OUTLOOK: Hopeful Treatment for Traumatic Brain Injury in Clinical Trial
Just a quarter inch of bone and a layer of fibrous membranes protect our brains from sudden trauma caused by a jolt, blow, or penetrating object. A traumatic brain injury (TBI) results from falls, sports injuries and car accidents, even an act as simple as a child tumbling off a swing. Every day, 4,700 people sustain a TBI in the United States. That’s 3 people per minute and adds up to 1.7 million Americans annually… more than the number diagnosed with breast, lung, prostate, brain, and colon cancer combined. In Europe, brain injuries cause 66,000 deaths and send 1.6 million people to emergency rooms every year.
Since the 1970s over 30 clinical trails for a drug to help persons with TBI have all been unsuccessful in showing a significant benefit and today there still are no effective drugs for treating this epidemic. TBI is an epidemic—the number one killer of young adults and children in the US.
Doctors have tested steroids, hyperbaric oxygen therapy, magnesium, calcium-channel blockers, and other receptor-blocking agents. Yet for the millions affected by TBI, science and medicine have little to offer. From 1980 to 2009, 27 Phase III TBI trial results showed no significant treatment effects.
One major problem for researchers is that brain injuries differ dramatically from patient to patient. Depending on the location, type, intensity, and duration of the injury, rips in the white matter, brain hemorrhage, swelling and bruising can occur immediately. As one insult is superimposed on another, the brain begins to experience reduced blood flow and oxygen deficiency. Within minutes or hours following an injury, small holes rip through neuronal membranes and ion channels get stuck open, leaking proteins and neurotransmitters. Free radicals and calcium spread, causing cell death (apoptosis) and tissue damage. Early gene activation of apoptotic enzymes sends more cells into a death spiral. Mitochondria will sputter, then fall silent. Astrocytes swell. The damage can be isolated or extensive. For these and other possible reasons, testing — even classifying — TBI is a nightmare for the researcher and, of course the clinician. The practical clinical implication is that every patient must be treated individually …from scratch.
As reported in The Scientist, researchers are currently testing a promising new approach to TBI treatment based on progesterone – a female sex hormone – in a phase III trial. This hypothesis began with anecdotal evidence that women recovered from stroke and brain injury better than men. Twenty-two different models of brain injury – in four species – now demonstrate the wide-ranging neuroprotective effects of progesterone. In the lab, this “gender steroid” has been shown to prevent the expression of inflammatory cytokines in the brain, block apoptosis, stimulate growth-promoting factors, and encourage remyelination of neurons.
Studies show that progesterone reduces the accumulation of fluids in the brain after injury. It also reduces secondary neuronal loss, and improves outcomes in rats. After a successful Phase II trial, progesterone is moving to the big ProTECT Phase III trial in humans.
ProTECT III, is a $28 million clinical trial funded by NIH and run through an NIH-supported network of 17 hubs and 31 participating hospitals. It began enrolling 1,140 patients last March. The study plan will begin progesterone treatment within 4 hours of injury. Newly proposed TBI evaluation and test standards – the Common Data Elements – will be used in addition to the conventional Glasgow Outcome Scale (GOS) —in a modified protocol.
Much is riding on the outcome of this trial. The need for more effective diagnosis and treatment Department of Defense, in reaction to the dramatic incidence of TBI in returning veteran — more than 100,000 troops have been diagnosed with mild TBI since 2003, according to the Army Times —TBI is called the signature injury in veterans of the Iraq and Afghanistan wars. More recently, it has become clear that concussion as a result of organized sports – from soccer to football – is responsible for an exploding number of TBI cases. Because so many sports head injuries involve youths, this issue will continue to add to the concern for answers to deal with the epidemic that is TBI.
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Report of the Cognitive Rehabilitation Task Force, Brain Injury – Interdisciplinary Special Interest Group, American Congress of Rehabilitation Medicine
Evidence-Based Cognitive Rehabilitation: Recommendations for Clinical Practice
Keith D. Cicerone, PhD, Cynthia Dahlberg, MA-CCC, Kathleen Kalmar, PhD, Donna M. Langenbahn, PhD, James F. Malec, PhD, Thomas F. Bergquist, PhD, Thomas Felicetti, PhD, Joseph T. Giacino, PhD, J. Preston Harley, PhD, Douglas E. Harrington, PhD, Jean Herzog, PhD, Sally Kneipp, PhD, Linda Laatsch, PhD, Philip A. Morse, PhD
ABSTRACT
IMPAIRMENTS OF COGNITIVE FUNCTION are a significant cause of disability after traumatic brain injury (TBI) and stroke. These cognitive impairments are often the most persistent and prominent sequelae of brain injury in patients with moderate or good neurologic recovery. Interventions designed to promote the recovery of cognitive function and to reduce cognitive disability are a standard component of brain injury rehabilitation: 95% of rehabilitation facilities serving the needs of persons with brain injury provide some form of cognitive rehabilitation, including combinations of individual, group, and community-based therapies. Cognition is defined as the process of knowing. It includes the discrimination between and selection of relevant information, acquisition of information, understanding and retention,
and the expression and application of knowledge in the appropriate situation. Cognitive disability may be seen in reduced efficiency, pace and persistence of functioning, decreased effectiveness in the performance of routine activities of daily living (ADLs); or failure to adapt to novel or problematic situations.
Cognitive rehabilitation is defined as a systematic, functionally oriented service of therapeutic activities that is based on assessment and understanding of the patient’s brain-behavioral deficits. Specific interventions may have various approaches, including (1) reinforcing, strengthening, or reestablishing previously learned patterns of behavior; (2) establishing new patterns of cognitive activity through compensatory cognitive mechanisms for impaired neurologic systems; (3) establishing new patterns of activity through external compensatory mechanisms such as personal orthoses or environmental structuring and support; and (4) enabling persons to adapt to their cognitive disability, even though it may not be possible to directly modify or compensate for cognitive impairments, in order to improve their overall level of functioning and quality of life.
Cognitive rehabilitation may be directed toward many areas of cognition, including (but not necessarily limited to) attention, concentration, perception, memory, comprehension, communication, reasoning, problem solving, judgment, initiation, planning, self-monitoring, and awareness. It can be distinguished from traditional rehabilitation and psychotherapy by its primary focus: alleviation of acquired neurocognitive impairment and disability. Although cognitive rehabilitation may incorporate interventions directed at the person’s emotional and psychosocial functioning when these issues relate directly to the acquired neurocognitive dysfunction, they are not the service’s sole focus. Regardless of the specific approach or area of intervention, cognitive rehabilitation services should be directed at achieving changes that improve each person’s function in areas that are relevant to their everyday lives. Given the prevalence, and relevance, of cognitive rehabilitation services for persons with acquired brain injury, a need
exists to establish empirically based recommendations for the practice of cognitive rehabilitation. Since 1982, this concern has been formally recognized by a subcommittee of the Brain Injury–Interdisciplinary Special Interest Group (BI-ISIG) of the American Congress of Rehabilitation Medicine. The initial recommendations of the committee were published in 1992 as the Guidelines for Cognitive Rehabilitation,2 a document that defined cognitive rehabilitation, set forth the qualifications of independent practitioners, and established minimal practice requirements. The recommendations made at that time were based on “expert opinion” and did not take into account empirical evidence on the effectiveness of cognitive rehabilitation.
Recently, an independent, nonfederal panel presented their findings before a US National Institutes of Health (NIH) consensus panel regarding the scientific basis of common therapeutic interventions for the cognitive and behavioral sequelae of TBI. This panel reviewed the literature for cognitive rehabilitation published from January 1988 through August 1998, including 11 randomized, controlled studies. Their review noted that data on the effectiveness of cognitive rehabilitation programs were limited by the heterogeneity of subjects, interventions, and outcomes studied. Nevertheless, the panel identified several studies, including randomized controlled studies and case reports, that documented the ability of interventions to improve specific neuropsychologic processes—predominantly attention, memory, and executive skills. The panel noted specifically that compensatory devices, such as memory books, improved particular cognitive functions and compensated for specific deficits. It was also noted that comprehensive, interdisciplinary programs that included individually tailored interventions for cognitive deficits were commonly used for persons with TBI. Although this personalized approach made it difficult to evaluate program effectiveness because of the heterogeneity of programs and persons served, several uncontrolled studies and a nonrandomized clinical trial supported the effectiveness of these approaches.
Since 1996, the BI-ISIG has been in the process of developing clinical recommendations for the practice of cognitive rehabilitation, based on an evidence-based review of the existing literature. The recommendations of the Cognitive Rehabilitation Committee, contained in the present report, were based on an exhaustive review and analysis of existing research. We reviewed papers addressing interventions for persons with both TBI and stroke, because they represent the most prevalent forms of acquired brain injury requiring intervention for cognitive impairments. The selected reports consisted of both treatment efficacy studies and studies of clinical effectiveness.
Treatment efficacy studies were defined as highly constrained studies that typically evaluated time-limited interventions of selected, homogenous samples, primarily for research purposes. Studies of clinical effectiveness were defined as empirical evaluations of treatments within clinical settings, which may incorporate clinical judgment and strategic modification of interventions, thus reflecting the actual use of an intervention. The most widely accepted means of evaluating treatment efficacy are randomized controlled trials that compare the intervention in question with a no-treatment control condition. In clinical practice, these conditions may be difficult or impossible to establish. Controlled studies of treatment effectiveness may therefore attempt to determine whether the intervention offers specific benefits, compared with an alternative treatment, although this approach may be less useful for initially establishing the effectiveness of an intervention. Ultimately, the effectiveness of any given treatment should be established by comparing its benefits with the “best available” treatment with known effectiveness. Within a typical clinical setting, the best available treatment may be the combined application of standardized treatment protocols and individualized treatments dictated by clinical experience. At present, the closest approximation to such a model is sound, single-subject research designs or controlled multiple-baseline designs across subjects or interventions. For this reason, these types of studies were considered in making the current recommendations.
To read the full published report, see Archives of Physical Medicine and Rehabilitation 2000;81:1596-615
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