Prognosis in TBI

Given the large costs to brain injured patients and their families, it would be ideal to be able to prognosticate the clinical course after TBI. However, individual outcomes vary greatly, and case reports of miraculous recoveries exist. Thus it is always important to remain hopeful about outcomes.

Still, it is possible to give family members important information about outcomes. First, however, discussions should focus on the patient and family—what is their knowledge about the events that have happened? What are their expectations? What is their concept of “good” outcomes versus “bad” outcomes? What are their hopes and fears? For example, some families may believe that a “good” outcome is being able to converse with family members, whereas others may believe that a “good” outcome is the patient’s preinjury baseline. By exposing these concepts, families and medical teams can begin conversations at a common point.

Most studies on prognosis in TBI have used the Glasgow Outcome Scale (GOS), which uses the following categories:

Therefore the definitions of “severe,” “moderate,” and “good” recovery are quite broad and may not correspond to patient and/or family goals.

Some important predictive factors are listed below:

The best predictor of outcomes after TBI is the length of posttraumatic amnesia (PTA). The longer the duration of PTA, the worse outcomes generally are. Clinically, resolution of PTA occurs when patients are able to incorporate daily events into working memory. Patients with PTA of less than 24 hours generally have a quick and full recovery with few exceptions, and patients with PTA of more than 4 weeks generally have permanent deficits. However, more stringent “threshold” criteria have been used in previous textbooks to preserve hope for caregivers. These criteria state that severe disability (on GOS) is unlikely with PTA of less than 2 months, and good recovery (on GOS) is unlikely when PTA is more than 3 months.⁷ It has been shown that 21% patients with PTA between 1 and 2 months did return to work within a year, whereas only 9% of patients with PTA of more olthan 70 days were able to return to work within a year.⁸

Age is the second most important predictor of outcome. Older age is associated with worse outcomes, and previous textbooks have stated that GOS of good recovery is unlikely when age is older than 65 years.

Length of coma, defined as time from injury to follow commands, can be an important milestone as well. Generally, severe disability (GOS) is likely when length of coma is more than 2 weeks. Good recovery (GOS) is unlikely when length of coma is more than 4 weeks. For more information, please see the section on Disorders of Consciousness.

The best Glasgow Coma Scale (GCS) score within 24 hours correlates with outcomes, with lower scores associated with worse outcomes, and with the best motor response subset as the most accurate predictor of outcomes. Unfortunately, there are no “threshold” criteria because patients with severe injury can have good recovery. Indeed, recent reviews of GCS in outcomes of TBI suggest that other measures, such as age and pupillary response, improve its predictive capacity.⁹

Neuroimaging has become increasingly important in predicting outcome. It has been suggested that an adequate threshold marker is the presence of bilateral brainstem lesions; good recovery (GOS) is unlikely when bilateral brainstem lesions are present on an early MRI. CT scan findings of subarachnoid hemorrhage, midline shift, extradural hematoma, bilateral injury, or transventricular injury correlate with worse outcomes, though a full range of outcomes is still possible with these injuries.⁷

Research continues in this field to delineate other possible markers of prognosis and outcome. Biomarkers such as S100, genetic markers such as APOE 4 status, the ratio of total brain volume to third ventricle size, T2 gradient echo MRI lesions, PET scanning, diffusion tensor imaging, magnetic resonance spectroscopy, and somatosensory evoked potential responses are currently under study and may provide important prognostic information in the future.¹⁰

Given the uncertainty surrounding various predictors, several authors are currently trying to mathematically model outcomes of TBI using predictive variables.^11–13 One such model, based on a large population study, is available at http://www.tbi-impact.org/. It must be noted that these models are still undergoing refinement, though they may also provide important prognostic information in the future.

Introduction

Much basic science research has been done on the mechanisms of neural recovery, particularly in stroke literature. Exact comparisons may be difficult for TBI because the nature of the injury is often diffuse but it seems likely that the basic mechanisms of recovery are similar. Trauma disrupts neuronal connections including the connectivity and organization of networks mediating executive functions and sensory and motor responses.¹⁴ In addition to the focal damage of TBI, dysfunction can occur in areas anatomically removed, likely because of diaschisis involving tissue hypometabolism, neurovascular uncoupling, and aberrant neurotransmission.¹⁵ In addition to local repair, neuroplasticity is thought to be a crucial feature of recovery from TBI with research from as far back as the 1960s demonstrating how brain structure and chemistry can be affected by environmental manipulation.¹⁶

Overview

Recovery of neurological function is dynamic and multifaceted but often limited partly because of the inability for dramatic anatomic reorganization in the brain following lesions. Three distinct phases of recovery have been described. The first involved activation of cell repair and reversal of diaschisis; the second, plasticity of existing neuronal pathways to produce a functional change; the third, neuroanatomic plasticity to produce nascent connections. Where damage is focal, recovery primarily engages ipsilateral brain tissue, but with more severe TBI it is likely that contralateral brain regions are also recruited.¹⁶ The recovery process begins immediately and extends over the course of many months to years.

Therapeutic Targets

To date there are no currently approved pharmacologic agents that help restore neural function lost in TBI. With a better understanding of inhibitory mechanisms that block regenerations and processes that enhance plasticity, newer therapeutic targets will become available.

One area of interest is growth promoters and inhibitors. When administered within days of the insult, functional recovery is promoted by growth factors through stimulation of neuronal plasticity. Several agents are currently in clinical trials and are diverse in nature, including erythropoietin, granulocyte colony stimulating factor, statin drugs, and phosphodiesterase-5 inhibitors.¹⁵ By contrast, growth inhibitors impair recovery with particular insights being gained into the effects of growth cone extension. Myelin-associated proteins, including Nogo-A, oligodendrocyte myelin glycoprotein, and myelin-associated glycoprotein (MAG), activate the inhibitory Nogo-66 receptor to prevent axonal sprouting.¹⁷ Intravenous or intrathecal delivery of antibodies or peptides aimed at either the Nogo protein or receptor dramatically enhance functional recovery after neural injury in animal models.

Finally, therapy may in the future focus on brain activation with early studies showing that amphetamine and possibly L-dopa enhanced recovery of function in animal models. The suggestion was that adrenergic and cholinergic neurotransmitter systems are critical to the recovery process, but human trials have had limited results.¹⁸ Brain tissue can also be activated by physical and environmental means, for example, repetitive physical activity or sensory experiences. As part of environmental stimulation, social interaction is felt to be important in that it induces multiple biologic effects on the brain.

While many questions remain about the mechanisms of recovery in TBI, the current sophisticated molecular tools available for researchers continue to yield insights and hopefully will lead to promising new therapies.¹⁵

Disorders of Consciousness

Up to 15% of patients with severe TBI are unable to respond consistently to commands at 4 weeks after injury, and the majority of these will have impairments of consciousness.¹⁹ There has been much confusion surrounding the different states of consciousness. By definition:

Coma—unarousable neurobehavioral unresponsiveness. Patients remain with eyes closed, without evidence of eye opening either spontaneously or in response to external stimulation. They do not follow commands, do not demonstrate goal-directed or volitional behavior, do not verbalize or mouth words, and cannot sustain visual pursuit movements beyond a 45-degree arc. Neurobehavioral signs and symptoms secondary to pharmacologic treatment with agents such as paralytic or sedative drugs must be excluded.

Vegetative state (VS)—arousable neurobehavioral unresponsiveness. Patients have periods of eye opening, either spontaneously or in response to external stimuli; subcortical responses to external stimuli (including posturing, tachycardia, diaphoresis with pain); return of autonomic functions (sleep-wake cycle, normalization of respiratory and digestive functions); roving eye movements without concomitant visual tracking ability.²⁰

Minimally conscious state (MCS)—a condition of severely altered consciousness in which the patient demonstrates minimal but definite behavioral evidence of self- or environmental awareness. The Aspen workgroup proposed that one or more of the following should be present: (1) following simple commands; (2) manipulation of objects; (3) gestural or verbal yes/no responses; (4) intelligible verbalization; or (5) stereotypical movements that occur in a meaningful relationship to the eliciting stimulus and are not attributable to reflexive activity. These responses must be reproducible or occur on a sustained basis.²¹

Conscious—reliable and consistent demonstration of interactive communication or functional use of objects.

Overall, there has been some controversy over the terms “persistent” and “permanent” vegetative state. The American Academy of Neurology has suggested that persistent vegetative state be defined as more than 1 month, while permanent vegetative state as more than 3 months for nontraumatic injury and more than 12 months for traumatic injury. However, there have been case reports of patients regaining consciousness more than 1 year out from their injury, and in one case series, 52% of patients who were vegetative at 3 months recovered consciousness by 12 months postinjury. Because of these issues, some experts have suggested eliminating the terms “persistent” and “permanent” altogether, and to use a probability for outcomes—for example, it is highly likely that patients who recover consciousness more than 1 year postinjury are severely disabled (unable to be independent for a 24-hour period of time).

Amantadine, bromocriptine, amphetamine, and methylphenidate and other neurostimulants have been proposed to help with arousal and vigilance.²² There has been a case report of a patient in MCS who regained full consciousness after treatment with amantadine who declined when the medication was withdrawn.¹⁰ However, Cochrane Reviews on monoaminergic agonists and excitatory amino acid inhibitors have not found good randomized trials to review.^23,24 Similarly, another recent Cochrane Review determined that there have not been any good studies to support the use of sensory stimulation in MCS or VS patients.²⁵ Unfortunately, most research surrounding treatment of disorders of consciousness in brain injury is poor, involving case reports or small numbers of patients without controls. More research is needed to further clarify treatment algorithms in the future.

Motor Recovery

As with everything in brain injury, motor recovery is highly individualized and varies from person to person. Though it seems that the majority of motor recovery happens in the first 6 months after injury, it is possible for patients to continue gaining function after that. Swaine and coworkers studied a small population of patients with severe TBI (GCS ≤ 8) for 6 weeks after injury, and demonstrated that, while the percentage of patients with basic primitive reflexes (asymmetric tonic neck reflex, flexor withdrawal) stayed relatively stable, equilibrium reactions, protective reactions, sitting reactions, and simple motor skills slowly increased over time. The sequence of recovery—reactions in sitting appeared before those in kneeling and before those in standing. Recovery of equilibrium reactions tended to occur before development of protective reactions. Similarly, with motor skills, rolling ability recovered before ability to sit unsupported, followed by the ability to stand, then walk independently, then climb stairs, then hop on one foot, then the ability to run. Surprisingly, some simple motor skills (rolling, sitting, even walking unsupported) seemed to recover faster than equilibrium. Also surprisingly, patients did not necessarily lose primitive reflexes before recovering simple motor tasks. Of note, in this case series, 60% of patients by 6 weeks could sit independently and 56% of patients could walk without assistance.²⁶ Watson and associates have suggested a path-tree analysis instead of a simple linear progression of motor skills and demonstrated that while there is an underlying pattern of recovery, there are many routes that a patient can follow.²⁷

Motor Trephine Syndrome

Following craniectomy, patients may suffer delayed or insidious headache, fatigue, and mood disturbance. A few may have delayed contralateral monoparesis that is reversible with cranioplasty—the motor trephine syndrome. In one retrospective review, up to 26% of patients with decompressive craniectomy developed delayed contralateral upper extremity weakness that improved with cranioplasty, with full recovery 1 month after cranioplasty. Weakness developed an average of 4.5 months later, was predominantly distal upper extremity proximal, causing difficulty with grip and extension of metacarpals, and was slowly progressive. There was no sensory or language impairment. These patients more often had blossoming of cerebral contusions after craniectomy and cerebrospinal fluid (CSF) flow disturbances (hygromas and hydrocephalus), and had a longer time to cranioplasty than patients without motor trephine syndrome. Mechanistically, it has been proposed that motor trephine syndrome is caused by disturbances of CSF flow, leading to edema in brain parenchyma. Cranioplasty allows egress of CSF, which resolves brain edema and restores function.²⁸

Evaluation of Cognitive Dysfunction

Initial evaluation of cognitive dysfunction, as with any neuropsychological or behavioral dysfunction, begins with medical evaluation. Infection, electrolyte imbalances, hypoxia or hypercapnia, endocrine disturbances, new neurological lesions (strokes or hydrocephalus), medications, medication withdrawal, sleep disturbances, seizures, and reactive mood disorders can all impair cognition in hospital patients. Of course, documentation of baseline cognitive abilities of the patient is important. After correction for these factors, formalized neuropsychological testing should be considered to fully evaluate the cognitive domains that are affected—language, visuospatial, attention/concentration (which includes arousal, selective attention, effort, and resource allocation), learning and memory, executive functioning, sensory perceptual, and psychomotor-visuomotor functioning. Neuropsychiatric testing can also help with determination of premorbid intelligence if previous data do not exist. Ideally, pharmacologic and nonpharmacologic treatment could then be targeted to deficits, though research is still preliminary in these fields.

Treatment of Cognitive Dysfunction

Overall, there have been very few class I studies to guide treatment of cognitive dysfunction in brain injury.³² However, some possible targets and treatments are outlined below (Table 342-1).

Methylphenidate: Recently, a Cochrane review concluded that there was not enough evidence to warrant using a monoaminergic agonist to improve recovery after TBI because none of the studies done fulfilled inclusion criteria.²⁴ Despite this, recent reviews have mentioned that the several small scale randomized controlled trials (RCTs) involving methylphenidate are among the strongest studies in pharmacologic therapy in brain injury. Overall, these reviews suggest that methylphenidate treatment leads to significant improvements for speed of processing, and certain areas of attention and concentration, such as attentiveness. It has also been suggested that those with slower baseline information processing demonstrate a greater drug response. Thus there is relatively strong evidence that methylphenidate improves speed of processing and attention in traumatic brain injury patients.^33,34 Dosages that have been used in the literature include 20 mg or 0.3 mg/kg.^10,35

Donepezil and other cholinergic medications: Donepezil, galantamine, and rivastigmine, all cholinergic agonists, have not been as rigorously studied as methylphenidate. There has been one small RCT and a few small case series that concluded an increase in sustained attention and short-term memory in donepezil up to 10 mg/day. One open label study of galantamine, donepezil, and rivastigmine demonstrated some positive response in attention and vigilance, but no difference in side effects. A single large rivastigmine trial failed to show benefit in all groups; however, those with more significant memory impairments had a trend toward improvement.³⁶ Overall, there has been moderate evidence of the use of cholinergic medications to enhance attention and concentration.³⁷

Amantadine: Amantadine is a dopamine receptor agonist and N-methyl-D-aspartate (NMDA) NMDA receptor antagonist. Case studies have suggested positive response with short-term memory, attention, planning, impulsivity, and disinhibition.³⁸ There has been one small double-blind, crossover RCT that did not demonstrate significant difference in rate of cognitive improvement.³⁹ Despite conflicting information, recent reviews in 2008 suggest “at doses of 200 to 400 mg/day, amantadine appears to safely improve arousal and cognition in patients with TBI,” though they warn that more studies are necessary.^37,40 Small case reports have suggested some benefit for other dopaminergic agents, such as bromocriptine, selegiline, and levodopa, but the data are still very limited with regard to these agents.

Sertraline and other SSRIs: It is well known that depression may confound cognitive impairment in TBI. Recent consensus opinion encourages the use of antidepressants in TBI, though notes that there may not be a strong effect on cognition. They suggest the use of sertraline as a first-line agent because it does not have as many side effects. One small, nonrandomized study without control suggested that fluoxetine may have improved attentional task and working memory in chronic TBI patients.^35,41

Modafinil and atomoxetine: Although there have not been any human studies on the effect of atomoxetine on cognition in TBI patients at this time, animal studies have been promising.⁴² Modafinil has been studied for underarousal and fatigue in TBI, but has not been studied in cognition.^43,44 Still, one recent review suggests that, given their effect on the dorsolateral prefrontal cortex, and mechanisms of action, atomoxetine and modafinil may be useful for attention and arousal in TBI patients.³⁵

Warnings: Although one class I study has suggested that valproate does not impair or improve cognitive function, many other medications used in brain injury may inhibit or impair cognitive function. For example, although no studies have been done on topiramate and TBI, some authors suggest that topiramate use may cause neuropsychological problems in patients who have underlying cognitive and behavioral problems.⁴⁵ The use of neuroleptics, such as haloperidol, is controversial in brain-injured patients because they may increase the length of PTA and have a negative impact on cognitive recovery.⁴⁶ In general, practitioners should be wary of neuroactive medications in the brain-injured patient, and seek to eliminate medications with cognitive side effects.

Definition

Following TBI, a subset of patients experience dysautonomia, a syndrome characterized by severe paroxysmal changes in heart rate, respirations, blood pressure, temperature regulation (including diaphoresis), and muscle tone.⁴⁹ Dysautonomia has been called various other names, including autonomic dysfunction syndrome, sympathetic storming, hypothalamic-midbrain dysregulation syndrome, acute midbrain syndrome, and diencephalic epilepsy.

Incidence and Effects

Dysautonomia in particular is associated with severe TBI. Other associations include severe diffuse axonal injury, preadmission hypoxia, younger age at time of injury, and possibly brainstem injury.⁵⁰ In the intensive care setting, the incidence of dysautonomia ranges from 8% to 33%, falling to 5% in the rehabilitation setting. This decreased incidence is consistent with the observation that over time paroxysmal autonomic overactivity gradually settles, coinciding with neurological recovery. TBI patients with dysautonomia, however, are more likely to experience significant long-term disability, both cognitive and physical, and have longer hospital and rehabilitation stays; length of ICU stay is similar to the nondysautonomic group.^50,51 A discrepancy in reported incidence is evidence of variability in criteria used in research and highlights the need for standardization in the literature.

Mechanisms

Understanding of the pathophysiology of dysautonomia in TBI remains problematic. Original thinking on the subject assumed an epileptogenic source, hence the popular moniker diencephalic seizures. Multiple attempts to identify epileptic discharges or treat epilepsy have yielded negative results. More recently this has been superseded by a range of disconnection theories. Autonomic control exists at several levels of the nervous system and disconnection theories suggest that dysautonomia is a result of the liberation of excitatory centers from higher central control. Debate exists as to whether the excitatory centers are located in the upper brainstem and diencephalon or in the spinal cord. More conventional theories suggest that the upper brainstem and diencephalon drive the autonomic paroxysms. An alternative theory suggests that these centers are inhibitory on spinal cord processes and damage to the centers or their connection to the cord results in inappropriate spinal cord autonomic activity.

Evidence suggests that the disconnection syndrome can result from structural and/or functional disconnection. Structural damage results from diffuse and focal injury sustained to the central nervous system in TBI patients. In contrast, functional disconnections may occur because of neurotransmitter abnormalities or through alterations of the functional environment (e.g., raised intracranial pressure [ICP]).⁵²

Anecdotally, various afferent stimuli have been identified as dysautonomic triggers including endotracheal tube suctioning, Foley catheter manipulation, passive movements (e.g., repositioning patient), and muscle stretch.⁴⁹

Symptoms

Identifying dysautonomia in the intensive care unit (ICU) or rehabilitation setting should be based on the operational definition of paroxysmal increases in at least five of the following seven clinical features: heart rate greater than 120 beats/min, respiratory rate greater than 30, temperature, systolic blood pressure greater than 160, sweating/flushing/piloerection, muscle tone, and posturing (e.g., decerebrate or decorticate). By definition, several of these components will occur simultaneously and typically to a marked degree.^53,54 The higher metabolic demand in the posturing dysautonomic patient, combined with postinjury gastrointestinal abnormalities results in an estimated 25% loss of body weight because of a highly catabolic state. This malnutrition increases the risk of infections and the development of critical illness neuropathy. In addition, dystonic posturing in the setting of weight loss increases the risk of developing pressure injury and contracture.⁵⁵

Treatment

The first step of any treatment paradigm should be to minimize noxious stimuli in patients at risk for or with documented dysautonomia. This includes aggressively identifying and treating pain, decubitus ulcers, infections, constipation, minor and undiagnosed injuries, and heterotopic ossification. For any patient that develops symptoms consistent with dysautonomia, the differential should remain wide and appropriate evaluation for other conditions that might produce similar findings including neuroleptic malignant syndrome, posttraumatic epilepsy, and pulmonary embolism should be conducted.

A wide range of medications has been used to treat patients with this disorder and have anecdotal support in the literature. These include morphine, α-blockers (predominantly clonidine), β-blockers (predominantly propranolol and metoprolol), anticonvulsants (valproic acid and phenobarbital), dopamine agonists (in particular bromocriptine), and benzodiazepines.⁵⁶ Much of the therapeutic approach has been directed at reducing efferent activity and more recent literature has suggested benefits from both intrathecal baclofen and gabapentin administration. Both are GABA analogues and it is possible that both act to normalize modulation of afferent stimuli in dysautonomic patients by enabling inhibitory pathways within the spinal cord, thus preventing the development of the efferent arm of the syndrome.⁵⁵

Each particular patient is likely to require a combination of drugs to ameliorate symptoms but it seems reasonable to initiate and uptitrate gabapentin therapy (in light of the benign side effect profile) as an initial step before other agents.

Treatment of Agitation

Similarly to cognitive dysfunction, treatment of agitation begins with a broad differential diagnosis of delirium. This differential should include medical issues such as pain, infection, hypoglycemia/hyperglycemia or other electrolyte imbalances, hypoxia, epilepsy, endocrine issues, medications, and medication withdrawal. Once those are ruled out, the diagnosis of posttraumatic agitation can be made.

Once other causes of increased psychomotor activity and confusion are ruled out, the first step in treating agitation is limiting environmental stimuli, especially at night. Though difficult in an acute care setting, limiting ambient noise, light, assessment of vital signs, and around-the-clock medication administration can help reset the circadian rhythm and thereby limit agitation. Limiting use of lines, tubes, and restraints, if possible, can also help reduce unwanted psychomotor activity. Abdominal binders and IV protectors can be useful in preventing patient-induced discontinuation of lines and tubes.

Once environmental causes have been treated, the option exists to use pharmacologic treatment. Though a recent Cochrane review of pharmacologic treatment of aggression or agitation in TBI noted that most studies were case studies, and therefore did not meet inclusion criteria, some possible treatments are listed below.

Medications to Avoid: Antipsychotics

Recently, there has been increasing concern with the use of antipsychotic medications in TBI patients. TBI experts often avoid these medications more than nonspecialized physicians.⁵⁸ While there have been case studies suggesting decreases in agitation with medication administration, animal studies with typical antipsychotics have had slower motor recoveries. Typical antipsychotics such as haloperidol have been shown to correlate with longer periods of posttraumatic amnesia in human studies, although some speculate that this may be caused by increased usage of antipsychotic in more severe injuries. Patients who are tapered off chronic typical antipsychotic medications have improved neuropsychiatric studies. While atypical antipsychotics such as olanzapine, clozapine, and risperidone have not had similar effects in animal models, recent work has suggested that high doses of risperidone may have similar cognitive effects in humans as haloperidol.

Medications to Avoid: Benzodiazepines

Benzodiazepine use in TBI has also caused concern in TBI experts. Though effective for treatment of agitation, animal models have suggested that use of benzodiazepines both acutely or chronically can lead to further cognitive impairment. Also, normal patients, when weaned off chronic benzodiazepines for insomnia, have been noted to have neuropsychological deficits when compared with controls. Therefore, several experts have suggested that benzodiazepines may be detrimental in patients with TBI and should not be prescribed in these populations.

Posttraumatic Epilepsy

Brain injury is a very common cause of acquired epilepsy, accounting for 30% of new-onset seizure patients between the ages of 15 to 34 years, and in up to 6% of all age groups. Seizures can occur in up to 50% of certain populations of brain injury survivors.⁷⁶ Posttraumatic seizures are defined by the time period after injury:

Major risk factors for developing late seizures include increasing severity of injury (mild TBI—relative risk of 1.5, moderate TBI—RR 4, severe TBI—RR 29), skull fracture, intracranial hematoma (especially subdural hematoma), dural penetration with bone or metal fragments, depressed consciousness at time of ED presentation, brain contusions (especially biparietal or multiple contusions), and development of early seizures. Of note, there is no data suggesting that immediate seizures lead to an increased risk of posttraumatic seizures. Seizures are generally generalized, focal or focal with secondary generalization. Mesial temporal lobe epilepsy is rare in adult TBI.

Most studies are focused on attempting to find prophylactic treatments for posttraumatic epilepsy, but none have been proved effective. Overall, though there has been some question as to whether phenytoin prevents early seizures,¹⁰ most studies suggest that phenytoin and carbamazepine have been shown to reduce early seizures. They do not, however, reduce late seizures.⁷⁷ Magnesium has been tested with early phenytoin and has had no benefit. Valproate was compared with phenytoin, and though not statistically significant, was not as effective for treating early seizures, and had no positive effect on late seizures.⁷⁸ Levetiracetam has been compared with phenytoin for early seizures, and seems to be as effective in preventing clinical early seizures though they did have increased abnormal findings on an electroencephalogram (EEG).⁷⁹ Steroids have not been shown to decrease risk of seizures.¹⁰

Currently, the most recent practice parameters set by the American Academy of Neurology recommend that for adult patients with severe TBI (prolonged loss of consciousness or amnesia, intracranial hematoma or brain contusion on CT scan, and/or depressed skull fracture), prophylactic treatment with phenytoin, beginning with an IV loading dose, should be initiated as soon as possible after injury to decrease the risk of posttraumatic seizures occurring in the first 7 days. Prophylactic treatment with phenytoin, carbamazepine, or valproate should not routinely be used to decrease the risk of posttraumatic seizures beyond the first 7 days after injury.⁸⁰ These are consistent with older practice parameters set out by the Brain Trauma Foundation.⁸¹ Unfortunately, recent reviews have stated that there are no studies to evaluate a treatment specifically for posttraumatic epilepsy, and treatment recommendations are to treat it as epilepsy caused by any other etiology.

Treatment

Significant practice diversity exists in the event of VTE occurring despite prophylactic therapy. Hospital surveys have shown that 75% of centers initiate full anticoagulation with LMWH or UFH followed by long-term oral warfarin. Nearly 90% of centers used IVC filters in combination with anticoagulation or as a single treatment.⁹⁰ This diversity of therapeutic approaches points to the need for prospective clinical trials.

Documented evidence of VTE despite prophylaxis requires an escalation of prophylactic therapy, typically involving full anticoagulation and possibly placement of an IVC filter.

Mechanism

The stretch reflex arc is the basic neural circuit that underlies the problem of spasticity. The arc consists of an afferent and efferent limb. The afferent limb originates in the muscle spindle and is carried in sensory neurons to the dorsal horn of the spinal cord. Here, synapse with a motor neuron occurs and the efferent limb exits via the anterior spinal root innervating the contractile muscle fibers. The contraction of agonist muscles must simultaneously be complemented by the relaxation of antagonist muscles, which occurs via an inhibitory neuron within the spinal cord gray matter. This basic loop is modulated by multiple synaptic influences that include descending cerebral pathways and various interspinal neurons. The treatment of spasticity aims to interrupt this arc at one or more points.⁹¹

Assessment

Several measures of hypertonicity exist and it is important to note that the definition of spasticity can have a significant impact on the validity of the assessment tool. A useful summary can be found in the review by Platz and coworkers.⁹² For routine assessment and clinical trials, the Ashworth Scale demonstrates good interrater reliability (Table 342-2).

TABLE 342-2 Ashworth Scale

In considering treatment for spasticity, assessment by a physiatrist is often useful because of the potential functional value that hypertonicity offers. For example, an extensor spasticity can provide rigidity needed for weight-bearing or to assist in bed transfers. Determining how and to what degree spasticity interferes with the patient’s activities is the most valuable way to ascertain if treatment is needed.

Treatment

Spasticity management is a multidisciplinary activity. Goals and available treatment modalities must be discussed with both the patient and caregivers and management for each patient is individualized. Before initiating treatment for spasticity any underlying provocative factors (e.g., poor posture, constipation, incontinence, limb pain, and skin or tissue damage) should be addressed because these may have a profound influence on the disorder).⁹³

Normal Swallowing

Normal swallowing is a complex process with three distinct phases. In the oral phase the cohesive bolus of food is passed to the back of the tongue voluntarily, triggering a swallowing reflex. The pharyngeal phase follows as food is transferred to the esophagus. Lastly, in the esophageal phase the bolus is shuttled via peristalsis into the stomach. This process requires the coordination of approximately 50 paired muscles and cranial nerves V through XII (excluding VIII). Volitional swallowing is thought to be controlled in the frontal lobe; additionally, adequate alertness is a necessary precondition for safe swallowing.⁹⁴

Etiology and Associations

Following TBI, between 25% to 61% of patients experience swallowing impairment that is associated with severity of injury, cognitive state, and ventilatory status. The majority of these patients—up to 90%—recover the ability to feed orally with the greatest improvement occurring within 6 months of the initial trauma, following the pattern of motor recovery.⁹⁵

Mechanisms of Dysphagia

Traumatic brain injury patients have neurological impairment affecting all three phases of swallowing, normal behavior, and the cognitive processes critical to a normal swallow. Abnormal muscle tone, reflexes, and sensory deficits all contribute to swallowing impairments in these patients. Marginal sensation is responsible for the poor motor response to an oral bolus. Loss of the sensory response in the pharynx dramatically impairs reflex swallowing ability and several of these abnormalities often occur in concert. Aspiration risk is increased because of delay in reflex swallowing mechanisms and reduction in tongue control. In the setting of aspiration, the physiologic response is reflex coughing, but neurological patients show a high percentage of silent aspiration, up to 60%.⁹⁵ As is common in this population, the need for tracheostomy and prolonged ventilation can also augment the risk of abnormal swallowing.⁹⁴

Assessment and Treatment

Clinically, dysphagia should be a concern in any patient with alteration in speech or voice quality, a cough related to swallowing, or an impairment in the gag reflex. Of note, approximately one third of normal patients do not have a gag reflex and this sign has been poorly correlated with aspiration risk. Because many TBI patients have severe speech impairments, assessment of speech and voice quality is difficult in this population.⁹⁶ The difficulty of clinical assessment and high frequency of dysphagia direct that all patients should be assumed to have swallowing dysfunction. Failure to diagnose and treat patients with dysphagia place them at high risk for aspiration pneumonia, malnutrition, and dehydration and can lead to prolongation of hospital and rehabilitation stays.

Video fluoroscopy is the “gold standard” evaluation method and it is important that speech and language pathology is involved in the care of patients at a very early stage.⁹⁷ Data suggest that almost half of patients that receive speech and language pathology intervention in a health care setting have dysphagia secondary to a neurological process and that more than two thirds will improve.⁹⁸ The goal of therapy is to achieve safe and effective swallowing and to prevent respiratory and nutritional complications. Diet at discharge can range from normal to exclusive gastrostomy feeding. Return to unrestricted dieting has been found to occur typically within 120 days of rehabilitation. By approximately 50 days, half of patients have reached this milestone.⁹⁹

Metabolism

Contrary to the previously held notion that comatose patients have very low metabolism, more recent work has shown that metabolism is actually increased by an average of 140% in these critically ill individuals.¹⁰⁰ Patients that are paralyzed still have requirements above normal but less than nonparalyzed patients, suggesting that muscle tone has a significant role to play. Nitrogen excretion from protein metabolism also significantly increases for as long as a month after TBI with related depletion in muscle mass and depressed immune function. The higher metabolic rate has to be taken into consideration in the planning of caloric replacement.¹⁰¹ Evidence-based guidelines, however, are lacking to support enhancing caloric intake to meet the accelerated metabolic needs. Should the need to measure metabolic rates in individual patients arise, the preferred method is indirect calorimetry.

Route

Two routes exist to provide nutrition to head injured patients, enteral and parenteral. Unfortunately, upper gastrointestinal dysfunction is common following TBI with a frequency from 44% to 100% acutely. Little data exists to inform about the longer-term course of gastrointestinal intolerance. Enteral feeding can be either gastric or postpyloric. The incidence of pneumonia and aspiration with both routes is similar, but postpyloric feeds are better tolerated in patients in whom gastric dysfunction is pronounced.¹⁰²

Parenteral feeding carries an increased risk of bacteremia and septicemia, possibly from catheter-related infections and possibly from inactivity of the gut. As such, enteral nutrition is clearly the preferential route for nutritional support in the TBI population.¹⁰³

Timing

Timing of nutritional support is influenced by the route chosen for feeding. Data suggest that in patients who are fed via the parenteral route, feeding is typically started early—between 1 and 3 days from the time of injury. For enteral gastric feeding, nutritional support is typically held until bowel sounds are appreciated, usually from 3 to 5 days after initial injury. Enteral jejunal feeding, however, can typically be started earlier, even in the face of poor gastric emptying. Data suggest that in patients in whom parenteral feeding is used typically are started earlier, between 1 and 3 days from the time of injury.¹⁰⁴ Early enteral nutrition has many advantages, including minimizing intestinal mucosal atrophy, hence preserving the integrity of the intestinal defense against bacterial translocation.¹⁰⁵ This leads to a decrease in infectious complications, preserves normal gut flora, and prevents malnutrition.¹⁰² Even in patients that are unable to tolerate nutritional support to meet their caloric needs, trophic feeds at lower, better-tolerated rates serve to maintain the integrity of the intestine.

Outcome studies have shown increased mortality rates in patients who are underfed or patients in whom feeding is delayed. Therefore the goal should be to have full caloric intake in place before postinjury day 7. While consensus on early initiation of feeds exists, recommendations of other aspects of nutrition in the TBI population are vague. Specific attention should be paid to ensure adequate fluid requirements are met and to select an appropriate formula with the assistance and involvement of dietary specialists. Electrolyte monitoring to maintain homeostasis is crucial since electrolyte and glucose shifts may be detrimental to the patient. All patients being fed enterally should have aspiration precautions as standard practice and interactions between feedings and medications as well as medication reactions that might impact the gut (e.g., diarrhea, should constantly be borne in mind).¹⁰³

Based on the above observations, the Brain Trauma Foundation Guidelines suggest protein and calorie replacements within 72 hours postinjury.¹⁰⁶

Definition and Epidemiology

Posttraumatic hydrocephalus (PTH) is the commonest neurosurgical complication in the rehabilitation setting in patients with severe TBI.¹⁰ The reported incidence in the literature varies widely from 0.7% to 29%, reflective of variable definitions of the condition. If imaging criteria of ventriculomegaly are used the reported incidence is higher, ranging between 30% to 86%.¹⁰⁷

Symptoms

Posttraumatic hydrocephalus is typically recognized in the rehabilitation setting or during neurosurgical follow-up. Several different clinical syndromes exist, all of which fall into two general categories: patients either plateau in a trajectory of previous clinical improvement or clinically deteriorate. The clinical syndromes include (1) obtundation, (2) psychomotor retardation, (3) memory impairment, (4) gait impairment, (5) incontinence, (6) behavioral disturbances, and (7) emotional disturbances.¹⁰⁸ Clinical deterioration may involve several symptoms; alterations in consciousness and behavior are typically the most indicative of this change.¹⁰⁹ Symptoms of hydrocephalus are not infrequently masked by the degree of brain injury sustained, making diagnosis difficult when the patient is too severely injured to display hydrocephalic symptoms or has atypical symptoms.

Risk factors for PTH are yet to be fully identified but data suggest severity of injury, age, duration of coma, and decompressive craniectomy acutely increase the risk.

Investigations

Ventricular enlargement is a common finding in the postacute phase of TBI. The controversy is to distinguish brain atrophy-related ventriculomegaly from active, symptomatic ventricular dilation. Typically PTH develops within 3 months from TBI, whereas ventriculomegaly because of cortical atrophy evolves over 6 or more months. Further, cortical atrophy appears to correlate with cerebral hypoxia and anoxia and diffuse axonal injury, whereas PTH is more clearly related to CSF blockage over the convexities.¹⁰⁹ A high level of clinical suspicion for PTH must be maintained and any suspicion explored with CT imaging, and if indicated, lumbar puncture (LP). If CSF pressure on LP is consistently above 18 cm H₂O, the diagnosis seems likely. On imaging, ventriculomegaly is a typical finding but not always a good predictor of therapeutic response to interventions. Ventricular dilation in the absence of prominent sulci and gyri (i.e., the absence of brain atrophy) is most suggestive of PTH.

Several studies have attempted to describe predictive tests for selection of the most appropriate candidates for treatment. Measurements of CSF dynamics may help formulate the diagnosis as might assessment of cerebral aqueduct flow void on MRI. SPECT scanning showing temporal lobe hypoperfusion may also be a useful indicator of patients that will respond to surgery. However, these methods remain ill-defined and as yet lack strong data to support their utility. Simple CT calculations of ventricular to biparietal ratios may be an effective and easy method to evaluate for hydrocephalus.¹⁰⁸

Treatment

In patients where high clinical suspicion exists or where testing is confirmatory for PTH, ventricular shunting is the definitive treatment. In patients who have undergone decompressive craniotomy, shunt implantation is most likely to improve outcome when combined with concomitant cranioplasty. Clinical improvement might be relatively rapid or might take several days to weeks. Shunt placement is associated with its own complications with an incidence of 20% to 40% for shunt failure and 8% to 23% for infection. Shunt failure may be seen with all types of shunts and is usually the result of delayed outflow or peritoneal catheter obstruction. The timing of treatment is another controversial issue; however, existing data suggests that patients who have been symptomatic for less than 6 months before implantation have a more favorable prognosis. Posttraumatic hydrocephalus is a prognostic factor for late functional recovery and for the development of posttraumatic epilepsy.¹⁰⁹

Peripheral Neuropathy

To our knowledge, the rate of peripheral neuropathy in adult TBI patients has not been reported, but in children the rates reach about 8%.¹¹⁰ Most common causes include direct trauma from the inciting incident, or compression neuropathy from positioning during neurosurgery or during recovery during hospitalization. Common compressive neuropathies are ulnar or common peroneal neuropathies. However, there have been case reports of sciatic neuropathy because of heterotopic ossification¹¹¹ and retroperitoneal hematoma.¹¹² Evaluation of peripheral neuropathies often require EMG studies; while EMG/NCS may be abnormal within 1 week of nerve injury, it often takes 3 weeks to develop denervation changes that will help localize the lesion.¹¹³

Definition

Headache is a common physical manifestation of TBI and either produces new primary symptoms or worsens preexisting headache syndromes in patients with a prior headache history.¹²⁹ Headaches are classified according to the International Classification of Headache Disorders (ICHD), which provides clinical criteria to categorize primary and secondary headaches. According to these criteria, posttraumatic headache is either acute or chronic. The headache must begin within 2 weeks and resolve within 2 months to meet acute criteria. Chronic posttraumatic headache requires the symptoms to continue for more than 8 weeks. The criteria also indicate that the causative trauma should be significant, causing abnormal clinical, neurological, or laboratory examination but also notes that mild head trauma may produce symptoms even in the absence of other signs of brain dysfunction.¹³⁰

Incidence

Headache is the most common somatic complaint among TBI patients.¹³¹ The estimated incidence is 30% to 90% of patients with mild or moderate head injury with apparently a lower incidence in patients with severe TBI, although this remains a topic of investigation.¹³² The presence of posttraumatic headache has not been correlated consistently with injury severity. Premorbid headache history, however, has been shown to increase the risk of posttraumatic headache.¹³³ Because acute posttraumatic headache resolves within a few weeks, the majority of cases are represented by chronic posttraumatic headache.¹³⁰ No specific headache type defines posttraumatic headaches; all the features typical of primary headaches may occur. The majority, up to 85% in some series, experience tension types of headaches, with up to 21% meeting criteria for a migraine. In addition, cervicogenic headaches are found in many patients, though figures for incidence are disparate because of variable diagnostic criteria and range between 8% and 88%. It is also noteworthy that chronic posttraumatic headache is not an isolated phenomenon, occurring instead as a part of the posttraumatic/postconcussive syndrome with its associated somatic, psychological, and cognitive complaints.¹³²

Mechanism

The mechanism of posttraumatic headache is poorly understood. Several abnormalities occur following even mild head injury, and it is reasonable to assume that acute and chronic posttraumatic headaches follow organic injury to the brain. Abnormalities have been detected with MRI, SPECT, and PET scans and EEGs. These include changes to regional and global cortical blood flow, parenchymal lesions that improved over time, and alterations in glucose use. An additional source of headache may be pain from traumatized pain-sensitive structures including muscles, ligaments, nerve roots, pathways, and vasculature. Readily ameliorable causes such as hydrocephalus and TMJ dysfunction should be evaluated for and excluded where possible.

Clinical Features

Posttraumatic headaches take on the features of the primary headache disorder they resemble. Tension types of headaches, for example, often show bilateral discomfort, occasionally in a band-like distribution and are steady as opposed to throbbing. A posttraumatic migraine often has the typical features of photophobia and phonophobia but usually in a milder form. Unlike tension types of headaches, these tend to be unilateral and throbbing. A cervicogenic headache is almost always posttraumatic with cervical spine pain radiating to the occiput or even the front of the head. It also is unilateral and should be suspected where an examination demonstrates limited range of cervical motion.¹³²

Therapy

Following TBI, headaches are treated much the same way as primary headache disorders. Acute therapy consists of NSAIDS, acetaminophen, and triptan medication for migraine-like symptoms. Symptomatic therapy with antiemetics should be aggressive. Should headaches become chronic and frequent, prophylactic therapy may become needed using either β-blockers, calcium-channel blockers, antiepileptic medications, or antidepressants. The choice of a prophylactic agent should be guided by the psychological and cognitive symptoms present at the time of treatment. Patients that have experienced only mild TBI will be able to participate in associated therapies such as biofeedback, stress management, therapeutic exercise, and neuromuscular reeducation.¹³⁴

Mechanisms

Nociception is the result of detection of intense stimuli by nociceptors, specialized sensory receptors. These receptors typically respond to the usual sensory inputs, but are distinguished by being high threshold. Once stimulated they transfer action potentials to the spinal cord and from there to the brain. Central pain occurs in the absence of such a stimulus and in the presence of reduced nociceptive thresholds so that usually innocuous stimuli produce pain. This hyperexcitability may be the result of enhanced facilitation or impaired inhibition of central processes coupled with cellular pathophysiology that includes electrolyte imbalances and abnormalities of neurotransmitter release.¹³⁶ The development of neuropathic pain involves not just neuronal pathways but also peripheral components such as Schwann cells, satellite cells in the dorsal root ganglia, and the immune system, as well as microglia and astrocytes in the spine.

There are both peripheral and central mechanisms through which neuronal injury causes neuropathic pain. Peripheral mechanisms include sensitization, ectopic discharge, collateral sprouting, and ephaptic communication. Central mechanisms include central sensitization, enhanced facilitation, attenuated inhibition, increased adrenoreceptor expression, phenotypic alterations in afferent neurons, and reorganization of synaptic connectivity.

Manifestations of central sensitization include allodynia (reduced sensory threshold for pain), hyperalgesia (increased responsiveness of sensory neurons to stimuli), and secondary hyperalgesia (expansion of the territory by which a sensory neuron is activated).^136,137

Clinical Presentation

It is important to recognize that in addition to causing pain and distress, central pain may also limit recovery by restricting a patient’s participation in the rehabilitative process. The pain induced has a central origin and hence may be vague or difficult to characterize. Most central pain conditions are a mixture of neuropathic and nociceptive types with allodynia and hyperalgesia being strongly suggestive of neuropathic components. Disruption of the normal sensory pathways leads to abnormal processing and varied and bizarre characteristics of the pain. In addition to hyperesthesia, dysesthesia and allodynia, patients may experience muscle pain (cramping, constricting, or crushing), circulatory pain (pins/needles, stings, jabs) and/or visceral pain such as bladder fullness, dysuria, bloating, or rectal discomfort. It is also important to be aware that motor spasticity and other nonsensory aspects including psychosocial elements may contribute to ongoing pain.

Treatment

A variety of drugs have been evaluated for efficacy with some promise being shown with the use of TCAs, SSRIs, gabapentin, pregabalin and potentially some of the newer antiepileptic drugs such as lamotrigine. Intravenous lidocaine is arguably the most effective single agent for central pain syndromes but practical considerations for administration limit its use. Mexiletine, lidocaine’s oral analogue, has not been found to be effective.

Topical agents have shown inconsistent results in trials. In the intractable case, the use of deep brain stimulation may have a role, although the evidence for this in trauma is merely extrapolated from stroke patients.¹³⁸

Epidemiology

Existing data on population-based incidence rates varies dramatically between 5.5 and 26.2 per 100,000 person years. The difference likely results from variations in case definition and methodology and highlights the need for uniform nomenclature and diagnostic criteria. Certain demographic characteristics appear common. Women are affected at an approximate ratio of 3.5 to 1 compared with men, and most cases are in groups over age 40. Data also show a predominance in Caucasian and Japanese populations.¹⁴¹

Etiology

Reports of CRPS occur after a wide subset of events including common injuries, cardiovascular events, malignancies, infections, and medication administration. Spontaneous onset is rare but has been reported. Fractures—upper extremity more so than lower—are the commonest precipitating events and classically involve the wrist. Severity of injury is unrelated to the risk of developing CRPS. There have been studies that make a correlation to intra-articular fractures and complaints of tightness and pressure during casting as positive predictive factors. However, fracture repositioning and the use of external fixation have not been associated.¹⁴¹

Mechanisms

Several different forms of pain are distinguished in CRPS including neuropathic, inflammatory, nociceptive, and functional. Classically CRPS has been regarded as a CNS disorder with the major pathogenesis being the dysregulation of sympathetic function. Recently, however, the contribution of peripheral mechanisms including inflammation and hypoxia has been better appreciated. Alterations have been found in small nerve fibers innervating blood vessels and the integument, as well as aberrations in vascular and muscular tissue and other deep somatic tissues thought to arise as a result of damage by initial inflammation.¹³⁹

The exact mechanism remains unclear but several possibilities have been entertained. Hypoxia triggers inflammatory responses and nociceptive input may lead to sensitization and alteration in cortical organization of sensory and motor units. Dorsal horn neuropeptides may facilitate sensitization by binding to NMDA receptors, whereas adrenergic receptors may have their sensitivity and expression altered through the effect of inflammation on nociceptive fibers. Sympathetic dysfunction may result from central sympathetic hyperactivity or hypersensitivity of peripheral adrenergic receptors. Sympathetic dysfunction may also cause hypoxia by impairing nutritive blood flow. Cytokine alterations affect the nitric oxide and endothelin balance and severe pain impairs movement, possibly resulting in inflammatory mediators and free radicals accumulating, thus preventing desensitization. Severe chronic pain causes psychological distress, which in turn influences sympathetic outflow and circulating catecholamine levels. While many of these concepts are hypotheses, their existence points to the likely multifactorial nature of this disease and the circular interaction between many of the factors involved.¹⁴¹

Diagnosis

Evaluation and diagnosis of CRPS is typically clinical, without a gold standard for confirmation. Three-phase bone scintigraphy may provide important information for the common osseous changes. Pathologic uptake in metacarpal and metacarpophalangeal bones has been proposed as a sensitive and specific marker. The best timing is in the subacute phase (i.e., under 1 year). Plain x-rays, bone densitometry, and MRI may be abnormal but are not sensitive or specific for this condition. Similarly, autonomic testing may reveal abnormal sweating patterns in the affected limbs, but this too is nonspecific.¹⁴²

Treatment

Pharmacologic and interventional options exist. It is important to note that traditional pain therapies appear to offer little benefit. A clearer understanding of mechanisms will permit more effective approaches to the care of these patients and therapies targeted to sensory-motor integration appear promising.¹⁴⁰

Clinical Features

Typical clinical features are local pain, decreased range of motion, erythema, edema, fever, and possible compressive phenomena (vascular or neurologic), which can mimic other pathologies such as DVT, cellulitis, osteomyelitis, and CRPS.

The hip is the commonest location, followed by the knee and elbow with 30% of patients having two joints affected. In the most severe forms, complete ankylosis of the joint occurs with massive bone formation.¹⁴³

Pathogenesis

Debate exists as to the exact mechanism of heterotopic bone formation, but four factors appear necessary. First, an inciting event; second, an inflammatory stimulus that arises from the site of injury (likely in the form of cytokine activity); third, the arrival of mesenchymal progenitor cells; and fourth, the differentiation of these cells into osteoblasts and chondroblasts. TBI results in accelerated fracture healing and reduced collagen degradation, which may also predispose to abnormal bone formation. Acute TBI patients are often hyperventilated to reduce ICP with resulting respiratory alkalosis.¹⁴⁴ The alkaline pH may promote calcium precipitation, which is an essential component of the bony matrix.

Investigations

The current gold standard is a triple-phase bone scan with the first and second phases becoming positive within 3 weeks after injury and the third phase 1 to 4 weeks later. CT scans and plain radiographs will show maturing bone and elevated serum alkaline phosphatase levels may be measured, but their utility is debated because of a poor correlation between levels and clinical syndrome. Calcium and phosphate are usually normal in the serum.¹⁴³

Treatment

The role of physical therapy in patients with HO is controversial. Prior studies have found that patients are at a higher risk if involved in a passive range-of-motion program while others have refuted this claim. Though this remains an area of debate, it is not uncommon to have plegic or paretic patients in a rehabilitation setting involved in regular stretching and passive ranging therapies.

Etidronate is considered a common first-line therapy for the management of HO and has been repeatedly shown to halt or slow the progression of disease in the SCI population. In the TBI population, there has been one prospective controlled trial that found a lower incidence of HO in the treatment versus control group.¹⁴⁵

The prophylactic use of NSAIDs, particularly indomethacin; COX2 inhibitors; and ibuprofen have been studied in patients with SCI and hip arthroplasty and have provided evidence that the early use of anti-inflammatory agents reduces the likelihood of developing HO by up to a magnitude of three.^145–147 These findings have not yet been translated in the TBI population.

Surgery is typically reserved for patients with significant skin breakdown, pain, or marked loss of function and is usually not considered until 18 months after development of HO to ensure full maturation of the newly formed bone. Based on several studies, however, there is only limited evidence that excision improves clinical outcomes in the TBI population.¹⁴⁵

The Future of Rehabilitation

A vast opportunity exists in understanding the mechanisms of neurorecovery after TBI and manipulating the end point of recovery. Exciting venues for future care include tailoring of therapeutic options by injury specificity, gender, and genotype. Enhancing training parameters by understanding the role of training intensity and interference in learning new skills will play a large role in the acquisition of motor skills. It is likely that either stimulation techniques (based on electrical or magnetic stimulation) or pharmacologic interventions will combine with training techniques to enhance recovery.

Critical to the future of rehabilitation is the development of biomarkers that can link interventions to the recovery process and allow for more refined titration of therapeutic plans.