Injuries to the central nervous system (CNS), both within the brain and the spinal cord, trigger a cascade of events which alter the normal homeostatic function of the neuroendocrine system. These systems regulate cellular nutrition, energy consumption, oxygenation, and waste removal, which in turn control tissue growth and repair. Subsequently, these changes impact normal organ system functions that lead to various hematological, metabolic, and endocrine complications. Some complications such as VTE and osteoporosis after CNS injury are also covered elsewhere separately as a specific topic.
Hematological, metabolic, and endocrine complications can result from traumatic brain injury (TBI) and spinal cord injury (SCI), as well as non-traumatic disorders involving the brain or spinal cord such as stroke and CNS cancer.
Epidemiology including risk factors and primary prevention
Immobilization hypercalcemia occurs in approximately 10-23% of patients with SCI. As many as 50% of patients with SCI will sustain osteoporotic or low impact fractures at some point post-injury.1Studies have shown a 52.3% incidence of mild anemia in patients with traumatic spinal cord injury.2Also in patients with SCI, over one-third of persons will have low HDL, which is a known risk factor for cardiovascular disease. Studies have also reported rates of diabetes from 13% to 22% in patients with spinal cord injury or disorders, elevated compared to about 6.6% in US population.3 Individuals with SCI also have increased odds for developing heart disease (adjusted odds ratio [OR] = 2.72) and stroke (adjusted OR = 3.72)4.
In TBI, studies have shown hormonal imbalances affect as many as 30-50% of patients after severe injury. In addition, up to an 80% incidence of gonadotropin deficiency in the acute phase, from 7 to 20 days, after TBI can be seen.5,6Specific hormonal deficiencies include 18% incidence of growth hormone deficiency, 16% incidence of corticotropin deficiency, and 40% incidence of vasopressin abnormalities. Approximately 25% of long-term survivors of TBI show deficiencies of one or more of the hypothalamic-pituitary hormones.5Risk factors for posttraumatic hypopituitarism includes severe TBI, diffuse axonal injury, and basal skull fracture.7 With aneurysmal SAH, clinical severity does not correlate with neuroendocrine dysfunction.8
The spectrum of acute and potentially life-threatening changes after brain injury and spinal cord injury vary widely, relating to the severity and level of injury. Anemia occurs acutely through blood loss from concurrent vascular trauma, and subacutely as a result of GI bleeding.2This is likely secondary to increased vagal tone, resulting in increased gastric secretions and diminished oral intake. Most remaining metabolic, endocrine, and hematologic complications evolve over weeks and months post-injury.
Damage to the pituitary or the hypothalamus results in impaired production of hormones produced and secreted by these glands.5Neuroendocrine dysfunction occurs due to primary and/or secondary injury to the hypothalamus and pituitary gland, leading to posttraumatic hypopituitarism. Those who suffer head trauma, local vascular compromise, and radiation therapy can suffer.
The complications that arise from SCI can be attributed to the associated paralysis with diminished weight bearing, loss of sympathetic control, and loss of muscular action, which disrupts essential mechanisms. These include a disruption in circulation and transport of blood constituents, nutrients, hormones and cellular metabolites that may normally act as stimulators or feedback inhibitors of glandular and organ function.
Disease progression including natural history, disease phases or stages, disease trajectory (clinical features and presentation over time)
|Condition||Hormones affected||Commonly Associated Disease|
|Hormone deficiencies due to damage to pituitary or hypothalamus||Acute phase: Adrenocorticotropic Hormone (ACTH)
Antidiuretic Hormone (ADH)
Thyroid Stimulating Hormone (TSH)
Insulin-like Growth Factor (IGF-1)
Growth Hormone (GH)
Follicle Stimulating Hormone (FSH)
Luteinizing Hormone (LH)
Dwarfism, growth defects (in children)
Sex hormone deficiency
Amenorrhea or Oligomenorrhea
|Hormone excess seen in brain injury||Antidiuretic Hormone (ADH)||Syndrome of Inappropriate ADH|
In acute setting, within days after injury, a patient should be evaluated for adrenal insufficiency if hyponatremia, hypoglycemia, and hypotension are present.
Signs of hypopituitarism, such as loss of secondary hair, change in menstrual cycle (oligomenorrhea or amenorrhea), impaired sexual function, weight changes, polydipsia, poor recovery, as well as hypoglycemia and hypotension, should be monitored between 3 and 6 months after injury.9 Posttraumatic pituitary dysfunction can be transient, most resolve by 3 months after injury, but in some cases worsen over weeks to months after injury.
Commonly encountered electrolyte disorders in patients with TBI or SCI include:
- Hypercalcemia: Immobilization after SCI results in increased osteoclastic activity, causing bone resorption and transient hypercalciuria for up to 18 months after injury. If the rate of resorption is extremely high (commonly in adolescents), or there is co-existing renal impairment, hypercalcemia results.10
- Serum sodium (Na+) abnormalities: During acute phase of TBI, hyponatremia can occur due to SIADH which is often a self-limiting disease. This along with cerebral salt-wasting syndrome is often associated with TBI and subarachnoid hemorrhage (SAH). Other possible etiologies of hyponatremia include fluid overload, adrenal insufficiency, and medication side effects. TBI can also result in Diabetes Insipidus (DI) which occurs from a failure of ADH release leading to hyponatremia. Severe hyponatremia may occur acutely after SCI as a result of impaired sympathetic influence on the renin-angiotensin response to acute injury. Furthermore, post-TBI, ACTH deficiency results in decreased secretion of corticosteroids from the adrenal glands and decreased sodium retention by the kidneys. Paralysis also causes overall reduction in blood pressure, which in turn increases secretion of ADH, resulting in hyponatremia. Impaired secretion of ADH results in increasing plasma sodium concentrations.3,11
|Cerebral Salt Wasting||SIADH|
|Urine sodium concentration||Elevated||Elevated|
|Urine volume||Polyuria||Oligouria (can be variable)|
|Treatment||Sodium and fluid resuscitation; controversial
|Fluid restriction; can also add oral salt repletion. If severe, ADH inhibitors; vaptans (vasopressin receptor antagonist)|
*volume status can be difficult to assess as it maybe extracellular.
Low and high sodium level have been associated with higher mortality and poorer outcome.
- TBI and SCI are both associated with hypercoagulopathy which predisposes patients to thromboembolic events. VTE is discussed in a separate section.
- Impaired glucose tolerance, higher risk of diabetes mellitus (DM) and hyperlipidemia have been associated with SCI.
- Metabolic syndrome have been associated with SCI and also in patients with growth hormone deficiency after TBI, SAH, and CNS cancer survivors.9,12
Specific secondary or associated conditions and complications
- Anemia occurs in patients with chronic SCI due to a combination of etiologies, including chronic inflammation (from recurrent decubitus ulcers, urinary tract infections, etc.), acute and chronic blood loss, and folic acid deficiency.2
- Impaired glucose tolerance and insulin resistance, which can also be seen in growth hormone deficiency.
- Diabetes Mellitus Type 2.
- Renal calculi (due to hypercalcemia).
- Osteoporosis, resulting in increased incidence of lower extremity and spinal fractures below the neurologic level of injury. Those with growth hormone deficiency are at risk for fractures and skeletal fragility.9
- Cardiovascular disease (due to adrenergic dysfunction, poor diet, and physical inactivity). Patients with SCI have increased prevalence of low levels of HDL compared to the general population.13, 14
- Venous thrombo-embolism, (Risk diminishes with time, and generally not significantly higher than in general population after 1 year post-injury).
- Testosterone deficiency.
ESSENTIALS OF ASSESSMENT
Proper history taking is essential in the diagnosis and management of potential complications. An inventory of new and chronic complaints helps to elucidate evolving complications. Key information to elicit from patients is:
- Pre- and post-injury medical and surgical history.
- Medication history and current medications.
- New onset shortness of breath, dizziness or headaches.
- New onset neurological symptoms, including pain or weakness above or below neurologic level of injury.
- New onset of extremity swelling, warmth or erythema.
- Worsening fatigue.
- Hair loss.
- Change in menstrual cycle (oligomenorrhea or amenorrhea).
- Erectile dysfunction.
- Impaired sexual function.
- Muscles weakness.
- Recent weight changes: weight gain or weight loss.
- Change in stool color or blood in stools.
- Polyuria, polydipsia.
- For DI: excessive thirst and large urine output refractory to fluid restriction.
- History of fragility fractures.
- Poor recovery.
- Decrease in cognitive performance.
- Increased abdominal fat.
In addition to other aspects of the general physical and neurological examination pertinent to the underlying CNS condition, it is important to assess and document findings related to specific metabolic and endocrine complications such as weight and Body Mass Index (BMI) calculation, presence of gynecomastia, testicular atrophy, or decreased pubic and axillary hair.
|Conditions||Routine Tests Ordered|
|Hormonal Abnormalities||Acute phase:
- A non-enhanced computed tomography (CT) scan of the head is the initial standard of brain imaging to properly aid all other workups. Magnetic resonance imaging (MRI) has shown to be at least 30% more sensitive than CT scan but the need to order imaging studies should always be made on a case-by-case basis. Both CT and MRI are used to detect extent of head injury and injury to the hypothalamus as well as the pituitary gland. Furthermore, CT scans can be helpful in identifying certain skull fractures that are more likely to be associated with injury to hypothalamus-pituitary axis.
- For osteoporosis, dual-energy x-ray absorptiometry (DXA) scan is currently the best available clinical tool for the diagnosis of osteoporosis. Furthermore, monitoring of bone mineral density (BMD) over time has shown to be helpful in management of disease.
- Plain x-rays for suspected lower extremity fractures.
Early predictions of outcomes
Extent of brain injury, manifested in residual cognition and level of paralysis after injury are predictors of subsequent prognosis. The severity of TBI seems to be related to the likelihood of developing post-traumatic hypopituitarism. Patients with hypopituitarism showed impaired quality of life and adverse metabolic profile.9Amenorrhea in women maybe associated with negative outcome.16Also, GH deficiency is correlated with lower quality of life and increased rates of depression.17Adolescent and young adult males are more commonly affected by hypercalcemia in SCI than other populations.10
- Optimization of the home setting for safe wheelchair mobility and transfers can help safeguard osteopenic patients from potential low impact trauma.
- Adaptive devices to facilitate access to and compliance with medications.
- Adequate heating and air conditioning to minimize metabolic demand.
- Provision of facilities for aerobic exercise can help improve cardiovascular health.18
Social role and social support system
Education provided by health care professionals directly to patients and indirectly through training given to their caregivers for reinforcement of health maintenance strategies can aid in managing complications associated with SCI and TBI. For instance, diabetic teaching provided to the family and the patient has been shown to improve compliance.19
Due to loss in neurologic feedback mechanisms, patients with SCI as well as patients with brain injury frequently remain asymptomatic in the face of evolving pathology. (Reduced or absent anginal symptoms, vague or blunted symptoms of renal calculi or appendicitis, lack of pain in the presence of large decubiti, etc.) Successfully achieving patient compliance with dietary, behavioral, exercise, and preventive regimens is frequently quite challenging for clinicians. Regular and accurate documentation of physical findings and patient education is crucial in achieving these objectives.
3. REHABILITATION MANAGEMENT AND TREATMENTS
Available or current treatment guidelines
Treatment for the various conditions listed are as follows:
- Osteoporosis: Oral bisphosphonate antiresorptive therapy (Alendronate, Etidronate, Clodronate, Tiludronate) have been tried. Some studies have suggested Vitamin D supplementation may be protective against bone loss in SCI, although this needs further study.20 Electrical stimulation (ES) leading to cyclical muscle contraction maybe beneficial.
- Renal Calculi due to Hypercalcemia: IV fluids (Acute management), dietary modifications tailored to each individual patient depending on most likely cause of stone formation (uric acid stones, struvite stones, etc.).
- Diabetes Mellitus: Strict glucose monitoring. Oral agents (Metformin, Glipizide, etc.), Insulin therapy (particularly for patients with long-standing disease, poor response to oral medications or noncompliance). Diet and lifestyle modification.21When oral agents are used for SCI population, potential side effects of GI complications and volume depletion should be monitored closely.4
- Anemia: Iron supplementation (if iron deficiency anemia) or treat underlying condition; B12 supplementation in Vitamin B12 deficiency.22
- Adrenal insufficiency: if aldosterone deficit is present, then treat with fludrocortisone, hydrocortisone, dexamethasone, or prednisone
- Hyperlipidemia: Diet and lifestyle modification. Statin therapy.
- Diabetes Insipidus (DI): Desmopressin in Central DI
- SIADH (Acute): Fluid restriction to 800 ml/day. Hydration with IV normal saline. Salt tablets in occasional cases.11
- Testosterone replacement therapy has shown to increase lean tissue mass and energy expenditure in hypogonadal men.23
- Hypothyroidism: levothyroxine
At different disease stages
Coordination of care
Lifelong care for patients with SCI and TBI after the acute management and initial rehabilitation requires collaboration between physiatrists, medical and surgical specialists and therapists. This care is most effectively coordinated by a physiatrist and a primary care physician who are in frequent contact and pursue a mutually derived plan of care. In general, a primary care approach to managing patients with SCI and SCD (spinal cord disorders) facilitates access to a larger team of clinicians who specialize in this care, and includes the physiatrist and the internist.
Patient & family education
Patient and family education should be geared with a goal-oriented approach to ensure that patients can deal with complications in the most effective manner. Common areas of focus include:
- Diabetic education
- Anticoagulation administration
- Clot prevention and management
- Insulin administration and glucose monitoring
- Diet and lifestyle modifications
- Monitoring wound and skin
Translation into practice: practice “pearls”/performance improvement in practice (PIPs)/changes in clinical practice behaviors and skills
Practice pearls include:
- Assess for worsening fatigue and diminished functional endurance on a routine basis to evaluate for underlying anemia and neuroendocrine dysfunction, especially if there is poor recovery.
- Regularly monitor patient’s diet, lifestyle, and weight for possible glucose intolerance.
- Regular specific inquiry about patient mood, libido, menses and general perception of energy level may alert the clinician to evolving hormonal abnormality.
4. CUTTING EDGE/EMERGING AND UNIQUE CONCEPTS AND PRACTICE
Along with electrolyte and hormonal changes monitoring, there also has been evaluation of biomarkers that may contribute to these abnormalities. Combining biomarkers, in addition to other clinical data, may help to create a better prognostic model.
5. GAPS IN THE EVIDENCE-BASED KNOWLEDGE
Gaps in the evidence-based knowledge
Although it appears clear that the rate of overall bone loss and subsequent evolution of osteoporosis in patients with SCI diminishes with time, this process does not appear to reach a steady state and efforts to prevent or even reverse bone density loss have been pursued for many years. The role for empiric use of bisphosphonates and duration of treatment remains controversial. Also, the role of receptor activator of nuclear factor of kappa B ligand inhibitors such as Densosumab in preventing and treating osteoporosis after SCI and TBI are not known. The overall benefit and optimal utilization of weight-bearing activities, and muscular action through functional electrical stimulations remains controversial.
- Battaglino RA, Lazzari AA, Garshick E, Morse LR. Spinal cord injury-induced osteoporosis: pathogethogenesis and emerging therapies.Curr Osteoporosis Rep. 2012; DOI 10.1007/s/11914-012-0117-0.
- Perkash A, Brown M. Anemia in patients with traumatic spinal cord injury.Journal of American Paraplegic Society.1986;9(1-2):10-15.
- LaVela, et al. Diabetes mellitus in individuals with spinal cord injury or disorder.J Spinal Cord Med. 2006;29(4):387-395.
- Bauman, William A, et al. “Endocrinology and Metabolism of Persons with Spinal Cord Injury.” Spinal Cord Medicine, Third ed., Demos Medical Publishing, 2018, pp. 278–317.
- Behan LA, Phillips J, Thompson CJ, Agha A. Neuroendocrine disorders after traumatic brain injury.J Neurol Neurosurg Psychiatry.2008;79(7):753-759.
- Agha A, Rogers B, Mylotte D, Taleb F, Tormey W, Phillips J, Thompson CJ. Neuroendocrine dysfunction in the acute phase of traumatic brain injury. Clinical endocrinology. 2004 May;60(5):584-91.
- Schneider M, Schneider HJ, Yassouridis A, Saller B, Von Rosen F, Stalla GK. Predictors of anterior pituitary insufficiency after traumatic brain injury. Clinical endocrinology. 2008 Feb;68(2):206-12.
- Schneider HJ, Kreitschmann-Andermahr I, Ghigo E, Stalla GK, Agha A. Hypothalamopituitary dysfunction following traumatic brain injury and aneurysmal subarachnoid hemorrhage: a systematic review. Jama. 2007 Sep 26;298(12):1429-38.
- Melmed S. Pathogenesis and Diagnosis of Growth Hormone Deficiency in Adults. New England Journal of Medicine. 2019 Jun 27;380(26):2551-62.
- Maynard FM. Immobilization hypercalcemia following spinal cord injury.Arch Phys Med Rehabil. 1986;67(1):41-44.
- Hoorn EJ, van der Lubbe N, Zietse R. SIADH and hyponatraemia: why does it matter? NDT Plus. 2009;2:iii5-iii11.
- De Haas EC, Oosting SF, Lefrandt JD, Wolffenbuttel BH, Sleijfer DT, Gietema JA. The metabolic syndrome in cancer survivors. The Lancet Oncology. 2010 Feb 1;11(2):193-203.
- Myers J, Lee M, Kiratli J. Cardiovascular disease in spinal cord injury: an overview of prevalence, risk, evaluation and management.Phys Med Rehabilitation.2007;86:142-152.
- Furlan JC, Fehlings M. Cardiovascular complications after acute spinal cord injury: pathophysiology, diagnosis, and nanagement.Neurosurg Focus. 2008:25(5):E13.
- Quinn M, Agha A. Post-Traumatic Hypopituitarism—Who Should Be Screened, When, and How?. Frontiers in Endocrinology. 2018 Feb 2;9:8.
- Ripley DL, Harrison-Felix C, Sendroy-Terrill M, Cusick CP, Dannels-McClure A, Morey C. The impact of female reproductive function on outcomes after traumatic brain injury. Archives of Physical Medicine and Rehabilitation. 2008 Jun 1;89(6):1090-6.
- Agha A, Rogers B, Sherlock M, et al: Anterior pituitary dysfunction in survivors of traumatic brain injury. J Clin Endocrinol Metab 2004; 89: pp. 4929-4936
- Warburton DER, et al. Cardiovascular health and exercise following spinal cord injury. Spinal Cord Injury Rehabilitation Evidence, vs 4.0. Vancouver, Canada: 2012;1-43.
- 19.Arnour TA, Norris SK, Jack L, Zhang X, Fisher L. The effectiveness of family interventions in people with diabetes mellitus: a systematic review.Diabetic Medicine.2005;22:1295-1305. doi: 10.1111/j.1464-5491.2005.01618.x
- Hochberg MC, Ross PD, Black D, et al. Larger increases in bone mineral density during alendronate therapy are associated with a lower risk of new vertebral fractures in women with postmenopausal osteoporosis. Fracture Intervention Trial Research Group.Arthritis Rheum. 1999;42:1246.
- American Diabetes Association. 5. Lifestyle management: standards of medical care in diabetes—2019. Diabetes Care. 2019 Jan 1;42(Supplement 1):S46-60.
- Frisbie JH. Anemia and hypoalbuminemia of chronic spinal cord injury: prevalence and prognostic significance.Spinal Cord. 2010;48: 566-569.
- Bauman WA, Cirnigliaro CM, La Fountaine MF, Jensen AM, Wecht JM, Kirshblum SC, Spungen AM. A small-scale clinical trial to determine the safety and efficacy of testosterone replacement therapy in hypogonadal men.Horm Metab Res. 2011;43(8):574-579.
Original Version of the Topic
Stephen R. Lebduska, MD, Bhargav Mudda, MD. Hematological, metabolic and endocrine complications. 09/20/2014.
Cherry Junn, MD
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