Individuals with traumatic brain injury (TBI) present with a number of medical and nursing complications whose management has a significant impact on outcomes.

Medications should be considered in the context of the identified impairments while taking into account the concurrent advantage of the medication for other impairments (e.g. Epival for seizure prophylaxis and need for mood stabilization), as well as the potential for adverse effects.

Bladder and bowel incontinence is a common complication in as many as 62% of individuals with moderate to severe TBI but can be managed with a carefully planned program. Incontinence has a negative impact on quality of life and can influence caregiver burden.

Post-traumatic seizure is defined as an initial or recurrent episode not attributable to another obvious cause after TBI; they can be further defined as immediate (occurring within the first 24 hours), early (within the first week of injury) and late (after the first week). Prophylactic anti-seizure medications are helpful in preventing early seizures (first week) but are not indicated after one week. Anti-convulsants can routinely result in significant cognitive side effects, and so their use must be carefully monitored.

Deep venous thromboembolism is common in the context of immobility, lower limb paresis and multi-trauma. Deep vein thrombosis (DVT) and pulmonary emboli (PE) can contribute to a significant amount of morbidity and mortality, and prophylaxis, especially with low-molecular weight heparin (LMWH), can be safe and effective. The risk of developing a DVT in the absence of prophylaxis is estimated to be approximately 20% post TBI.

Neuroendocrine disorders, particularly hypopituitarism and growth hormone deficiencies are common particularly following moderate to severe injuries with 27-40% of patients having at least one deficiency and 10-15% with more than one deficiency. Endocrine abnormalities may not appear until 3-6 months post TBI and the gold standard for diagnosis is serum tests assessing hormonal function. Abnormalities of antidiuretic hormone and adrenal insufficiency are the most commonly reported abnormalities.

Heterotopic ossification (HO) is the formation of pathological bone within soft tissues, often muscles, where bone formation does not usually occur. It can symptomatically occur in 10-15% of patients and can be quite painful and limit joint mobility thereby impeding rehabilitation progress. Once developed, treatment of HO (usually surgical) can be challenging.

A number of secondary medical complications occur after a moderate to severe TBI. Bladder and bowel incontinence require early assessment followed by a highly coordinated program of nursing care, medications, behavioural scheduling, and in some cases, urodynamic and use of catheters. At the same time, any continence program must involve patients and their caregivers to ensure any program of care can be carried through at home. Management of seizures and deep venous thromboses involve standardized treatment regimens including early prophylaxis in high risk cases. Heterotopic ossification and neuroendocrine dysfunction require careful monitoring and access to appropriate laboratory testing and bone scans. 

Indicators exemples

• Proportion of individuals with TBI and continence problems discharged home before appropriate continence aids and services have been arranged.

• Average delay between TBI and initiation of venous thromboprophylaxis.

• Proportion of individuals with TBI for whom specific target symptoms/behaviors are monitored during pharmacological treatment.

The following are suggestions of tools and resources that can be used to support the implementation of the recommendations in this section. Healthcare professionals must respect the legal and normative regulations of the regulatory bodies, in particular with regards to scopes of practice and restricted/protected activities, as these may differ provincially

Clinical Tools:

• JFK Coma Recovery Scale – Revised (CRS-R)
• Patient Health Questionnaire (PHQ-9)
• Generalized anxiety Disorder 7-item (GAD-7)
• Agitated Behaviour Scale
• Galveston Orientation and Amnesia test (GOAT)
• Deep Vein Thrombosis: Diagnostic (Clinical Guide) – Thrombosis Canada
• Guidelines for Management of Neurogenic Bowel Dysfunction in Individuals with Central Neurological Conditions
• Provincial guidelines for the management of epilepsy in adults and children – Critical Care Services Ontario Guideline 2015
• American Association of Clinical Endocrinologists – Guideline
• American Epilepsy Society Algorithm: Proposed Algorithm for convulsive Status Epilepticus from treatment of convulsive Status Epilepticus in children and adults (2016) Epilepsy currents. 16-1
• Bowel/Bladder screening Developed by Rehab Stroke Best Practice Team Vancouver Island Health Authority (2004)
• Example of Passive and Assistive Range of Motion Exercises
• Standardized urinary function retraining program
• Indications of use (Health Canada) and insurance coverage (for Quebec only) for the Pharmacological Management of TBI related Impairments

Patient and Family Resources:

• Venous Thromboembolism (VTE) Pocket Cards
• Heterotopic Ossification – Craig Hospital

Other Resources:

• Bladder re-education basic Information – Patient
• Mild Traumatic Brain Injury: Neuroendocrine Dysfunction – Defense Centers or Excellence

Some individuals acquire secondary medical complications post TBI. The management of excretory systems, seizure prevention, thrombosis, and heterotopic ossification requires extensive co-ordination between rehabilitation teams, caregivers and the patient. Treatments should be administered as soon as appropriate and should be given prophylactically, if possible.

Bladder and bowel function should be assessed shortly after admission. As many as 62% of patients with TBI experience incontinence on admission to rehabilitation (Chua, Chuo, & Kong, 2003). Urinary disturbances are associated with impaired cognitive functioning and motor difficulties (Moiyadi, Devi, & Nair, 2007). Fecal incontinence frequency has been shown to be correlated with the severity of brain injury (Foxx-Orenstein et al., 2003). Promisingly, a case series found that recovery of bowel and bladder function could predict favourable functional outcomes following a TBI (Kushner & Johnson-Greene, 2014). In general, antibiotic treatment of asymptomatic bacteriuria is not recommended but cognitive or physical deterioration could be considered as a complication of urinary tract infection (Colgan et al., 2006; Lin & Fajardo, 2008).

Following a TBI, patients are susceptible to developing seizures. When managing seizures there are several pharmacological treatments available; however, these carry the risk of adverse effects. Intramuscular midazolam has been shown to be effective for acute seizure cessation (Wroblewski & Joseph, 1992). In terms of seizure prophylaxis, phenytoin is the most commonly studied medication. Numerous studies have found phenytoin to be only as effective as a placebo (McQueen, Blackwood, Harris, Kalbag, & Johnson, 1983; Temkin et al., 1990; Young et al., 1983). The use of anticonvulsants for treatment of late post traumatic seizures has been shown to increase seizure occurrence (Formisano et al., 2007), and have longer hospital stays and worse functional outcomes (Bhullar et al., 2014). Phenytoin and levetiracetam have comparable efficacies in terms of seizure rates (Inaba et al., 2013; Kruer et al., 2013), complications (Jones et al., 2008), mortality rates (Inaba et al., 2013) and length of stays (Kruer et al., 2013). A meta-analysis by (Zafar, Khan, Ghauri, & Shamim, 2012) also concluded that there was no superiority of either drug at preventing early seizures. However, phenytoin use is associated with greater days of fever (Gabriel & Rowe, 2014), adverse reactions (Inaba et al., 2013), and worse neurological status (Szaflarski, Sangha, Lindsell, & Shutter, 2010).

The reader is referred to the ERABI for more detailed review http://www.abiebr.com/module/10-post-traumatic-seizure-disorder.

Deep vein thrombosis (DVT) is a common complication following TBI; the risk of developing a DVT in absence of prophylaxis is estimated to be 20% after a TBI (Haddad & Arabi, 2012). Low-molecular weight heparin (LMWH) has been shown to reduce the risk of DVTs and PEs within the first 48 hours after injury (Glassner et al., 2013; Norwood, Berne, Rowe, Villarreal, & Ledlie, 2008). LMWH medications are also popular because they can be injected subcutaneously allowing for ease of administration and dosage adjustment; however, these drugs are expensive (Watanabe TK & MO., 2001). When comparing LMWH to low-dose unfractionated heparin (LDUH) in a mixed trauma population, a study found that patients receiving LDUH were more likely to experience DVT compared to those receiving LMWH (Geerts et al., 1996). Physical methods for venous thromboprophylaxis are still limited. One study found that sequential compression devices are not that effective in reducing the risk of developing DVT or pulmonary embolism after a TBI (Gersin et al., 1994). However, the use of compression stockings combined with LMWH has been shown to be more effective in preventing venous thromboembolism than stockings alone (Agnelli et al., 1998).

Endocrine disorders such as hypopituitarism can evolve over time post ABI; therefore, screening should be conducted as soon as possible. During the acute stage of recovery, cortisol levels of less than 7.2 µg/dL may indicate adrenal insufficiency (Bernard, Outtrim, Menon, & Matta, 2006). Treatment should also be considered and initiated in those cases where hyponatremia, hypotension and hypoglycemia are present and cortisol levels are between 7.2 and 18 µg/dL (Schneider, Kreitschmann-Andermahr, Ghigo, Stalla, & Agha, 2007). In the acute stage of recovery it is not necessary to assess growth, gonadal or thyroid hormones as there is no evidence to suggest that supplementation of these hormones during this phase is beneficial (Ghigo et al., 2005; Schneider et al., 2007); however, during the post recovery stage, at 3-6 months, a clinical assessment for hypopituitarism should be completed (Powner & Boccalandro, 2008; Powner, Boccalandro, Alp, & Vollmer, 2006; Schneider et al., 2007). This is especially important if any of the following symptoms are noted: loss of secondary hair, impaired sexual function, weight changes, polydipsia, or amenorrhea. Hormonal screening should include 0900 AM serum cortisol, fT3, fT4, TSH, FSH, LH, testosterone in men and E2 in women, prolactin, and Insulin-like Growth Factor (IGF-I). In patients with polyuria or suspected diabetes insipidus, urine density, sodium and plasma osmolality should also be evaluated. Low IGF-I levels strongly predict severe GH deficiency (in the absence of malnutrition). Normal IGF-I levels may be found in patients with GH deficiency; therefore, provocative tests are necessary in patients with another identified pituitary hormone deficit. Provocative testing is recommended if IGF-I levels are below the 25th percentile of age related normal limits (Ghigo et al., 2005).

Studies have found that following a TBI disruptions to salt and water levels can lead to inappropriate secretion of antidiuretic hormone (Doczi, Tarjanyi, Huszka, & Kiss, 1982; Makulski, Taber, & Chiou-Tan, 2008). Restricting fluid intake has proven effective, but studies are conflicting about the amount of fluid that should be limited; Doczi et al. (1982) suggest limiting daily fluid intake to less than 600 to 800 mL, whereas Born, Hans, Smitz, Legros, and Kay (1985)suggest limiting intake to 250 to 500 ml.

A review by Estes and Urban (2005) notes that for those who sustain a mild TBI, growth hormone deficiency has been identified during regular blood work, but no other symptoms have appeared. The authors suggest waiting 3 years post trauma before beginning treatment in attempt for the endocrine system to correct itself. However, if there is a clear indication of anterior or posterior pituitary dysfunction, consulting an endocrinologist is strongly recommended.

Heterotopic ossification (HO) is another common complication following TBI. Among individuals with TBI the most commonly sites of HO are the soft tissues around the hip, elbow, shoulder and knee (Garland, 1991; Garland, Blum, & Waters, 1980; van Kampen, Martina, Vos, Hoedemaekers, & Hendricks, 2011; Vanden Bossche & Vanderstraeten, 2005). The hip is the most frequent site of ossification (Dizdar et al., 2013; Vanden Bossche & Vanderstraeten, 2005), with total ankylosis of the joint occurring in 5-16% of affected hips (Stover, Niemann, & Tulloss, 1991). HO of the shoulder has been found to affect 5% of individuals with a brain injury (Cipriano, Pill, & Keenan, 2009), while the knee is a less common site for HO following a head injury (Sarafis, Karatzas, & Yotis, 1999). Of the joints affected by HO after head injury, ankylosis is most likely to occur in the posterior elbow (Garland et al., 1980). Triple phase technicium-99 bone scan is gold standard for diagnosing HO (Freed, Hahn, Menter, & Dillon, 1982).

Etidronate has been used as a prophylaxis for HO in other disease populations, but its use in TBI is understudied. A study found that Etidronate usage did significantly lower incidence of HO when compared to a control (Spielman, Gennarelli, & Rogers, 1983). Similar to Etidronate, the effects of nonsteroidal anti-inflammatory drugs (NSAIDS) as a prophylaxis are not well studied in the TBI literature.

There are few treatments for HO post ABI. Range of motion exercises are beneficial for treating HO post TBI. Studies have found that forceful manipulation is not only useful in maintaining motion but also aids in the prevention of bony ankylosis and does not appear to exacerbate the ossification process (Ellerin et al., 1999; Garland, Razza, & Waters, 1982; Garland & Varpetian, 2003). Anaesthesia may be needed to help differentiate between spasticity and ankylosis and to allow sufficient muscle relaxation to perform the joint manipulation (Garland & Varpetian 2003).

Surgical excision is also a treatment option for HO post ABI. A systematic review by Lee, Namdari, Hosalkar, Keenan, and Baldwin (2013) focused specifically on the surgical excision of HO in the elbow and found it resulted in improvements in range of motion with low levels of recurrence (14.3%). However, complications such as fracture, infection, nerve palsies, wound complications and loss of motion without recurrence were found in 27.5% of cases (Lee et al., 2013). In many studies, the recurrence of HO was evaluated months following the initial operation, with rates ranging from 0 to 27% (Fuller, Mani, & Keenan, 2013; Fuller, Mark, & Keenan, 2005; Ippolito, Formisano, Caterini, Farsetti, & Penta, 1999; Ippolito, Formisano, Farsetti, Caterini, & Penta, 1999; Moore, 1993). The majority of the studies did not specify what qualified as recurrence; however, a study by Kolessar, Katz, and Keenan (1996) found recurrence rates differed based on the classification system utilized (23.8% versus 4.8% using the Brooker classification and the Stover and colleagues classification, respectively). Overall, the surgical excision of HO resulted in improved range of motion, although, one study noted a decrease in range of motion for a small portion of participants (Ippolito, Formisano, Farsetti, et al., 1999). Improvements in activities of daily living and ambulation were also reported (Fuller et al., 2005; Ippolito, Formisano, Caterini, et al., 1999; Ippolito, Formisano, Farsetti, et al., 1999; Melamed et al., 2002). Although therapy was provided after the surgery in many of the studies, only one study formally evaluated its effectiveness; (Lazarus, Guttmann, Rich, & Keenan, 1999) found that patients who had continuous passive range of motion exercises post operatively made significantly greater gains compared to those individuals who did not (57.9° versus 24.1°, p=0.04).

REFERENCES
Agnelli, G., Piovella, F., Buoncristiani, P., Severi, P., Pini, M., D'Angelo, A., . . . Brambilla, G. (1998). Enoxaparin plus compression stockings compared with compression stockings alone in the prevention of venous thromboembolism after elective neurosurgery. N Engl J Med, 339(2), 80-85.

Bernard, F., Outtrim, J., Menon, D., & Matta, B. (2006). Incidence of adrenal insufficiency after severe traumatic brain injury varies according to definition used: clinical implications. British journal of anaesthesia, 96(1), 72-76.

Bhullar, I. S., Johnson, D., Paul, J. P., Kerwin, A. J., Tepas III, J. J., & Frykberg, E. R. (2014). More harm than good: antiseizure prophylaxis after traumatic brain injury does not decrease seizure rates but may inhibit functional recovery. Journal of Trauma and Acute Care Surgery, 76(1), 54-61.

Born, J., Hans, P., Smitz, S., Legros, J., & Kay, S. (1985). Syndrome of inappropriate secretion of antidiuretic hormone after severe head injury. Surgical neurology, 23(4), 383-387.

Brain Trauma Foundation, B. (2007). Guidelines for the management of severe traumatic brain injury. J Neurotrauma, 24 Suppl 1, S1-106.

Chua, K., Chuo, A., & Kong, K. H. (2003). Urinary incontinence after traumatic brain injury: incidence, outcomes and correlates. Brain Inj, 17(6), 469-478.

Cipriano, C. A., Pill, S. G., & Keenan, M. A. (2009). Heterotopic ossification following traumatic brain injury and spinal cord injury. J Am Acad Orthop Surg, 17(11), 689-697.

Colgan, R., Nicolle, L. E., McGlone, A., & Hooton, T. M. (2006). Asymptomatic bacteriuria in adults. Am Fam Physician, 74(6), 985-990.

Dizdar, D., Tiftik, T., Kara, M., Tunc, H., Ersoz, M., & Akkus, S. (2013). Risk factors for developing heterotopic ossification in patients with traumatic brain injury. Brain Inj, 27(7-8), 807-811.

Doczi, T., Tarjanyi, J., Huszka, E., & Kiss, J. (1982). Syndrome of inappropriate secretion of antidiuretic hormone (SIADH) after head injury. Neurosurgery, 10(6 Pt 1), 685-688.

Ellerin, B. E., Helfet, D., Parikh, S., Hotchkiss, R. N., Levin, N., Nisce, L., . . . Moni, J. (1999). Current therapy in the management of heterotopic ossification of the elbow: A review with case studies. American Journal of Physical Medicine and Rehabilitation, 78(3), 259-271.

Estes, S. M., & Urban, R. J. (2005). Hormonal replacement in patients with brain injury-induced hypopituitarism: Who, when and how to treat? Pituitary, 8(3-4), 267-270.

Evidence-Based Review of Moderate To Severe Acquired Brain Injury (ERABI). (2016). www.abiebr.com/.;

Formisano, R., Barba, C., Buzzi, M. G., Newcomb-Fernandez, J., Menniti-Ippolito, F., Zafonte, R., . . . Spanedda, F. (2007). The impact of prophylactic treatment on post-traumatic epilepsy after severe traumatic brain injury. Brain Injury, 21(5), 499-504.

Foxx-Orenstein, A., Kolakowsky-Hayner, S., Marwitz, J. H., Cifu, D. X., Dunbar, A., Englander, J., & Francisco, G. (2003). Incidence, risk factors, and outcomes of fecal incontinence after acute brain injury: findings from the Traumatic Brain Injury Model Systems national database. Arch Phys Med Rehabil, 84(2), 231-237.

Freed, J. H., Hahn, H., Menter, R., & Dillon, T. (1982). The use of the three-phase bone scan in the early diagnosis of heterotopic ossification (HO) and in the evaluation of Didronel therapy. Paraplegia, 20(4), 208-216.

Fuller, D. A., Mani, U. S., & Keenan, M. A. (2013). Heterotopic ossification of the shoulder in patients with traumatic brain injury. J Shoulder Elbow Surg, 22(1), 52-56.

Fuller, D. A., Mark, A., & Keenan, M. A. E. (2005). Excision of heterotopic ossification from the knee: a functional outcome study. Clinical orthopaedics and related research, 438, 197-203.

Gabriel, W. M., & Rowe, A. S. (2014). Long-Term Comparison of GOS-E Scores in Patients Treated With Phenytoin or Levetiracetam for Posttraumatic Seizure Prophylaxis After Traumatic Brain Injury. Annals of Pharmacotherapy, 48(11), 1440-1444.

Garland, D. E. (1991). A clinical perspective on common forms of acquired heterotopic ossification. Clin Orthop Relat Res(263), 13-29.

Garland, D. E., Blum, C. E., & Waters, R. L. (1980). Periarticular heterotopic ossification in head-injured adults. Incidence and location. J Bone Joint Surg Am, 62(7), 1143-1146.

Garland, D. E., Razza, B. E., & Waters, R. L. (1982). Forceful joint manipulation in head-injured adults with heterotopic ossification. Clinical orthopaedics and related research, No. 169, 133-138.

Garland, D. E., & Varpetian, A. (2003). Heterotopic Ossification in Traumatic Brain Injury.

Geerts, W. H., Jay, R. M., Code, K. I., Chen, E., Szalai, J. P., Saibil, E. A., & Hamilton, P. A. (1996). A comparison of low-dose heparin with low-molecular-weight heparin as prophylaxis against venous thromboembolism after major trauma. New England Journal of Medicine, 335(10), 701-707.

Gersin, K., Grindlinger, G. A., Lee, V., Dennis, R. C., Wedel, S. K., & Cachecho, R. (1994). The efficacy of sequential compression devices in multiple trauma patients with severe head injury. J Trauma, 37(2), 205-208.

Ghigo, E., Masel, B., Aimaretti, G., Leon-Carrion, J., Casanueva, F. F., Dominguez-Morales, M. R., . . . Urban, R. (2005). Consensus guidelines on screening for hypopituitarism following traumatic brain injury. Brain Inj, 19(9), 711-724.

Glassner, S., Srivastava, K., Cofnas, P., Deegan, B., DeMaria, P., Denis, R., & Ginzburg, E. (2013). Prevention of Venous Thrombotic Events in Brain Injury: Review of Current Practices. Rambam Maimonides Medical Journal, 4(1), e0001.

Haddad, S. H., & Arabi, Y. M. (2012). Critical care management of severe traumatic brain injury in adults. Scand J Trauma Resusc Emerg Med, 20, 12.

Inaba, K., Menaker, J., Branco, B. C., Gooch, J., Okoye, O. T., Herrold, J., . . . Demetriades, D. (2013). A prospective multicenter comparison of levetiracetam versus phenytoin for early posttraumatic seizure prophylaxis. Journal of Trauma and Acute Care Surgery, 74(3), 766-773.

Ippolito, E., Formisano, R., Caterini, R., Farsetti, P., & Penta, F. (1999). Operative treatment of heterotopic hip ossification in patients with coma after brain injury. Clin Orthop Relat Res(365), 130-138.

Ippolito, E., Formisano, R., Farsetti, P., Caterini, R., & Penta, F. (1999). Excision for the treatment of periarticular ossification of the knee in patients who have a traumatic brain injury. J Bone Joint Surg Am, 81(6), 783-789.

Jones, K. E., Puccio, A. M., Harshman, K. J., Falcione, B., Benedict, N., Jankowitz, B. T., . . . Okonkwo, D. O. (2008). Levetiracetam versus phenytoin for seizure prophylaxis in severe traumatic brain injury. Neurosurg Focus, 25(4), E3.

Kolessar, D. J., Katz, S. D., & Keenan, M. A. (1996). Functional outcome following surgical resection of heterotopic ossification in patients with brain injury. Journal of Head Trauma Rehabilitation, 11(4), 78-87.

Kruer, R. M., Harris, L. H., Goodwin, H., Kornbluth, J., Thomas, K. P., Slater, L. A., & Haut, E. R. (2013). Changing trends in the use of seizure prophylaxis after traumatic brain injury: a shift from phenytoin to levetiracetam. J Crit Care, 28(5), 883.e889-813.

Kushner, D. S., & Johnson-Greene, D. (2014). Changes in cognition and continence as predictors of rehabilitation outcomes in individuals with severe traumatic brain injury. J Rehabil Res Dev, 51(7), 1057-1068.

Lazarus, M. D., Guttmann, D., Rich, C. E., & Keenan, M. A. E. (1999). Heterotopic ossification resection about the elbow. NeuroRehabilitation, 12(2), 145-153.

Lee, E. K., Namdari, S., Hosalkar, H. S., Keenan, M. A., & Baldwin, K. D. (2013). Clinical results of the excision of heterotopic bone around the elbow: a systematic review. J Shoulder Elbow Surg, 22(5), 716-722.

Lin, K., & Fajardo, K. (2008). Screening for asymptomatic bacteriuria in adults: evidence for the U.S. Preventive Services Task Force reaffirmation recommendation statement. Ann Intern Med, 149(1), W20-24.

Makulski, D. D., Taber, K. H., & Chiou-Tan, F. Y. (2008). Neuroimaging in posttraumatic hypopituitarism. Journal of computer assisted tomography, 32(2), 324-328.

McQueen, J. K., Blackwood, D. H. R., Harris, P., Kalbag, R. M., & Johnson, A. L. (1983). Low risk of late post-traumatic seizures following severe head injury: Implications for clinical trials of prophylaxis. Journal of Neurology Neurosurgery and Psychiatry, 46(10), 899-904.

Melamed, E., Robinson, D., Halperin, N., Wallach, N., Keren, O., & Groswasser, Z. (2002). Brain injury-related heterotopic bone formation: treatment strategy and results. Am J Phys Med Rehabil, 81(9), 670-674.

Moiyadi, A. V., Devi, B. I., & Nair, K. P. (2007). Urinary disturbances following traumatic brain injury: clinical and urodynamic evaluation. NeuroRehabilitation, 22(2), 93-98.

Moore, T. J. (1993). Functional outcome following surgical excision of heterotopic ossification in patients with traumatic brain injury. J Orthop Trauma, 7(1), 11-14.

Norwood, S. H., Berne, J. D., Rowe, S. A., Villarreal, D. H., & Ledlie, J. T. (2008). Early venous thromboembolism prophylaxis with enoxaparin in patients with blunt traumatic brain injury. J Trauma, 65(5), 1021-1026; discussion 1026-1027.

Powner, D. J., & Boccalandro, C. (2008). Adrenal insufficiency following traumatic brain injury in adults. Current opinion in critical care, 14(2), 163-166.

Powner, D. J., Boccalandro, C., Alp, M. S., & Vollmer, D. G. (2006). Endocrine failure after traumatic brain injury in adults. Neurocritical Care, 5(1), 61-70.

Sarafis, K. A., Karatzas, G. D., & Yotis, C. L. (1999). Ankylosed hips caused by heterotopic ossification after traumatic brain injury: a difficult problem. J Trauma, 46(1), 104-109.

Schneider, H. J., Kreitschmann-Andermahr, I., Ghigo, E., Stalla, G. K., & Agha, A. (2007). Hypothalamopituitary dysfunction following traumatic brain injury and aneurysmal subarachnoid hemorrhage: a systematic review. Jama, 298(12), 1429-1438.

Sesmilo, G., Halperin, I., & Puig-Domingo, M. (2007). Endocrine evaluation of patients after brain injury: what else is needed to define specific clinical recommendations? Hormones (Athens), 6(2), 132-137.

Spielman, G., Gennarelli, T., & Rogers, C. (1983). Disodium etidronate: its role in preventing heterotopic ossification in severe head injury. Arch Phys Med Rehabil, 64(11), 539-542.

Stover, S. L., Niemann, K. M., & Tulloss, J. R. (1991). Experience with surgical resection of heterotopic bone in spinal cord injury patients. Clin Orthop Relat Res(263), 71-77.

Szaflarski, J., Sangha, K., Lindsell, C., & Shutter, L. (2010). Prospective, randomized, single-blinded comparative trial of intravenous levetiracetam versus phenytoin for seizure prophylaxis. Neurocritical Care, 12.

Temkin, N. R., Dikmen, S. S., Wilensky, A. J., Keihm, J., Chabal, S., & Winn, H. R. (1990). A randomized, double-blind study of phenytoin for the prevention of post-traumatic seizures. N Engl J Med, 323(8), 497-502.

Van Kampen, P. J., Martina, J. D., Vos, P. E., Hoedemaekers, C. W., & Hendricks, H. T. (2011). Potential risk factors for developing heterotopic ossification in patients with severe traumatic brain injury. J Head Trauma Rehabil, 26(5), 384-391.

Vanden Bossche, L., & Vanderstraeten, G. (2005). Heterotopic ossification: a review. J Rehabil Med, 37(3), 129-136.

Watanabe TK, & MO., S. ( 2001). Common medical complications of traumatic brain injury. . Physical Medicine and Rehabilitation: state of the art reviews, 15, 283-299.

Wroblewski, B. A., & Joseph, A. B. (1992). The use of intramuscular midazolam for acute seizure cessation or behavioral emergencies in patients with traumatic brain injury. Clin Neuropharmacol, 15(1), 44-49.

Young, B., Rapp, R. P., Norton, J. A., Haack, D., Tibbs, P. A., & Bean, J. R. (1983). Failure of prophylactically administered phenytoin to prevent early posttraumatic seizures. Journal of neurosurgery, 58(2), 231-235.

Zafar, S. N., Khan, A. A., Ghauri, A. A., & Shamim, M. S. (2012). Phenytoin versus Leviteracetam for Seizure Prophylaxis after brain injury – a meta analysis. BMC Neurology, 12(1), 1-8.