design resulted in data thatwere retrospective. Premorbid differences in neurocog-nitive performance and symptoms could have resultedin the within-subject interaction with time reported inthe present study. The nonrandomized design resulted Figure 2. Verbal memory covariate appearing in the model is
in both participants and clinicians being aware of the evaluated at the following value: concussion history = 0.68.
use of amantadine. As such, placebo and experimenter bias (ie, the desire for amantadine efficacy) effects could Copyright 2012 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
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explain the results of the current study. In summary, tion time performance in adolescents compared with the limitations of the current study warrant additional matched controls. This finding provides tentative sup- research using a double-blind, randomized control de- port for the efficacy of amantadine as pharmacologic sign involving a large sample to substantiate the findings treatment of patients who fall outside of the normal recovery trajectory (i.e., >3 weeks) following concus-sion. However, given the small sample size and retro-spective case-control design, the results of this study CONCLUSION
should be viewed cautiously. The authors advocate for In the current study, treatment with amantadine re- double-blind randomized control trials of the efficacy of sulted in a significant decrease in reported symptoms amantadine following concussion in a sufficiently large as well as improvements in verbal memory and reac- sample to corroborate the findings of this study.
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