Neuroendocrine dysfunction following mild TBI: When to screen for it

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Applied Evidence

Neuroendocrine dysfunction following mild TBI: When to screen for it

J Fam Pract. 2014 January;63(1):11-16

By

Therese A. West, DNP, APN, BC

Col (R) Stephen Sharp, MD

Consider lab studies when suggestive symptoms last >3 months, or if delayed symptoms appear anytime up to 3 years after the injury.

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References

1. Injury prevention & control: Traumatic brain injury national TBI estimates. Centers for Disease Control and Prevention Web site. Available at: http://www.cdc.gov/traumaticbraininjury/statistics.html. Accessed August 12, 2013.

2. Armed Forces Surveillance Center. DoD Worldwide Numbers for TBI. Defense and Veterans Brain Injury Centers Web site. Available at: www.dvbic.org/dod-worldwide-Numbers-tbi. Accessed August 12, 2013.

3. Department of Veterans Affairs, Department of Defense. VA/DoD clinical practice guideline for management of concussion/mild traumatic brain injury (mTBI). Available at: http://www.healthquality.va.gov/management_of_concussion_mtbi.asp. Published April 2009. Accessed August 12, 2013.

4. Ghigo E, Masel B, Aimaretti G, et al. Consensus guidelines on screening for hypopituitarism following traumatic brain injury. Brain Inj. 2005;19:711-724.

5. Krahulik D, Zapletalova J, Frysak Z, et al. Dysfunction of hypothalamic-hyperphysical axis after traumatic brain injury in adults. J Neurosurg. 2010;113:581-584.

6. Behan LA, Phillips J, Thompson CJ, et al. Neuroendocrine disorders after traumatic brain injury. J Neurol Neurosurg Psychiatry. 2008;79:753-759.

7. Tanriverdi F, Unluhizarci K, Kelestimur F. Pituitary function in subjects with mild traumatic brain injury: a review of literature and proposal of a screening strategy. Pituitary. 2010;13:146-153.

8. Bondanelli M, Ambrosio MR, Zatelli MC, et al. Hypopituitarism after traumatic brain injury. Eur J Endocrinol. 2005;152:679-691.

9. Wilkinson CW, Pagulayan KF, Petrie EC, et al. High prevalence of chronic pituitary and target-hormone abnormalities after blast related mild traumatic brain injury. Front Neurol. 2012;3:11.

10. Bondanelli M, Ambrosio MR, Cavazzini L, et al. Anterior pituitary function may predict functional and cognitive outcome in patients with traumatic brain injury undergoing rehabilitation. J Neurotrauma. 2007;24:1687-1697.

11. Benvenga S, Campenmi A, Ruggeri R, et al. Hypopituitarism secondary to head trauma. J Clin Endocrinol Metab. 2000;85:1353-1361.

12. Schneider H, Kreitschman-Andermahr I, Ghigo E, et al. Hypothalamopituitary dysfunction following traumatic brain injury and aneurysmal subarachnoid hemorrhage: a systematic review. JAMA. 2007;298:1429-1438.

13. Amar AP, Weiss MH. Pituitary anatomy and physiology. Neurosurg Clin N Am. 2003;14:11-23.

14. Tanriverdi F, Unluhizarci K, Kocyigit I, et al. Brief communication: Pituitary volume and function in competing and retired male boxers. Ann Intern Med. 2008;148:827-831.

15. Bondanelli M, De Marinis L, Ambrosio MR, et al. Occurrence of pituitary dysfunction following traumatic brain injury. J Neurotrauma. 2004;21:685-696.

16. Klose M, Watt T, Brennum J, et al. Posttraumatic hypopituitarism is associated with an unfavorable body composition and lipid profile, and decreased quality of life in 12 months after injury. J Clin Endocrinol Metab. 2007;92:3861-3868.

17. Aimeretti G, Ambrosio MR, Di Somma C, et al. Residual pituitary function after brain injury-induced hypopituitaryism: a prospective 12-month study. J Clin Endocrinol Metab. 2005;90:6085-6092.

18. Agha A, Phillips J, Thompson CJ. Hypopituitarism following traumatic brain injury. Br J Neurosurg. 2007;21:210-216.

19. Cohan P, Wang C, McArthur DL, et al. Acute secondary adrenal insufficiency after traumatic brain injury: a prospective study. Crit Care Med. 2005;33:2358-2366.

20. Rothman MS, Arciniegas DS, Filley CM, et al. The neuroendocrine effects of traumatic brain injury. J Neuropsychiatry Clin Neurosci. 2007;19:363-372.

21. Defense Centers of Excellence. Neuroendocrine screening post mild TBI clinical recommendation. Available at: http://www.dcoe.mil/Content/Navigation/Documents/DCoE_TBI_NED_Reference_Card.pdf. Published February 2012. Accessed August 12, 2013.

22. Agha A, Rogers B, Mylotte D, et al. Neuroendocrine dysfunction in the acute phase of traumatic brain injury. Clin Endocrinol (Oxf). 2004;60:584-591.

23. Agha A, Phillips J, O’Kelly P, et al. The natural history of post-traumatic hypopituitarism: implications for assessment and treatment. Am J Med. 2005;118:1416.

24. Guerrero AF, Alfonso A. Traumatic brain injury related hypopituitarism: a review and recommendations for screening combat veterans. Mil Med. 2010;175:574-580.

PRACTICE RECOMMENDATIONS

› Consider neuroendocrine dysfunction (NED) following confirmed traumatic brain injury of any severity when symptoms suggestive of NED persist for >3 months after injury. A
› Order blood studies to detect deficiencies in pituitary and other key hormones when NED is suspected. A

Strength of recommendation (SOR)

A Good-quality patient-oriented evidence
B Inconsistent or limited-quality patient-oriented evidence
C Consensus, usual practice, opinion, disease-oriented evidence, case series

The Centers for Disease Control and Prevention (CDC) reports that >1.7 million cases of traumatic brain injury (TBI) occur annually in the United States.¹ More than 266,000 military service members sustained at least one TBI from 2000 to 2012.² Most TBIs (80%-85%), military and civilian, are classified as mild (mTBI), and most mTBI patients (80%-85%) experience a complete functional recovery within 3 months of injury.^1,3 The remaining 15% to 20% of mTBI patients experience persistent symptoms and difficulty in rehabilitation, particularly if there are concomitant disorders, such as post-traumatic stress disorder (PTSD), sleep disorders, acute stress disorder, substance abuse disorder, and depression.^4,5Symptoms that mTBI and these other disorders have in common can make differential diagnosis difficult, requiring a high degree of clinical awareness by primary care providers. An additional concern following mTBI is neuroendocrine dysfunction (NED). This association has not been widely discussed and therefore may go largely undiagnosed.⁶ Consider NED in the setting of prolonged symptoms or in patients experiencing difficulty with rehabilitation following mTBI.^7,8

NED following mTBI is more common than once thought

The term “neuroendocrine dysfunction,” as discussed in this article, refers to a variety of conditions caused by imbalances in the body’s hormone production directly related to the pituitary, hypothalamus, and their axes following TBI. Until the past decade, the incidence of TBI-associated pituitary dysfunction was thought to be an uncommon event, usually associated with catastrophic head injuries. Studies of NED in TBI patients focused primarily on moderate or severe TBI, usually from motor vehicle incidents, falls, and assaults.⁷ Other research has since shown that NED occurs more commonly than once believed.⁹ And while the risk of NED may be higher for patients who sustain more severe brain injuries, NED also occurs in mTBI.^7,9,10,11 Interestingly, a recent literature review indicated that the incidence of NED in mTBI was 16.8%, while the incidence with moderate TBI was reported at 10.9%.⁷ Other research has noted that the incidence of NED in mTBI may be as high as 42%.^9,12 No evidence suggests that the severity of NED is related to a specific hormonal dysfunction, nor is there evidence that NED may be associated with a specific mechanism of injury.

Anterior pituitary deficiencies (GH and gonadotropin) account for the majority of chronic neuroendocrine disorders following mTBI.Pituitary anatomy is susceptible to injury and dysfunction

The anatomic and physiologic complexities of the hypothalamus and pituitary gland increase their susceptibility to injury from TBI. The pituitary gland is connected to the hypothalamus by a blood vessel-containing stalk, making the pituitary gland—particularly the anterior portion—susceptible to damage during a head injury.¹³ The hypothalamus secretes thyrotropin-releasing hormone (TRH) and luteinizing-releasing hormone (LRH) to stimulate or suppress the production of anterior pituitary gland hormones, which in turn stimulate the release of hormones and other substances from target organs. Anterior pituitary hormones are growth hormone (GH), luteinizing hormone (LH), follicle-stimulating hormone (FSH), adrenocorticotropic hormone (ACTH), thyroid-stimulating hormone (TSH), and prolactin (PRL). The posterior pituitary secretes oxytocin and vasopressin, also known as antidiuretic hormone (ADH).¹³

Impact from a direct blow with an object or from a concussive blast can cause focal trauma or rotational shearing of tissue internally. Resultant vascular injury, rupture, cerebral edema, vasospasm, pituitary swelling, or inflammation may then initiate an endocrine response that drives a cascade of complex hormonal processes.^5,7,8 Anterior pituitary deficiencies account for the majority of chronic neuroendocrine disorders following mTBI. GH and gonadotropin deficiencies are the most common, but TSH deficiency (secondary hypothyroidism) and ACTH deficiency (adrenal insufficiency) may occur as well, although in <10% of cases with TBI associated NED.¹²

Clinical features of NED mimic those of other conditions

The symptoms of NED include fatigue, insomnia, impaired cognition, memory loss, difficulty concentrating, and emotional and mood disturbances (TABLE).^7,12,14-17 Various combinations of these symptoms may occur and are similar to those of other post-mTBI conditions, such as sleep problems, postconcussive syndrome (PCS), and memory and attention difficulties.¹⁸ The onset of NED may be immediate (eg, in diabetes insipidus [DI] or syndrome of inappropriate antidiuretic hormone [SIADH], which are very rare in mTBI) and potentially life-threatening (eg, in sodium and potassium imbalances), or may be nonspecific and take years to manifest.^6,10,15,19 Additionally, symptoms of NED may spontaneously resolve or persist. Studies have demonstrated pituitary dysfunction in the acute postinjury phase as well as its development as late as 2 to 3 years after injury.^7,8,11,20