6.4 Pharmacoligical Interventions to Assis with Cognitive Recovery Post ABI
6.4.1 Donepezil
The effectiveness of the cholinesterase inhibitor, Donepezil, for improving cognitive functioning and memory dysfunction following brain injury has been assessed. Memory dysfunction following an ABI is a common occurrence. The long term impairment of an ABI affects a persons ability to return to work, school and it can affect their ability to live alone (Katz et al., 1989). According to Zhang et al. (2004), pharmacologic intervention using a cholinergic agonist to help facilitate cognitive deficits following TBI had not been studied previously; however, when tested with individuals who have been diagnosed with Alzeihmers, donepezil has been found to be useful in treating memory problems (Walker et al., 2004; Morey et al., 2003).
Individual Studies
Table 6.18 Effect of Donepezil on Memory and Cognitive Functioning
| Author/ Year/ Country/ Study design/ PEDro and D&B Score |
Methods |
Outcome |
|
Zhang et al., (2004) USA RCT PEDro = 7 D&B = 23 |
N=18 Individuals with a history of TBI of any severity with attention or short-term memory impairments as shown by WMS III, and PASAT were randomly assigned to treatment group A (received donezepil orally for 10 weeks, followed by a 4 week washout period, followed by 10 weeks of a placebo) and group B (opposite order as group A). Outcomes measured at baseline, wk 10 and wk 24. There were no statistical differences between groups at baseline. |
Group A (donepezil phase) showed significant improvement over group B (placebo phase) on immediate auditory (p=0.002) and visual memory (p<0.001) measures of WMS-III and PASAT (p<0.001) at wk 10. Increased scores in Group A were continued following washout. Group B improved following donepezil phase (wk 24)– but inter-group comparisons were not significant (audio: p=0.588; visual: p=0.397, PASAT presentation rates p=0.545, 0.12, 0.783, 0.410) due to Group A’s sustained high scores. |
|
Khateb et al., (2005) Switzerland Case Series D&B = 13 |
N=10 Individuals who had sustained a moderate or severe TBI we administered 5 mg/day for 1 month, followed by 10 mg/day for 2 months. The following assessments were completed: Affective & Behavioural assessment (HAD & DEX questionnaire), Neuropsychological Evaluation (executive functioning, learning and memory and attention) outcome measurements and analysis |
Changes on the neuropsychological evaluation show modest improvement. For executive functioning, significant improvement was only seen on the Stroop Colour naming test; for learning and memory the RAVMT (learning) and for attention (from the test for attentional performance) significant improvement was only seen on the subsection divided attention (errors). Patients reported increased energy and a decrease in feelings of apathy. Scores on the Affective Behaviour Assessment indicated a reduction in anxiety, depression & fatigue post administration of donepezil; however this improvement was only marginally significant (p<0.058). |
|
Morey et al., (2003) USA Case Series D&B=15 |
N=7 Single subject ABAC design with patients (5 males and 2 females) who received 5-10 mg/day of donepezil (Aricept). Each participant served as his/her own control. Repeated measures analysis of variance was used. | Significant improvements in immediate and delayed memory were found when taking 10 mg/day of Aricept, as measured by the Brief Visual Memory Test-Revised. |
|
Masanic et al., (2001) Pre-Post D&B=14 |
N=4 Sixteen-week open-label study of patients with chronic, severe TBI who were given donepezil 5 mg daily for 8 weeks followed by donepezil 10 mg daily for 4 weeks. | Mean scores for short-term and long-term recall on the Rey Auditory Verbal Learning Test improved by 1.04 and 0.83 standard deviations above baseline. Additionally, Complex Figure Test short-term and long-term recall mean scores improved by 1.56 and 1.38 standard deviations above baseline as well. |
|
Taverni et al., (1998) USA Case study No score |
N=2 Case study of patients who were treated with donepezil was completed. | Improvements in memory were seen in both patients within 3 weeks of beginning donepezil. |
PEDro = Physiotherapy Evidence Database rating scale score (Moseley et al., 2002).
D&B = Downs and Black (1998) quality assessment scale score.
Discussion
Zhang et al. (2004) conducted a randomized placebo controlled double-blind cross-over trial of 18 post acute TBI patients which demonstrated that donezpil significantly increased scores on tasks of sustained attention and short-term memory when compared to placebo and that these improved results were sustained after the wash-out period. Khateb et al.(2005)found only modest improvement on the various neuropsychological tests used to measure executive function, attention and learning and memory. Of note results from the learning phase of Rey Auditory Verbal Memory Test (RAVMT) showed significant improvement (p<0.05). To assess improvement in executive function, results from the Stroop-colour naming test showed significant changes (p<0.03). On the test for Attentional Performance (TAP) a significant change was noted on the divided attention (errors) subsection of the test.
In a sixteen-week open-label study, mean scores for short-term and long-term recall on the Rey Auditory Verbal Learning Test improved by 1.04 and .83 standard deviations above baseline. Complex Figure Test short-term and long-term recall mean scores improved by 1.56 and 1.38 standard deviations above baseline as well (Masanic et al., 2001). In a case study conducted by Taverni et al (1998) patients (n=2) who participated reported improvements in memory within three weeks of beginning donepezil. Similar findings were also reported by Morey et al., (2003).
Conclusions
Based on a single RCT, there is Level 1 evidence that Donepezil improves attention and short-term memory post ABI.
|
Donepezil helps to improve attention and short-term memory following brain injury.
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6.4.2 methylphenidate
Methylphenidate is a stimulant whose exact mechanism is unknown (Napolitano, et al., 2005). Although it is thought to act on the presynaptic nerve and it also acts to restrain the reabsorption of serotonin and norephinephrine (Kim et al., 2006). Methylphenidate has been extensively used as a treatment for attention deficit disorder, as well as narcolepsy with both the TBI and non-BTI populations (Glenn, 1998).
Individual Studies
Table 6.19 Effect of Methylphenidate on Cognitive Functioning
| Author/ Year/ Country/ Study design/ PEDro and D&B Score |
Methods |
Outcome |
|
Willmot and Ponsford 2009 PEDro = 10 D&B =26 |
N=40 Patients received either methylphenidate 0.3mg/kg BID rounded to the nearest 2.5 mg or a placebo. Patients were seen for 6 sessions across 2 week period. Sessions were in 3 blocks, with patients receiving the MHD on one session of each block. Placebo was given on the other session. | MHD was seen to improve the speed of processing information without reducing the accuracy of the information being processed. When looking at the results of the various scales used to measure speed at which information is processed, significant increases were seen on all (the Ruff 2 and 7 attention test, Selective Attention Task, Four Choice Reaction Time Task, Sustained Attention to Response Task, Symbol Digit Modalities test, Letter Number Sequencing Task, Wechsler Test of Adult Reading, Rating Scale of Attentional Beh.) while patients were on the MHD. If note individuals with lower GCS also had much slower processing speed. Results of symbol digit modalities test was seen to significantly improve in these patients while on the MHD. |
|
Kim et al., (2006) Korea RCT D&B = 17 PEDro = 6 |
N=18 Double-blind placebo-controlled trial of subjects with TBI. The participants were randomly divided into one of two treatment groups: (1) single-dose (20mg) of methylphenidate; or (2) placebo. Outcome measured using visuospatial attention tasks. | Improvements in response accuracy were demonstrated in favour of the treatment group although not to a level of statistical significance. |
|
Plenger et al., (1996) USA RCT D&B = 17 PEDro = 5 |
N=23 Double- blind RCT of subjects ranging in age from 16 to 64 years administered .30 mg/kg of methylphenidate twice a day. 9 subjects completed the study | Methylphenidate significantly improved attention. |
|
Whyte et al., (2004) USA RCT D&B = 19 PEDro = 8 |
N=34 Double-blind crossover study of methylphenidate (0.3 mg/kg/dose) versus placebo measured by sustained/divided arousal, attention, distraction tasks with varying target rates on subjects, between 16 and 60 with a non-penetrating TBI resulting in LOC (GCS<12), PTA > 1 hour or a focal abnormality (neuro-imaging); outcome measures included subject response as well as reports from treating clinicians and caregivers. | 54 dependent variables reduced to 13 composite factors revealing significance in three treatment effects: information processing speed (p<0.001), work task attentiveness (p=0.01), and caregiver attention ratings (p=0.01). Of 13 independent variables, one showed significant treatment effects: reaction time before errors in sustained attention to response task (p=0.03). No treatment-related improvements observed in susceptibility to distraction, and divided or sustained attention. |
|
Speech et al., (1993) USA RCT D&B = 18 PEDro = 7 |
N=12 Moderate-to-severe closed-head-injury patients randomly assigned to a treatment group receiving 0.3mg/kg bid of methylphenidate for 1 week followed by placebo, and control group receiving a placebo for 1 week followed by methyphenidate treatment. Attention, cognitive processing speed, learning and social personality functioning measures applied at the end of each week, 1 hr after last dose. | No significant differences found between drug and placebo condition in any outcome measure. |
|
Pavlovskaysa et al., (2007) Israel D&B =14 |
N=6 Individuals who had sustained a TBI were selected to participate in the current study. Participants were administered 5 to 10 mg of MHP over a 2 week period. Medication was gradually reduced at this point. Participants were evaluated before, during and after the administration of MPH. | Prior to treatment, patients were found to have great difficulty in shifting attention between hemifields. Once patients were placed on MHP, an improvement in the asymmetry was noted. This improvement was also noted 2 weeks after the medication was discontinued. Study authors noted that left side recovery improved once the medication was begun. Overall MPH improved attentional imbalance in patients post TBI. |
PEDro = Physiotherapy Evidence Database rating scale score (Moseley et al., 2002).
D&B = Downs and Black (1998) quality assessment scale score.
Discussion
Several studies have investigated the effectiveness of methylphenidate on cognitive rehabilitation post ABI. Willmott and Ponsford (2009) found that administering methylphenidate to a group of patients during inpatient rehabilitation, did significantly improve the speed of information processing. In a RCT examining the effects of methylphenidate, a psychostimulant on attention, Whyte et al. (2004) indicated that speed of processing, attentiveness during individual work tasks and caregiver ratings of attention were all significantly improved with methylphenidate treatment. No treatment related improvement was seen in divided or sustained attention or in susceptibility to distraction. Another RCT by Plenger et al. (1996) also found that methylphenidate significantly improved attention.
Speech et al. (1993) conducted a double blind placebo controlled trial evaluating the effects of the stimulant medication methylphenidate following closed head injury. Here the administration of methylphenidate did not significantly improve attention, information processing speed, or learning compared to placebo on. This is in contrast to the results noted by Whyte et al. (2004) and Plenger et al. (1996). Kim et al. (2006) examined the effects of a single-dose treatment of methylphenidate and, although a trend was found in favour of improved working and visuospatial memory for the treatment group, once again results did not reach significance. In the case series conducted by Pavlovskaya et al. (2007), methylphenidate was found to significantly improve the patients’ ability to shift their attention from a precure on the right to one on the left.
Conclusions
Although several of the studies reviewed found methylphenidate did improve cognitive functioning post ABI, the results were conflicting. To date there is no clear evidence supporting the administration of methylphenidate to improve cognitive functioning in individuals who have a moderate to severe ABI.
|
The effectiveness of methylphenidate treatment to improve cognitive impairment following brain injury is unclear.
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6.4.3 Sertraline
Individual Studies
Table 6.20 Effect of Sertraline on Cognitive Functioning Post ABI
| Author/ Year/ Country/ Study design/ PEDro and D&B Score |
Methods |
Outcome |
|
Banos et al., (2010) USA RCT PEDro = 9 D&B= 22 |
N=99 Individuals with a moderate to severe TBI were recruited within the first 8 weeks post injury. All were randomized to either the treatment group (n=49 - sertraline 50 mg 1xdaily) or placebo (n=50). Patients were assessed at 3, 6 and 12 months. Outcome measures used to assess patients were: Wechsler memory scale, trail making test, Wechsler adult intelligence scale, neurobehavioral functioning inventory. | More subjects in the treatment group were seen to have dropped out at each of the 3 assessment points. Those in the placebo groups at the 6th and 12th month assessment period were older than the control group and had higher GCS. Overall, there were not significant differences between the two groups, thus early administration of sertraline was not found to improve cognitive functioning during the first year post ABI. In both groups 40-50% of study participants dropped out. |
PEDro = Physiotherapy Evidence Database rating scale score (Moseley et al. 2002).
D&B = Downs and Black (1998) quality assessment scale score.
Discussion
In an effort to improve cognitive function, Banos et al. (2010) randomly assigned a group of 99 TBI patients to either a control group (n=50) or a treatment group (n=49). The treatment group was administered 50 mg of sertraline once daily , while the control group was administered a placebo. Patients were assessed at 3, 6 and 12 months post sertraline administration. Various neuropsychological tests were completed at each time period. Cognitive functioning was not found to improve following the administration of sertraline.
Conclusions
There is Level 1 evidence showing that sertraline does not improve cognitive functioning in individuals who have sustained a moderate to severe ABI.
|
Sertraline has not been shown to improve cognitive functioning within the first 12 months post injury.
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6.4.4 Amantadine
Amantadine is a non-competitive N-methyl-D-aspartate receptor antagonist and is currently used as an antiviral agent used as a prophylaxis for influenza A, for the treatment of neurological diseases such as Parkinson’s Disease and in the treatment of neuroleptic side-effects such as dystonia, akinthesia and neuroleptic malignant syndrome (Schneider et al.,1999). It is also thought to work pre- and post-synaptically by increasing the amount of dopamine (Napolitano et al., 2005).
One study was identified that investigated the effectiveness of amantadine as a treatment for the remediation of learning and memory deficits andcognitive functioning following brain injury.
Individual Studies
Table 6.21 The Effect of Cerebrolysin on Cognitive Functioning Following Brain Injury
| Author/ Year/ Country/ Study design/ D&B Score |
Methods |
Outcome |
|
Schneider et al., (1999) USA RCT D&B = 18 PEDro= 5 |
N=20 TBI rehabilitation subjects randomly assigned to treatment and placebo groups to test the effectiveness of amantadine on cognitive and behavioural rehabilitation. | Although there was a general trend towards improvement, results did not reach significance when treatment and placebo groups were compared using ANOVA and regression analysis (p=0.732). |
|
Kraus et al., (2005) USA Pre-Post D&B = 14 |
N=22 subjects with chronic brain injury and complaints of cognitive impairment participated in this pre- and post- 12-week treatment. Patients were given 400mg of amantadine. | No significant differences were noted on measures of attention or memory deficits. |
|
Nickels et al., (1994) USA Case Series D&B=12 |
N=12 Retrospective chart review of subjects with brain injury treated with amantadine. | 10 of the 12 subjects experienced some improvement in cognitive and/or physical function while using amantadine. 5 of the 12 subjects experienced side effects that included pedal oedema, hypomania, generalized seizure, and visual hallucinations. |
D&B = Downs and Black (1998) quality assessment scale score.
Discussion
In this RCT completed by Schneider et al. (1999) the effects of amantadine on cognition and behaviors was assessed. Here, twenty patients were included in the study and each were prescribed amantadine for 2 weeks. Statistical comparison of results evaluating the five subsets of attention, executive/flexibility, memory, behavior and orientation did not demonstrate any significant effect for the use of amantadine. Kraus et al. (2005)again looked at the effects on executive functioning amantadine has on individuals who have sustained a moderate to severe TBI. Of note no significant differences were found for measures of memory deficits or attention. In a chart audit conducted by Nickels et al. (1994), although some improvement in attention was noted, serious side effects from the medication were also seen, thus questioning the use of this medication with this population.
Conclusions
There is Level 2 evidence that amantadine does not help to improve learning and memory deficits based on the conclusions of a single group intervention study.
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Amantadine may not be an effective treatment to improve learning and memory deficits and executive function following brain injury.
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6.4.5 Pramiracetam
Pramiracetam is a nootropic (noo = mind, tropic = towards) or cognitive activator that facilitates learning and treats memory deficiencies and other cognitive problems. It produces an increased turnover of acetylcholine in hippocampal cholinergic nerve terminals and is at least 100 times more effective than its original compound piracetam (McLean Jr.et al., 1991).
Individual Studies
Table 6.22 Effect of Pramiracetam on Memory Post ABI
|
Author/Year/ Country/Study design/PEDro & D&B Score |
Methods | Outcome |
|
McLean et al., (1991) USA RCT PEDro=7 D&B=16 |
N=4 Double-blind RCT of a small group of males aged 24-37 treated with two 3-week blocks each of 400 mg of oral pramiracetam TID and placebo over 12 weeks. | Clinically significant improvements were found for memory after the administration of pramiracetam. These improvements remained at one month after discontinuation of the drug. |
PEDro = Physiotherapy Evidence Database rating scale score (Moseleyet al. 2002).
D&B = Downs and Black (1998) quality assessment scale score.
Discussion
McLean et al. (1991) conducted a double-blind, placebo-controlled, randomized trial on pramiracetam on 4 males aged 24-37. The medication was given orally to the subjects in a 400 mg dose three times per day and its effects on memory and cognition were assessed. Clinically significant improvements were found for memory and these improvements remained at one month following discontinuation of the drug.
Conclusions
Based on a single RCT, there is Level 1 evidence that pramiracetam produces significant clinical improvements on males’ memory which is sustained at one month following discontinuation of the drug.
|
Pramiracetam may improve memory in males.
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6.4.6 Physostigmine
Physostigmine is a cholinergic agonist that temporarily stops acetylcholinesterase, which in turn slows the destruction and increases the concentration of acetylcholine at the synapse. Its use in Alzheimer’s disease has been examined at length. It has also been proposed to improve memory in head-injured patients (McLean Jr. et al., 1987).
Individual Studies
Table 6.23 Effect of Physostigmine on Memory Post ABI
|
Author/Year Country/ Study design/ PEDro & D&B Score |
Methods | Outcomes |
|
Cardenas et al., (1994) USA RCT PEDro=6 D&B=18 |
N=36 Double blind RCT of men with brain injury who were randomized to receive physostigmine, scopolamine, and placebo. | 44% of the participants experienced improved memory scores with the use of physostigmine. |
|
McLeanJr. et al., (1987) USA Case Study No score |
N=1 Double blind, placebo-controlled, single-subject ABA design involving 2 single-case studies who received physostigmine combined with a memory training programme. | Both cases experienced a clinically significant improvement in memory function, but no significant improvements in attention, concentration, cognitive flexibility, or motor speed. |
PEDro = Physiotherapy Evidence Database rating scale score (Moseleyet al. 2002).
D&B = Downs and Black (1998) quality assessment scale score.
Discussion
Cardenas et al. (1994) conducted a double-blind, placebo-controlled study on 36 men with brain injury who were randomized to receive either oral physostigmine, scopolamine, or placebo. Improved memory scores were found for 44% of the subjects who received oral physostigmine with the Long-term Storage section of the Selective Reminding Test being the most sensitive measure of this.
A double-blind, placebo-controlled, single-subject ABA design involving two single-case studies examined the effects of physostigmine combined with a memory training programme (McLean, Jr. et al., 1987). In both cases, a clinically significant improvement was experienced in memory function, while no significant changes were experienced in attention, concentration, cognitive flexibility, or motor speed.
Conclusions
Based on a single RCT, there is Level 1 evidence that physostigmine improves memory in men with brain injury.
There is Level 5 evidence, from one case study, that physostigmine combined with a memory training programme produces a clinically significant improvement in memory function, but does not produce significant changes in attention, concentration, cognitive flexibility, or motor speed.
|
Physostigmine improves memory in men with brain injury, but not attention, concentration, motor speed, or cognitive flexibility.
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6.4.7 Bromocriptine
Bromocriptine is a dopaminergic agonist, which primarily affects D2 receptors (Whyte et al., 2008) It has been suggested that dopamine is an important neurotransmitter for prefrontal function (McDowell et al., 1998).In a study looking at the effects of bromocriptine on rats, Kline et al. (2002) noted that the animals showed improvement in working memory and spatial learning; however, this improvement was not seen in motor abilities. Four studies have been identified investigating the use of bromocriptine as an adequate treatment for the recovery of cognitive impairments following brain injury.
Individual Study
Table 6.24 Effect of Bromocriptine on Executive Functioning Following Brain Injury
|
Author/Year/ Country/Study design/PEDro & D&B Score |
Methods | Outcome |
|
Whyte et al., (2008) USA RCT PEDro=7 D&B=22 |
N=12 Bromocriptine or placebo was administered for 4 weeks, (starting dose was 1.25 mg/BID, final dose was 5 mg/BID). Medication was increased every 2 days until the dose reached 5 mg BID. During week 4 the medication was tapered until it was eliminated. Once this phase was complete the group was put on the placebo. The placebo group then became the bromocriptine group. Study continued for about 8 weeks. During the study participants encaged in various attention tasks: Sustained arousal and attention task (50/50), sustained arousal and attention task (20/80), speed/accuracy trade off task, distraction task, choice RT task, dual task, sustained attention to response to task, test of every day attention, inattentive behaviour task, classroom attentiveness, attention ratings. | It was noted that several participants did experience moderate to severe drug effects and withdrew or were withdrawn from the study. Test results for all subjects indicate bromocriptine had little significant effect on their abilities to perform on a range of measures of attentional function. |
|
McDowell et al., (1998) USA RCT PEDro = 4 D&B = 16 |
N=24 Subjects suffering a TBI (closed or open) with loss of consciousness (GCS < 8). Patients randomized into treatment (Bromocriptine 2.5 mg) and placebo groups. Measures required prefrontal cortex function (working memory, executive control) and were administered using a laptop computer (except trail making and control task) Testing took place 90 minutes after pill administration. | Central executive testing: following drug treatment there were significant improvements on dual task counting (p=0.028), dual task digit span (p=0.016), trail making test (p=0.013), Stroop Interference Test (p=0.05), FAS Test (p=0.02), Wisconsin Card Sorting (p=0.041). The treatment drug had no significant effects on working memory tasks (p=0.978), or control tests (p=0.095) |
|
Powell et al., (1996) UK Case series D&B=12 |
N=11 An open, multiple baseline design of a group of patients (6 men and 5 women) who were administered bromocriptine. | The use of bromocriptine was associated with improvements in all measures of motivational deficits except mood, as measured by innovative structured tools that could quantify these deficits. |
|
Dobkin and Hanlon (1993) USA Observational case study No Score |
N=1 A blinded, controlled, alternating repeated-measures design of a 33-year-old woman who was treated with bromocriptine. | Significant improvements in verbal learning, functional memory, and daily recall were observed. |
PEDro = Physiotherapy Evidence Database rating scale score (Moseley et al., 2002).
D&B = Downs and Black (1998) quality assessment scale score.
Discussion
Bromocriptine is a dopaminergic agonist, which is believed to have an effect on frontal lobe functioning. In a randomized placebo controlled cross over study Whyte et al. (2008) administered bromocritpine to a group of individuals. Administration of bromocriptine was begun at 1.25mg/BID and increased to 5mg/BID. Individuals received the medication for 3 weeks before being titrated off the medication and placed on a placebo. Test results for all subjects indicate bromocriptine had little significant effect on their abilities to perform on a range of measures of attentional function. It was noted that several participants did experience moderate to severe drug effects and withdrew or were withdrawn from the study. In an earlier study, McDowell et al. (1998) examined the effects of low dose bromocriptine in a double-blinded, placebo-controlled cross-over design trial. Testing revealed that a low dose of bromocriptine (2.5 mg/daily) improved functioning on tests of executive control including a dual task, trailmaking test, the Stroop test, the Wisconsin Card-Sorting Test and the controlled oral word association test (FAS test). However, bromocriptine did not significantly influence working memory tasks.
A blinded, controlled, alternating repeated-measures design by Dobkin and Hanlon (1993) looked at the effects of bromocriptine on memory impairment. The 33-year-old woman included in their study experienced significant improvements in verbal learning, functional memory, and daily recall.
Powell et al. (1996) carried out a multiple baseline design on eleven patients with TBI or subarachnoid haemorrhage who were administered bromocriptine. Motivational deficits were the main outcomes measured and they were quantified using innovative structured tools that could measure anxiety and depression for instance. Improvements were found on all measures assessed except mood.
Although the McDowell et al. (1998) study demonstrated benefits following administration of bromocriptine, there was only a single administration of bromocriptine or placebo and the dose was considerably lower than that given by Whyte et al. (2008). Spontaneous recovery may have been a factor leading to the improved abilities in individuals receiving a single dose (2.5mg daily) of the medication; however, study results did not answer this question. Results from Whyte et al. (2008) noted that the placebo group demonstrated better (although not significant) trends in improvement on the various tasks administered.
Conclusions
Based on a two RCTs there is conflicting evidence supporting the use of bromocriptine to enhance cognitive functioning.
There is Level 4 evidence that bromocriptine improves all motivational deficits except mood.
There is Level 5 evidence, from one observational study, that bromocriptine significantly improves memory impairments.
|
Bromocriptine improves some executive cognitive functions such as dual-task performance and motivational deficits, but it does not consistently improve memory. More research is needed before the benefits of using bromocriptine to enhance cognitive functioning are known.
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6.4.8 Cerebrolysin
As explained by Alvarez et al. (2003), “Cerebrolysin (EBEWE Pharma, Unterach, Austria) is a peptide preparation obtained by standardized enzymatic breakdown of purified brain proteins, and comprises 25% low-molecular weight peptides and free amino acids.” Cerebrolysin has been demonstrated to have neuroprotective and neurotrophic effects, and has been linked to increased cognitive performance in an elderly population.
Individual Studies
Table 6.25 Effect of Cerebrolysin on Cognitive Functioning Following Brain Injury
| Author/Year/ Country/Study design/D&B Score |
Methods |
Outcome |
|
Alvarez et al., (2003) Spain Pre-Post D&B = 15 |
N=20 Post-acute TBI subjects (etiology not specified, severity determined by initial GCS score) received 20 – 30 ml I.V. Injections of Cerebrolysin solution over 4 weeks. Research staff measured brain bioelectrical activity, cognitive performance and clinical outcome. | Significant decrease in slow brain bioelectrical activity (delta: p < 0.01; theta: p < 0.05); significantly enhanced relative beta activity power (p < 0.01). EEG power ratio scores significantly reduced (p < 0.01) after treatment. Patients with a multi-point evaluation of EEG/brain mapping activity, power ratio scores decreased significantly after treatment (p < 0.05) compared with baseline. Significant improvement in Syndrom-Kurztest (SKT) cognitive performance test scores after treatment (p < 0.01). Patients with a multi-point cognitive evaluation, SKT scores decreased significantly compared to baseline after treatment (p <0.05), but not 3 months later. Significant improvement in GOS scores after treatment (p < 0.05). Significant decrease in serum urea levels and body temperature after treatment (p < 0.05). |
D&B = Downs and Black (1998) quality assessment scale score.
Discussion
In an open label trial of 20 brain-injured patients, Alvarezet al. (2003) investigated the potential benefits of using Cerebrolysin which was administered intravenously 20 times over a 4-week period. Although the study included patients with mild, moderate or severe traumatic brain injury based on the Glasgow Coma Scale score, all patients had significant disability ranging from moderate disability to persistent vegetative state on the Glasgow Outcome Scale. The time since injury varied from 23 to 1107 days with 9 cases less than 1 year post injury and 11 cases greater than 1 year post injury. A brief neuro-psychological battery (SKT) using 9 tests to specifically evaluate memory and attention demonstrated overall significant improvement for the 9 of 20 patients for whom it could be administered. Glasgow Outcome Scores also significantly improved comparing pre to post intervention scores.
Conclusions
There is Level 4 evidence that cerebrolysin, a neurotrophic and neuroprotective medication appears to have potential benefit to improve outcome and cognitive functioning post-brain injury; however, controlled trials will be necessary to evaluate this further.
|
Cerebrolysin may be beneficial for the improvement of cognitive functioning following brain injury.
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6.4.9 Growth Hormone (GH) Replacement Therapy and Cognitive Rehabilitation Post ABI
Following an ABI, it is not uncommon for individuals to be diagnosed with hypopituitarism. In fact as many as 25 to 40 % of individuals with a moderate to severe ABI have demonstrated chronic hypopituitarism (Bondanelli et al., 2007; Kelly et al., 2006; Schneider et al., 2008). Despite this few patients are screened for Growth Hormone Deficiencies (GHD), thus the link between cognitive impairment and GHD has not yet been definitively established (High, Jr. et al., 2010). There is very little literature available on the benefits of GH replacement therapy after a TBI.
Individual Studies
Table 6.26 rh(GH) and its Impact on Cognitive Functioning Post ABI
| Author/Year/ Country/Study design/PERdo & D&B Scores | Methods | Outcome |
|
High Jr et al., 2010 USA PEDro = 8 D&B = 21 |
N=23 Those in the treatment group (n=12) were given rhGH. Initially the drug was administered at 200 ug, followed by a 200ug increase every month until the dosage reached 600 ug. IGF-1 levels were then tested. The control group (n=11) was given a placebo. Both groups received these injections (placebo or rhGH) for one year. During the time patients were given a variety of neuro-psychological tests to assess language, visual/spatial functioning, upper extremity motor functioning, information processing efficiency, working memory/ attention, learning and memory, executive, intellectual and emotional functioning. | Overall study results did not show great improvements on the majority of neuropsychological tests between the two groups. There was however improvement on 4 of the tests used: (1) Finger tapping demonstrated a significant improvement between the treatment and the control group (p<0.01). (2) Processing Speed Index: the treatment group improved significantly over the one year period (p<0.05) and although the control group showed improvement at the end of the first 6 months (p<0.01) this was not seen at the end of the first year. Significant improvement was also noted on the (3) Wisconsin Card Sorting Test (executive functioning) for the treatment group. (4) On the California Verbal learning Test-II improvement was noted for the treatment group on learning and memory. |
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Reimunde et al., 2011 Spain D&B = 14 |
N=19 Patients (only males involved with the study) in the treatment group (n=11) were administered recombinant human GH (rhGH), subcutaneously, .5mg/day for 20 days, then 1 mg/day for 5days each week. The control group (n=8) was given a placebo (1mg/day 5/days/week). All patients were also involved with an individualized cognitive program. | Individuals receiving the GH treatment were found to have significant improvement in their IGF-I plasma levels following 3 months of treatment (p<0.01). These values were similar the control group. Results of the WAIS indicated that the control group improved significantly on the digits and manipulative intelligence quotient (p<0.05). For those in the treatment groups improvement was noted on: understanding digits, numbers and incomplete figures (p<0.05) and similarities vocabulary, verbal IQ, Manipulative IQ, and total IQ (p<0.01). |
PEDro = Physiotherapy Evidence Database rating scale score (Moseley et al. 2002).
D&B = Downs and Black (1998) quality assessment scale score.
Discussion
Two studies were included examining the effects of growth hormone administration on cognitive improvement in those who had sustained a moderate or severe TBI. High Jr et al. (2010) found patients who had been randomly assigned to receive Recombinant Human Growth Hormone (rhGH) performed better on various neuropsychological tests (Finger Tapping, WAIS-III: Processing Speed Index, Wisonsin Card Sorting Test, California Verbal Learning Test II) compared to the control group. Within the treatment group (n=12), study authors were unable to determine who benefited more from the rhGH treatment, those who were GH-insufficient or GH-deficient.
Reimunde et al. (2011) in a cohort study looking at the benefits of administering rhGH to a group of patients who have sustained either a moderate or severe TBI for a three month period. Results of the study indicate that those receiving the rhGH improved significantly on the various cognitive subtests such as: understanding, digits, numbers and incomplete figures (p<0.05) and similarities vocabulary, verbal IQ, Manipulative IQ, and Total IQ (p<0.01). The control group also showed significant improvement but only in digits and manipulative intelligence quotient (p<0.05). Of note IGF-I levels were similar between both groups at the end of the study.
Conclusions
There is Level 1 evidence suggesting rhGH does assist in cognitive
functioning in individuals who are GHD post ABI.
There is Level 2 evidence showing the administration of rhGH does improve cognitive rehabilitation in those who have sustained a moderate to severe TBI.
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The administration of rhGH results in improved cognitive performance in patients who been diagnosed has having a growth hormone deficiency post ABI. Due to the small sample sizes of both studies, further research with larger samples is recommended.
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