Fatigue is one of the most common complaints of people who have sustained traumatic brain injury (TBI). Investigators have found the incidence of fatigue to be 21% in mild forms of TBI and as high as 73% in more severe cases, though one research group reported that 46% of their patients surveyed had fatigue.
TBI is an enormous problem in the U.S. Each year in this country, an
- 1.4 million people sustain a TBI. Of those, 235,000 are hospitalized and survive.
- 50,000 people die from a TBI.
- 80,000 to 90,000 people experience the onset of long-term or lifelong disability associated with a TBI.
At the present time, there are 5.3 million Americans who have some disability resulting from TBI.
Figure 1: The relationship between fatigue and IGF-1 levels
Figure 2: The relationship between IGF-1 levels and reports of depression
The largest group of traumatic brain injured individuals fall within the 15- to 24-year-old age group, but the frequency is nearly as high for children and teens younger than 15. Because of the high incidence of TBI in the teenage and young adult population, the actual cost in health care dollars and lost years of productivity is higher than for many other serious health conditions primarily affecting an older population. It has been estimated that direct medical costs and indirect costs (such as lost productivity) of TBI totaled an estimated $56.3 billion in the U.S. in 1995.
Treating TBI-related fatigue has been problematic, so researchers are exploring new avenues for addressing the problem. Fatigue after TBI is obviously secondary to multiple other factors. Although an exhaustive discussion of the issue would require more space than is available in this article, some of the factors are worth mentioning: biochemical changes, disturbances in sleep and wake cycles, disruption of the reticular activation system, depression and impairments in attention and cognitive function.
My team has explored the relationship between fatigue, depression and the function of the anterior pituitary in individuals who have sustained a TBI. In our study, we found an inverse relationship between levels of insulin growth factor-1(IGF-1) — which is closely correlated with the level of growth hormone (GH) — and subjective reporting of fatigue and depression. Additional research is needed to obtain more objective information and to evaluate treatment effects of replacement therapy.
In many other disorders, hormonal abnormalities, especially those of the anterior pituitary, have been shown to play a role in fatigue and depression. The hormones secreted by the anterior pituitary control thyroid function, the adrenal glands, sexuality, muscle mass and bone density. Either directly, or through secondary actions, these hormones affect energy, mood, metabolism, stress response and strength. So it was reasonable for our research team to investigate the relationship between abnormalities of the anterior pituitary and the complaints of fatigue and depression associated with TBI.
Older TBI literature suggested that while acute problems with the posterior pituitary were not uncommon, anterior pituitary problems were rarely seen. Only 53 cases of hypopituitarism associated with TBI had been reported prior to the year 2000, with a rate as low as 4%. Recent research has suggested a much higher incidence of endocrine dysfunction after TBI — as much as 36.4% of patients in one study had some anterior pituitary abnormality. In 2001, in another study that evaluated 70 patients using provocative testing, 59% of the sample showed an anterior pituitary abnormality, while another group had an incidence of 28.4%. These patients were advised to undergo periodic testing.
This information further increased our interest in studying the relationship between fatigue and anterior pituitary function. In our work, the subjects participated in a single session where they underwent subjective assessments of fatigue, depression and quality of life. In addition, trial measures of mental vigilance were assessed using the Digit Vigilance Test and assessment of physical fatigue was gauged using the timed “wall sit”— a supported squat where the patient presses his back against a wall and slowly sits down until his legs are flexed at about 130 degrees. Blood samples were also collected for a series of assays for assessment of anterior pituitary function. The function of the adrenal and thyroid glands and sexual organs were studied, and the tests were correlated with an assay of growth hormone (GH).
Since GH is secreted in a pulsatile fashion, levels could not be assessed with a random blood draw and would require a stimulation test with potentially greater morbidity. Instead, IGF-1 — whose level is closely correlated with GH — was assayed. While measuring levels of IGF does not replace stimulation testing, it is safer and correlates fairly well.
Twenty-three patients with moderate to severe TBI, between the ages of 18 and 65, have been evaluated. The results demonstrated a strong inverse correlation between IGF-1 levels and the participants’ subjective reporting of their levels of fatigue as measured using a Visual Analogue Scale, Fatigue Severity Scale and Epworth Sleepiness Inventory.
A similar inverse relationship was noted between IGF-1 levels and depression, as measured using the Beck Depression Inventory-II. The more objective measures, such as the “wall sit” and the subject’s performance on the DVT, failed to demonstrate any correlations, though the difficulty many participants had in performing these tasks raises questions as to its meaning.
The pilot study suggests the potential of identifying a reversible cause of fatigue and depression following TBI. Clearly this work is preliminary and needs further development, but our team is excited about the results. Further refinements of the metrics that will be used to objectively assess both physical and mental fatigue need to be made. The relationship between these improved metrics and anterior pituitary function also needs to be explored. Finally, the benefits of replacement therapy in patients demonstrating a deficiency should be evaluated.
Elie P. Elovic, MD, is the director of TBI Research at KMRREC and associate professor in the Department of Physical Medicine and Rehabilitation (PM&R) at UMDNJ-New Jersey Medical School. He obtained his medical degree from the University of Pennsylvania and completed his residency in PM&R at the Hospital of the University of Pennsylvania. Dr. Elovic has published more than 50 peer-reviewed articles and book chapters in the area of acquired brain injury.