Moderate-to-severe traumatic brain injury.

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Moderate-to-Severe Traumatic Brain Injury Paul Pasquina, MD1,2

Robert Kirtley, MD1

Geoffrey Ling, MD, PhD2

1 Departments of Physical Medicine and Rehabilitation, Uniformed

Services University of the Health Sciences, Bethesda, Maryland 2 Department of Neurology, Uniformed Services University of the Health Sciences, Bethesda, Maryland

Address for correspondence Geoffrey Ling, MD, PhD, Department of Neurology, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814 (e-mail: [email protected]).

Abstract Keywords

► traumatic brain injury ► traumatic brain injury rehabilitation ► blast injury ► neurointensive care ► posttraumatic seizures ► deep vein thrombosis spasticity in TBI ► heterotopic ossification ► vestibular dysfunction ► endocrine dysfunction

Managing patients with moderate-to-severe traumatic brain injury (TBI), particularly those with combat-related blast injury, is exceptionally challenging. Optimal care requires the coordinated efforts of numerous providers, contributing to an interdisciplinary team. Given the complexities of TBI and the variety of physiologic, physical, cognitive, behavioral, and emotional manifestations of the injury, a holistic approach to patient care is needed throughout the entire continuum of care. In this article, the authors provide an overview of how interdisciplinary care is provided from the acute to the chronic settings, and illustrate the important role that rehabilitation plays throughout the continuum of care in facilitating maximizing recovery, functional independence, and quality of life. Common conditions associated with TBI are illustrated through a case presentation of an individual with blast-related polytrauma and help to frame a more detailed discussion of subtopics including neurointensive care, posttraumatic seizures, venous thromboembolic disease prevention, spasticity management, vestibular disorders, endocrine dysfunction, and psychological trauma.

Traumatic brain injury (TBI) is considered to be one of the most prevalent and severely disabling neurologic disorders within the United States and perhaps the world. It is estimated that over 1.7 million Americans sustain a TBI each year, and that nearly 3.2 million individuals are currently living with disability related to TBI in the United States.1,2 Due to the heterogeneity of TBI and the difficulty in standardizing diagnostic and classification systems for different injury patterns, exact epidemiological data are unavailable. However, it is reported that approximately 80% of individuals with TBI will visit the emergency department, leading to approximately 275,000 hospitalizations and 52,000 deaths per year. The global impact of TBI is even more staggering, where estimates suggest that the incidence of TBI in Europe, Australia, and Asia is more than two to three times greater than that of the United States.3 It should be recognized that these statistics are now widely recognized as gross underestimations. Total TBI numbers

Issue Theme Neurologic Rehabilitation; Guest Editors, Karunesh Ganguly, MD, PhD, and Gary M. Abrams, MD, FAAN

have not previously accounted for the perceived wide prevalence of mild TBI or concussion. For these, the epidemiology is unknown. The Centers for Disease Control and the World Health Organization both suggest that the actual numbers of total TBI may be as much as 10-fold higher than those reported. This is largely due to lack of awareness of the signs and symptoms of mild TBI among health care providers and the public. This results in patients either being misdiagnosed or not seeking medical attention. The most accurate epidemiologic data for TBI are from the U.S. Armed Forces Health Surveillance Center (AFHSC) and the Defense and Veterans Brain Injury Center (DVBIC). Since 2009, it has been a requirement that all U.S. service members be screened for TBI if they have been involved in an incident in which a TBI may have occurred.4 From this data, by March of 2014, there have been 300,707 TBI cases among all service members since 2000. Of note, these data include those deployed to a combat setting and those in garrison, with

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DOI http://dx.doi.org/ 10.1055/s-0034-1396010. ISSN 0271-8235.

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Semin Neurol 2014;34:572–583.

the vast majority of TBI (up to 80%) not occurring in the war theater. Approximately 10% to 20% of service members who deploy overseas to Iraq and Afghanistan have sustained a brain injury.5 From the AFHSC data, the majority of TBI is classified as mild TBI (mTBI),6 up to 80 to 85%. The remaining 10% to 20% still represents a significant proportion of injuries, which includes those with moderate to severe TBI, many being life threatening.7 Combat casualties with moderate-to-severe TBI differ from those commonly encountered in civilian practice by their mechanism of injury. Moderate-to-severe TBI is primarily the result of a blast event, which is estimated to be approximately 74.4% of all combat casualties.8 Blast injuries may cause injury to the brain by the initial blast wave (primary blast injury), propelling debris that strikes the head (secondary blast injury), or displacing the casualty causing impact to the head on the ground or another object (tertiary blast injury). Given the mechanism of blast injury, it is often common for combat casualties who sustain a moderate to severe TBI to also have other comorbid injuries, such as sensory impairment (vision and/or hearing) as well extremity trauma, including amputation.9 In addition, there is a strong association with combat exposure and the development of mental health disorders, such as depression and posttraumatic stress disorder (PTSD).10 The heightened awareness and enhanced surveillance for TBI during the global war on terror (GWOT) has documented the frequent occurrence and serious consequences of TBI among U.S. service members and veterans. Due to this concern, the Department of Defense (DoD) created the “first ever” large systematic, widely standardized approach to TBI. It includes mandatory point of injury screening, clinical practice guidelines for treatment (both in the war theater and at U.S. tertiary care centers), far forward concussion care centers staffed by occupational therapists, in-theater neurologists to educate and direct TBI care, and neurosurgeons and neurointensivists to manage moderate-to-severe TBI. Enhanced epidemiologic surveillance and new rehabilitative approaches to promote overall improved outcomes have also been developed. This DoD-led effort has contributed to the increased awareness among the U.S. civilian population, including organized professional sports, and serves as a model for civilian TBI management. We present a representative example case of a service member who sustained a blast-related moderate–severe TBI and a below-knee amputation to highlight some of the important aspects of comprehensive acute, subacute, and chronic care for these complex combat injuries. We then proceed to a brief discussion about each of the patient’s problems, including emerging practices that we believe can be translated into civilian clinical practice and stimulate discussion for further research.

Clinical Case A 24-year-old male active-duty soldier was on a dismounted patrol when he was struck by an improvised explosive device (IED), sustaining a traumatic transtibial (below knee) ampu-

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tation, lower extremity burns, and moderate–severe TBI from a penetrating foreign body to his left inferior frontal and superior temporal areas, which was also complicated by secondary anoxic injury. He initially presented with a Glasgow Coma Score (GCS) of 8. A military medic secured his airway, and a tourniquet was placed on his left lower extremity. Upon rapid medical evaluation to the combat support hospital (CSH), an endotracheal tube was placed, and because he was able to ventilate spontaneously, continuous positive airway pressure (CPAP) was initiated. An intraventricular catheter (IVC) was placed to monitor intracranial pressure (ICP). His ICP was 15 mm Hg, systolic blood pressure remained above 90 mm Hg, and his oxygen saturation was 99%. There were no signs of brain herniation; therefore, hyperventilation, diuretics, and hyperosmolar therapies were not initiated. Acute surgical interventions included wound debridement and vessel closure to control hemorrhage. In addition to his amputation, his neurologic impairments included expressive aphasia, partial left eye blindness, a mild right-sided spastic hemiparesis, and mild cognitive difficulties primarily characterized by decreased short-term memory and poor concentration. Other problems included fatigue, PTSD, depression, and sexual dysfunction. During this service member’s acute and subacute care, he was initially managed with seizure prophylaxis (divalproex sodium), but because he did not display any seizure activity within the first 7 days, the medicine was discontinued. He was treated with low-molecular-weight heparin (LMWH; enoxaparin sodium) for prevention of deep venous thrombosis (DVT), and aggressively treated with a multimodality approach to pain including physical modalities (ice/heat and electrical stimulation), regional anesthesia, and a combination of nonsteroidal anti-inflammatory (celecoxib) and antiseizure (pregabalin) medications. Once his residual limb sutures were removed, he was fitted with a gel liner and thermoplastic check socket, suction suspension, and a dynamic response foot. During his rehabilitation, he reported a decrease in balance upon initial standing and prosthetic training. This improved with balance training in physical therapy, as well as with training in a Computer-Assisted Rehabilitation ENvironment (CAREN). He also developed pain in his residual limb and skin breakdown with his prosthetic fitting because of the formation of heterotopic ossification in the soft tissues of his distal stump. His phantom limb pain responded well to pregabalin and mirror therapy, and remained under control with continued prosthetic wearing and training. His right upper limb spasticity responded well to botulinum toxin injections to his pronator teres, brachialis and flexor carpi ulnaris muscles, which were performed under ultrasound guidance. These treatments enhanced his ability to perform activities of daily living, including feeding, hygiene, toileting, and dressing. His mood disorder improved with both psychiatric and neuropsychology interventions, including cognitive–behavioral therapy and improved sleep hygiene. He also responded very well to quetiapine and sertraline, which improved his sleep, decreased his nightmares, and lessened his depression and anxiety. His speech fluency and articulation improved Seminars in Neurology

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with daily speech-language pathology, as did his ability to swallow, eventually advancing him to solid foods. To further augment his cognitive rehabilitation, he was enrolled in our Brain Fitness Laboratory, where he routinely participated in sessions of computer-aided cognitive training modalities. Approximately 6 months after his injury, the patient continued to complain of sexual dysfunction. He was subsequently treated with testosterone replacement therapy, under close endocrinologic supervision. Finally, to facilitate community reintegration, he and his wife frequently participated in multiple outings, including adaptive skiing, creative arts (painting), and golf, under the direction of our recreation therapist. He has started initial driving therapy with a driving rehabilitative specialist, who is utilizing a virtual reality simulator to enhance both cognitive function and motor skills, including reaction time.

Current Methods of Management Prehospital Clinical Care Considerations Optimal clinical outcome requires that TBI care be instituted as early as possible, which typically means the prehospital setting. Moderate-to-severe TBI is more easily recognized than mild TBI, even by laypersons. Such patients will all have a decreased sensorium. Moderate TBI patients will be lethargic or somnolent, with a GCS < 13 and > 8. Severe TBI patients will be obtunded or comatose with a GCS 8. Many may also have focal neurologic deficits, such as a paresis or asymmetric cranial nerve exam. Activating the 911 system is the first step. For moderateto-severe TBI, most laypersons will recognize this as a serious medical condition and call 911. In the military, medical care is readily available through the unit’s combat medic. Military care is described in the DoD’s and Brain Trauma Foundation’s “Guidelines for Field Management of Combat Related Head Injury” and the National Association of Emergency Medical Technicians’ and the American College of Surgeons’ “Head Trauma” in the “Prehospital Trauma Life Support, Military Version.”11,12 For civilian first providers, there is the Brain Trauma Foundation’s “Guidelines for Prehospital Management of Traumatic Brain Injury.”13 Care begins with the “ABCs” of airway, breathing, and circulation. Analysis from the Trauma Coma Database reveals that the most critical predictors of TBI outcome are hypotension, hypoxemia, and hypercapnea.14 Hypotension is defined as a systolic blood pressure (SBP) < 90 mm Hg. Hypoxemia is defined as apnea, cyanosis, or O2 saturation < 90%. Hypercapnia refers to PaCO2 > 60 mm Hg. The first step is to secure the airway. A moderate-to-severe TBI patient typically is unable to protect his airway due to a poor sensorium. If the patient is suffering from additional trauma, particularly to the head or neck, there may be other reasons for securing the airway. As a rule, a patient with a GCS of 8 or less needs to have an artificial airway provided. An oropharyngeal or nasopharyngeal device may be adequate. However, an endotracheal tube may be needed if hyperventilation therapy is to be instituted for intracranial hypertension. A nasopharyngeal device should not be used if there is Seminars in Neurology

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concern for cribriform plate fracture, as this device may be inadvertently directed cephalad into the brain. Clear or serosanguineous discharge from the nose suggests cerebrospinal fluid (CSF) leak, and thus raises the potential of cribriform plate fracture. Supportive ventilation and supplemental oxygen should be used to keep the oxygen saturation > 90% (or PaO2 > 60 mm Hg). Hyperventilation should be reserved only for obvious clinical evidence of brain herniation — unilateral pupillary dilation, motor posturing, etc.11,12 To maintain adequate tissue perfusion, especially in the brain, the systolic blood pressure should be 90 mm Hg or greater. As there is concern toward early brain edema developing, hypertonic crystalloid should be used. Normal saline is the most common resuscitation fluid in this setting, as it is hyperosmolar compared with normal blood osmolality.11,12 If there is evidence of brain herniation, elevating the head, hyperventilation, diuretic, and hyperosmotic therapies should be initiated. One of the easiest and effective maneuvers to treat brain herniation is elevating the patient’s head to 30 degrees with a pillow and soft collar while keeping it midline. Doing so optimizes cerebral venous outflow, which helps reduce intracranial volume and thus pressure. The goal of hyperventilation is a pCO2 between 34 to 36 mm Hg, which reduces cerebral arterial blood flow.15 This is usually achieved with a rate of 14 to 16 breaths/min. A cautionary note is that excessive hyperventilation has the potential of exacerbating cerebral ischemia.16–18 Hyperosmotic and diuretic therapy is used to create an osmotic gradient between brain and the intravascular space, with the intent to move extracellular water from the former to the latter. Again, this reduces intracranial volume. Normal saline is the most typical hyperosmolar resuscitative fluid, and mannitol is the most common hyperosmolar agent used for this purpose. A bolus of 23.4% hypertonic saline can also be considered. This therapy has the benefit of increasing serum osmolarity without compromising intravascular volume and decreasing the systemic blood pressure.19 Once the ABCs have been addressed, a neurologic examination needs to be performed. Determining the GCS is important. Its principal value is conveying information about the patient’s neurologic state. The GCS is a single number that is highly clinically meaningful in preparing the receiving medical team regarding the patient’s neurologic state. A general neurologic assessment is critical. Examining the patient provides the most clinically relevant data that is essential for making decisions about what treatments need to be enacted, including neurosurgical interventions. A proper examination must minimally include determining the level of consciousness, motor, sensory, and cranial nerve function, with particular attention to any deficits and/or asymmetry. For patients in pain, analgesics should be considered. These should be limited to those without central nervous system effects, such as acetaminophen, or are short acting and easily reversed, such as fentanyl. For combat-related TBI, the clinical practice guidelines allow for administration of antibiotics and sedatives. Antibiotics are allowed, as many of these TBIs are penetrating lesions where the calvarium is violated. Sedatives are allowed in deference to combat


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operation considerations— an agitated patient crying out may reveal the position to the enemy.11 However, for civilian patients, these are not routinely recommended for prehospital care. Transport to a medical facility with neurosurgical and neurocritical care capability should be done in the most expeditious and direct method. Often, this means by rotary wing aircraft to a level 1 trauma center.

Acute Neurocritical Care Considerations A major advance in TBI clinical care was the introduction of clinical practice guidelines (CPGs) for the management of moderate to severe TBI developed by the American Association of Neurological Surgeons and the Congress of Neurosurgery in 1996. These CPGs have been updated twice since then.20 For the DoD, these CPGs were put into practice at the outset of the GWOT. Some additions were added due to the nature of war-related injuries.21 It is clear that these treatment guidelines have had significant beneficial effects for TBI patients. Once the patient arrives to definitive care, ABCs should be reassessed to be sure they are being adequately met. Many moderate-to-severe TBI patients will need prolonged airway protection. If not already placed in the field, an endotracheal tube (ETT) or laryngeal mask airway (LMA) should be considered. Most will also require mechanical ventilation. The respiratory rate, FiO2, positive end expiratory pressure (PEEP), and inspiratory–expiratory (I:E) ratios are guided by the clinical goals of each patient. Typically, the clinical goals are PaO2 > 60 mm Hg, PaCO2 ¼ 40 mm Hg, O2 saturation > 90% and airway plateau pressure < 30 mm Hg. It is cautioned that PEEP, especially if > 20 cm H2O, may exacerbate ICP as it may cause an increase in intrathoracic pressure that might compromise venous drainage into the thorax. The mode of mechanical ventilation to be used is dependent on specific patient needs, such as ability to spontaneous ventilate, lung pathology, level of consciousness, presence of elevated ICP, etc. A commonly used mechanical ventilation mode during the acute phase is assist control (AC). The benefits of this mode are that it provides full ventilatory support and the rate can be titrated to meet specific ventilatory goals—hyperventilation. However, it may be uncomfortable for some patients. For TBI patients who can spontaneously ventilate and do not have significant lung pathology, pressure support (PS) ventilation or CPAP may be sufficient. Airway pressure release ventilation (APRV) and oscillatory ventilation are much less commonly used, and are typically reserved for those TBI patients who are also suffering from severe acute respiratory distress syndrome (ARDS), in which other modes of ventilation are unable to meet oxygenation needs without worsening ICP or airway pressures.22 Cerebral perfusion needs to be maintained. The goal is to keep cerebral blood flow (CBF) in the range of autoregulation, which is approximately 50 cc/100 g of brain per minute. As CBF cannot be measured directly using common clinical devices, clinicians rely on a cerebral perfusion pressure (CPP) goal. Cerebral perfusion pressure is the difference

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between mean arterial pressure (MAP) and ICP. The CPG CPP goal is 70 mm Hg.23,24 This can be done using volume resuscitation, and if needed, vasopressors. Shortly thereafter, a comprehensive neurologic examination must be done by a skilled advanced provider. This is crucial. There is no more clinically valuable diagnostic tool for assessing a neurologically injured patient than the neurologic examination. As noted above, it determines what treatments are to be instituted, how emergently these must be done, and gives prognostic information. Also, any exam changes are highly relevant, so it must be done repeatedly. Thereafter, neuroimaging should be done to identify lesions for which neurosurgery may be required. Most commonly, these are intracranial hematomas in the subdural or epidural spaces, as well as skull fractures. A head computed tomography (CT) scan without contrast is the usual mode of imaging. This can be done quickly and provides actionable data. Bone, blood, and edema are both well visualized by this technique. Importantly, if there is a penetrating lesion, this method can identify the foreign body and the lesion track without placing the patient at further risk as magnetic resonance imaging (MRI) might if the foreign body has magnetic properties. Brain MRI is a useful adjunct to CT in trauma, as it provides much more brain parenchyma detail. It is best used to aid in prognostication. Thus, it is not necessary to obtain in the acute and subacute TBI management period.22 Intracranial pressure monitoring should be instituted if there is any concern for intracranial hypertension.25 As a general rule, a TBI patient with a GCS 8 needs an ICP monitoring device. Several different ICP monitors are available.26 All require access through a skull bur hole. The epidural fiberoptic catheter benefits from a very low complication rate, but can only be used for 5 days before it needs replacing due to measurement drift. The Richmond screw or bolt has a slightly higher risk of infection, but can be zeroed, and thus has a longer utility. Both of these methods can be inaccurate, as they measure ICP at the surface of brain on one side. The intraventricular catheter (IVC) or external ventricular drain (EVD) is the most invasive option and thus has the highest complication rate, particularly infection. However, it provides the most accurate measure of ICP, and very importantly, another ICP treatment option. An IVC/EVD is inserted through a bur hole and advanced through the brain parenchyma until the tip of the device is in the third ventricle. There, the ICP measured is the most accurate as brain shifting will not affect it. Because CSF can be removed by this device, it is a way of further reducing intracranial volume, and thus is an effective method for managing ICP.22 When using an IVC/EVD for both monitoring and managing ICP following a TBI, the drainage valve is typically set at zero in the acute period, which means at the height of the third ventricle. This will cause the CSF to preferentially drain from the patient into the collection apparatus. The benefit is removal of blood products from the CSF as well as maximal reduction of intracranial CSF to reduce intracranial volume. As the patient improves, the drainage valve may be elevated, which allows a portion of the CSF to pass through the ventricular system. Ultimately, when the patient can tolerate Seminars in Neurology

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it, the valve is closed, typically after the patient has been shown to tolerate the valve at a height equivalent to 20 mm Hg (the upper limit of normal ICP). After which, the device can be removed.26 Both hyperventilation and mannitol diuresis have limitations and should not be continued after their initial use. It is well recognized that hyperventilation can be used only temporarily. Within a few hours, metabolic compensation of the induced hyperventilation respiratory alkalosis state occurs. Due to the concern of causing cerebral ischemia, further hyperventilation is not recommended unless there is a method for objectively determining the adequacy of cerebral perfusion, such as by cerebral oxygen saturation or brain tissue partial pressure of oxygen. Induced diuresis will reduce intravascular volume. This can compromise systemic blood pressure and thus tissue perfusion pressure. This is especially worrisome in multitrauma patients for whom hemorrhagic shock is often a concern. Because the goal of diuresis is creating a hyperosmotic gradient, using hyperosmotic agents is the most direct way to create and maintain this state without compromising intravascular volume.27 Administration of 23.4% hypertonic saline as a 30 cc bolus over 20 minutes can rapidly reduce intracranial hypertension. It should be given through a central line to avoid phlebitis. This is then followed by a continuous infusion of 3% saline. This can be as a 50% acetate/50% chloride mixture to minimize development of hyperchloremia. The infusion rate should be set to meet adequate hydration. Boluses can be administered as needed. Serum sodium levels will need to be monitored every 6 to 8 hours. Usually, a serum sodium goal of 145 to 150 mEq/L is set, but higher levels may be needed to achieve normal ICP. As the patient recovers, this treatment can be stopped. Recalcitrant intracranial hypertension will require a pharmacologically induced coma. Pentobarbital is the most commonly used agent, but propofol and general inhalation anesthetics have also been used. The goal of induced coma is ICP control or achieving a burst-suppression electroencephalographic (EEG) pattern. The aim is to reduce the cerebral metabolic rate. Patient selection is important, as using these agents at the required doses will have a generalized suppression effect on the myocardium, immune system, and others. If after achieving burst suppression the ICP still remains elevated, this is an ominous sign. Previous studies have shown that patients in whom the ICP cannot be controlled by medical means have a very poor prognosis; virtually none survive. Heroic neurosurgical intervention may be considered, but this must be balanced with what is a reasonable expectation of recovery for the patient.28,29 The role of decompressive craniectomy in treating TBI remains controversial. The recent Decompressive Craniectomy (DECRA) trial did not demonstrate any clinical benefit to this neurosurgical intervention over medical management alone.30 Military neurosurgeons have used this intervention, but this is with the understanding that military patients face a long evacuation time with very limited options to treat worsening edema or high ICP.31,32 If used, the surgery is performed very early after injury, typically with a few hours. Seminars in Neurology

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In DECRA, the mean time to surgery was over 24 hours after injury. Induced hypothermia has not yet been shown to be effective in improving outcome from TBI.33 There is emerging evidence that longer periods of cooling than previously studied may be effective, but this needs confirmation.34 Hyperthermia has been shown to worsen outcome after stroke, and thus is to be avoided in TBI as well.35 The clinical goal is normothermia.36 Antipyretics such as acetaminophen and external cooling devices should be used to maintain normothermia. However, corticosteroids should not be administered following TBI. There is insufficient evidence to support their routine use for this clinical indication.37

Nutrition and Gastric Ulcers Adequate nutrition is important in treating TBI.38 As soon as reasonably possible, either a nasogastric or orogastric tube should be placed so that these patients can be fed. Ideally, feeding can begin by the second day after injury. The best method is enterally, but parenteral nutrition may be given until the patient can tolerate feeding via the gut.39 As cerebral edema may be a concern, hyperosmolar enteral formulas should be used to minimize free water. Prevention of gastric stress ulcers is important. There is limited evidence demonstrating benefit for pharmacological prophylaxis in TBI patients. Most clinicians base their therapy on evidence derived from general trauma populations.40 Gastric stress ulcers may be prevented with H2 antagonists or proton pump inhibitors. For older patients (> 65 years old), chronic use of proton pump inhibitors is associated with an increased risk of allcause mortality, so discontinuation after leaving the intensive care unit should be considered.41 Posttraumatic seizures have long been a recognized complication of TBI. Posttraumatic seizures (PTSs) refer to a single recurrent seizure after TBI. Early PTSs, defined as occurring within the first week (24 hour–7 days), are felt to be acute symptomatic events with a low probability of recurrence, whereas late seizures (occurring after the first week) may represent posttraumatic epilepsy if episodes are not attributable to any other etiology than TBI. Posttraumatic seizures are a significant complication after TBI, and comprise 20% of symptomatic seizures and 5% of all seizures in the general population.42 Posttraumatic seizures are associated with limitations in activities of daily living (ADLs) and increased disability. A robust study from 1998 evaluated 4,541 patients with TBI (characterized by loss of consciousness, posttraumatic amnesia, subdural hematoma, or skull fracture), and found the incidence of seizures in mild TBI to be 1.5%, moderate TBI to be 2.9%, and severe TBI to be 17%. The evidence demonstrated that as the risk factors increased so did the incidence of seizures. Risk factors included penetrating head injury, intracranial hematoma, early PTS, depressed skull fracture, prolonged coma or posttraumatic amnesia, age, foreign body, alcohol abuse, and use of tricyclic antidepressants.43 The pathophysiology is not well understood; however, neuroinhibitory molecules such as GABA and adenosine provide relative protection, while genetic variability within the adenosine A1 receptor has been associated with increased


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risk.44,45 Diagnostic evaluation in PTS patients with moderate-to-severe TBI includes head CT imaging to evaluate for intracranial bleeding, and/or MRI, which is more sensitive for posttraumatic intracranial abnormalities such as diffuse axonal injury. Workup also includes standard as well as 24-hour, sleep-deprived EEG; however, they are of limited utility and often are nonspecifically altered during the acute phase of head injury. Increased prolactin levels can confirm true seizure activity if taken 10 to 20 minutes after an event, but a normal level does not rule out seizure activity.46 There is no ideal antiepileptic drug (AED) for the management of early seizures; however, phenytoin is often used because it does not cause significant sedation and is easily loaded intravenously. Phenytoin acts by decreasing excitatory tone and bolstering inhibitory neurotransmitter systems in subcortical and cortical structures. Studies using phenytoin, carbamazepine, and valproate have shown efficacy in preventing early, but not late posttraumatic seizures. No benefit is seen with prophylaxis for more than 1 week.47,48 The most commonly used antiepileptic drugs (AEDs) for preventing early post-TBI seizures are phenytoin and fos-phenytoin. Other options are valproate and levetiracetam.49 All are preferred, as they can be administered intravenously. As only 50% of closed head TBI patients are at risk of developing late occurring posttraumatic seizures, it is recommended that AEDs be given only for the first 7 days after TBI and then discontinued.50 If a patient should develop seizures after that, then AEDs can be reinstituted.

Deep Venous Thrombosis and Pulmonary Embolism Venous thromboembolic disease (VTE) is one of the most significant complications of TBI due to its association with increased mortality. The annual incidence of VTE is estimated to exceed 600,000, with nearly 300,000 fatalities, which makes it the most common preventable cause of hospitalrelated death.51 The incidence of DVT in TBI rehabilitation admissions ranges from 10 to 18%, and the incidence of DVT in severe TBI is estimated to be as high as 40%.41,44 Severe TBI patients often demonstrate a higher risk for VTE because of major trauma, recent surgery, immobility, paralysis, prolonged hospitalization, and invasive devices, all of which contribute to venous stasis, endothelial injury, and a hypercoagulable state. Often the TBI patient creates a difficult situation for safe administration of anticoagulants with increased fall risk, agitation, and chance of surgical bleeding, requiring physicians to perform a balancing act of risk versus benefit. Venous thromboembolic disease may be clinically silent in the TBI population. A recent study using subcutaneous heparin showed no significant reduction in DVT/PE; sudden death was the first clinical sign in 70% to 80%.41 The diagnostic gold standard is venography; however, because of its cost, invasive nature, and other limitations, it is rarely used. Doppler ultrasound has 95% sensitivity and 99% specificity, and has become the optimal test for diagnosing DVT in patients with symptoms. Prevention of DVT is important; unfortunately, the evidence to demonstrate benefit using currently available therapies is limited. However, it is recommended that patients should be given sequential pneumatic

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stockings and anticoagulation, starting with either low-dose heparin or LMWH, as soon as possible.52 Anticoagulation may be delayed for 24 hours if a neurosurgical intervention has been done. However, it should be noted that anticoagulation in TBI patients with intracranial hemorrhage should be done cautiously, as there may be minimal benefit with a risk for hematoma exacerbation.53 Some groups advocate that TBI patients be stratified as low-, moderate-, and high risk for this complication and treated accordingly.54,55 A meta-analysis indicated that LMWH could prevent VTE in patients without contraindications.56 If there is a contraindication or risk of bleeding, intermittent pneumatic compression devices (ICD) and/or inferior vena cava filter should be considered based on level of risk. If an ICD is used, it should be appropriately sized and used for maximum hours daily.

Rehabilitation in the Intensive Care Setting Similar to acute medical and surgical management, rehabilitative approaches to TBI are primarily focused on implementing interventions and creating an environment that will maximize recovery and promote successful reintegration and active participation in society. Fundamental early rehabilitative interventions include preventing or mitigating secondary complications, which may cause unnecessary lengths of stay, as well as worsening morbidity or even mortality. In addition to evaluating the patient’s metabolic and neurophysiological parameters such as tissue oxygenation and intracranial pressure (ICP), the rehabilitation team plays a key role in assisting the neurocritical care team in providing patient and family education as well as holistic evaluation of the patient, including all organ systems. Issues such as positioning of limbs and range of motion exercise to avoid joint and soft tissue contractions, identification of secondary injuries that might have been missed by the initial trauma survey, vigilant inspection and care of the skin to avoid pressure ulcers, proper nutritional support, as well as recognizing and preventing DVT, PE, and heterotopic ossification (HO), are all important to achieving a successful transition from the acute medical–surgical ward to a rehabilitation unit. Initial management of pain, bowel and bladder function, respiratory health, and diminishing external stimulation to create a calm setting where the patient can be better oriented and less confused may have a profound positive impact on patients who are agitated, and avoid use of sedative medications that may interfere with brain function and recovery. Finally, working with the intensive care staff to better regulate the patient’s sleep/wake cycles should all be initiated prior to transfer to inpatient rehabilitation.

Transition to Inpatient Rehabilitation Although evidence suggests that a more rapid transition to rehabilitation services may enhance outcomes,57 the general trend in health care over the past two decades has been a steady decline in hospital lengths of stay for both acute/ surgical care as well as rehabilitation. Despite this trend, data suggests that long-term outcomes are likely not adversely affected. However, for those patients with significant residual disability from TBI, a greater burden may be placed Seminars in Neurology

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on their family and home caregivers. In addition, a greater demand is typically placed on outpatient rehabilitation services, requiring significant coordination.58 Transition to rehabilitation services is generally considered when the focus of care switches from life-saving measures to functional restoration. Patients with severe TBI may remain in a coma or persistent vegetative state for a protracted time, with some never recovering. Although multiple studies have examined various interventions to promote arousal from a minimally conscious state, considerable controversy continues regarding their efficacy. As a patient emerges from coma they often display significant impairments in cognitive, emotional, behavioral, and physical functioning. Though rehabilitation strategies can be employed to address each of these impairments, they are genuinely most successful when the patient is able to attend to therapy sessions and follow basic commands. For many patients with severe TBI this may take weeks to months. Serial monitoring of the patient’s responsiveness is performed by assessing their level of posttraumatic amnesia (PTA), which is generally considered to resolve when a patient can begin forming new memories. The Galveston Orientation and Amnesia Test (GOAT) is a commonly used objective measure of PTA. Patients may also follow a recovery course that is characterized by progressive awareness, cognition, behavior, and interaction with the environment. This is best represented by the levels within the Rancho Los Amigos Level of Cognitive Functioning Scale.59

Restoration versus Compensation Much debate exists regarding the role of rehabilitative therapy and whether it promotes neurologic repair or teaches compensatory strategies to achieve functional independence. Considerable evidence currently exists to suggest that both factors likely play a significant role in recovery. The potential for promoting and enhancing neuroplasticity and/ or regenerative changes in the brain are likely influenced by multiple internal and external factors, including age, genetics, neuroendocrine function, gender, pain, mood, general health, as well as environment and exercise.60–63 Therefore, neurorehabilitation strategies often seek to employ multiple modalities to enhance overall well-being, while training patients on specific skills to achieve independence in such activities as mobility, self-care, feeding, bathing, toileting, and hygiene. Similarly, cognitive and behavioral therapies are employed to improve processes such as memory, attention, communication, executive functioning, irritability, impulsivity, mood, and psychomotor function. These are achieved by a combination of pharmacological and nonpharmacological interventions. Rehabilitation for patients with moderate-to-severe TBI requires the interdisciplinary interaction of a team of specialists that generally includes neurology, physiatry, physical therapy, occupational therapy, speech language pathology, neuropsychology, nursing, case management, social work services, nutrition, and an orthotist/prosthetist (especially for patients with limb loss or significant motor weakness such as paraparesis). In addition, the rehabilitative engineer or Seminars in Neurology

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therapist, who is certified in assistive technology (AT), may be a vital component of the rehabilitation team. They may prescribe cognitive assistive devices, enhance computer assistive access, or configure the appropriate manual or power wheelchair with an optimized user control interface. Each member of the team has a unique role; however, their combined efforts should be integrated seamlessly within the patient’s treatment regimen to maximize efficiency and efficacy. Because of the significant heterogeneity of types of brain injury and the multitude of symptom complexes that may manifest in each patient, an individualized treatment plan must be established for every patient and re-evaluated on a regular frequency to ensure success. Driving each therapy session should be short- and long-term goals, which are established between the rehabilitation team and the patient and assessed frequently. Examples of some common goals may include progressive standing tolerance for 15 minutes, independent stand-pivot transfers from the wheelchair to the commode, read and articulate multisyllable words, don a prosthetic socket independently, etc.

Spasticity Increased motor tone is common after severe TBI, and depending on the location of upper motor neuron damage, may affect various areas in the body, including axial, extremity, and/or sphincter muscles. Spasticity is defined as a “velocitydependent increase in tonic stretch”; therefore, it can generally be discriminated from joint or muscle contracture by physical examination. However, spasticity and joint contracture may also coexist, thereby complicating treatment and obscuring results from therapeutic approaches. Initial approaches to the management of spasticity include regular stretching exercises with the addition of either heat or cold modalities. For patients with poor sensation or altered cognition, caution must be taken when using heat or cold to not cause injury. If physical modalities are not effective, pharmacological agents are often utilized; however, many of these pharmaceuticals such as baclofen and diazepam have significant side effects (sedation, fatigue, and weakness), which may be especially counterproductive for patients with TBI. Dantrolene may be an effective alternative, but requires frequent monitoring of hepatic enzymes, because of its potential for liver toxicity. In addition, its use should be carefully titrated to not induce excessive weakness. Tizanidine or clonidine is often tried in isolation or in combination with other medications. Intramuscular botulinum toxin has gained increasing popularity over the past decade in managing spasticity, especially for upper limb dysfunction, which impairs ADLs or contributes to excessive pain. Before aggressively treating lower limb spasticity, it is first important to assess the patient’s reliance on the increased tone for transfers and mobility, as increased lower limb tone may support otherwise weak muscles. Excessive spasticity in the gastrocsoleus complex, however, often interferes with ambulation, as the excessive ankle plantar-flexion results in a “longer-limb,” making it more difficult to clear the toe during the swing phase of gate. This leads to excessive ground reaction force anterior to the knee that may cause genu-recurvatum and


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pain. Botulinum toxin injection to the gastrocsoleus complex in combination with a rigid ankle–foot–orthosis (AFO) can be used to help control excessive ankle plantar flexion from spasticity.

Heterotopic Ossification Ectopic bone formation within soft tissue is common after TBI and has been reported to occur in approximately 20% of patients. The incidence of HO, however, is much higher for patients with concomitant multitrauma, especially those who sustain extremity trauma and amputation from blast injury, where the incidence may be as high as 64%.64 Depending on the location of the HO, it may lead to significant loss of function of an extremity or compromised vasculature or peripheral nerves. It remains unclear what genetic, systemic, or local tissue factors promote progenitor cells to differentiate and initiate osteogenesis in the soft tissue. It is likely that a cascade of events leads to this condition. For the majority of patients, HO can be effectively treated with gentle range of motion exercises to maintain joint and soft tissue mobility. For those patients in whom the condition becomes debilitating because of pain or impaired function, surgical resection may be necessary. Surgery, however, is generally delayed until the ectopic bone formation is mature. Early manifestation of HO may present as pain, extremity swelling, erythema, and decreased range of motion. Early X-rays may not detect HO formation. Triple-phase bone scan or ultrasound can be helpful to diagnose or rule out other conditions such as DVT. Prophylaxis with low-dose radiation therapy has been shown to be effective, but is contraindicated when applied over fracture or soft tissue wounds, especially those subject to infection. Similarly oral nonsteroidal anti-inflammatory drug (NSAID) therapy can be effective in preventing HO, but may have secondary side effects such as gastrointestinal irritation, bleeding, and/or impaired fracture healing. For individuals with amputation and HO formation in their residual limb, careful attention and modifications to the prosthetic socket are needed to help accommodate the soft tissue deformity and reduce pressure that might exacerbate pain or further limb dysfunction.

Vestibular Dysfunction A significant proportion of TBI patients complain of dizziness, or changes in balance and coordination. Reports of vestibular dysfunction range from 15% to 78% in mild TBI, 30% in military personnel, and as high as 100% with temporal bone fractures.64 The etiology of vestibular disorders centers around the mechanism of injury, infection, and/or aging. Sense of balance and orientation to gravity is a dynamic coordination of inputs from vestibular, proprioceptive, and visual systems that converge in the brainstem. There are six main inputs to the brainstem (two inner ear, two eyes, two main sides of proprioceptive inputs), and injury to one is typically compensated by the brain and recovery is straightforward. However, the vestibular system has overriding input, and damage can have long-term consequences. For patients with TBI, visual impairment, and amputation, vestibular compromise is often more problematic and requires aggressive rehabilita-

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tion strategies. Vestibular disorders after TBI may be the result of peripheral injury, central injury, or both. Peripheral injuries include benign paroxysmal positional vertigo (BPPV), which is the most common cause of complaints of dizziness and imbalance clinically, and is seen in 9% of all patients over 65 years of age.50 It is described as brief episodes of vertigo provoked by movement of the head. Important treatment includes canalith repositioning through various maneuvers and exercises. Other peripheral vestibular injuries include labyrinth concussion and temporal bone fractures caused by trauma. Bloody otorrhea and severe pain must be differentiated from a traumatic tympanic membrane rupture. Perilymphatic fistula is another peripheral cause that is characterized by episodic vertigo and/or hearing loss provoked by Valsalva (sneezing, lifting, straining, etc.).65 Central causes of dizziness include direct trauma to the brainstem or cerebellum. Auditory function is often spared in these cases, but oculomotor abnormalities are common and symptoms include nystagmus at rest, eye movement abnormalities, diplopia and abnormal pupillary responses. History and physical examination in the diagnosis of dizziness and vertigo is challenging in TBI patients, as memory and recall may be impaired. To avoid missing important historical elements, the presence of a knowledgeable third party is very helpful. Evaluation should include a targeted history, comprehensive neurologic exam, bedside vestibulo-ocular reflex testing, DixHallpike maneuver, postural sway, and stepping test. Other important tests include oculomotor examination, otologic examination, hearing assessment, and Weber/Rinne test. Imaging, if not already obtained, should include targeted MRI, if not contraindicated, or CT with contrast. Treatments commonly include a combined therapy of medications, surgery (if indicated) as well as vestibular and balance rehabilitation therapy (VBRT).64 Vestibular and balance rehabilitation therapy uses existing neural mechanisms of plasticity, adaptation, and compensation to promote functional balance recovery. Types of VBRT include habituation, adaptation, substitution, and Dix-Hallpike maneuver. Medications utilized to suppress vestibular symptoms are typically only used for a short time because of their ability to slow the natural compensation process and effectiveness of VBRT. Commonly prescribed medications include antihistamines (meclizine and promethazine), anticholinergics (scopolamine), prochlorperazine, and benzodiazepines (preferred over anticholinergics in patients with prostatism and glaucoma). Novel interventions, such as virtual reality platforms, including the Computer-Assisted Training ENvironment (CAREN), may become increasingly incorporated into the care of patients with complex vestibular, motor, cognitive, and visual deficits.66

Endocrine Dysfunction after TBI Endocrine dysfunction after TBI is reported to range from 30% to greater than 50% of patients. Up to 25% of long-term survivors have pituitary dysfunction.67 The mechanism involved is direct and indirect trauma to the hypothalamus and pituitary gland as well as supportive structures such as the hypophyseal portal vascular system, which is vulnerable to traumatic injury. Necrosis and pituitary hemorrhage have Seminars in Neurology

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been noted in autopsy studies performed on TBI patients after succumbing to their acute injuries.68 The syndrome of inappropriate antidiuretic hormone (SIADH) is common in patients with TBI and is associated with euvolemia, low blood urea nitrogen (BUN) test, and urine osmolality greater than serum osmolality. Treatment is often fluid restriction and in rare cases hypertonic saline. Cerebral salt wasting causes hyponatremia with hypovolemia and dehydration; thus, treatment consists of fluid replacement and salt. Diabetes insipidus (DI) is rare and often associated with fractures of the skull, especially in or near the sella turcica. Onset is 5 to 10 days after trauma, and symptoms include polyuria, low urine osmolality, high serum osmolality, and normal to high sodium. Treatment includes complete endocrine/renal evaluation and hormonal replacement. Anterior hypopituitarism dysfunction is common, often presents weeks to months after moderate to severe TBI, and has an insidious onset with symptoms of hypotension, hyponatremia, hypothermia, bradycardia, or failure to progress in therapy. One study suggested an algorithm for endocrine function evaluation at 3 months and 1 year postinjury regardless of severity.41 Screening includes AM cortisol, IGF-1, follicle-stimulating hormone test (FSH), luteinizing hormone (LH), testosterone, estradiol, prolactin, urinary free cortisol, 25-hydroxyvitamin D (25-OH Vit D) test, parathyroid hormone (PTH) blood test, magnesium (Mg), and renal panel. In TBI, 30% of men experience erectile dysfunction and 40% have orgasm problems.64 Sexual dysfunction is multifactorial and has its roots in adjustment/psychological issues, side effects of medications, pain, gross anatomical injury, and hormonal issues to name a few. In severe TBI, serum testosterone levels decline below control levels by 48 to 72 hours after injury, and chronic hypogonadism can affect 10% to 17% of patients with TBI. Symptoms consist of decreased muscle mass, energy levels, libido, and cognitive performance. One report suggests chronic GH deficiency occurs in 16% to 18% of the TBI population and correlates with lower quality of life (QoL) and increased rates of depression. Consultation with an endocrinologist and specific hormone replacement significant impacts overall recovery and QoL.69

Pain Management Effective pain management in patients with complex trauma, including moderate–severe TBI, requires a multimodal approach. This becomes more challenging when a patient has multiple sources of nociception, such as soft tissue injury, fracture, peripheral nerve injury, headache, postsurgical pain, and phantom limb pain. In the perioperative setting, utilization of patient controlled analgesia (PCA) can be very effective to control intravenous opioid delivery. Peripheral nerve block anesthesia is frequently utilized for patients with limb amputation. All infusion-based therapies, however, need to be monitored regularly with set parameters to avoid undertreatment or oversedation. Because opioids may further impair cognition, reduce motor skills and reaction time, as well as increase sedation, contributing to inability to attend to tasks, they must be utilized sparingly in patients with TBI. In addition, constipation should be anticipated with opioid Seminars in Neurology

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use and therefore should be monitored closely and aggressively treated with stool softeners and stimulants. Nighttime pain is likely to impair sleep, and poor sleep may magnify the patient’s pain response. Medications such as trazodone, quetiapine, and prazosin may help to improve sleep, especially for patients who may also have anxiety related to posttraumatic stress. Neuropathic pain and phantom limb pain are often treated with antiepileptic medications, despite poor literature to support their effectiveness. Other adjuvant medications, such as tricyclic antidepressant (TCA) medications should be used with caution because of their risk of sedation and cognitive slowing. Mirror therapy or even a virtually generated limb may be an effective alternative to managing phantom limb pain.70 Complementary interventions, such as acupuncture, music therapy, and the creative arts, can often also be introduced.

Depression Depression is the most common psychological problem after TBI.71 Reports indicate 20% to 40% are affected in the first year and 50% are reported to have depression at some stage. Development of posttraumatic depression is reported as a possible result of head injury, postinjury psychological response to trauma, or a premorbid predisposition. Early symptoms are thought to be more likely related to injury, while late symptoms (> 1 year) are thought to be influenced by psychosocial factors.72 Certain risk factors affect postinjury depression rates more than others: minority status, unemployment, low income, low education, and alcohol abuse. Posttraumatic depression is associated with poor outcome after injury.50 Depression is also associated with decreased cognitive functioning (psychomotor slowing), impaired neurokinetics (speed of information processing), memory, and problem solving. Nonpharmacological management should be effectively utilized first before drug therapy is initiated. Psychiatric medications should only be prescribed after a neuropsychiatric evaluation has been performed. Once initiated, general principles of drug therapy include starting low and going slow, allowing for adequate therapeutic trials, continuous reassessment, and monitoring for interactions and augmentation. Selective serotonin reuptake inhibitors are first-line therapy: Sertraline and citalopram have the most supporting evidence and may also improve headache, fatigue, and sleep disturbance.73,74 Tricyclic antidepressants are not often used in TBI, with side effects such as Q-T prolongation and anticholinergic effects. Methylphenidate, dextroamphetamine, amantadine, and modafinil are all used in TBI rehabilitation for arousal and alertness; however, methylphenidate has been shown to improve mood as well as cognition in a double-blinded study with a placebo and sertraline.71

Conclusion The appropriate acute, subacute, and chronic care of individuals with moderate–severe TBI, especially those with multiple trauma as the result of a blast event, requires a comprehensive and dynamic system of specially trained


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Acknowledgments The authors would like to acknowledge the support of the Center for Rehabilitation Sciences (CRSR) and Center for Neuroscience and Regenerative Medicine (CNRM) at the Uniformed Services University of the Health Sciences, Bethesda, MD.

Disclaimer The opinions expressed herein belong solely to the authors. They should not be interpreted to be those of or endorsed by the Uniformed Services University of the Health Sciences, the U.S. Army, the Dept. of Defense or any other agency of the federal government.

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Vol. 34

No. 5/2014

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Severe traumatic brain injury.

Mild traumatic brain injury.

Mild traumatic brain injury.

Traumatic brain injury.

Traumatic brain injury.

Cerebral Vascular Injury in Traumatic Brain Injury.

Blood-brain barrier and traumatic brain injury.

Sleep and traumatic brain injury.

Sports-related traumatic brain injury.

Imaging of Traumatic Brain Injury.

Rehabilitation after traumatic brain injury.

Traumatic brain injury and cognition.

Progesterone in traumatic brain injury.

Traumatic brain injury and hyperglycemia.

Headaches after traumatic brain injury.

Fatigue and traumatic brain injury.

Sleep in traumatic brain injury.

Neurostimulation for traumatic brain injury.

Pathology of traumatic brain injury.

Apathy following traumatic brain injury.

Akathisia following traumatic brain injury.

Hypopituitarism after traumatic brain injury.

Mechanisms of traumatic brain injury.

Sleep in traumatic brain injury.