O. Fatigue and Sleep Disorders

Brain injury frequently causes changes in sleep patterns likely through injury to brainstem functions that affect the daily circadian rhythms. Individuals with brain injury frequently complain of fatigue that is likely partially due to decreased nerve function and connectivity in the brain and the extra effort required for cognition. These issues may be combined with other causes of fatigability such as deconditioning and other concomitant medical conditions. Individuals with complaints of fatigue and sleep disturbance require a medical and sleep workup to rule out treatable causes. People with traumatic brain injury (TBI) should be taught strategies to optimize fatigue (e.g. energy conservation, pacing) and good sleep hygiene. In those with persistent fatigue where TBI is believed to be the main cause medications may be considered.

The rehabilitation team should have a structured and systematic process for assessing sleep disturbances and fatigue in individuals with traumatic brain injury. Clinicians with expertise in non-pharmacological therapeutic approaches for sleep-related disturbance, particularly cognitive behavioral therapy, should be available early on in the rehabilitation process. The rehabilitation environment and schedule should facilitate adequate sleep hygiene.

Indicators exemples

• Proportion of individuals with TBI formally assessed for fatigue and sleep disorders.
• Proportion of individuals with TBI and fatigue and/or sleep disorder who received at least one of the following five non-pharmacological interventions:
  1. Cognitive behavioural therapy (CBT);
  2. Light therapy;
  3. Regular exercise;
  4. Energy conservation strategies;
  5. Sleep hygiene

The following are suggestions of tools and resources that can be used to support the implementation of the recommendations in this section. Healthcare professionals must respect the legal and normative regulations of the regulatory bodies, in particular with regards to scopes of practice and restricted/protected activities, as these may differ provincially

Wiseman-Hakes et al. (2013) states that sleep disturbances associated with TBI can exacerbate cognitive, communication and mood deficits that are trauma-related. Similarly, Bushnik, Englander, and Wright (2008) found that when fatigue worsened over the course of 2 years, it was accompanied by poorer cognitive and motor outcomes as well as reduced levels of general functioning. Dealing with sleep disturbances is necessary for optimal recovery and fatigue and sleep disorders should be assessed. Common objective assessments for fatigue and sleep disorders included questionnaires, polysomnography, actigraphy, multiple sleep latency tests and maintenance of wakefulness tests (Mollayeva, Colantonio, Mollayeva, & Shapiro, 2013).

In terms of treatment, both pharmacological and non-pharmacological options have been studied:   

Non-pharmacological Treatments

Non-pharmacological interventions may include pacing, cognitive behavioural therapy (CBT), light therapy, or exercise among others.

Cognitive Behavioural Therapy (CBT). A small randomized controlled trial by Raina et al. (2016) evaluated the feasibility of conducting an internet-based cognitive behavioural intervention in 38 individuals with post-TBI fatigue. This study delivered an 8-week intervention that consisted of 30-minute 1:1 videoconferencing sessions, delivered twice per week and compared its effects to an online health education program. The study showed it is feasible to administer virtual cognitive behavioral intervention in individuals with TBI. Secondary outcomes of the study included measures of fatigue impact (Modified Fatigue Impact Scale, Patient-Reported Outcomes Measurement Information System Fatigue Scale) and fatigue severity (Fatigue Severity Scale) assessed at baseline and postintervention. No significant group differences were observed on these measures. These results should be interpreted with caution, since the primary goal of the study was to assess the feasibility of delivering the intervention and conducting a larger RCT rather than evaluate its efficacy.

Previously, a pre-post case series found that 8 sessions of CBT improved sleep disturbances by improving total wake time (p<0.001), sleep efficacy (p=0.01), fatigue (p<0.012), and insomnia (p<0.01) but not total sleep time (Ouellet & Morin, 2007). No additional significant gains were made once the treatment had concluded, although gains were maintained at a 3-month follow-up.

A randomized controlled trial by Nguyen et al. (2017) evaluated the effects of an 8-week CBT intervention compared to usual care on sleep and fatigue in 24 participants with chronic TBI. The CBT group showed significant improvements in measures of sleep quality (Pittsburgh Sleep Quality Index), insomnia severity (Insomnia Severity Index) and fatigue (Brief Fatigue Inventory) compared to the control group at post-intervention evaluation and at 2-month follow-up. The study found no significant differences between the groups on measures of fatigue severity (Fatigue Severity Scale) and daytime sleepiness (Epworth Sleepiness Scale).

There is a concern that CBT may be difficult to accomplish for patients with a high level of cognitive impairment due to moderate to severe TBI.

A pilot randomised trial by Ymer et al. (2021) compared a CBT program for sleep disturbance and fatigue (CBT-SF) with an 8-week health education (HE) intervention in 22 participants with TBI and 29 participants with stroke. Both programs were adapted to make them accessible for individuals with cognitive impairments. Participants were assessed at baseline, post-treatment, and at 2- and 4-month follow-up. The study found that CBT-SF led to improvements in sleep quality measured by the Pittsburgh Sleep Quality Index at 4 months post-treatment as well as significant gains in self-efficacy and mental health. These results should be interpreted with caution because only 43% of the study population had TBI. However, it provides insight into the feasibility of offering CBT to individuals with TBI and cognitive impairments.

Light therapy. A randomized controlled trial by Bell et al. (2021) compared bright white light to red light in 131 participants with recent TBI. The intervention group received bright white light (1260 lux at 20 inches, 440–480 nanometers length) for 30 minutes each morning at 12–24 inches from the face between 7:30 and 9:30 am for up to 10 treatments or until discharge from inpatient rehabilitation. The control group received red light (<450 lux, no light between 440 and 480 nanometers) using the same regimen. The study found no significant differences in sleep duration, sleep efficiency, awakenings as assessed using actigraphy recording. between the two groups. No significant differences were found for sleepiness, mood, or cooperation with therapy between bright white light and red light groups. 

A randomized controlled trial by Quera Salva et al. (2020) compared blue-enriched white light therapy to no treatment control in 20 individuals with chronic TBI and significant fatigue. Participants were exposed to bright, blue-enriched white light for 30min in the morning upon waking for 4weeks. The intervention group significantly improved measures of fatigue (Fatigue Severity Scale) and depression (17-item Hamilton Depression Scale) compared to the control group at post-intervention assessment, but the benefits did not persist at the 8-week follow-up. 

An earlier RCT conducted by Sinclair, Ponsford, Taffe, Lockley, and Rajaratnam (2014) examined the effectiveness of blue and yellow light therapy versus a control group. The blue light therapy was shown to significantly decrease fatigue (p<0.001) and daytime sleepiness (p<0.01) but yellow light therapy did not show improvements compared to the control group. The improvements measured during the treatment phase did not persist at follow-up (week 8). 

Exercise. Exercise has been considered in the treatment of fatigue and sleep disorders in individuals with moderate and severe TBI.  A pre-post study by Krese et al. 2020 looked at the effects of yoga-based therapy compared to physiotherapy and seated rest. A crossover RCT by Kolakowsky-Hayner et al. (2017) provided some evidence that a home-based walking program may reduce fatigue compared to a nutritional counselling program in patients with moderate to severe TBI. More evidence is needed before a definitive recommendation can be made. 

Access to exercise is important. It is a vital issue of equity and accessibility with pronounced sociodemographic and regional inequities. 

Other (relaxation strategies and sleep hygiene). Other non-pharmaceutical interventions including relaxation strategies and sleep hygiene have been suggested to be beneficial in improving aspects of sleep and fatigue post TBI. However, evidence in this area is very limited. A feasibility crossover RCT by Chiu et al, (2017) looked at the effect of a warm foot bath compared to usual care on sleep and reported benefits related to sleep onset latency and wake after sleep onset in the intervention phase.

A pilot RCT by Makley et al. (2020) in 18 participants with acute TBI showed promising feasibility and acceptability of a sleep hygiene protocol vs. usual care but found no significant effects on sleep metrics (total sleep time, sleep efficiency or wakefulness after sleep onset).

Due to the size, duration of intervention and feasibility nature of these studies, more robust evidence is needed to make recommendations regarding emerging areas of non-pharmacological interventions intended to treat sleep disturbances post-TBI.

Pharmacological Treatments

Pharmacological treatments to improve sleep quality have also been suggested.

Trazodone. In research in cats, Aton et al. (2009) found that trazodone administration did not affect EEG but may have affected cortical plasticity. While trazodone has been found to be commonly prescribed in humans for insomnia, and shown some benefit, in other study populations, the research supporting trazodone’s effects on insomnia among a brain injury population is minimal (Larson & Zollman, 2010).

Lorazepam, zopiclone. Shan and Ashworth (2004) compared lorazepam with zopiclone to assess the effects of these medications on sleep and cognition in a randomized, double-blinded, crossover trial. There was no difference in average sleep duration or in subjective measures of sleep. Cognition as assessed by the Mini Mental Status Exam revealed no difference in the zopiclone arm compared with the lorazepam arm.

Melatonin. Indolamine melatonin is a hormone secreted or synthesized by pineal gland in the brain which helps to regulate sleep and wake cycle. Melatonin production has been found to be associated with REM sleep (Shekleton et al., 2010). Melatonin has been shown to be a versatile hormone having antioxidative, antiapoptotic, neuroprotective, and anti-inflammatory properties (Naseem & Parvez, 2014). Further, melatonin production levels were lower in individuals with TBI compared to healthy controls which suggests the disruption of the circadian regulation of melatonin synthesis (Shekleton et al., 2010). (Ponsford & Sinclair, 2014; Ponsford, Ziino, et al., 2012) conducted a large cohort study of community-based patients with TBI, recruited from a TBI rehabilitation program, completed measures of subjective fatigue and sleep disturbances, as well as attentional measures. A subgroup of participants completed polysomnography and assessment of dim light melatonin onset. They found that objective sleep studies show reduced sleep efficiency, increased sleep onset latency, and increased time awake after sleep onset. Depression and pain exacerbate but cannot entirely account for these problems. Individuals with TBI show lower levels of evening melatonin production, associated with less rapid-eye movement sleep (Ponsford & Sinclair, 2014; Ponsford, Ziino, et al., 2012).

There are, however, limited studies examining the administration of exogenous melatonin among a brain injury population. (Kemp et al., 2004) conducted a RCT cross-over trial comparing melatonin and amitriptyline for a month for those with TBI (n=7). No significant improvements were found for either group on any of the sleep variables examined: latency, duration, quality, or daytime alertness; however, it was found that melatonin had a moderate effect on daytime alertness (Kemp et al., 2004).

A crossover RCT by Grima et al. (2018) evaluated the effect of a 4-week melatonin treatment (2 mg prolonged release) compared to placebo in 33 participants with mild to severe TBI. Participants showed significant improvements in measures of sleep quality (Pittsburgh Sleep Quality Index), sleep efficiency (wrist actigraphy), and fatigue (Fatigue Severity Scale) after four weeks of the melatonin treatment phase compared to the placebo phase. There was no significant difference between treatment and placebo phases in measures of sleep onset latency or daytime sleepiness (Epworth Sleepiness Scale).

Pharmacological treatments to reduce fatigue are also an option if sleep disturbances have been ruled out and brain injury is suspected as the cause.  

Modafinil. Modafinil has been studied in two RCTs and although both studies found no significant difference between groups in fatigue, as measured by the Fatigue Severity Scale, the treatment groups both showed a significantly greater decrease in Epworth Sleepiness Scale scores when compared to controls, representing a greater improvement in excessive daytime sleepiness (Jha et al., 2008; Kaiser et al., 2010).