Abstract
Dear Editor:
In the late 1990s, Dr. Brent Masel, a major contributor to this work, approached me at the request of a local philanthropist with the question as to whether traumatic brain injury (TBI) could cause dysfunction of the anterior pituitary hormones. My search yielded several anecdotal case reports, but no rigorous studies addressing this question. This philanthropist had a son who had suffered a severe TBI at the age of 18, and he employed his resources to explore ways to improve his son's life. When I reported to him that there were no studies to answer his question, he funded a research project to examine the impact of TBI on anterior pituitary hormones. At a facility that he founded that focused on helping patients with moderate to severe TBI to have more functional lives, we studied the pituitary function of 70 patients admitted consecutively to the facility. Surprisingly, we found approximately 30% of patients exhibited pituitary dysfunction, of which growth hormone (GH) deficiency was the most common. 1 We published an article on this seminal study in 2001 soon after an article in 2000 with similar findings. 2 These two initial studies led to many retrospective studies assessing pituitary function in patients after TBI. 3,4
We began to study the potential benefit of GH replacement in patients with moderate to severe TBI with abnormal GH secretion to see if we could improve cognitive and physical function. A glucagon stimulation test (GST) was used to assess GH secretion in these patients because many had a history of seizure and we did not want to risk seizures using the gold standard GH stimulation test, the insulin tolerance test. Although the majority of symptomatic patients tested as GH deficient (GH response less than 3 ng/dL), we also found symptoms in GH-insufficient patients (GH response between 3 ng/dL and 8 ng/dL). These intermediate-response patients were included because we did not want to limit the possibility of improving this cohort of patients with few treatment options. Our initial study in patients severely affected by their TBI found improved cognition including processing speed and executive function. 5 Because many patients in this study were unable to walk, we were limited in the ability to test for improvements in physical function. We therefore conducted a follow-up study in patients with less profound moderate to severe TBI who were able to function normally and live independently. In this group of patients, we found that GH replacement resulted in significant improvements in physical function tests relating to an increase in activity and fitness. 6
As the endocrinologist in our study group, I continued to care for the patients in our studies by continuing GH replacement. Treating these patients over the years, I have come to understand that they present with a consistent set of complaints that constitute a reproducible syndrome. The primary complaint is profound, life-altering fatigue. These patients struggle to maintain work performance, often moving to jobs with fewer hours or reduced responsibility. Many times they nap during their lunch hour and are exhausted when they get home from work.
The second complaint is related to cognition with “foggy brain” being a consistent complaint. Patients complain of difficulties with word selection and a slow reaction time in normal conversation. Short-term memory and executive function are severely impaired with patients often depending on lists to function in the course of the day. Many also complain of difficulty with sleep, which may also improve with treatment. Although depression is not a characteristic symptom of this syndrome, emotional lability can occur. Often, these patients have seen multiple doctors complaining of fatigue. The majority of the time they have normal secretion of their anterior pituitary hormones except for GH when tested by endocrinologists. Patients may suffer situational depression dealing with the frustration of knowing that something is wrong, without the validation of an explanation or plan of treatment from the medical community. By characterizing and defining the cluster of symptoms that includes insufficient-GH response, fatigue, and cognitive impairment as a unified syndrome, we hope to relieve this frustration for patients and clinicians alike. We named this syndrome Brain Injury Associated Fatigue and Altered Cognition (BIAFAC).
Many of the symptoms associated with BIAFAC are similar to those experienced in post-concussion syndrome. However, BIAFAC is distinct as the symptom onset may not occur for at least 6 months following the initial trauma and may manifest years after the initial TBI. Regardless of the timing, the vast majority of patients who present with BIAFAC symptoms and test below 8 ng/dL following GST stimulation respond favorably to GH replacement. The patients with BIAFAC are distinctly different in the severity of their symptoms from patients with GH deficiency from causes such as tumors or surgery. When patients presenting with BIAFAC receive GH replacement, it takes approximately 3 months for fatigue to improve. The improvement in cognition often occurs between 4 and 5 months. The majority of patients have significant improvement in the syndrome such that they return to their normal lives. It is not uncommon as their physician to hear the gratifying phrase “You changed my life” at an office visit.
Over the years I have attempted to provide drug holidays from GH replacement (many times this is caused by insurance coverage refusal) and to date, all patients continue to require GH replacement. The BIAFAC symptoms recur off of GH exactly as they improve on GH: the fatigue returns in 3 months and the foggy brain in 4 to 5 months. Although GH replacement relieves BIAFAC symptoms, it does not cure the underlying cause as symptoms reoccur with GH withdrawal. In conjunction with the BIAFAC symptoms of fatigue and cognition, we also observed altered post-meal amino acid profiles in TBI patients. 7 This realization guided us to begin exploring how the gastrointestinal system and the gut–brain axis might be altered in this clinical population.
Although we can help these patients significantly, we are still working to understand the mechanism causing BIAFAC and to identify biomarkers that define the syndrome. The two studies published in this issue of the Journal of Neurotrauma begin to characterize the syndrome and act as a nidus for further treatment options. In the first study we examined alterations in brain morphometry and functional connectivity in BIAFAC patients on GH replacement. GH treatment was associated with improved BIAFAC symptoms as well as changes in the brain including increased gray matter volume and cortical thickness in frontal regions and altered connectivity in somatosensory brain networks. In the second study, we found significant differences in the gut microbiome between patients with moderate to severe TBI compared with normal controls and similar gut microbiomes in patients with TBI in two different long-term care facilities in two different states. The results suggest that individuals with TBI-related fatigue and altered cognition have altered fecal community structure including altered genomic content associated with modified amino acid and short-chain fatty acid metabolism.
Although our research up to this point has done a great deal to characterize BIAFAC and demonstrate the efficacy of GH replacement at reducing symptoms, many questions remain. Are some people predisposed to develop a chronic inflammatory condition in the brain after a TBI? Why are some people symptomatic soon after injury, while the condition may lie dormant for years before manifesting in others? What are the mechanisms and sequelae of symptoms that manifest as BIAFAC? By what mechanism does GH improve connectivity in the brain? Does GH replacement reduce chronic inflammation directly or does it affect the gut leading to changes in the microbiome that alter inflammation?
We are hopeful that the publication of the two current studies 8,9 will focus the collective wisdom of the research community to better understand and treat BIAFAC. Because these symptoms can manifest months to years after the initial injury and because this cluster of symptoms has not been previously defined as a unified syndrome, it often goes unidentified in the medical community. We suspect that many patients are suffering from this syndrome and increased awareness will reduce frustration and provide hope to clinicians and patients to improve the lives of many.