Interventional Drugs for TBI Rehabilitation of Cognitive Impairment : The Cholinesterase Inhibitor Rivastigmine

Abstract

As it is increasingly clear that traumatic brain injury (TBI) leads to cognitive problems, particularly posttraumatic memory and attention difficulties at different levels of severity ( ), leading to disability and increased burden not only on sufferers but also on their family and social circle, it is vital to offer treatment options to help overcome the long-lasting cognitive sequela derived from injury ( ).

In this chapter, we will discuss one approach to pharmacological treatment of cognitive abnormalities following TBI: the use of cholinesterase inhibitors, specifically, the intermediate-acting rivastigmine.

Keywords

Attention, Cholinesterase inhibitors, Cognitive impairment, Memory, Rivastigmine, Traumatic brain injury

Introduction

Traumatic Brain Injury: Prevalence, Affected Population, and Sequelae

Traumatic brain injury (TBI) is a noncongenital injury arising from blunt or penetrating injury to the head or from acceleration/deceleration forces. TBI is an important public health problem; an estimated of 1.5–2.0 million Americans are injured each year. TBI accounts for at least 1.4 million of the emergency room visits, close to 300,000 hospital admissions and 52,000 deaths each year. Currently, TBI is considered one of the principal causes of death and disability in active young adults ( ).

The leading causes of TBI in the general populations include motor vehicle crashes, interpersonal violence, and falls ( ). Disabilities resulting from TBI depend on injury severity, location, age, and general health of the individual, although many people who sustain even a mild TBI can experience significant and persistent physical and neuropsychiatric problems ( ). Importantly, reports indicate that between 69% and 80% of patients with TBI will experience a detrimental effect on memory and cognitive abilities ( ).

Overall, approximately three million people in the United States alone are living with disability as a result of TBI. Personal and social costs are estimated to be between 9 and 10 billion dollars per year ( ).

Special Groups: Veterans as High-Risk TBI Population

TBI is one of the most significant health risks related to military duty. Even in peacetime, military personnel have higher rates of TBI than civilians ( ), with the risk of TBI increasing significantly during wartime ( ). In recent conflicts, the most common injuries are caused by improvised explosive devices, rocket-propelled grenades, and land mines ( ). Descriptive studies estimate that approximately 60% of blasts to which military personnel are exposed result in brain injuries ( ). Those injured in combat were found more likely to be medically evacuated, and to have multiple TBI diagnoses, a greater number of all diagnoses, and a more severe TBI, than those not injured in battle ( ).

Cognitive Impairment in TBI

Despite significant variation in the severity of TBI sustained by individuals, data consistently indicate deficits in cognitive functions such as memory, attention, speed of information processing, and executive functions among individuals with mild to severe head injury ( ). These data indicate that approximately 10–15% of people with mild TBI have persistent cognitive and behavioral complaints, and 50% of those with moderate TBI experience cognitive difficulties. Among individuals with mild to severe closed head injury, memory and selective or divided attention are particularly affected ( ). In more severe injuries, executive functions mediated by the frontal lobes and their connections can also be affected; these include abstract reasoning, cognitive flexibility, and problem solving ( ). These deficits have negative impact on both patients’ rehabilitation and daily life functioning, leading to long-term disability ( ).

Cholinergic Mechanism and Cognitive Impairment in TBI

The cholinergic system has been long known to play a pivotal role in memory function ( ). In light of the high prevalence of cognitive impairment, particularly memory problems, in TBI patients, researchers suspected that an impairment of the cholinergic system might, at least in part, contribute to these deficits following TBI. Indeed, research using both animal models and human subjects increasingly points to cholinergic deficits following TBI ( ).

Firstly, studies in animal models of cognitive impairment in TBI indicate dysfunction in the cholinergic system. Chen and colleagues demonstrated that the anatomical regions most frequently damaged in animal models of head injury (severe closed head injury was induced under anesthesia; the neurological severity score was determined after 1 hour (h), 1, 7, and 14 days after trauma; the drugs, placebo or rivastigmine, were injected 5 min after injury) include the hippocampal formation and the thalamus. These areas are heavily innervated by acetylcholine (ACh) projections in the normal brain ( ). Findings of decreased M-2 muscarinic receptor binding at 24 h posttraumatic injury in hippocampal CA2-3 region and dorsal blade of the dentate gyrus were demonstrated in rat TBI brain model studies ( ). Dixon and collaborators also found evidence of reductions in high-affinity [3H] choline uptake at two weeks after cortical impact in animal models ( ). Additionally, findings in animal models also show a low tolerance to ACh antagonists (eg, scopolamine), indicating decreased reserve of cholinergic function ( ). Finally, showed a decrease in cholinergic activity 2 h following TBI with an increase in cholinergic deficits over a 72-h follow-up period in a rat model using controlled cortical impact (CCI) ( Table 17.1 ).

Table 17.1

Anticholinesterase (Ache) Inhibitors Principal Characteristics: Donepezil, Galantamine, and Rivastigmine

Name	Brand Name	FDA Approved Year	Half-Life	Affinity for AChe	Adverse Effects
Donepezil	Aricept	1996	70 h	High	Nausea, vomiting, diarrhea, loss of appetite/weight loss, dizziness, drowsiness, weakness, trouble sleeping, shakiness (tremor), or muscle cramps
Galantamine	Razadyne	2001	1–7 h	High	Nausea, vomiting, diarrhea, dizziness, drowsiness, loss of appetite, and weight loss
Rivastigmine	Exelon	2006	3.4 h	High	Dizziness, headache, abdominal pain, diarrhea, nausea, vomiting, weight loss

Importantly, studies in humans also indicate cholinergic abnormalities in subjects with TBI with acute (over hours to days) elevations of cerebral ACh followed by chronic damage to cerebral cholinergic nuclei, projections, and cholinergically dependent information processing circuits ( ). Similar changes have been observed in animal models ( ). Following an assessment of choline acetyltransferase activity in human postmortem brains from patients who died following head injury and control samples, Murdoch and colleagues reported a deficit of cholinergic presynaptic terminals in postmortem brains following head injury, specifically in inferior temporal gyrus, cingulate gyrus, and superior parietal cortex ( ).

Collectively, these findings suggest that cholinergic function is chronically deficient among subjects with TBI and that cholinergic deficits may be a significant contributor to posttraumatic cognitive impairments—particularly memory impairments. As such, cholinergic deficits may be a useful target for the pharmacotherapy of TBI-related cognitive impairments.

Cholinesterase Inhibitors in TBI

Based on data indicating cholinergic deficits in traumatically injured brains, researchers turned to cholinergic compounds, the cholinesterase inhibitors (ChEIs), as potential treatment modality of cognitive deficits, primarily memory impairment, in TBI. The first ChEI, tacrine was introduced in 1993. Its us has been severely limited due to hepatotoxicity, and today most clinicians consider the three currently available ChEIs, donepezil, galantamine, and rivastigmine, to be the first-line pharmacotherapy for mild to moderate (and donepezil for severe) Alzheimer’s type dementia. These drugs have slightly different pharmacological properties, but they all work by inhibiting the breakdown of ACh by blocking the enzyme acetylcholinesterase, while rivastigmine inhibits both butyrylcholinesterase and acetylcholinesterase enzymes.

The initial indication of the potential utility of these compounds in TBI arose with the report by , who found that rivastigmine improved cognitive function in a mouse TBI model. Following these findings, researchers began exploring the potential role of ChEI in the treatment of cognitive abnormalities in patients with TBI. described improvement in memory in two patients with long-term memory impairment (1-year post-TBI) who received donepezil. showed improvement in memory in four TBI patients receiving donepezil. performed a prospective double-blind, controlled, crossover design study of donepezil for chronic memory impairment in TBI in seven subjects and found significant improvement in immediate and delayed memory with 10 mg (first phase of the treatment for 5 months) when comparing with 5 mg of donepezil on the second phase of treatment for 6 months.

conducted a placebo-controlled crossover design study with donepezil (10-week donepezil and 10-week placebo) in 18 TBI patients and found improvement in short-term memory and sustained attention in patients when receiving donepezil. conducted a single-subject, unblended multiple baseline study, in three adolescents with TBI. The subjects were given a dosage of donepezil in 5 and 10 mg and better memory recall was demonstrated after taking 10 mg of donepezil; therefore, authors suggested that donepezil in the highest dose may be effective in improving memory.

Finally, followed 111 outpatients with TBI (>1 year posttrauma) who received donepezil ( n = 27), rivastigmine ( n = 54), and galantamine ( n = 30). Response was rated based on interview with patients and family. Follow-up duration was up to 33 months. The authors reported response rates ranging from 41% to 60% (included better vigilance and attention). Of those using rivastigmine, 59% reported a positive response (see Table 17.2 ).

Table 17.2

Clinical Trials of ChEI in TBI

ChE (dose)	n	Study Design	Inclusion Criteria: Time Post-TBI	Results
Donepezil 5 mg	2	Case trial	2 years or more after injury	Both patients showed improvement in memory after 3 weeks of treatment, compared to baseline in the memory test.
Donepezil 5 mg/10 mg	4	16 week open-label study	At least 2 years	Participants were on 5 mg for 8 weeks and 10 mg for 4 weeks. Mean scores for learning and short- and long-term recall improved by 0.4, 1.04, and 0.83 SDs above baseline. The mean scores for short-term recall and long-term recall improved by 1.56 and 1.38 SDs above baseline.
Donepezil 5 mg/10 mg/5 mg	7	Single-subject ABAC design	At least 1.5 years	Participants received 5 mg/day of donepezil for 1 month and 10 mg for 5 months and additional 6 months with 5 mg. Participants showed significant improvement on immediate and delayed verbal memory when they were in 10 mg dose. Side effects were greater with the highest dose of 10 mg.
Donepezil 5 mg/10 mg	18	24-week, randomized, placebo-controlled, double-blind crossover trial	2–24 months after brain injury	5 mg for 2 weeks and 10 mg for 10 weeks. Results indicated that patients improved on measures of short-term memory and attention. Group A showed an improvement in neuropsychological testing even after washout of 4 weeks, compared to group B, with SDs of 4.9 and 1.9 above baseline measures. A cholinergic augmentation may be an approach to restore memory and attention after TBI.
Donepezil 5 mg/10 mg	3	Single-subject, unblinded, multiple baseline ABAB design	2 years post-TBI	All participants showed improvement in their overall memory. No improvements in delayed memory.
Donepezil 7.2 mg	27	Randomized experiential study	About 1 year or more after trauma	Forty-one subjects received more than one drug, and only three patients received all three options. In total, 61% of patients had a positive response on vigilance and attention as assessed by self-report. No significant differences were found between the three drugs.
Galantamine 5 mg	30
Rivastigmine 2.3 mg	54
Rivastigmine 3–6 mg	157	Prospective, randomized, double-blind, placebo-controlled study	2 years postinjury	Rivastigmine was safe and well tolerated in patients with traumatic brain injury with cognitive deficits. Rivastigmine shows promising results in the subgroup of patients with traumatic brain injury with moderate to severe memory deficits.
Rivastigmine 7.9 mg	127	26-week, multicenter, open-label extension of a double-blind study	12 months after injury	Statistically significant changes from week 12 to week 38 were observed in recall tests of memory, with an improvement of 1.0 SD above baseline.
Rivastigmine 1.5 mg/12 mg	86	12-week randomized, placebo-controlled, double-blind crossover trial	12 months after injury	Sixty-nine participants completed and 17 withdrew due to adverse effects. The mean dose was 10.5 mg. Results indicated that rivastigmine has a positive outcome in the treatment of chronic sequels of TBI, when compared to a placebo; 45% of patients considered the use of rivastigmine beneficial.