Post Head Injury Endocrine Complications

By Milton J. Klein, DO, MBA

The greatest challenge associated with endocrine complications in individuals with traumatic brain injury (TBI) is early recognition of these subtle problems. Endocrine complications can produce significant impact on the progress and outcome of TBI rehabilitation. Prompt diagnosis and treatment of endocrine complications following TBI facilitate the rehabilitation process of patients with TBI.

The release of pituitary hormones, orchestrated by the neuropeptide signals from the hypothalamus, provides a tight control of hormone-regulated homeostasis. The pituitary gland is protected well within the sella turcica of the sphenoid bone; however, the pituitary stalk, connected to the anterior pituitary and hypothalamus, is vulnerable to the effects of TBI, especially in patients with associated facial fractures, cranial nerve injuries, and dysautonomia.

Pathophysiology

Autopsy studies in fatal traumatic brain injury cases demonstrate a fairly high prevalence of hypothalamic and pituitary abnormalities, including anterior lobe necrosis, posterior lobe hemorrhage, and traumatic lesions of the hypothalamic-pituitary stalk. Some variability is noted in studies. Anterior pituitary infarction has been seen to occur in 9 to 38% of patients, posterior pituitary hemorrhage in 12 to 45% of cases and traumatic lesions of the stalk in 5 to 30% of patients.

The traumatic rupture of the pituitary stalk results in anterior lobe infarction because of disruption of the portal blood supply between the hypothalamus and the anterior pituitary. Ninety per cent of the anterior lobe is nourished by the hypophyseal portal veins, which originate from and follow the pituitary stalk. An alternative explanation is that post-traumatic edema of the pituitary gland within the bony sella turcica compromises the portal blood supply, resulting in anterior lobe ischemia/necrosis. Both mechanisms may contribute to anterior lobe dysfunction following TBI.

Anterior hypothalamic trauma is often observed on postmortem studies and may be associated with pituitary hemorrhage or infarction related to TBI. Anterior pituitary hormones (e.g. growth hormone [GH] 1, thyrotropin, corticotropin, gonadotropins) are released by the neuropeptide-releasing hormones from the hypothalamus. The posterior pituitary hormones (e.g. vasopressin, oxytocin) are produced by the hypothalamus and are carried by long axonal projections into the posterior pituitary; they are released later. The posterior lobe vascular supply is not affected by pituitary stalk trauma, because it is supplied by the inferior hypophyseal arteries, which arise from the internal carotid artery below the level of the diaphragma sella. Infarction of the posterior lobe is therefore rare, and the mechanism of the development of diabetes insipidus (DI) is by denervation-losing neural integrity with the hypothalamus2,3,4,5,6,7.

The most common endocrine complication after a TBI is a syndrome of inappropriate antidiuretic hormone (SIADH). SIADH causes a dilutional hyponatremia secondary to inappropriate renal water conservation. Relatively less common post-TBI endocrinopathies include anterior hypopituitarism (AH), DI, cerebral salt wasting (CSW) and primary adrenal insufficiency (PAI).The most common endocrinopathies associated with hypopituitarism, in descending order, include hypogonadism, hypothyroidism, adrenal insufficiency, hyperprolactinemia, DI, and GH deficiency. CSW and PAI are peripheral causes of hyponatremia after a TBI. SIADH, AH and DI have central endocrine etiologies.

History

Approximately 30 to 50% of patients who survive post-traumatic brain injury (post-TBI) demonstrate endocrine complications. Most post-TBI endocrinopathies do not have typical specific history patterns.

• Diabetes insipidus (DI) is an exception, as it does have a specific history. DI most commonly is associated with severe TBI and basilar skull fractures with cranial nerve involvement, craniofacial trauma and postcardiopulmonary arrest. Delayed onset of DI is associated with a poor prognosis due to hypothalamic involvement causing permanent DI. Acute DI following a mild to moderate TBI indicates a posterior pituitary lesion with only a temporary antidiuretic hormone (ADH) deficiency.
• Anterior hypopituitarism (AH) also has a specific history. AH is usually associated with moderate to severe TBI. With improvement of emergency and neurosurgical care for these patients, there are more survivors demonstrating AH. AH may present weeks to months after the TBI, typically in the acute or chronic rehabilitation phase. Any patient with unexplained malaise or a setback with regard to functional status should be examined and tested for AH or the other post-TBI endocrinopathies. In summary, risk factors for AH include relatively serious TBI (Glasgow Coma Scale score <10), diffuse brain swelling and hypotensive or hypoxic episodes.
• A syndrome of inappropriate antidiuretic hormone is the most common TBI-associated neuroendocrinopathy causing hyponatremia. The incidence is reportedly as high as 33%.
• Cerebral salt wasting (CSW) is a less-common cause of hyponatremia in the post-TBI population. These patients are dehydrated and lose weight.
• Primary adrenal insufficiency (PAI) is rare and presents with the superimposed psychiatric symptoms of depression, confusion and apathy. PAI is associated with fatigue, weakness, anorexia and weight loss. These problems may present insidiously over a prolonged period. The acute presentation of PAI includes nausea, vomiting and hypertension.

Physical

• Physical examination findings may be obscured by the altered cognitive status of patients who have had a traumatic brain injury.
• Common post-TBI findings, such as lethargy, fatigue and slowed mental processing time, also are associated with endocrine complications.
• In extreme cases, hyponatremia can cause seizures, confusion and coma.
• Primary adrenal insufficiency (PAI) may present with acute psychiatric problems, such as psychosis, depression, apathy or a schizophrenia-like syndrome.
• General physical examination findings may include myxedematous, addisonian-appearing or slowed mentation.
• Vital signs include the following.
  • Slowed pulse
  • Hypothermia
  • Orthostatic hypotension
• Dermatologic findings include the following.
  • Pale, soft, waxy skin
  • Hyperpigmentation
  • Decreased axillary and pubic hair
  • Areolar depigmentation
  • Decreased male facial hair
  • Decreased sweating and sebum secretion
• Neurologic findings include the following.
  • Mental status changes (e.g. lethargy, confusion, slowed mentation)
  • Muscle weakness (may be proximal due to endocrine myopathy)
  • Hyporeflexia or areflexia
  • Hypotonia

Causes

The most common post-traumatic brain injury (post-TBI) endocrine complications are as follows.

Syndrome of Inappropriate Antidiuretic Hormone (SIADH)

• SIADH is the most common neuroendocrine complication following TBI, with a reported incidence as high as 33%. In the TBI rehabilitation setting, SIADH is the most common cause of hyponatremia.
• Hyponatremia is often seen in the rehabilitation setting among survivors of either traumatic or non-traumatic brain injury (e.g. hemorrhagic stroke, brain tumours, CNS infections). This problem is associated most often with SIADH. Approximately 30% of patients who undergo neurosurgery demonstrate SIADH. SIADH also can be induced by medications such as carbamazepine, major tranquilizers and antidepressants.
• Hyponatremia can cause several problems, including cerebral ischemia (by volume depletion), lassitude, seizures, confusion and coma.
• SIADH causes renal water conservation, with a secondary hyponatremia because of dilution. In patients who are not dehydrated or using diuretics, the laboratory diagnosis is based upon a urine osmolality greater than serum osmolality. The serum osmolality in patients with SIADH is less than 280 osm/kg, serum sodium is less than 135 mEq/L, and urine sodium is greater than 25 mEq/L.
• The treatment in most cases is fluid restriction and, in unusual situations, IV hypertonic saline.

Cerebral Salt Wasting (CSW)

• Although most cases of hyponatremia due to brain injury are caused by SIADH, a less-common etiology is CSW syndrome. Peters and colleagues first described CSW in 195013.CSW is caused by impaired renal tube function that results in the inability of the kidneys to conserve salt. The etiology may be attributable to direct neural influence on renal tube function. Salt wasting with volume depletion is the hallmark of this syndrome. Clinically, patients manifesting CSW are dehydrated, lose weight, have orthostatic hypotension, and demonstrate a negative fluid balance. In cases of CSW and SIADH, the laboratory values often are the same for serum/urine osmolalities and electrolytes; however, elevated serum blood urea nitrogen (BUN), serum potassium and serum protein concentration are also supportive of the diagnosis of CSW. Additionally, serum uric acid is normal in patients with CSW and is low in persons with SIADH.
• Treatment of this type of hyponatremia with associated dehydration consists of replacement of fluids and salt, which is best managed by IV normal saline or, in rare cases, by IV hypertonic saline. Rehydration significantly reduces the risk of cerebral ischemia or cerebrovascular accident.

Diabetes Insipidus (DI)

• DI is rare, with an estimated one case per 100,000 hospital admissions. Post-traumatic DI occurs in 2 to 16% of all cases. The most common etiologies of post-traumatic DI include severe closed head injury, frequently with basilar skull fractures; craniofacial trauma; thoracic injury; postcardiopulmonary arrest; and intraventricular hemorrhage in neonatal patients. DI frequently is associated with cranial nerve injuries. The usual onset is 5 to 10 days following trauma.
• Characteristic features of DI include polyuria, low urine osmolality, high serum osmolality, normal serum glucose and normal to elevated serum sodium. Urine output usually is greater than 90 mL/kg/d, with a specific gravity of less than 1.010 and an osmolality of 50 to 200 mOsm.

Anterior Hypopituitarism (AH)

• AH, anterior hypopituitarism or panhypopituitarism, is not as rare a complication after a closed head injury; it usually follows moderate to severe craniocerebral trauma. With improvements in emergency and acute neurosurgical care for patients with head injuries, a greater number of severely involved patients are surviving than had previously done so. This subset of patients is most susceptible to the development of AH. The mechanism through which AH develops in patients with severe head injuries is an interruption of the major blood supply to the anterior lobe of the pituitary gland because of trauma to the unprotected stalk connecting the anterior pituitary to the median eminence of the hypothalamus.
• Additionally, the hypothalamus secretes releasing and inhibitory hormones into the portal or stalk circulation, for controlling the release of the anterior pituitary hormones. Although the pituitary gland is well protected by the bony sella turcica, the pituitary stalk is not covered by dura mater and lies in the subarachnoid space. Severe craniocerebral injury may traumatize the stalk directly, or an anterior lobe infarction can occur due to impaired portal system circulation secondary to shock and cerebral edema.
• The arterial blood supply of the posterior lobe of the pituitary comes directly from the inferior hypophyseal arteries branching from the internal carotid arteries. The posterior pituitary hormones are secreted by the hypothalamus.
• Autopsy studies of 100 patients who died from craniocerebral trauma demonstrated pituitary lesions in approximately 60% of the group. Of those subjects with pituitary lesions, 59 demonstrated capsular hemorrhage, 42 demonstrated posterior lobe hemorrhages, and 22 revealed anterior lobe ischemic necrosis. Most patients (20 of 22) with anterior lobe ischemic necrosis died within the first seven days following injury because of the severity of the craniocerebral trauma associated with shock and severe cerebral edema. Clinical AH is so rare in association with closed head injuries because most of these patients do not survive secondary to the severity of their injuries. This clinical syndrome presents itself only when two-thirds of the anterior pituitary has been destroyed.
• The syndrome of AH may manifest an insidious onset weeks to months after the original closed head injury. The patient may become progressively lethargic or anorexic and may demonstrate hypothermia, bradycardia or hypotension with hyponatremia. These symptoms result in a significant setback if they occur during the acute phase of rehabilitation of a patient who has sustained a closed head injury. Any unexplained onset of malaise and generally decreased vital signs with associated stagnation of the rehabilitation progress in a patient following closed head injury should prompt the clinician to suspect the presence of AH.
• AH following TBI can be obscured by the cognitive impairment of the patient and can contribute to delayed progress in rehabilitation.
• The endocrine workup for AH includes serum hormonal assays, such as cortisol (0900), testosterone, triiodothyronine (T3), thyroxine (T4), thyrotropin, follicle-stimulating hormone (FSH), luteinizing hormone (LH) and estrogen (for females). Insulin-like growth factor-I (IGF-I) is a screening assay for growth hormone (GH) deficiency. Advanced provocative GH testing may be necessary to confirm this diagnosis. Also perform a complete blood cell (CBC) count and serum electrolyte evaluation.
• Treatment involves multiple hormonal replacement therapy, as well as monitoring of the patient’s serum levels and clinical response. The patient usually responds with improved vital signs, improved constitutional symptoms, and increased endurance for participation and progress in the rehabilitation program. The hormonal replacement therapy usually is required long-term.

Primary Adrenal Insufficiency (PAI)

• PAI usually presents with the psychiatric symptoms of depression, confusion and apathy.
• Additional features include self-mutilation, paranoia, psychosis and schizophrenic behaviours.
• The mechanism of the psychiatric presentation is related to factors such as hypoglycemia, elevated exogenous endorphins, and axonal conduction changes.
• Progressive deficiency of glucocorticoid and mineralocorticoid hormonal activity leads to hypotension, fatigue, anorexia/nausea, hyperpigmentation and progressive, generalized weakness. Diagnosis of PAI is difficult in patients with TBI, because these particular symptoms may be ascribed to the TBI itself.
• The most common cause of PAI is autoimmune or idiopathic adrenalitis (in 65 to 84% of cases). The next most common etiology is adrenal parenchymal destruction secondary to tuberculosis, sarcoidosis, malignancy, acute sepsis (including systemic fungal infections) and acquired immunodeficiency syndrome (AIDS).
• Acute adrenal crisis may result from bilateral adrenal hemorrhage from trauma, sepsis, surgery or acute burns. If this problem is unrecognized, acute adrenal crisis may lead to acute shock and death. Adrenal failure is usually permanent in patients who survive the acute phase of the adrenal crisis.
• Several rare hereditary syndromes are associated with PAI, such as familial glucocorticoid insufficiency, adrenoleukodystrophy and adrenomyeloneuropathy. PAI results from a deficiency of glucocorticoid and mineralocorticoid hormonal activity, combined with a reduction of feedback to the anterior pituitary gland. The cortisol deficiency results in excessive secretion of corticotropin from the anterior pituitary gland and excessive secretion of corticotropin-releasing hormone from the hypothalamus.
• The presentation of PAI may be acute, characterized by nausea, vomiting and hypertension. Alternatively, this clinical entity may present insidiously, with slow development of non-specific symptoms over a prolonged period. The most common features include fatigue, weakness, anorexia and weight loss. Additional findings include hyponatremia, hyperkalemia, skin hyperpigmentation and gastric motility impairment that leads to complete gastric stasis.
• Physiatrists must be aware of PAI, even though it is rare, because the presentation of adrenal insufficiency can be similar to the presentation of TBI. The symptoms limiting rehabilitation of patients following TBI can be attributed to the brain injury itself or to deconditioning secondary to prolonged bed rest. Treatment of this underlying problem by mineralocorticoid and glucocorticoid replacement therapy can result in a significant improvement of rehabilitation progress and outcome.

Other Post-TBI Endocrine Complications

• Early puberty is defined as secondary sexual development in females younger than eight years and in males younger than nine years. Precocious puberty can occur in children with head injuries because of an inappropriate secretion of gonadotropin-releasing hormone (GRH), resulting in the subsequent release from the anterior pituitary of LH and FSH. These hormones cause the early onset of puberty by increasing levels of gonadal steroids and gametogenesis.
• Hypogonadism can also occur following head trauma. In one study, approximately one-third of female patients who had head injuries (26 of 78) experienced temporary amenorrhea, usually for no longer than three months. This phenomenon is secondary to hypothalamic dysfunction, resulting in absent or decreased secretion of GRH.
• In male patients, gonadotropin and testosterone levels are low immediately following head injury. Later, in response to exogenous GRH, the anterior pituitary responds with the release of high levels of LH and FSH, which is typical of hypothalamic dysfunction. At three to six months after the head injury, five of 21 male patients demonstrated persistently low serum testosterone levels. Depending on the clinical situation, consider appropriate testosterone replacement therapy.

Summary

• Approximately 30 to 50% of patients with moderate to severe head injury demonstrate endocrine complications. These problems may not present in a classic textbook fashion in persons who are severely impaired following TBI. The only clue to determining endocrine complications may be an unexplained failure to progress or a setback in the TBI rehabilitation program.
• The most common endocrine abnormality is SIADH, followed by DI.
• SIADH is the most common cause of hyponatremia; however, other causes include fluid overload or extra-cellular fluid depletion from GI or renal loss of sodium. Criteria for diagnosis of SIADH include low serum osmolality, hyponatremia and inappropriately concentrated urine (with urine sodium >25 mEq/L).
• Hyponatremia that remains unresponsive to standard treatment for SIADH should point the clinician to other causes of hyponatremia.
• Another clue to recognizing adrenal insufficiency is hyperkalemia associated with the hyponatremia secondary to a loss of mineralocorticoid activity at the kidney, causing urine sodium loss, impaired excretion of potassium, and hydrogen ion retention.
• Azotemia may also be associated with adrenal insufficiency.

Surgical Intervention

Endocrine complications following traumatic brain injury (TBI) are treated by medical management and usually do not require surgical intervention.

Consultations

Endocrinology subspecialty consultation may be needed following traumatic brain injury (TBI) in patients who demonstrate subtle findings of underlying endocrine abnormalities, as evidenced by a slowdown or complete halt in the progression of a TBI rehabilitation program. This group of patients includes those who have a growth delay (pediatric patients) or unexplained constitutional symptoms of lethargy/poor appetite following TBI, and young female patients with amenorrhea following TBI.

From the endocrinologist’s perspective, patients with vital endocrinopathies such as diabetes insipidus, secondary adrenal failure and secondary hypothyroidism should be promptly treated with hormone replacement therapy (HRT). Secondary hypogonadism and severe growth hormone (GH) deficiency should be considered later, after replacement of other deficits and after retesting. Patients who are severely involved in a persistent vegetative state would not likely benefit from HRT for secondary hypogonadism or GH deficiency. GH replacement therapy outcomes include increased muscle mass/exercise tolerance and improved quality of life/sense of wellness.

Post-TBI patients functioning at a very low level who are institutionalized should receive HRT only for vital endocrine hormones, including hydrocortisone, vasopressin and T4. All patients with moderate to severe TBI should receive a baseline pituitary hormone deficiency evaluation, especially if they were hospitalized for at least one day post-TBI.

Medication

The goals of pharmacotherapy are to reduce morbidity and prevent complications.

Hormone Replacements

Because most endocrinopathies following traumatic brain injury are due to failure at the anterior pituitary level, treatment involves hormonal replacement. Individual hormonal replacement is also indicated, depending on the specific endocrine gland involved. Posterior pituitary failure is also treated by replacement therapy.

Levothyroxine (Levoxyl, Synthroid)

In the active form, this drug influences growth and maturation of tissues. Involved in normal growth, metabolism and development. Primary use is for synthetic thyroid hormone replacement. Secondary use is for suppression of pituitary thyrotropin for management of thyroid carcinoma or thyroid nodules. Titrate to degree of hypothyroidism.

Desmopressin Acetate (DDAVP)

Synthetic analogue of hypothalamic/posterior pituitary hormone 8-arginine vasopressin (ADH) for treatment of central DI. Not for treatment of nephrogenic DI. Dose should be titrated to plasma/urine osmolality and urine volume.

Testosterone (Andro-LA, Androderm, Depo-Testosterone)

For treatment of primary hypogonadism or hypogonadotropic hypogonadism.

Hydrocortisone (Cortef, Solu-Cortef)

Used for treatment of primary or secondary adrenocortical insufficiency.

Used short-term to treat flare-ups of rheumatologic conditions. Used for prolonged maintenance of collagen diseases (e.g. systemic lupus erythematosus, polymyositis/dermatomyositis). Also used for dermatologic (e.g. pemphigus), allergic (e.g. atopic dermatitis) and respiratory diseases (e.g. sarcoidosis).

Pediatric growth and development may be suppressed and should be monitored.

Follow-Up

Further Inpatient Care

The clinical response of the patient after treatment has been instituted is the most important factor in determining the necessity of additional treatment. Follow-up endocrine studies (i.e. hormonal levels) are necessary at least weekly until homeostasis has been achieved. Serum electrolytes, BUN and creatinine levels need to be assessed at least daily until normalized, and then these levels should be monitored at routine intervals.

Further Outpatient Care

The outpatient follow-up care of these patients is individualized, depending on the endocrine problem under treatment and the patient’s metabolic stability.

Inpatient and Outpatient Medications

As stated previously, medication management consists primarily of hormone replacement until clinical response and normal serum levels have been achieved. In most cases, the HRT continues on a long-term outpatient basis. Most inpatients with associated electrolyte disorders are stabilized with intravenous electrolyte therapy before hospital discharge, and no further medication management is necessary.

Deterrence

No deterrence/prevention program exists for endocrine complications following traumatic brain injury. Early recognition of these problems through a high index of suspicion, close monitoring of serum electrolyte balance and prompt corrective treatment minimizes any negative impact these complications have on the rehabilitation outcome.

Complications

The most significant complication is failure to recognize these treatable endocrine complications, ultimately prolonging the rehabilitation program and decreasing the patient’s functional outcome following traumatic brain injury.

Osmotic demyelination of the CNS, caused by an excessively rapid correction of hyponatremia with IV hypertonic saline, is an unusual complication of TBI, albeit a serious and sometimes lethal one.

Prognosis

The prognosis for the patient with endocrine complications following traumatic brain injury is good to excellent, assuming these sometimes subtle problems are diagnosed and treated promptly. Failure to recognize and treat these problems negatively affects the rehabilitation progress and eventually the long-term functional outcome 17, 18.

Patient Education

Depending on the level of patient cognitive impairment, the patient and his or her caregivers/guardians are advised to be aware of any changes exhibited by the patient, such as unexplained lethargy, decreased tolerance to activity or cold intolerance. These particular problems require immediate notification of the attending physician. The patient should undergo physician re-evaluation and, if necessary, an endocrine workup. Rapid corrective hormonal replacement therapy then can be initiated and monitored at a follow-up session with the treating physician. For excellent patient education resources, visit eMedicine’s Endocrine System Center. Also, see eMedicine’s patient education article Anatomy of the Endocrine System.

Medicolegal Pitfalls

The most significant medical/legal pitfall is delayed diagnosis or failure to diagnose neuroendocrine abnormalities following traumatic brain injury (TBI), especially in a patient with severe cognitive impairment. Should this problem remain untreated, the progress and eventual outcome of the patient’s rehabilitation may be significantly compromised. Non-reversible loss of function would be costly in terms of patient care needs and, more importantly, the patient’s quality of life.

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Reprinted with permission from eMedicine.com, 2010. Available at http://emedicine.medscape.com/article/326123-overview.