Archives of Physical Medicine and Rehabilitation
Volume 89, Issue 3, Supplement 1 , Pages S27-S31, March 2008

Congenital and Acquired Brain Injury. 5. Emerging Concepts in Prognostication, Evaluation, and Treatment

  • Sunil Kothari, MD

      Affiliations

    • Institute for Rehabilitation and Research, Houston, TX
    • Corresponding Author InformationCorrespondence to Sunil Kothari, MD, The Institute for Rehabilitation and Research, 1333 Moursund Ave, Houston, TX 77030
    • ,
  • Steven R. Flanagan, MD

      Affiliations

    • Mount Sinai Hospital, New York, NY
    • ,
  • Christina Kwasnica, MD

      Affiliations

    • Barrow Neurologic Institute, Phoenix, AZ
    • ,
  • Allen W. Brown, MD

      Affiliations

    • Department of Physical Medicine and Rehabilitation, Mayo Clinic, Rochester, MN
    • ,
  • Elie P. Elovic, MD

      Affiliations

    • Kessler Medical Rehabilitation Research and Education Center, West Orange, NJ.

Article Outline

Abstract 

Kothari S, Flanagan SR, Kwasnica C, Brown AW, Elovic EP. Congenital and acquired brain injury. 5. Emerging concepts in prognostication, evaluation, and treatment.

This self-directed learning module describes recent developments in the field of traumatic brain injury (TBI) rehabilitation. In particular, it focuses on the implications of recent technological advances for evaluation, prognostication, and treatment. It is part of the chapter on TBI medicine in the Self-Directed Physiatric Education Program for practitioners and trainees in physical medicine and rehabilitation. This article specifically focuses on neuroplasticity and its implications for rehabilitation interventions, the role of innovative neuroimaging modalities, improvements in our ability to prognosticate made possible by newer technologies, technologically based enhancement of motor rehabilitation, and the role of alternative and complementary medicine in TBI rehabilitation.

Overall Article Objective

To describe recent advances in our ability to evaluate, prognosticate, and treat traumatic brain injury.

Key Words: Brain injuries, Complementary medicine, Neuronal plasticity, Outcome assessment (health care), Projections and predictions, Rehabilitation

 

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5.1 Educational Activity: To discuss the neurobiologic concepts that may support late recovery for a 24-year-old patient who is 2 years postinjury, has decreased balance, and is enrolled in a program to improve motor function 

INJURY TO THE BRAIN AS A result of head trauma is caused by a combination of forces often randomly acting on the skull and its contents. Injury-related alteration of metabolic, regulatory, and synthetic cellular processes as well as changes in neurochemical and functional brain systems happen in predictable and unpredictable ways in areas adjacent to and remote from the injury site.1 These widespread effects activate multiple processes that influence recovery in the acute and chronic phases after injury. Although some cellular and neurochemical responses, such as the excitotoxic effects of brain injury, have been well characterized, the basic mechanisms of repair and behavioral recovery after traumatic brain injury (TBI) are yet to be fully characterized.1 There currently exists no generally accepted pharmacologic treatment that limits damage or promotes recovery after injury.

Diffuse axonal injury is an injury mechanism unique to brain trauma. Injuries of this kind range from local changes in axolemmal permeability and transport to Wallerian degeneration and deafferentation. This combination of cell loss, axonal damage, and deafferentation can lead to widespread disruption of neural systems and cerebral metabolism, causing neurologic impairment beyond what is evident neuropathologically.1 In this way, diffuse injury can influence the function of brain regions and systems remote from areas of primary injury. Diaschisis, the temporary functional suppression of neural activity in areas surrounding and remotely associated with an injury site, describes these effects that contribute to the initial impairment after injury and can partially account for early recovery as it dissipates.2 In addition to the resolution of diaschisis, some immediate functional restoration may also be caused by the unmasking of previously silent or redundant neural networks that become active with sudden injury, as occurs in phantom sensation phenomena.

The neural systems and cellular mechanisms that determine behavioral changes during recovery after brain lesions in the subacute and chronic phases have been most directly studied in the sensorimotor system, often injured after moderate to severe TBI and commonly after stroke. Motor behaviors are represented as widely distributed overlapping corticospinal neural networks that diverge, connecting to multiple motoneuron pools by horizontal fibers both local and association. The primary sensorimotor cortex and associated systems constantly change in connectivity and cortical representation under normal circumstances in response to experience, with repetition crucial to maintaining these associations. This ability to change permits new motor learning to occur. These processes also support recovery after lesions to the motor system. Nonlesioned motor cortex, under use-dependent stimulation, becomes rededicated during training to support the impaired motor behavior. This reorganization occurs within the sensorimotor system adjacent to the lesion, in associated systems ipsilateral and contralateral to the lesion, and in the contralateral homologous sensorimotor cortex.3 The cellular changes that support these system changes appear related to use-dependent increases in dendritic arborization and spine density as well as changes in synaptic number and type.

Other mechanisms that contribute to recovery after focal and diffuse injury primarily depend on neural vicariation including the ability of noninjured structures, both within an injured system and in associated systems, to be rededicated to restoring function altered by the injury.2 However, this rededication of cortical sensorimotor representations may diminish performance of other behavioral skills and thus be potentially maladaptive. As with focal injury, this rededication process requires repetitive use-dependent activity if it is to develop and be maintained. It is important to consider that many integrated neural systems are dynamic, and their organization at any given time is determined by experience and context. For these reasons, treatment approaches should be based on the evaluation of clinical circumstances that are unique to each patient.

Consistent with the concept of neural vicariation, willful, task-specific, and repetitive motor behavior in the postacute and chronic phases clearly is crucial to the dynamic reorganization of motor systems that support recovery.4 How this behavior is elicited appears irrelevant, although the repetitive motor behavior and treatment outcome should be meaningful to the patient. The essential thing is that the repetitive motor behavior be incorporated into TBI rehabilitation. Abnormal function of the frontal lobes has been linked to alterations in goal-directed behavior regulated by the prefrontal cortex.5 These lobes are frequently injured by brain trauma, which causes cognitive impairment and frontal lobe syndromes.5 Basic research of this kind performed by using concepts in common with use-dependent restoration of sensorimotor impairment will inform the field of cognitive rehabilitation, an intervention shown to be beneficial in the rehabilitation of TBI.

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5.2 Educational Activity: To discuss the utility of advanced imaging techniques in the evaluation of a 24-year-old patient with TBI who is 18 months postinjury 

Advances in neuroimaging techniques have led to a more comprehensive understanding of the brain. The adult human brain is now known to be a dynamic organ with considerable potential to reorganize in response to various stimuli. Recent technologic innovations permit imaging of in vivo biologic processes. These innovations may offer researchers and clinicians considerable opportunity to better understand the pathophysiologic consequences of brain injury, the efficacy of therapeutic interventions, and ways to guide treatment. At the present time, these techniques are primarily used as research tools, are not widely available, and therefore are of limited clinical utility.

Functional magnetic resonance imaging (fMRI) is based on regional blood flow and local metabolic activity. It acts on the differing magnetic properties of oxygenated and deoxygenated hemoglobin. This response is known as the blood oxygen level–dependent difference. As increased localized cerebral activity alters the concentrations of oxygenated and deoxygenated hemoglobin, the locale of that activity shows up as a bright signal on fMRI. The temporal and spatial resolutions of fMRI are better than those obtained by either single-photon emission computed tomography or traditional positron emission tomography (PET) scans, and the lack of radiation permits for multiple imaging. However, several factors impact the interpretation of fMRI data. These factors include a patient’s ability to fully cooperate, medication effects, adequacy of cerebral blood flow, cerebral dominance, and inadvertent subject movement during image acquisition. When interpreting data, it is important to consider the possible reasons for altered activation patterns. Considerations include the establishment of alternative pathways, practice effects, or differences in performance difficulty that exist between injured subjects and normal controls. One must also consider lesion location and size, time from injury, age, and study design (cross-sectional vs longitudinal studies). Also, only simple functional tasks can be performed in the scanner, which limits its utility. Although it is currently used as a research tool, fMRI may in the future be used to guide treatment.

Diffusion tensor imaging takes advantage of the variability of both the speed and direction of water diffusion. Water diffuses faster along an axon, a property known as anisotropy, as opposed to across it, a property known as isotropy. Determining anisotropy values permits investigation of white-matter tract integrity, providing evidence of axonal shear, even in the presence of normal standard magnetic resonance imaging.6 Anisotropy values have been correlated with injury severity and may be useful in predicting outcomes.7

Transcranial magnetic stimulation uses a short magnetic pulse applied over the skull to induce an electric current in the cortex. This instrument may be used as either an imaging technique or possibly a treatment modality. When applied over the primary motor cortex, evoked potentials can be recorded over corresponding muscles. Transcutaneous magnetic stimulation is useful for examining cortical motor representation after cerebral injury. There may be a role for repetitive stimulation in treating major depression,8 although it may induce seizures. Repetitive transcutaneous magnetic stimulation has also been explored as a means to treat various motor disorders and improve cognitive skills, although studies have been small and its efficacy remains uncertain at this time.9 Unlike fMRI and PET, transcutaneous magnetic stimulation is independent of subject performance. Subcortical structures cannot be directly stimulated by this method.

Magnetic resonance spectroscopy (MRS) analyzes the molecular composition of specific cerebral regions. It provides valuable information regarding the diagnosis of several cerebral disorders and may be a potent tool both to predict and to monitor recovery after TBI.10 N-aceytaspartic acid, one of several key cerebral molecules measured by MRS, is present only in neuronal tissue. Low concentrations of this acid are indicative of neuronal loss, even in the presence of normal appearing standard neuroimages. Along with other molecular changes, low concentrations have been correlated to outcomes after TBI.11, 12 Other metabolites of interest measured by MRS include creatinine (energy utilization), choline (cell membrane disruption marker), myoinositol (astrocyte marker), glutamate, and lactate. MRS is useful in differentiating certain cerebral diseases (eg, recurrent neoplasm from radiation-induced necrosis); it also has reported utility in identifying cerebral regions impacted by neurodegenerative diseases13 and may be used to better plan radiotherapy treatments.14

PET images radioactive tracers such as H215O and [F18] fluorodeoxyglucose, which localize to metabolically active regions. The number of images obtained by PET is limited by radiation exposure, which is a disadvantage compared with fMRI and magnetoencephalography (MEG). However, implanted metallic objects and claustrophobia do not prevent image acquisition. PET imaging is more sensitive than standard neuroimaging in detecting abnormalities after TBI, although it has poor specificity.

MEG involves the detection of magnetic fields generated by electric activity in the brain. Unlike encephalographic recordings, an MEG image is not distorted by other tissues, permitting precise localization of its source, and its temporal resolution is measured in fractions of a millisecond. Data derived from MEG may be integrated with other modalities to produce images of cerebral function. These images are useful in the following ways: as a clinical tool when preparing for neurosurgical interventions, in research to better delineate the neuronal circuits involved in various cognitive activities, and as a way to assess the local effects of psychopharmacologic agents.

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5.3 Educational Activity: To educate the staff of the level 1 trauma center about recent technologic developments that might improve our ability to predict outcome after TBI 

Early prognostic indicators such as the initial Glasgow Coma Scale (GCS) or computed tomography imaging provide limited individual prognostic information. More powerful predictors such as the length of posttraumatic amnesia often are not available for weeks to months after an injury. Recent advances in technology, such as MRS, serum biomarkers, genetic markers, and evoked potentials, might provide better predictors of outcome.

MRS provides information about the neurochemical status of the brain. Although not used to construct an anatomic image of the brain, information obtained about the concentrations of certain metabolites may indicate the extent of brain damage and, therefore, expected outcome. Researchers10 have found that MRS studies performed acutely (within 2wk of injury) or subacutely (≈6wk postinjury) correlate with outcome at 6 months or later. More importantly, several studies found threshold values that seem to discriminate between various possible outcomes, for instance by identifying metabolite values above which no subject had less than a good recovery and below which none had a good recovery. Finally, several studies found that MRS data improved the accuracy of predictions made with traditional variables from about 80% to 96%. More detail about these and other studies are provided in a recent review.10

Serum biomarkers are substances found in the brain that are released into the bloodstream after injury. It is hypothesized that the level of these substances would correlate with the degree of injury severity and, thus, with outcome. Advantages of these biomarkers are that they are easy to obtain (through a blood-draw) and are available within the first hour or 2 after injury. Many serum markers, including serum 100b protein, neuron-specific enolase, interleukin 6, cleaved tau protein, and glial fibrillary acidic protein, have been proposed as prognostic factors after TBI. Of these, the most promising work has involved serum 100b protein (S100b), which is released into the bloodstream after damage to glial cells. The protein is released immediately and peaks within a few hours, making early values helpful in prognostication. The potential role of this marker in prognostication after TBI was recently reviewed15; what follows is a brief summary of their conclusions.

Many studies found that early S100b values help predict outcome at 6 months postinjury or later. Most of them reported the sensitivity and specificity of potential threshold values of the marker. They found that these had high specificities (>90%) and moderate sensitivities (≈70%). Many studies also compared the accuracy of predictions based on S100b levels with those based on other variables such as GCS score, imaging abnormalities, and so on. In almost every case, the S100b value was the most powerful predictor of outcome. Finally, although the discussion so far has focused on severe injuries, there is interest in using S100b values to predict which patients are at the highest risk of developing persistent postconcussion symptoms after a mild TBI.

Even when 2 brain injuries seem identical in severity and location, the different genetic constitutions of the individuals could result in very different outcomes. The best studied genetic marker in TBI is apolipoprotein E (APOE). Although earlier studies suggested that possession of the E4 allele (APOE-e4) is associated with a worse outcome after TBI, more recent studies have not replicated these findings. Given these inconsistent findings, it is unlikely that a patient’s APOE status will play a role in prognostication at the present time. Although other genes are identified as potential predictors (eg, interleukin-1), work in this area is at a very preliminary stage.16

Although the role of evoked potentials in prognostication has been studied extensively, recent developments may more clearly define their clinical utility. Evoked potentials represent the passive electrophysiologic response of the brain to sensory stimuli. These waveforms have different components, most often distinguished by their time of onset after the stimulus (latency). The early (short latency) evoked potentials responses, such as the somatosensory, visual, and brainstem auditory responses, are most useful in predicting negative outcomes during the acute stage of TBI, most notably the failure to emerge from a coma.17

Other components of evoked potentials might provide additional information, enabling clinicians to make more comprehensive predictions. Most of the recent work has been done on long latency responses (which occur more than 70ms after stimulation), often known as event-related potentials (ERPs). Unlike evoked potentials, which usually represent a passive response to stimuli, ERPs generally reflect the electrophysiologic state of the brain when it is actively performing a cognitive task. Thus, these waveforms are generally associated with higher-order cortical functions such as stimulus evaluation and subsequent decisions. A recent review18 suggested that these electrophysiologic measures will play a more prominent role in prognostication in the future.

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5.4 Educational Activity: To provide guidance regarding the most effective way to use a donation from a benefactor in order to obtain new technology that will facilitate motor recovery in your patients with TBI 

The potential benefit of providing high-intensity therapy to promote motor recovery has been shown in people with acquired brain injury.19 As financial pressure increases on the field of rehabilitation, it is unlikely that the resources to increase staffing will be available. Technologic advances have the potential to substantially augment services. Advanced technology offers a way to increase therapy intensity without requiring an enormous expenditure on human resources. A review20 discussed the potential utility of technology, including virtual reality, electric neurostimulation, injectable bions as a potential neuroprosthesis, and robotic trainers and evaluators. Another interesting area of promise is low-cost telerehabilitation.21

Telerehabilitation 

Too often the individual with acquired brain injury is not able to attend rehabilitation therapy in person. The reasons are many including medical condition, geographic location, problems with transportation, and so on. For people with acquired brain injury faced with these obstacles, telerehabilitation has the potential, with new haptic (tactile) technology, to facilitate motor recovery. Interactive haptic technology features feedback that uses forces, vibration, and movement accessed through the sense of touch.

Virtual Reality 

Virtual reality devices simulate a real-life scenario, often with the use of computer assistance with or without haptic feedback. They have been used for years to train and test airplane pilots. More recently, rehabilitation facilities have used these devices for driving simulation and for other motor training tasks. Virtual reality is a safe way to test or train a person to meet hazardous situations, such as dangerous scenarios when driving.22 It has also been hypothesized that virtual-reality sessions may facilitate neuroplasticity and promote greater motor recovery.20 The therapy is well accepted by the patient population and has shown generalization beyond the task trained. Finally, when used for motor training, virtual reality therapy has a favorable side-effect profile because patients are spared the simulator sickness reported in other uses of this technology.22

Neuroprosthetics Bions to Promote Improved Ambulation 

Several types of electric stimulation devices applied to the skin to facilitate foot clearance are now on the market. These systems use various modalities to activate and facilitate foot clearance.23 In development are microstimulators that can be implanted proximal to a nerve. Because these devices work with far less stimulation than external stimulators, they offer greater comfort.24 A more physiologic gait with less discomfort than surface stimulation has been reported.23, 24

Robotic Trainers and Evaluators 

The potential of robotics to promote motor recovery in persons with brain injury is just beginning to be explored. These devices have the potential to maximize therapy intensity and to make task practice more convenient.20 Robotic machines can also completely and objectively evaluate the entire limb position during movement in a manner far superior to human observation. Great potential also exists for the use of robotics in partial weight–supported ambulation. Although this treatment approach is efficacious in various populations, it has the tremendous drawback of being extremely therapy labor intensive. The pilot work of Werner et al25 suggests at least equal benefit from using a robotic device as compared with standard partial weight support with far less therapy time required. Finally, Hesse et al26 showed that the use of a robotic arm trainer in the rehabilitation of stroke patients 4 to 8 weeks after stroke was superior to electric stimulation, as measured by improvements in the Fugl-Meyer Assessment scores and muscle strength.

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5.5 Clinical Activity: To advise a family who is spending private funds about the potential risks and benefits of complementary treatments intended to enhance neural recovery in a 22-year-old patient who is minimally conscious 12 months postinjury 

Research into the use of complementary and alternative treatments after TBI is limited. Possible interventions include herbal products, nutritional supplements, homeopathy, and nontraditional interventions. Herbal treatments are aimed at enhancing the same neurotransmitters targeted by traditional medications. Among those studied in a TBI population are substances such as huperizine-A, acetyl-L-carnitine, S-adenosylmethionine, and L-deprenyl. When these supplements were studied in Alzheimer’s disease, improvements were shown in memory, cognition, and behavior. The findings have either been replicated in case studies or they have been extrapolated to this population.27 Scientific evidence is still lacking that naturopathic remedies serve any preferential benefit over traditional treatments. Rehabilitation physicians need to discuss herbal remedies their patients are using in order to help them understand drug-herb interactions and side effects.28

Other substances available commercially and not requiring a physician’s prescription have been suggested in TBI treatment. Recent study into the use of cytidine diphosphate (CDP)-choline (Citicholine) has been done in both animals and humans. In rats treated with CDP-choline after a controlled cortical impact model TBI, neuronal death in the hippocampus, contusion volume, and severity of injury were decreased.29 In a single-blind study of 216 patients with moderate to severe brain injury, those receiving CDP-choline showed improvement in cognitive and motor status and had shorter stays in the intensive care unit.30

The use of homeopathic doses of medications in the treatment of postconcussion symptoms in mild TBI has been studied. Homeopathic remedies use minimal doses of substances that are hypothesized to facilitate the body’s healing processes. One recent study shows promising results, including improvement in patient-reported function and symptoms, with the use of these remedies, warranting further study in this area.31

Hyperbaric oxygen treatment (HBOT) delivers 100% oxygen under pressure, thus increasing the amount of oxygen dissolved in the blood. The treatment sessions take place in a sealed chamber that delivers oxygen at a pressure of 1.5 to 3 atmospheres. Adverse events include seizures, pulmonary injury, and otic trauma. The use of HBOT in the acute and chronic treatment of TBI has been studied in a very limited fashion.32 Recent reviews of the literature by the Agency for Healthcare Research and Quality33 and the Cochrane Database of Systematic Reviews34 found few controlled studies, with none of them rated better than “fair.” In a prospective, randomized trial by Artru et al,35 the use of HBOT acutely after TBI showed no effect on overall mortality at 12 months. The early use of HBOT does have a risk of pulmonary and infectious complications.35 Another study36 of the effects of HBOT acutely after injury showed no difference in the proportion of patients who died or who became severely disabled, even though there was a decrease in number of patients who died. Unfortunately, these results have not been replicated to date. No randomized trial exists in the treatment of patients in the subacute or chronic phase after TBI. Only 3 case reports and 2 case series have been published in chronic brain injury. The official position of the Undersea and Hyperbaric Medical Society37 is that insufficient evidence exists to recommend the use of HBOT in treatment of chronic brain injury, either traumatic or nontraumatic. This expensive and time-intensive treatment is often financed by patients and families. Clinicians must be aware of these positions and the pertinent literature in order to guide patients in decision making.

Biofeedback allows people to modify body processes by providing quantitative measures of that performance. In electroencephalographic biofeedback, or neurofeedback, patients modify the amplitude, frequency, or coherency of their own scalp electrode recordings. Limited controlled studies have shown improvement in subjects’ self-reported symptoms after mild TBI.38 These studies have not been extrapolated to other TBI populations, including those with more severe injuries. In the best designed study to date,39 patients with chronic symptomatic mild TBI showed improvement in multiple domains, both cognitive and symptomatic. The limitations of this study include its small sample size, heterogeneity of sample injury severity, and repeated measures within a short period of time. Although insufficient evidence exists to support the use of encephalographic biofeedback routinely in the rehabilitation of TBI, this therapy warrants further study.

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  • ⁎ Key reference.

 No commercial party having a direct financial interest in the results of the research supporting this article has or will confer a benefit upon the authors or upon any organization with which the authors are associated.

 Reprints are not available from the author.

PII: S0003-9993(07)01862-X

doi:10.1016/j.apmr.2007.12.014

Archives of Physical Medicine and Rehabilitation
Volume 89, Issue 3, Supplement 1 , Pages S27-S31, March 2008

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