Evaluation of Outcomes in Patients Receiving Amantadine to Improve Alertness After Traumatic Brain Injury

Abstract

Background: Amantadine has been used off-label to improve alertness after traumatic brain injury (TBI). The goal of this study is to assess the mean change at 72 hours and in course of therapy (COT) Glasgow Coma Scale (GCS) score after amantadine initiation and to correlate the change in GCS score with participation in physical therapy (PT) and occupational therapy (OT) among patients with TBI receiving amantadine during the first hospitalization. Methods: This single-center, retrospective, cohort study included patients ≥18 years old hospitalized for a TBI from August 2012 to February 2018 and received ≥1 dose of amantadine to increase alertness. The primary endpoint is the mean change in 72-hour GCS score after amantadine initiation. The secondary endpoint is the mean change in COT GCS score after amantadine initiation and the correlation between the change in GCS score and percent PT and OT participation at 72 hours and during the COT. Results: Seventy-nine patients were included. The mean age of patients was 41 years, and 79.8% of the patients were men. The mean change in 72-hour GCS score was +0.75 (95% confidence interval [CI] = 0.09-1.42, P = .027), and the mean change in COT GCS score was +2.29 (95% CI = 1.68-2.90, P < .001). There was no significant correlation between the increase in GCS score and percent PT/OT session participation at 72 hours and during the COT, r = −0.15 (P = .24) and r = −0.02 (P = .74), respectively. The percent PT/OT session participation at 72-hour post-amantadine initiation was 61.3% compared with 65.9% during the COT. Conclusion: There were small but statistically significant increases in the mean change at 72 hours and in COT GCS score; however, they were not correlated with percent PT/OT participation. Other studies are needed to determine the appropriate time and GCS score to initiate amantadine along with the optimal dose in the inpatient setting.

Introduction

According to the Centers for Disease Control and Prevention (CDC), there were approximately 2.8 million emergency department visits, hospitalizations, and deaths due to traumatic brain injury (TBI) in the United States. ¹ The CDC also estimates approximately 3.2 to 5.3 million people have a TBI-related disability. ² One of the most common complaints among patients after a TBI is decreased alertness and fatigue.^3,4 There are many clinical tools used to assess alertness in patients with a TBI; however, the most commonly used score to assess the severity of a TBI is the Glasgow Coma Scale (GCS). The GCS score uses eye opening, verbal, and motor response to generate a maximum score of 15 points. GCS scores ranging from 13 to 15 are classified as mild, 9 to 12 as moderate, and ≤8 as severe.^{5 -7}

Medications such as amantadine have been used off-label to improve wakefulness in patients with TBI. ⁸ Amantadine is an Food & Drug Administration (FDA)-approved medication for the treatment of influenza A and Parkinson disease (PD). ⁸ Amantadine is, however, used off-label for the treatment of sleep-wake disorders such as multiple sclerosis (MS)-related fatigue and TBI. ⁸ Amantadine is thought to improve wakefulness and arousal by blocking the N-methyl-D-aspartate (NMDA) receptor, acting as an indirect dopamine agonist, decreasing dopamine reuptake, and increasing the density as well as changing the configuration of postsynaptic dopaminergic receptors.^{3,9 -11} Within a few hours after a TBI, a catecholamine surge leads to depletion of neurotransmitters, including norepinephrine and dopamine.^3,12 Subsequently, there is decreased regeneration of dopamine, which regulates arousal, cognitive function, and motor control. ¹³ Therefore, dopamine depletion and slow turnover are thought to be one of the mechanisms of decreased alertness and increased fatigue. ¹³ Consequently, medications that increase dopamine, such as amantadine, have been used to increase alertness in patients with TBI.^3,4,12,13

Prolonged impaired consciousness can delay rehabilitation and recovery as patients must be awake and alert to participate in physical therapy (PT) and occupational therapy (OT). ¹³ Rehabilitation delay is particularly problematic because extended bed rest has been associated with significant muscle loss and decreased bone mineral density occurring as early as 1 week post-TBI. ¹⁴ Theoretically, improved alertness should result in improved participation in rehabilitation. Clinical studies have shown that amantadine was effective in improving functional recovery in patients with TBI in the chronic phase, mainly 4 to 16 weeks post-TBI.^9,10,12 Amantadine is also considered to be neuroprotective in the acute phase post-TBI, within the first month, by preventing excessive excitotoxicity due to glutamate and aspartate by blocking the NMDA receptor.^{3,10,15 -18}

Although amantadine is one of the most common drugs used to treat TBI-associated disorders of consciousness, to our knowledge, no previous study has correlated GCS score improvement with clinical outcomes such as the ability to participate in rehabilitation during the initial hospitalization after a TBI. The aim of this single-center, retrospective, cohort study is to assess the mean change at 72 hours and in course of therapy (COT) GCS score after amantadine initiation and to correlate the change in GCS score with participation in PT and OT among TBI patients receiving amantadine during the first hospitalization.

Methods

Study Design

This study was a single-center, retrospective, single-group, cohort study conducted at University Medical Center New Orleans (UMCNO), a Level 1 Trauma Center. The study was approved by the Xavier University of Louisiana Institutional Review Board and the UMCNO Research Review Committee. Informed consent was waived due to the retrospective nature of the study. All patients admitted to UMCNO from August 2012 to February 2018 with a primary diagnosis of a TBI and received at least one dose of amantadine were screened. Patients were identified using International Classification Diseases Revision, Ninth Revision (ICD-9) codes (850-854) and International Classification Diseases Revision, Tenth Revision (ICD-10) codes (S06.0-S06.9). ICD-9 and ICD-10 codes can be found in Appendix A.

Inclusion and Exclusion Criteria

The inclusion criteria for the study were the following: age ≥18 years old, primary diagnosis of a TBI during the hospitalization, amantadine use to increase alertness, and ability to receive medications by mouth or via a nasogastric or enteral feeding tube. Exclusion criteria consisted of amantadine use for indications other than increasing alertness in TBI patients, baseline idiopathic hypersomnia, narcolepsy, obstructive sleep apnea (OSA), MS-related fatigue, PD, Alzheimer disease (AD), preexisting neurologic injury (prior TBI, stroke, and brain tumor), amantadine allergy, pregnancy, bowel obstruction, end-of-life care, and patients with missing GCS score data.

Data Collection

All patient data were obtained from the UMCNO electronic medical records. The following demographic data were collected: age, sex, race, height, weight, admission date, discharge date, serum creatinine (SCr), creatinine clearance calculated using the Cockcroft-Gault equation using actual SCr and 40% adjusted body weight (adjusted body weight = ideal body weight + 0.4 × [actual body weight − ideal body weight]) for patients whose actual body weight was ≥ 30% above their ideal body weight. For patients with actual body weight less than 30% above their ideal body weight, the smaller weight value of either ideal body weight or actual body weight was used in the Cockcroft-Gault equation. We also collected baseline comorbid conditions (hypertension, MS, depression, OSA, PD, seizures, psychiatric conditions), GCS score (on admission, baseline, 72 hours, amantadine discontinuation, and at discharge), duration of treatment in days, total amantadine dose at 72 hours and during COT in milligrams, intensive care unit (ICU) length of stay (LOS) in days, non-ICU LOS in days, total LOS in days, time from TBI to initiation of amantadine in days, wakefulness and PT participation at 72 hours, use of concurrent psychotropic medications that could affect study outcomes: antipsychotics, dopaminergic agents, anticonvulsants, anxiolytics, anticholinesterase inhibitors, antidepressants, benzodiazepines, anticholinergics, sympathomimetics, antihistamines, NMDA receptor antagonist, and sedatives. The complete list of concurrent psychotropic medications can be found in Appendix B.

Definitions

Concurrent psychotropic medication was defined as a medication that was administered at least once during amantadine COT. Admission GCS score was defined as the first GCS score documented after admission whereas baseline GCS score referred to the GCS score documented before amantadine initiation. COT GCS score was the change from baseline GCS score to discharge GCS score.

Study Endpoints

The primary endpoint is the mean change in 72-hour GCS score after amantadine initiation. The secondary endpoint is the mean change in COT GCS score after amantadine initiation and the correlation between the change in GCS score and percent PT and OT participation at 72 hours and during the COT. In addition, we assessed the percentage of PT and OT (%PT/OT) session participation at 72 hours and at discharge. Other descriptive results evaluated include duration of treatment, the amount of amantadine administered at 72 hours and at discharge, time to initiation of amantadine, total LOS, ICU LOS, non-ICU LOS, severity of TBI based on GCS score, and concurrent use of psychotropic medications.

Statistical Analysis

Descriptive statistical analysis was performed for baseline characteristics. A two-tailed paired t test was used to analyze mean change in GCS score. Subgroup analysis was conducted to compare the change in GCS score from baseline to 72 hours among groups. The subgroup analysis included time from TBI to amantadine initiation (within 72 hours and >72 hours), TBI severity (mild, moderate, severe) on admission and baseline, and concurrent psychotropic medications. Differences among the subgroups were compared using analysis of variance (ANOVA). Last, the change in GCS score was also compared for patients who took concurrent psychotropic medications versus those patients who did not take the concurrent psychotropic medications. STATA Statistical Software (Release 12, College Station, Texas) was used to perform the statistical analyses. ¹⁹

Results

During the study period, 169 patients were hospitalized with a primary diagnosis of a TBI who received at least one dose of amantadine. Ninety patients were excluded, and the most common exclusion criteria were baseline psychological conditions, missing GCS data, and pre-TBI neurological injury such as previous TBI, stroke, diffuse-axonal injury, blunt, or penetrating trauma (see Figure 1).

Figure 1.

Flowchart.

Note. GCS = Glasgow Coma Scale; TBI = traumatic brain injury; AD = Alzheimer disease; PD = Parkinson disease.

The mean age of patients was 41 years, and 79.8% of patients were men. Most patients were Black or Caucasian, 50.6% and 40.5%, respectively. On admission, 17.8% of patients had mild TBI, 13.9% had moderate TBI, and 68.4% had severe TBI. However, at baseline (prior to amantadine initiation), 36.7% of patients had mild TBI, 26.6% had moderate TBI, and 34.2% had severe TBI. The most common concurrently administered medications were anticonvulsants (65.8.1%), benzodiazepines/anxiolytics (54.4%), sedatives (44.3%), and antipsychotics (34.2%). The complete baseline characteristics results can be found in Table 1.

Table 1.

Baseline Characteristics (N = 79).

Baseline characteristics	No. (%)
Mean age, y (SD, range)	40.6 (15.7, 18-77)
Male	63 (79.8)
Race
Black	40 (50.6)
Caucasian	32 (40.5)
Other	7 (8.9)
Median creatinine clearance (CrCl) in mL/min	121 mL/min
TBI severity on admission based on GCS score, No. (%)
Mild (GCS score = 13-15)	14 (17.8)
Moderate (GCS score = 9-12)	11 (13.9)
Severe (GCS score ≤8)	54 (68.4)
TBI severity at baseline (amantadine initiation) based on GCS score, No. (%)
Mild (GCS score = 13-15)	29 (36.7)
Moderate (GCS score = 9-12)	21 (26.6)
Severe (GCS score ≤8)	27 (34.2)
Concurrent psychotropic medications, No. (%) a
Anticonvulsants	52 (65.8)
Anxiolytics	3 (3.8)
Sedatives	35 (44.3)
Antipsychotics	27 (34.2)
Anticholinergics	18 (22.8)
Antihistamines	17 (21.5)
Antidepressants	3 (3.8)
Benzodiazepines	40 (50.6)
Sympathomimetics	2 (2.5)

Note. TBI = traumatic brain injury; GCS = Glasgow Coma Scale; NMDA = N-methyl-D-aspartate.

^aNo patients received NMDA receptor antagonists, other dopaminergic agents, or acetylcholinesterase inhibitors.

Outcomes

The primary outcome, the mean change in 72-hour GCS score from baseline, was +0.75 (95% confidence interval [CI] = 0.09-1.42, P = .027). Similarly, the mean change in COT GCS score from baseline was +2.29 (95% CI = 1.68-2.90, P < .001). The Pearson correlation analysis produced no significant relationship between change in GCS score and %PT/OT participation at 72 hours and during the COT (r = −0.15 and −0.02, respectively). In the first 72 hours, patients participated in 61.3% of PT/OT sessions that were ordered, whereas during the COT, participation was 65.9%. The complete results of the primary and secondary endpoints can be found in Table 2.

Table 2.

Results—Study Endpoints.

GCS and PT/OT endpoints	Mean (95% CI)	r	P
Primary endpoint (n = 79)
Mean change in 72-hour GCS (72-hour GCS—baseline GCS)	+0.75 (0.09-1.42)		.027
Secondary endpoints (n = 79)
Mean change in COT GCS (COT GCS—baseline GCS)	+2.29 (1.68-2.90)		<.001
Correlation between GCS & PT/OT session
72-hour GCS and 72-hour % PT/OT session participation		−0.15	.24
COT GCS and COT % PT/OT session participation		−0.02	.74
Additional endpoints
Mean 72-hour %PT/OT session participation (SD, range), n = 58	61.3 (43.0-100)
Mean COT %PT/OT session participation (SD, range), n = 76	65.9 (34.0-100)

Note. GCS = Glasgow Coma Scale; PT = physical therapy; OT: occupational therapy; CI = confidence interval; COT GCS = Course of Therapy Glasgow Coma Scale.

Time from TBI to amantadine initiation was approximately 8.2 days and the mean amantadine COT was 12.1 days. Only 7.6% of the patients received amantadine for <72 hours. Patients received a median TDD of 200 mg in the first 72 hours. During the COT, patients received a median TDD of 127 mg. The mean LOS was 22.8 days, whereas ICU LOS was 11.3 days, and non-ICU LOS was 11.6 days. The complete results of additional descriptive results can be found in Table 3.

Table 3.

Results—Descriptive (n = 79).

Median amantadine total daily dose, mg (range)
72-hour amantadine dose	200 (33-267)
COT amantadine dose	127 (9-211)
Mean amantadine COT in days (SD, range)	12.1 (9.3, 0.5-49.5)
Mean time from TBI to amantadine initiation in days, (SD, range)	8.2 (10.5, 0.08-65)
Baseline GCS score (at amantadine initiation), mean (SD, range)	10.4 (3.4, 3-15)
72-hour GCS score (post-amantadine initiation), mean (SD, range)	11.1 (3.7, 3-15)
COT GCS score (GCS at amantadine discontinuation), mean (SD, range)	12.7 (2.9, 6-16)
Discharge GCS score, mean (SD, range)	12.7 (2.9, 6-16)
Total LOS in days, mean (SD, range)	22.8 (15.0, 20-76)
ICU LOS	11.3 (8.1, 0-37)
Non-ICU LOS	11.6 (12.7, 0-69)

Note. COT = course of therapy; TBI = traumatic brain injury; GCS = Glasgow Coma Scale; COT GCS = Course of Therapy Glasgow Coma Scale; LOS = length of stay; ICU LOS = intensive care unit length of stay; non-ICU LOS: non–intensive care unit length of stay.

Subgroup Analysis

For the primary endpoint, a subgroup analysis was performed for confounding variables. There were no statistically significant differences among subgroup categories of admission TBI severity, baseline TBI severity, time to amantadine initiation, and concurrent psychotropic medications. However, there was a trend toward a higher mean 72-hour change in GCS score when amantadine was initiated earlier in the hospital admission (<72 hours [+1.36] vs >72 hours [0.105]). The complete results of the subgroup analysis can be found in Table 4.

Table 4.

Subgroup Analyses.

Subgroup analyses	Mean change in 72-hour GCS	P
Admission TBI severity (n = 79)
Mild (n = 14)	−0.50	.405
Moderate (n = 11)	+1.36
Severe (n = 54)	+0.52
Baseline TBI severity (n = 79)
Mild (n = 29)	−0.52	.138
Moderate (n = 21)	+0.62
Severe (n = 27)	+1.33
Time to amantadine initiation
<72 hours (n = 22)	+1.36	.169
>72 hours (n = 57)	+0.105
Concurrent psychotropic medication vs no psychotropic medication
Anticonvulsants (n = 52) vs none (n = 27)	+0.71 (vs −0.04)	.405
Benzodiazepines (n= 40) vs none (n = 39)	+0.23 (vs +0.69)	.552
Sedatives (n = 35) vs none (n = 44)	+0.14 (vs +0.70)	.491
Antipsychotics (n = 27) vs none (n = 52)	+0.04 (vs +0.67)	.472
Anticholinergics (n = 18) vs none (n = 61)	+0.22 (vs +0.52)	.785
Antihistamines (n = 17) vs none (n = 62)	+0.59 (vs +0.42)	.827
Antidepressants (n = 3) vs none (n = 76)	−4.67 (vs +0.65)	.155
Anxiolytics (n = 3) vs none (n = 96)	+0.33 (vs +0.46)	.813
Sympathomimetics (n = 2) vs none (77)	+3.00 (vs +0.39)	.410

Note. TBI = traumatic brain injury; GCS = Glasgow Coma Scale.

Discussion

Although amantadine is commonly used to improve arousal in adult patients with acute TBI in the inpatient setting; its efficacy, dosing, and timing of initiation in the inpatient setting are unclear. ²⁰ Prior literature for amantadine use has primarily focused on the subacute and chronic phases, and there is heterogeneity among these studies.^9,10,12,20 Differences in dosing regimens and scoring systems in these studies make them difficult to interpret efficacy and appropriate time to initiate amantadine. ²⁰ For example, Meythaler et al ¹² compared amantadine 200 mg per day with placebo in patients 4 days to 6 weeks post-TBI if their admission GCS score was ≤10, and the study’s primary outcomes were the Disability Rating Scale (DRS) score, Mini-Mental Status Exam (MMSE), the GOS, Galveston Orientation and Amnesia Test (GOAT), and the Functional Independence Measure-Cognitive (FIM-COG^TM) Scale (see Appendix C). On the contrary, in the largest study of amantadine in chronic TBI by Giacino et al, amantadine was titrated up from 100 mg twice daily to a maximum dose of 200 mg twice daily if patients did not show a 2-point improvement in the DRS score.^9,21,22

The aim of this single-center, retrospective, cohort study was to assess the mean change at 72 hours and in COT GCS scores after amantadine initiation during the first hospitalization and to correlate the change in GCS scores with participation in PT and OT among patients who sustained a TBI. We hypothesized that amantadine would improve wakefulness post-TBI at 72 hours and increase the percentage of participation in PT and OT in patients with a TBI. We used the mean change in 72-hour GCS score as our primary outcome because the GCS score is the most commonly used clinical tool to assess arousal in the inpatient setting.^6,7 We found a modest, but statistically significant improvement in our primary outcome, the mean change in 72-hour GCS score from baseline (+0.75 [95% CI = 0.09-1.42], P = .027). We also found a statistically significant improvement in the mean change in COT GCS score from baseline (+2.29 [95% CI = 1.68-2.90], P < .001). Our findings are consistent with Oommen et al ²³ who found a 2.5-point increase in discharge GCS score from baseline when amantadine was initiated to improve the level of consciousness in adult patients with TBI admitted to an ICU. Saniova et al ¹⁵ also observed a significantly higher GCS score at discharge (amantadine group: 9.76 ± 3.95 vs standard of care group: 5.73 ± 3.57, P < .0001) and a significantly lower mortality rate (P < .001) in ICU patients with a severe TBI receiving intravenous amantadine 200 mg twice daily for 3 days compared with the standard of care group. Although our study evaluated the mean change in COT GCS score from baseline, our discharge GCS score was identical to our COT GCS score (see Table 3) making our study finding comparable with the Oommen et al ²³ and Saniova et al ¹⁵ study results which showed improvements with amantadine use on the discharge GCS score. Similarly, Ghalaenovi et al ²⁴ also found a significantly higher change in GCS score at day 7 from baseline in ICU patients with a TBI receiving amantadine 100 mg twice daily compared with placebo (4 vs 2.34, P = .044). They concluded their findings suggest a faster recovery and a clinically significant improvement. ²⁴ The changes in GCS scores we observed in our study may suggest some neurological improvement. However, the mean change at 72 hours and in COT GCS scores was not correlated with the percentage of PT/OT session participation at both time points, r = −0.15 and r = −0.02, respectively. Although there is heterogeneity among these studies and there is no consensus on the change in GCS score that is considered clinically significant, these findings suggest amantadine may be used to improve arousal in the acute setting post-TBI.

There are several factors that could have contributed to the small change in mean 72-hour GCS score in our study. Amantadine initiation later in the hospital course may have blunted the mean change in 72-hour GCS and COT GCS scores we found. In the subgroup analysis, we observed a trend toward a higher mean change in 72-hour GCS score when amantadine was initiated within 72 hours after admission (+1.36) compared with >72 hours (+0.105) (see Table 4). It is worth noting that our sample size for subgroup analyses based on time to amantadine initiation may have been too small to detect a significant difference (P = .169, see Table 4). In the study by Ghalaenovi et al, ²⁴ amantadine was initiated as early as 3.2 days after TBI, whereas patients in our study initiated amantadine approximately 8.2 days after TBI. Given these findings, earlier initiation of amantadine may lead to a greater improvement in GCS score due to its neuroprotective properties in the acute phase post-TBI by decreasing excitotoxicity and apoptosis.^{16 -18,24} Furthermore, concurrent psychotropic medications administered during amantadine COT, such as antipsychotics, anticonvulsants, and benzodiazepines, may have further contributed to decreased alertness. These medications are commonly used in inpatient TBI management. ¹⁰ In a multicenter, prospective, observational, cohort study of acute inpatient rehabilitation centers and hospitals, Hammond and colleagues ²⁵ also reported similar use of anticonvulsants, antipsychotics, and anxiolytics. However, in our subgroup analysis, there were no statistically significant associations between these medication classes with the primary outcome.

One of the strengths of this study was the use of the GCS score as the primary outcome. Although there is no gold standard tool for assessing the level of consciousness in patients with TBI, the GCS score is the most widely used clinical tool worldwide in the inpatient setting. ⁹ Similar studies have used the GCS score as a primary outcome.^15,19,20 Post-traumatic amnesia duration and the GCS score have been used to determine the severity of a TBI with lower GCS scores being associated with longer post-traumatic amnesia duration and mortality.^9,24 Higher GCS scores are associated with increased likelihood of recovering from a TBI without developing a disability, whereas a decline in the GCS score from admission score has been associated with an increase in early mortality.^9,25 Furthermore, we also evaluated the impact of GCS score improvement on clinical outcomes: PT and OT participation.

Our study had several limitations. Given that our study has a single-center, retrospective, single-group design, it reduces the external and internal validity of our study. Specifically, the single-center design narrows the generalizability of our study while the retrospective design of this study led to missing or incomplete data, which affects our study’s internal validity. Furthermore, the single-group design is not ideal as having a comparator group would help to better assess the true effect of amantadine on our study endpoints compared with a control group or another treatment group. In addition, GCS scores are reported as numerical totals of the 3 subsections in the electronic medical record. As a result, if patients had a tracheostomy and were unable to speak, they may have missed some points in the verbal response section. We were also unable to capture comorbid conditions such as hypotension and infection. Last, the average COT was 12 days. Consequently, we were only able to monitor outcomes during this short time period.

Conclusion

There was a modest but statistically significant increase in the mean change in 72-hour GCS score and COT GCS score; however, these GCS score improvements were not correlated with percent PT/OT participation. Therefore, the clinical significance of the GCS score improvement needs further clarification. Furthermore, other studies are needed to determine the appropriate time and GCS score to initiate amantadine and the optimal dose of amantadine in the inpatient setting.

Appendix

Appendix A.

ICD Codes.

ICD-9 codes for TBI	ICD-10 codes for TBI
• 850 Concussion • 851 Cerebral, cerebellar, or brain stem contusion or laceration • 852 Subarachnoid, subdural, or extradural hemorrhage following injury • 853 Other and unspecified intracranial hemorrhage following injury • 854 Intracranial injury of other and unspecified nature	• S06.0 Concussion • S06.1 Traumatic cerebral edema • S06.2 Diffuse TBI • S06.3 Focal TBI • S06.4 Epidural hemorrhage • S06.5 Traumatic subdural hemorrhage • S06.6 Traumatic subarachnoid hemorrhage • S06.8 Other specified intracranial injuries • S06.9 Unspecified intracranial injury

Note. ICD = International Classification Diseases; TBI = traumatic brain injury.

Appendix B.

Concurrent Medications.

Antipsychotics	Dopaminergic agents	Anticonvulsants	Antidepressants	Anxiolytics	Benzodiazepines	Anticholinesterase inhibitors	Anticholinergics	Sympathomimetics	Antihistamines	NMDA receptor antagonist	Miscellaneous
Droperidol Haloperidol Fluphenazine Pimozide Thiothixene Trifluoperazine Molindone Loxapine Chlorpromazine Mesoridazine Thioridazine Clozapine Olanzapine Quetiapine Risperidone Ziprasidone Melperon	Carbidopa/levodopa Bromocriptine Pergolide Pramipexole Ropinirole Selegiline	Phenobarbital Clonazepam Primidone Topiramate	Amitriptyline Amoxapine Clomipramine Desipramine Doxepin Imipramine Maprotiline Notriptyline Trimipramine Protriptyline Isocarboxazid Phenelzine Tranylcypromine Citalopram Escitalopram Fluoxetine Fluvoxamine Paroxetine Sertraline Bupropion Mirtazapine Nefazodone Venlafaxine Duloxetine	Buspirone Chloral hydrate Zolpidem Zopiclon	Chlordiazepoxide Clonazepam Clorazepate Diazepam (valium) Flurazepam Estrazolam Lorazepam Temazepam Alprazolam Midazolam Oxazepam Triazepam	Donepezil Galantamine Rivastigmine	Atropine Benztropine Bepiriden Cyclopentolate Dicyclomine Glycopyrrolate Hyoscyamine Mepenzolate Methscopolamine Procyclidine Scopolamine Tolterodine Triheylpehidyl Trimethobenzamide	Methylphenidate Dexmethylphenidate Dextroamphetamine Dextroamphetamine Dextroamphetamine and racemic amphetamine Pemoline Phentermine Sibutramine Atomoxetine	Promethazine	Memantine	Metoclopramide

Note. NMDA = N-methyl-D-aspartate.

Appendix C.

Scoring Systems.

Scoring	Description
GCS score5 -7	Used to assess severity of TBI and level of consciousness. Three components, eye opening, verbal, and motor response are used to generate a maximum score of 15 points. • Mild: 13-15 • Moderate: 9-12 • Severe: ≤8 as severe
DRS 16	A modified GCS score with the following components: eye opening, communication ability, motor response, employability, level of functioning, and cognitive ability by assessing feeding, toileting, and grooming ability. It ranges from 0 to 29 with higher scores indicating a more severe disability.
GOS Score 17	The GOS score is a functional assessment tool for outcomes after a severe brain injury. Scores range from 1 (death) to 5 (good recovery).
CRS-R 18	CRS-R is a standardized and validated neurobehavioral assessment tool with the following 6 components: auditory, visual, motor function, oromotor/verbal function, communication, and arousal. The scores range from 0 to 23 and higher scores are associated with higher functionality.
MMSE score19,20	The MMSE is a cognitive assessment tool used to assess cognitive impairment. Some components of the MMSE include orientation to time and place, recall, naming, etc. The maximum score is 30 points and scores <24 are associated with cognitive impairment.
FOUR score21,22	A validated tool to assess the level of consciousness in patients with TBI. Components include eye response, motor response, brain stem reflexes, and respiration. The scores range from 0 to 16 and higher scores are associated with a higher level of consciousness. It can be used in patients who are intubated and can be used to recognize locked-in syndrome.
FIM-COG™ Scale 26	The FIM scale is a clinical tool with 7 sections that is used to determine the level of assistance a patient requires to complete activities of daily living. The FIM-COG™ is a subscale of the FIM scale, which focuses on social cognition and communication. The FIM-COG™ scores range from 5 to 35 points and lower scores are associated with more cognitive dependence.

Note. GCS = Glasgow Coma Scale; TBI = traumatic brain injury; DRS = Disability Rating Scale; GOS = Glasgow Outcome Scale; CRS-R = Coma-Recovery Scale–Revised; MMSE = Mini-Mental Status Exam; FOUR = Full-Outline of Unresponsiveness; FIM-COG™ = Functional Independence Measure Cognitive; FIM = Functional Independence Measure.