Endocrinopathy After Traumatic Brain Injury (2011)

A 25-year-old woman with no significant medical history and who was not previously on medications is admitted to your inpatient rehabilitation unit. She sustained a traumatic brain injury due to a high-speed motor vehicle crash 4 weeks ago. She was restrained. There was prolonged extrication of 30 minutes, but no clear documentation of hemodynamic instability. The initial Glasgow Coma Scale (GCS) score was 3. She was intubated at the scene. The initial head computed tomography demonstrated bifrontal contusions, a left frontoparietal subdural hemorrhage, and evidence of diffuse axonal injury. No skull or facial fractures were noted. She underwent an emergent craniotomy for evacuation of the subdural hemorrhage. Intracranial pressure monitoring did not demonstrate elevations of intracranial pressure after surgery, and cerebral perfusion remained adequate. She was weaned from the ventilator after 3 weeks. Since then, she has reportedly been lethargic but occasionally lifts her thumb to command. She has been afebrile, with some tachycardia (100-110 beats per minute) but normotensive. Laboratory values have been notable for mild hyponatremia (sodium, 128-135 mmol/L). On admission, her pupils are responsive, her eyes are open, she appears to track objects, but she has a left cranial nerve VI palsy and does not follow any commands. She is afebrile, blood pressure is 140/80 mmHg, pulse 100 beats per minute, respirations 20 per minute. She has a tracheostomy, with minimal secretions. There has been recent literature that has suggested a rather high prevalence of endocrine abnormalities after brain injuries but no clear guidelines regarding who should be screened for these deficits, what tests should be ordered to evaluate, and, if present, when to treat deficits. The situation is complicated because many of the clinical signs and symptoms of endocrine abnormalities may also be due to a number of other neuromedical complications of traumatic brain injury or the brain injury itself. From the information presented, when should a laboratory workup for endocrinopathies be initiated for this patient and what tests (if any) should be ordered? Endocrinopathy after traumatic brain injury (TBI) has become an area of significant interest both to researchers and clinicians in the last several years. Endocrine disorders are present in a significant percentage of both men and women after TBI [1-4], and numerous hormonal disturbances have been documented in the acute period after TBI. Lieberman et al [1] demonstrated that 50% of patients exhibited some form of endocrinopathy at a median postinjury period of 13 months, which demonstrate both the significant incidence and the chronicity of endocrine dysfunction after TBI in a cross-sectional analysis. Although severity of injury is positively correlated with the degree of endocrine dysfunction during the acute period of TBI recovery, the relationship between chronic endocrinopathy and injury severity is less well established [1-4]. Cross-sectional studies have documented the incidence of pituitary dysfunction in TBI to range from 16%-67% [5]. Although as many as 85% of patients who are deficient in the acute phase will recover pituitary function by 1 year, some patients will present with new onset dysfunction within the subacute phase of recovery. Hypogonadism has been noted in up to 80% of patients acutely and in 14%-40% chronically. Growth hormone deficiency (GHD) has been noted in 9%-30%, hypothyroidism in 4.5%-8%, cortisol deficiency in 7.1%-19%, and hyperprolactinemia in 13%. Longitudinal studies as well as studies of patients in the postacute phase of TBI have documented pituitary dysfunction up to 3 years after injury [6]. The location of the hypothalamus and the pituitary gland on the floor of the calvarium, with the pituitary located within the bony sella turcica, make it particularly susceptible to trauma. The infundibulum, or the connecting stalk between the hypothalamus and the pituitary, can easily be disrupted. In addition, the vascular supply of the pituitary may be disrupted as well. The pituitary gland is also particularly susceptible to hypoperfusion and hypoxemia, both of which are commonly associated with TBI. Also, many medications used in the intensive care unit setting may affect hormone function. Lastly, the “stress response,” in which adrenal function is preferentially upregulated and gonadal function downregulated in response to the stress of injury and hospitalization, may contribute to pituitary dysfunction in this population. Neuroendocrine dysfunction after TBI was recognized as early as 1918 [5] but remains underdiagnosed and undertreated. Patients with hypopituitarism from any reason may present with anergia; osteoporosis; reduced lean body mass; decreased muscle mass and poor exercise tolerance; decreased energy; mood disorders; impaired cognition, concentration, and memory; insomnia; and infertility. Many of these symptoms are common sequelae of TBI [1]. This contributes to the lack of recognition of endocrine dysfunction in this population. It is also clear to see how these symptoms, if due to pituitary dysfunction, can significantly impact the rehabilitation course of an individual. Although some studies have evaluated the neurobehavioral impact of neuroendocrine dysfunction after TBI, few studies have examined the direct functional implications during the acute rehabilitation setting. Young et al [7] evaluated the association between hypogonadism in men after TBI and function in acute rehabilitation and found that men with low testosterone levels trended toward lower functional status and longer lengths of stay in acute rehabilitation, although the findings failed to reach statistical significance. Another study [8] did find a significant correlation between low testosterone levels and functional status at both admission and discharge from inpatient rehabilitation. Possible explanations of this finding are the impact of testosterone on physical function, metabolic function, mood, and cognitive function. Results of other research have suggested that testosterone may play a role in neuroprotection of the central nervous system [9]. Female gonadal hormones have also been implicated in both neuroprotection and neurorecovery after TBI. Investigation into gender differences in outcomes in animals after experimental brain injury has shown that estrogen and progesterone exert a number of effects after trauma that are both neuroprotective and potentially neuroregenerative [10]. Some of these effects include improving cerebral blood flow, reducing vasospasm, preventing apoptosis, decreasing excitotoxicity, and reducing cerebral edema. Research has also supported the concept that estrogen may have neuroregenerative properties, because it has been found that estrogen receptors are expressed in higher numbers in areas of cerebral trauma [11], and activation of the receptors appears to lead to genetic mechanisms that are known to play a key role in neurogenesis. Progesterone has also been the subject of a recent human study that reported significant reductions in mortality and improved functional outcomes in individuals with moderate-severe TBI who received intravenous progesterone in the acute period after injury [12]. In the subacute recovery period after TBI, menstrual dysfunction in women, which is an indicator of endocrine dysfunction, has been associated with worse outcomes after TBI [13]. Other endocrine abnormalities have been associated with worse outcomes and symptoms after TBI, especially growth hormone abnormalities [1]. Thyroid dysfunction and adrenal dysfunction can also affect physical and cognitive performance in the rehabilitation setting but appear to be less common. The timing of screening for endocrine dysfunction also remains a source of controversy. Consensus guidelines were published in 2005 [14] to discuss the issue of what hormones should be screened as well as timing of screening. It was recommended that screening be performed prospectively in individuals after TBI who are asymptomatic at 3 months and 1 year after discharge from the intensive care unit or earlier if symptoms were suggestive of endocrinopathy. However, as stated previously, there is significant overlap between symptoms reported by individuals with idiopathic pituitary dysfunction, and individuals who have sustained a TBI. Given that recent evidence suggests that deficiency in certain hormones may impact recovery, it would seem prudent that earlier screening is warranted. The consensus for the timing of screening seems to be primarily based on the evidence that many individuals recover function after injury over the long term. However, because there is evidence that hormonal dysfunction may be associated with functional performance at the time of admission to inpatient rehabilitation, this seems a convenient and reasonable time to screen for hormone abnormalities, and treatment of some of these abnormalities may positively affect long-term outcomes. Regarding the patient presented in this case, the presence of hyponatremia suggests that pituitary dysfunction may be present. Initially, the type of hyponatremia must be determined, with evaluation of the serum and urine osmolarity and electrolytes. If the patient is either hyper- or hypovolemic, then this must first be corrected. A screening for other abnormalities of the hypothalamic-pituitary axis would also be indicated and should be performed as soon as possible. A suggested panel would include follicular stimulating hormone (FSH), luteinizing hormone (LH), prolactin, thyroid function tests, adrenocorticotropic hormone (ACTH), fasting morning cortisol, insulin-like growth factor (IGF-1), serum chemistry, and sex hormone binding globulin, as well as appropriate gonadal steroids (testosterone and dehydroepiandrosterone in men, progesterone and estradiol in women). Provocative testing for GHD may be considered for individuals demonstrating a low IGF-1, although this may not be feasible in certain patients for behavioral or medical reasons. In summary, although the timing of screening for endocrine abnormalities after TBI remains controversial, there is ample evidence in the literature to support screening earlier in the rehabilitation process than previously recommended by the consensus panel, with the hope that correction of certain abnormalities may facilitate recovery and enhance performance in rehabilitation. In other words, for our patient, the time is now! Certainly, there should be little disagreement that correction of thyroid abnormalities, sodium and fluid abnormalities, and adrenal insufficiency should be performed. Although correction of female gonadal steroids at this time has not yet been examined for safety, replacement of testosterone in men to physiological levels appears to have enough evidence to suggest that this may facilitate recovery and is relatively low risk. Over the next few years, it is hoped that more information that delineates the natural recovery of hormone dysfunction, as well as evidence from clinical trials that are ongoing, will provide more information regarding this important clinical issue. Although posttraumatic hypopituitarism (PTH) was first described in 1918 [1], until recently, PTH was described mostly as case reports in the literature. Results of recent studies have shown the incidence of PTH to be approximately 35% in chronic moderate-severe traumatic brain injury (TBI), with GHD being approximately 20% [2] . Powner et al [3] reviewed acute and chronic endocrine dysfunction after TBI. They found an incidence of acute hormonal reduction of adrenal, 15%; thyroid, 5%-15%; growth hormone, 18%; and gonadal, 25%-80%. Guerrero and Alfonso [4] in a recent article in Military Medicine recommended that “all patients who had a TBI of any severity should undergo baseline hormonal evaluation at 3-6 months after discharge from acute care.” They also recommended screening for adrenal insufficiency immediately after the TBI. Nevertheless, there is a large void in the literature regarding acute treatment of PTH: who to screen, when to screen, how to screen, and when to treat. This case discussion lends itself well to this issue. Although we are all trained to look for diabetes insipidus from traumatic posterior pituitary lobe dysfunction that results in vasopressin eduction, the incidence has been poorly investigated. Agha et al [5] studied 102 patients with moderate-severe TBI and found that 21.6% developed acute diabetes insipidus, with 6.9% having the problem permanently. We are also taught to look for posttraumatic syndrome of inappropriate antidiuretic hormone (SIADH) caused by the uncontrolled release of vasopressin from damage to the pituitary stalk and/or the posterior pituitary gland. As a result, vasopressin levels are elevated at times when secretion should be depressed. In the Agha study,13 subjects (12.7%) developed acute SIADH. Our case for discussion demonstrates that electrolyte abnormalities after a TBI are the guide for when to screen for diabetes insipidus and SIADH. Although the mild hyponatremia can be due to a myriad of causes after an acute TBI, SIADH should always be considered. Agha et al [5] defined their group as having SIADH if they met the following criteria: plasma osmolalality of less the 270 mOsm/kg, with a corresponding urine osmolality of more than 100 mOsm/kg, and a spot urine sodium of more than 40 mmol/L in a patient who is euvolemic with normal glucocorticoid secretion and thyroid function. Certainly, this young woman should have a plasma and urine osmolality and spot check of the urine sodium and, if abnormal, then the next step would be a review of this patient's drug regimen for medications that can cause SIADH. Included in the list of potential causes are medications commonly used in the TBI population, such as the selective serotonin re-uptake inhibitors, omperazole, carbamazepine, and oxcarbazepine. If the diagnosis of SIADH is made, then the treatment would be that of altering her fluid intake and electrolyte composition, and removal of any possible contributory medications. Aimeretti et al [6] studied pituitary dysfunction in 70 individuals at 3-12 months after injury to clarify if deficiencies at 3 months would improve or worsen over time. They found that, if an individual had panhypopituitarism (decreased secretion of all pituitary hormones) at 3 months, then it was permanent at 12 months; 5.5% who tested normal at 3 months had developed hormonal dysfunction at 12 months; 13.3% who had only 1 hormonal deficit at 3 months developed other hormonal deficits at retesting. Conversely, 50% of subjects had some degree of hypopituitarism at 3 months, and, at 12 months, 60% now had normal pituitary function. Schneider et al [2] also performed a very similar study with very similar results. These studies present the confusing picture that, with the exception of panhypopituitarism, pituitary deficits at 3 months can resolve or become permanent at 12 months and that individuals free of deficits at 3 months can develop pituitary dysfunction at 12 months. There is no argument, however, about the timing of adrenal hormone replacement. Failure to produce mineralocorticoid or glucocorticoid hormones immediately after a TBI is associated with poor neurologic outcome, hyponatremia, relative or absolute hyperkalemia, greater requirements for vasoactive drug therapy, and rapidly progressive hypotension [3]. This patient sustained a severe TBI and has a low serum sodium. Although she is normotensive, which suggests that the yield will be low, adrenal function with a random serum cortisol should be tested in this patient. Because serum concentrations of cortisol may vary with the physiological response to the trauma, an adrenocorticotropin hormone stimulation test should be performed if the serum cortisol is inconclusive. After a TBI, the normal conversion of T4 to T3 is dramatically reduced; however, the incidence of true central hypothyroidism (low T4 and low or normal thyroid stimulating hormone (TSH), as well as a failure of thyroid releasing hormone to stimulate TSH release) acutely after a TBI is unknown. Many medications used in the intensive care unit setting, such as dopamine and glucocorticoids, can reduce TSH production and release. There are also no studies on acute thyroid replacement after a TBI. This young woman should be screened for true central hypothyroidism, and, if present, she should receive intravenous levothyroxine. Acute transient dysfunction of the hypothalamic-pituitary axis has been reported in critical illness, independent of TBI [7]. Therefore, the suppression of the gonadal axis may not be TBI specific but rather can be a general response to a critical illness. Hypogonadism with low testosterone has been found after acute myocardial infarction, elective surgery, multiple trauma with TBI, and ischemic and hemorrhagic stroke [7]. Wagner et al [8] studied the gonadotrophic and somatotrophic axis acutely for 10 days in 101 patients after a moderate-severe TBI. In the men, 100% had at least 1 low testosterone value; 93% had low values for the entire 10 days. In premenopausal women, 43% had at least 1 low estradiol value, and 39% had low values for the entire 10 days. Results of long-term studies, however, indicate that suppression of the gonadal axis is transient in the overwhelming majority of patients [7]. Tanriverdi et al [9] studied 52 patient at 24 hours and 12 months after a TBI. Although 40% had gonadotropin deficiency acutely, only 7.7% were deficient at 1 year. In the setting of panhypopituitarism (deficits of all pituitary hormones) or in a patient with multiple deficits, Consensus guidelines [10] recommend immediate replacement of gonadal hormones. For individuals with isolated secondary hypogonadism, the guidelines are not as clear, which suggests forestalling hormonal replacement and monitoring menses over time. A case, therefore, could be made to merely this young woman if she has no other hormonal In the noted study by Wagner et al the somatotrophic axis was also They found that growth hormone levels in of and low levels were in of the however, was a general of and recovery over the levels remained either relatively normal or elevated during the 10 days. secretion is during Because the of is only minutes, random levels are of the secretion of The is to be an of secretion and, therefore, the for for levels have not been because to vary from laboratory to et al [11], however, reported that, in patients with chronic TBI, an of less than is a clinical for A diagnosis of deficiency can only be made The test is the for however, it is not feasible in this is a to the however, the by by this of testing is as well. Because deficiency can only be testing and the correction of other pituitary deficiencies may the somatotrophic the guidelines suggest that replacement should be for at least 3-6 months after of replacement of the other pituitary hormones. Although a recent study reports the of in moderate-severe TBI the subjects were all more than after injury. The literature on PTH relative to when to screen and when to treat is very inconclusive. In the acute setting, PTH may stay the or resolve over time. 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