Myrna E. Watanabe, PhD

It's now months after Hurricane Katrina hit Louisiana. That storm drove hundreds of thousands of people from their homes. Many lost everything, including their work, family heirlooms, beloved pets, and the unaccounted clutter of the history of their lives. Some lost family members as well. By now, many of them should be adjusting to their new homes and new communities. For others, the pain continues and is intense. Some of these people, as well as those hurt by hurricanes Rita and Wilma, will be diagnosed with post-traumatic stress disorder (PTSD). PTSD experts have some recommendations for neurologists and primary care physicians.

PTSD is one of the most serious and longest-lasting of the human responses to trauma. It is diagnosed in individuals who manifest a particular spectrum of behavioral and emotional responses a month or more after experiencing a traumatic event. If PTSD lasts for less than 3 months, it is classified as acute; if it lasts longer than 3 months, it is classified as chronic. If symptoms develop 6 months or more after the traumatic event, the diagnosis is classified as delayed-onset PTSD.

According to psychiatrist and pharmacologist Matthew Friedman, MD, PhD, executive director of the National Center for PTSD at the US Department of Veterans Affairs (VA), at the White River Junction VA Medical Center in New Hampshire, "most people with PTSD will seek primary care rather than mental health care." Thus, a primary care physician--or possibly a neurologist--is likely to be the point of first contact for the patient suffering from this constellation of mental and physical problems. Friedman added, "People with PTSD are much more likely to be high users of medical services than those without."

 Ronald Glaser and Janice K. Kiecolt-Glaser of the Institute for Behavioral Medical Research and the Comprehensive Cancer Center of Ohio State University in Columbus noted that stressors affect the hypothalamic-pituitary-adrenal axis, leading to release of glucocorticoid hormones from the adrenal gland. At the same time, the sympathetic-adrenal-medullary axis is stimulated, releasing epinephrine and norepinephrine. Both the hormones and the nervous system connections have direct and indirect effects on immune cells, which, through cytokines, have additional effects on the hypothalamus and pituitary gland. Thus, stress leads to more stress and to immune system dysregulation. This, in part, may help explain the physical manifestations seen in patients with PTSD.

Psychologist Edna Foa, PhD, a professor at the University of Pennsylvania Department of Psychiatry, defined a traumatic experience: "A traumatic event usually is defined as an event either the person had experienced themselves or had witnessed another person experience. Either he or she or the witness is injured, or dying, or died, or in danger of dying." The person who is experiencing the event is "horrified, terrified, or feeling helpless," she noted.

"The perception of death or danger to one's life is a very important one," Foa said. Among the types of events that may trigger PTSD are shootings, witnessing torture or being tortured, being in a traffic accident, being in a war, being raped, or suffering because of a natural or man-made disaster. Thus, witnessing the devastation of Hurricane Katrina or being near ground zero on September 11, 2001, are the kinds of mass events that can trigger PTSD.

In the normal course of life, people who have been exposed to a traumatic event heal naturally. "Most people are resilient; most people will recover on their own," explained Friedman. "Most people will never progress to full PTSD."

He noted that the classic book on a post-traumatic reaction is the Civil War novel 

. This book illustrates, Friedman explained, "an acute post-traumatic reaction . . . , an immediate, intense stress reaction." Recovery from such a reaction occurs in 3 to 4 days. In cases in which a person has been terrified or has witnessed or suffered through a terrifying event, a physician will "want to assume normal recovery," said Friedman. "A significant minority may not recover and may develop acute stress disorder and may go on to PTSD," said Friedman.

Foa and her colleagues reviewed studies on whether immediate psychological debriefing after a traumatic event prevents subsequent PTSD.

 Unfortunately, many of these studies are flawed, and the jury is out on whether such immediate intervention is helpful, ineffective, or even results in more cases of PTSD.

Both Friedman and Foa recommend that primary care physicians screen their patients for PTSD, something they both say is done too infrequently in primary care practices. Such a screening device may identify patients who suffer from the disorder, but who, because of fear of stigma about suffering from a mental health problem, may otherwise be reluctant to seek treatment. Friedman noted that this is especially a problem in the military, because soldiers may believe that admitting to a mental health problem may negatively affect promotion to higher rank.

Foa also recommends that neurologists screen patients who are potentially affected by these latest disasters. "It can be completed in about 10 to 15 minutes in the waiting room," she said.

Friedman formulated a series of 4 questions for patients (Table). If the patient answers yes to any 3 of the 4 questions, he or she is probably suffering from PTSD. Foa, who is on the committee that defined PTSD in the 

Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition

, has developed a more complex screening tool. "It's the only questionnaire that also asks whether you have been traumatized and when did it happen, what is the trauma, what is the trauma that disturbs you the most, what kind of symptoms do you have, and does it interfere with your functioning," she said.

"The symptoms are divided into 3 clusters," Foa explained. "The first one is called the 'reexperiencing' cluster, and that includes recollection of the event." These recollections include nightmares, flashbacks, and emotional reactivity when the person is reminded of the event. The second cluster of symptoms includes avoidance of anything that is likely to remind the person of the trauma, such as attempting to push the event away, avoidance of thinking about the event, or avoiding anything that could be a reminder of the event or that is similar to the event.

An important group of symptoms, said Foa, are the "emotional numbing symptoms." These include detachment from others; loss of interest in once-favored activities; inability to experience the range of emotions one once had; and a feeling of emotional alienation, especially from spouses or children. The final group of symptoms is classified as hyperarousal symptoms: sleep disturbance, hypervigilance, startle responses, exaggerated startle responses, irritability, and outbursts of anger.

Once a patient--such as one who has come through the Hurricane Katrina disaster--has been identified as having experienced a trauma, the next question is what to do about it. Foa used a Katrina victim as an example because more than a month has elapsed since the disaster.

"If a person has very severe symptoms, [he or she] should be treated," she said. "If [patients] have moderate symptoms or mild symptoms, they're likely to improve with time." Those in the latter group, she noted, should be educated so that they will understand that such symptoms "are normal after a traumatic event; they should go away."

For a diagnosis of PTSD, explained Foa, a patient must have at least 1 reexperiencing symptom, 3 avoidance symptoms, and 2 arousal symptoms, along with severe distress, impairment, and dysfunction. Friedman said that a positive response to any 3 of the questions on his screen (Table) means that the patient "ought to receive a more careful assessment because [of] the likelihood [of] PTSD." He said that the VA is now using this 4-question screen annually for all primary care patients.

A patient with these symptoms should be treated with either medication or cognitive-behavioral therapy, according to Foa. She also noted that it's important for therapists to have experience in treating PTSD.  Furthermore, it is particularly important to treat patients with PTSD who have experienced the trauma a year or more before presenting for care. Spontaneous recovery after a year is unlikely, she explained.

Joyce Herling, MSW, LCSW, whose psychotherapy practice is in Bronxville and Patterson, NY, receives patient referrals for PTSD treatment from psychiatrists, internists, and neurologists, but the bulk of her referrals come through patient calls to health insurance companies. Insurers, she explained, have social workers and nurses. "If the person calls up [the insurance company] and talks about it, [the screener] would say, 'It sounds to me like you have post-traumatic stress disorder. Here are some professionals in the area,'" said Herling, who once served as an insurance company mental health screener.

Herling uses cognitive-behavioral therapy and sometimes biofeedback to treat these patients. Cognitive-behavioral therapy confronts how the patient is feeling and deals with mechanisms to change these feelings. Techniques may include relaxation exercises or biofeedback.

In biofeedback, the patient is hooked up to a computer that measures breathing and heart rate and teaches the patient methods--the results of which he or she can see on-screen--that will decrease the level of anxiety. Herling said that some of the more advanced biofeedback methods use computer games.

The therapist needs to tailor the treatment to the patient. "Everybody's different," said Herling. "It depends on the person, and it depends on the trauma as well." But, she noted, PTSD does not go on forever in someone receiving treatment. "There's definitely an end point. The dreams get less; they're able to function better; the thoughts aren't as intrusive."

Friedman noted that because so many people who experience PTSD or depression are heavy users of medical care, some medical practices have incorporated primary behavioral health treatment, which tends to yield better results for patients than does treatment at distant mental health centers. Foa said that specialized treatment for trauma is usually available at major medical institutions.

Friedman pointed out, however, that the realities of primary care practice might mean that the primary care physician will treat the patient. He recommended that a patient be given a trial of selective serotonin reuptake inhibitors. If medication is not effective, the patient should be referred to a mental health practitioner.

Foa noted that patients might relapse after medication is discontinued, but relapses do not occur after cognitive behavioral therapy.

 Herling, who works in the mental health practitioner-dense New York City suburban area, said that drugs are a last resort and should be used only when other treatment modalities fail.

PTSD doesn't develop in everyone who suffers a trauma or witnesses a traumatic event. Some of the latest research on the disorder focuses on identifying high-risk populations. A team of researchers led by Rachel Yehuda, PhD, professor of psychiatry and director of the Traumatic Stress Studies Division at Mount Sinai School of Medicine and Bronx VA Medical Center in New York, noted that the immediate response to the stressor--such as panic--may predict later development of PTSD.

 It's possible that other characteristics, such as lower intelligence, prior trauma, prior psychiatric disorders, lack of a support network, low socioeconomic status, and abnormal physiologic responses, may result in PTSD.

Friedman said that current research is focusing on the social, genetic, and neurohormonal markers that may confer resilience to trauma in some people. He said that researchers are studying several genes to determine the biologic mechanism of resilience. Noted Friedman, "If you understand resilience, you can start talking about prevention; you can start talking about prophylaxis."	*

• Foa's Posttraumatic Stress Diagnostic Scales (PDS) is available through Pearson Assessments (www.pearsonassessments.com).

• Joint Veterans Affairs/Department of Defense practice guidelines on PTSD are on the Internet at www.oqp.med.va.gov/cpg/PTSD/PTSD_Base.htm.

• The National Center for PTSD's Web site (www.ncptsd.va.gov) contains huge amounts of information about the epidemiology, diagnosis, and treatment of the disorder, and information about specific, current disasters that may cause psychological effects in victims.

1. Glaser R, Kiecolt-Glaser JK. Stress-induced immune dysfunction: implications for health. 

2. Foa EB, Cahill SP, Boscarino JA, et al. Social, psychological, and psychiatric interventions following terrorist attacks: recommendations for practice and research. 

3. Yehuda R, Bryant R, Marmar C, Zohar J. Pathological responses to terrorism. 

Articles

Post-Katrina Medicine: Be Aware of Symptoms of Traumatic Stress

Recent developments and recommendations could mean that better treatment and improvements in procedures are on the way for people who arrive in emergency rooms (ERs) in the midst of a stroke. Under the new Medicare prescription drug plan, hospitals soon will be getting higher reimbursements for emergency stroke treatments. Boston Scientific Corp. has received FDA approval to market a stent that doctors can use to open up clogged arteries. The journal 

 has published recommendations to use simple standardized forms to ensure that more patients get the best treatment possible.

Each year, 700,000 to 800,000 people in the United States will suffer a stroke. Some will not reach the hospital in time to receive treatment to prevent serious brain damage. Others will get there in time but will not be treated with the best drugs for the condition or follow a specific stroke treatment protocol. Some will suffer from small cortical strokes, but they may not be treated effectively to prevent future, more extensive strokes.

But some of this may be about to change. Tissue plasminogen activator (tPA), Genentech's clot-buster drug, has been on the market since 1996. A biotechnology-produced thrombolytic agent, which breaks down blood clots that cause ischemic stroke--stroke resulting from a clot released into the brain's blood vessels or from narrowing of the vessels by plaque deposits--tPA is not used all that frequently to prevent further damage. There are several reasons: the drug is expensive; in the hands of a physician inexperienced with its use, the drug can be dangerous; and in some cases, the hospital may lack a protocol for stroke treatment.

Part of the issue has been that Medicare reimbursed hospitals only $4000 to $6000 for care of stroke patients. The drug alone costs about $2000 per dose. But starting in October, the Centers for Medicare & Medicaid Services (CMS) will reimburse hospitals $11,578 for treatment of ischemic stroke with a thrombolytic agent, according to the final rule published August 12 in the 

 This figure should encourage use of tPA, because it allows the hospital some profit for treating patients with this drug and, according to critical care neurologist Colin McDonald, MD, director of stroke at South Shore Hospital in Weymouth, MA, the payment is "substantially more than tPA costs and substantially more, we believe, than it will cost the hospital for that patient's hospital stay."

Because tPA, by breaking down clots, may cause bleeding into the brain, physicians administer it infrequently in stroke patients: reportedly, it is used in only 10% of all patients who would be eligible for it, and in only 2% of all stroke patients.

 McDonald noted the risk: "Even in the best of circumstances, 6 out of 100 patients . . . will take a stroke that was due to a lack of oxygen and change it into a bleeding event." Hemorrhagic strokes, which make up the minority of all strokes, result from bleeding of a ruptured blood vessel directly into brain tissue.

McDonald has been using tPA in his patients since 1995. "At my hospital, we deliver tPA on a near-weekly basis and consider its use on a near-daily basis," he said. But, he explained, in other hospitals, "in many situations, the medicine is not even considered." Even if it were considered, "these hospitals realize they don't have the technology or staffing to deliver the medicine safely," because the patients need to be carefully monitored for side effects or serious complications from the drug.

A Genentech spokeswoman said that the company will be monitoring the use of tPA to see whether the new reimbursement scheme will increase the drug's use. But, she added, certain steps must be in place for monitoring patients who receive tPA for side effects. "What we believe is that the hospitals need to create the structure and the systems so those stroke patients that would benefit the most from tPA would receive it," she explained.

The group of clinicians and researchers who published the report in the August issue of 

 on quality-of-care indicators in treating stroke patients

 surveyed 7 hospitals over 2 years to determine percentages of patients who received any of 6 interventions: thrombolysis; thrombolysis within 3 hours of symptom onset; antithrombotic medication given within 48 hours of arrival in the hospital; prophylaxis for deep venous thrombosis; smoking cessation counseling if indicated; and prescription of lipid-lowering and antithrombotic medications at discharge from the hospital. In the first year, the hospitals had no standardized orders for treatment of stroke victims and only 44% of the patients received all 6 treatments. In the second year, 6 of the 7 hospitals instituted standardized orders at admission and discharge of stroke patients. That year, 63% of the patients in those hospitals received all 6 treatments.

Although the mitigating factor against use of thrombolytics within the first 3 hours after symptoms appear is that, as the study found, most patients do not arrive in the ER within those first 3 hours, having such orders with a checklist may improve care. "I'm a big believer in protocols and guidelines," stated McDonald. "I was gladdened to see that document in 

." He noted that using standardized guidelines can mean that patients survive the first 24 hours after stroke and are moved into rehabilitation more quickly. "More importantly," said McDonald, "it's going to improve outcome and improve patient safety," because guidelines may deal with such issues as pneumonia prevention and clot prevention while the patient is hospitalized. He noted that when a hospital follows such care guidelines, the patient can feel safe in knowing that the risk of having another stroke will be reduced.

Because most patients don't reach the hospital within the 3-hour window for thrombolytic treatment, researchers are looking at ways of expanding that window. Marc Ribo, MD, PhD, and colleagues from Hospital Vall d'Hebron in Barcelona, Spain, reasoned that new imaging techniques may allow them to screen patients who are beyond the 3-hour window but who may, nevertheless, benefit from tPA administration. Ribo told 

 that the 3-hour window "was set in the CT era. The new, improved imaging technology, such as TCD/MRI [multimodal transcranial Doppler/magnetic resonance imaging] is capable of identifying those patients who may still benefit from tPA after 3 hours from onset and to reject those who wouldn't."

 determined that 77% of the 56 patients they imaged with this method, who were in the 3- to 6-hour time frame after onset of symptoms, were eligible for tPA administration. They compared the responses to tPA of these patients with those of a group of patients who were within the 3-hour post­first symptoms time frame and treated with tPA. The 2 groups' results were similar: same approximate rate of recanalization of the occluded blood vessel 2 hours after drug administration, same approximate rate of hemorrhage, same rate of improvement at discharge, and same approximate rate of worsening. However, 76.2% of patients in the 3- to 6-hour group benefited from the treatment, compared with 58.2% of patients in the 0- to 3-hour group. Approximately the same percentages of patients were independent 3 months after treatment.

Ribo was buoyed by their findings: "Since many patients get to the ER in this time frame [3-6 hours], not using this selection criteria--or similar ones--means not giving potentially beneficial treatment to a large number of stroke patients." But, he warned, "I don't think these criteria should be generalized to every single ER; but in those centers that already have some experience with these treatments, physicians should gradually adopt new imaging techniques to safely extend the therapeutic window." He added that only physicians experienced in use of tPA could consider expanding the time frame of its use.

McDonald, however, would prefer that efforts go to educating the public that if symptoms suggest a stroke, they should get to an ER immediately. He said it is important that "the public understand that there are time-sensitive and time-critical therapies that could be life-changing. I would respectfully put more of our efforts in[to] getting patients into [the] emergency department earlier and earlier than trying to salvage the few later and later," said McDonald, who also is founder and chief medical officer of Brain Saving Technologies, a telemedicine provider in Wellesley Hills, MA.

Which patients should receive tPA treatment is still an ongoing research topic, but some basic criteria include time between symptom onset and arrival in the hospital ER, initial severity of stroke, the patient's age, and the patient's glucose levels. For a review on tPA and other treatment options, see the article "Stroke: While Current Treatment is Limited, New Options Are on the Horizon," by Marc Fisher, MD and Jurgen Bardutzky, MD, in 

In some cases, patients who have suffered ischemic strokes caused by atherosclerotic disease of the cerebral arteries or other arteries feeding the brain may experience future strokes, even when they're treated with anticoagulants. In some cases, such second strokes may affect the basilar artery, which serves the brain stem. The ideal way to prevent restenosis of these vessels would be by balloon angioplasty and stenting, the same procedure that is done to keep blood vessels open in the heart.

However, Kiwon Lee, MD, director of the Neurological ICU at Thomas Jefferson University in Philadelphia, said that although stents are placed in the heart and the carotid artery, "we haven't been brave enough to explore doing the same stenting technique in the brain." The reason for this, explained Lee, is that the "brain vessel [is] a little more fragile; it can rupture and that can be fatal." He noted that for patients who have had a brainstem ministroke, the only treatment--until now--was to "stay on the best therapy, stay on antiplatelet therapy/chronic warfarin therapy, and pray that the stenotic artery does not occlude and cause brain stem stroke." Lee said that about 2 basilar artery occlusions occur in every 1000 cases, and that the rate of mortality from basilar artery thrombosis/stroke is consistently more than 90%.

In early August, Boston Scientific Corp. of Natick, MA, received a Humanitarian Device Exemption approval for its Wingspan Stent System with Gateway PTA (plasma thromboplastin antecedent) Balloon Catheter. Boston Scientific's press release noted that the catheter is indicated for improving cerebral artery lumen diameter in patients with intracranial atherosclerotic disease who are unresponsive to medical therapy. "This is a breakthrough," said Lee. "I think it's a great thing that Wingspan is coming out; we can use a balloon and can also place this stent."

The goal for patients who have suffered initial strokes is to prevent a recurrence. But even with the best knowledge and treatment today, strokes recur in some patients. A group led by co­principal investigators Oscar Benavente, MD, and Robert G. Hart, MD, at the University of Texas Health Science Center at San Antonio, is studying treatments to lower blood pressure and prevent blood clots that can result in ischemic strokes in individuals who've already suffered a small ischemic stroke, called a small subcortical stroke. These strokes, said Benavente, make up about 25% to 30% of all ischemic strokes, and they result from small blood vessel disease.

Small subcortical strokes occur more frequently in African Americans and Hispanic Americans, explained Benavente, and have a high rate of recurrence. Hypertension and diabetes, also prevalent in minority populations, are predisposing factors. Although the initial strokes, which probably affect about 200,000 people a year in the United States, do not tend to be fatal, recurrent strokes "produce cognitive decline or memory problems, eventually vascular dementia," Benavente noted.

The researchers are carrying out a large study, called the Secondary Prevention of Small Subcortical Strokes (SPS3) study, with a total enrollment of 2500 patients, at more than 50 clinical sites in the United States and Canada, plus sites in Latin America and Spain. They are assigning patients to 2 levels of blood pressure control: less than 130 mm Hg systolic or between 130 and 149 mm Hg systolic. The patients are then maintained on either aspirin alone or aspirin and the antiplatelet drug clopidogrel (Plavix, Bristol-Myers Squibb/Sanofi). The goal of the study is to determine whether these regimens will prevent strokes from recurring. The study, based at University of Texas in San Antonio, is funded by the National Institute of Neurological Disorders and Stroke. In early August, about 700 patients had been enrolled.

The study is still enrolling patients at various sites. Physicians interested in enrolling their patients, aged 40 and older, who have had small subcortical MRI- confirmed strokes in the study should contact the group at 210-592-0404. More information is available at www.clinicaltrials.gov/ct/show/NCT00059306? order=38.	*

1. California Acute Stroke Pilot Registry Investigators. The impact of standardized stroke orders on adherence to best practices. 

2.Department of Health and Human Services. Medicare Program; Changes to the Hospital Inpatient Prospective Payment Systems and Fiscal Year 2006 rates; Final Rule. 

 2005:70:47277-47707. Available at: http://a257.g.akamaitech.net/7/257/2422/01jan20051800/edocket.access. gpo.gov/2005/05-154-6.htm. Accessed August 25, 2005.

3. Brown DL, Barsan WG, Lisabeth LD, et al. Survey of emergency physicians about recombinant tissue plasminogen activator for acute ischemic stroke. 

4. Ribo M, Molina CA, Rovira A, et al. Safety and efficacy of intravenous tissue plasminogen activator stroke treatment in the 3- to 6-hour window using multimodal transcranial Doppler/MRI selection protocol. 

stroke, tissue plasminogen activator, tPA, stent, transcranial Doppler, MRI 

A Boost in Hope for Stroke Treatment

The day after the July 7 London bombings, George Zitnay, PhD, an expert on TBI, spent the morning on the phone with callers from London who needed to tap his expertise. Zitnay, founder and president of Virginia NeuroCare Inc, a rehabilitative facility in Charlottesville, VA, and a core member of the Defense and Veterans Brain Injury Center (DVBIC), refers to brain injury as a "silent" public health epidemic.	

In the United States alone, more than 3 million cases of TBI are reported annually, according to Jonathan Silver, MD, Thomas McAllister, MD, and Stuart Yudofsky, MD.

 they note, "Unfortunately, the psychiatric impairments caused by TBI often are unrecognized because of the deficiency of appropriate education in this area for psychiatrists and other mental health professionals. Most clinicians lack experience in treating and evaluating patients with TBI and are, therefore, unaware of the many subtle but disabling symptoms."

As pointed out by Jess Kraus, MPH, PhD, and Lawrence Chu, MPH, PhD, in the textbook's chapter on epidemiology,

 the incidence rates of TBI are, at best, an estimate. Numbers of fatal brain injuries may be miscounted because the diagnosis given on a death certificate may not indicate the specific area of the body that suffered trauma. Numbers of nonfatal brain injuries may be confounded by self-reporting of concussion and by whether a patient was treated in an emergency room or a non-emergency facility.

But even if we use Zitnay's conservative estimate that 1.5 million TBIs occur annually in the United States, we see that the annual incidence of TBI is greater than that of all cancers, estimated by the American Cancer Society to be at 1.37 million in year 2005.

Specific protocols exist for handling a patient in the emergency room who is known or suspected to be suffering from a TBI.

 These patients include anyone who has fallen, especially someone older than 64 years; a person who has been in a motor vehicle accident; someone with a gunshot wound or violence-related injury; or an adolescent or young adult who has a sports-related injury. Men are more likely to suffer TBIs than are women, and the 2 highest risk groups are young people aged 15 to 24 years and the elderly.

Initial neurologic examination of patients older than 4 years includes evaluation using the Glasgow Coma Scale (GCS),

 which assigns points for eye opening, verbal response, and motor response. A score of 13 to 15 indicates a mild TBI, a score of 9 to 12 indicates moderate TBI, and a score of 8 or lower indicates severe TBI.

 In a civilian hospital in the United States, 80% of patients admitted for TBI will have a score in the mild range, while 10% each will have moderate or severe injury.

 The Brain Trauma Foundation guidelines note that 20% of those with the lowest GCS scores (worst injury) will survive, and about half of those patients "will have a functional survival."

Diagnostic imaging is an important modality in determining the location and extent of brain trauma and is helpful in determining possible sequelae.

Studies of TBI have used different parameters for determining the seriousness of the injury. "Just as in other areas of medicine, where we wish we had a bigger evidence base, the gold standard is randomized trials," noted Deborah Warden, MD, of Walter Reed Army Medical Center in Washington, DC. Clinical trials would determine which methods of treatment work best for a particular level of TBI, but there have been few randomized trials on the effects of pharmaceuticals in patients with brain injury.

In fact, by setting up the DVBIC, the US military has taken a lead role in treating and monitoring military personnel who suffer TBIs, and it is creating the database necessary to determine which clinical treatments work best for different levels of injury.

Zitnay points out that even during peacetime, approximately 10,000 head injuries occur each year among members of the US armed forces as a result of vehicular and other accidents, including falls. During times of war, this number increases, and the types of injury change. About 23% to 24% of all the soldiers returning to Walter Reed Army Medical Center, have had a TBI, said Warden, the director of the DVBIC. From January 2003 through early July 2005, the center has seen about 520 soldiers returning from Iraq or Afghanistan who have suffered a TBI, she said. People who are at a high risk for TBI include those who have been injured in a blast, have fallen, have been in a motor vehicle accident, or have sustained a gunshot wound to the neck or the head, said Warden.

The wars in Iraq and Afghanistan differ from previous wars in that a larger percentage of injured soldiers have TBIs. According to a recent article in 

 by Susan Okie, MD, one reason for this is that the improved body armor and Kevlar helmets better protect soldiers, increasing survival rates.

 Thus, the types of body injuries that would have killed soldiers in past wars are not occurring. But one of the weapons of choice for insurgents in this war is the improvised explosive device.

Even if a person near the site of a blast is not hit by shrapnel or large objects that were thrown by the force of the explosion, the change in air pressure from the explosion can damage the brain--a phenomenon that may have affected some of the survivors of the London Underground and double-decker bus bomb blasts.

Regardless of whether fractured bone or foreign objects puncture the brain, a blast or an injury that causes a sharp acceleration in the movement of a person's head can damage the axons.

 Diffuse axonal injury is seen in patients who die as a result of brain injury and in patients who survive several hours after injury.

 In mild to moderate TBI, some of this neuronal damage may occur as much as 72 hours after the injury.

Most brain injuries are mild and, in most mild brain injuries, the patient does not lose consciousness, has transient loss of consciousness, or is unconscious for less than 5 minutes. Indeed, in most cases of mild TBI, the patient loses consciousness for less than 60 minutes.

 However, no consensus definition exists for mild TBI, and the scientific literature is too sparse to conclusively determine its negative effects.

Walter Reed's Warden pointed out that length of loss of consciousness is only one of the criteria that define mild TBI. Physicians also are looking for post- concussive symptoms. Somatic symptoms include:

Warden, who is the military's expert on TBI, explained that the vast majority of patients who have a mild TBI improve over time; however, a subset will decline. Patients at risk for a worse outcome include those older than 40 years and those who have had a previous head injury, said Warden. Patient education is important to recovery. "If you explain to peo- ple what post-concussive symptoms are and that they get better over time, [this] decreases the length of time they will have the symptoms."

According to Constance Mil- ler, MA, managing director and founder of the Brain Injury Resource Center (www.headinjury. com), a patient who is made aware of the secondary psychological consequences of head injury may be able to take steps to avoid them. Thus, the US military has adapted the book 

Traumatic Brain Injury: Rehabilitation for Everyday Adaptive Living

The patient may have behavioral issues. Define what they are first, Warden advised. The physician should understand the severity of the patient's depression, anxiety, or anger. Are these issues of concern to the patient and the patient's family? After a TBI, Warden said, patients who may have been "holding it together" may be sent home from the hospital only to display more depression, anxiety, or irritability than when they were inpatients. She explained that it is important to "evaluate safety in the home. [For example,] does someone want to smack his kids around?" Is there concern among family members that the patient is displaying rage?

Evaluate whether the patient's questionable behavior manifested after the trauma or was a pattern before the trauma occurred. If it was prevalent before the trauma occurred, establish whether the patient received treatment for it and in what form. "You also want to make sure they're not doing things that make it harder for them to maintain control," explained Warden. Patients should have a routine, get a lot of sleep, and avoid caffeinated drinks and alcohol.

Warden advises that when a patient walks into a physician's office and talks about these behaviors, the physician should ask:

Zitnay points out that many people with brain injuries are misdiagnosed. "People think they're basically depressed or they're crazy." That's not the case. Asking the right questions of the patient may elicit responses that will indicate a history of TBI.

A patient experiencing the after effects of TBI should be referred to a specialized center for evaluation, explained Eduardo Lopez, MD, a specialist in TBI and neurorehabilitation, who is medical director in the Department of Physical Medicine and Rehabilitation at Jamai- ca Hospital Medical Center in Queens, NY. The hospital is home to the Brady Institute, which is dedicated to the treatment of brain injury.

These patients, said Lopez, require evaluation and screening by a neuropsychologist and may require psychometric testing to determine whether they have deficits in functioning at higher levels. He noted that it is not always easy to determine whether a patient who has had a TBI has deficits without the use of specialized testing. "Some of these patients [have] socially appropriate [behavior] and they're oriented temporally, and they're very familiar with their biographical information," said Lopez. "It's really at the higher level of executive functioning that there are deficits." A patient with more obvious deficits, such as physiologic functional problems, should be referred to a specialist in physical medicine or a physician specializing in rehabilitation.

A small number of soldiers and civilians are participating in a 24/7 community-based rehabilitation program run by Virginia NeuroCare. Zitnay, who developed the program and runs it, believes that "neurorehabilitation needs to take place in the real world." The live-in program has room for 10 patients at most. "It really takes 6 to 9 months for the brain itself to get out of that depressed state from the initial injury," said Zitnay. "It's important to recognize the subtle signs and symptoms that we see can often dissipate and we don't need to overmedicate.

"All our rehabilitation is to get the person to function in the community," said Zitnay. "So often in neurorehabilitation, when you have executive problems, other forms of frontal lobe injury, it's hard enough to learn." According to him, it is important for patients to relearn how to interact in social environments. That is, for a patient to go to a bank and reaccustom himself to what goes on there. "We'll take people right into the restaurants where they order off the menu; they'll pay the bill. Our program is geared to get people back to the community as quickly as possible."

Sometimes, it is difficult for persons with normal brain function to understand what a person with a TBI is experiencing. For example, said Warden, her patients have related that they wait to go to the cafeteria to eat until just before it closes to avoid crowds. "If they go when it's very crowded, they're bombarded with stimuli. Someone reaches in front of them, they're caught off guard and afraid they'll lash out."

Sometimes, said Zitnay, "they can't do the simplest things." Sally  (name changed to protect the person's identity), a scientist who suffered a TBI when her car was hit head-on by a panel truck, remarked, "I remember having to relearn to stop pouring boiling water into a cup when the cup got full. The first time I made tea, I kept pouring till I burned my hand, then stopped. I am very hypervigilant when I pour because I've over-poured a couple of other times." She also recalls having difficulty with subtraction and having to relearn arithmetic.

The operation of a used-book store is part of Virginia NeuroCare's inpatient program. The store is located in the downtown mall in Charlottesville. "Instead of sitting down working with pegs, working with abstract things that are ridiculous for people," noted Zitnay, comparing the Virginia NeuroCare therapy to standard occupational therapy, "we're working with books." The patients must look at the book title, subject matter, and cover type to decide where it should be shelved. Because the bookstore sells to customers who walk in, along with selling on the Internet, patients who work there have to greet the customers. "It's a fabulous cognitive exercise," said Zitnay. "It's a wonderful social exercise."

Many of the soldiers suffer from post-traumatic stress disorder as a result of their blast injuries. At Virginia NeuroCare, soldiers receive group and individual counseling. They use neurofeedback--on a biofeedback machine--to help them deal with impulses and control. They practice tai chi for motor control and receive hippotherapy (therapeutic horseback riding). The soldiers learn how to control and care for the horses. "All of our clients every day go to a full day of therapy. No one stays in their beds. Everyone is engaged," said Zitnay. Language skills are an important focus, for which notebooks, computers, iPods, and assisted memory devices are used.

"What we have found works the best is getting people involved with other human beings, a sense of purpose, a sense they have something to give," added Zitnay. Inpatients also are required to do volunteer work at places such as  the Society for the Prevention of Cruelty to Animals, the local soup kitchen, or the children's museum.

Thirty-five percent of the head-injured soldiers who complete the Virginia NeuroCare program return to active duty. The rest go home. When they return home, they are given a package of information for the local physician who will be caring for them.

Virginia NeuroCare provides a day program for about 40 civilian patients from the local community. Most have more severe injuries and have lived with their disability longer (10 to 15 years) than the inpatients. The program provides support staff to help with activities of daily living and assists their participation in volunteer work.

Despite the rigorous rehabilitation program, Zitnay laments that "we have reduced mortality, but the morbidity problem still exists. We haven't been able to really break through to make the brain get better."

In the hope of finding the right direction, he is hosting a meeting of experts on brain damage at Memorial Hospital in Johnstown, PA, on October 13-16. "We're going to explore what we need to do next to look at this neuroanatomy," said Zitnay. "How do we get the brain healed?"	*

1. Silver JM, McAllister TW, Yudofsky SC, eds. 

. Washington, DC: American Psychiatric Publishing, Inc; 2005:xix.

2. Kraus JF, Chu LD. Epidemiology. In: Silver JM, McAllister TW, Yudofsky SC, eds. 

. Washington, DC: American Psychiatric Publishing, Inc; 2005:3-26.

. Atlanta: American Cancer Society; 2005.

4. Tolias C, Sgouros S, Dulebohn SC, et al. Initial evaluation and management of CNS injury. Emedicine. Available at: http://www.emedicine.com/ med/topic3216.htm. Accessed July 18, 2005.

5. Brain Trauma Foundation, Inc. Part 1: Guidelines for the management of severe traumatic brain injury. Brief summary. Available at: http:// www.guideline.gov/summary/summary.aspx?doc_id=3794&nbr=3020&string=Coma. Accessed July 18, 2005.

6. Brain Trauma Foundation, Inc. Part 2: Early indicators of prognosis in severe traumatic brain injury. Brief summary. Available at: http://www. guideline.gov/summary/summary.aspx?doc_ id=3122&nbr=2348&string=Coma. Accessed July 18, 2005.

7. Hartl R, Ghajar J. Neurosurgical interventions. In: Silver JM, McAllister TW, Yudofsky SC, eds. 

. Washington, DC: American Psychiatric Publishing, Inc; 2005:51-58.

8. Okie S. Traumatic brain injury in the war zone. 

9. Besenski N. Traumatic injuries: imaging of head injuries. 

10. Gennarelli RA, Graham DI. Neuropathology. In: Silver JM, McAllister TW, Yudofsky SC, eds. 

. Washington, DC: American Psychiatric Publishing, Inc; 2005:27-50.

. East Sussex, UK: Lawrence Erlbaum Associates Ltd; 1995.

he Defense and Veterans Brain Injury Center (DVBIC) is made up of 8 institutions: Walter Reed Army Medical Center in Washington, DC; Wilford Hall USAF Medical Center at Lackland Air Force Base in Texas; the Naval Medical Center in San Diego; Hunter McGuire VA Medical Center in Richmond, VA; James A. Haley VA Hospital in Tampa, FL; the Minneapolis VA Medical Center in Minnesota; the VA Palo Alto Health Care System in California; and Virginia NeuroCare in Charlottesville.

The center serves current and retired military personnel and their dependents and provides evaluation, treatment, and follow-up care for brain injury. The center also assists in managing the long-term effects of the injury and does research on care and treatment.

Active-duty military personnel or their family members or retired military who are being treated for traumatic brain injury (TBI) in private practices are eligible for referral to DVBIC. Furthermore, the DVBIC staff is available for consultation to any physician. Information about the DVBIC is available on its Web site: www.dvbic. org/aboutus.html. The center may be reached by phone at 800-870-9244 or by e-mail at info@dvbic.org.

George Zitnay, PhD, and the staff at Virginia NeuroCare are willing to provide consultative services to any physician anywhere. They may be accessed online at www.vanc.org or by telephone at 434-984-5218.

Constance Miller of Seattle, who suffered a head injury 23 years ago, realized there was a dearth of information on TBI and other neurologic dysfunctions. Her Web site, http://www.headinjury.com, gives a vast array of resources, including lists of rehabilitation hospitals, information on types of brain injuries, a question-and- answer forum for people who want online advice, and information for patients and families about how to deal with brain injury and what to expect. She also runs a telephone hotline (206-621-8558). "Brain injury affects every aspect of [the patient's] life," she explained. Her hotline receives calls from all over the world.

he need for radiographic procedures should be assessed in patients who present at an emergency room or physician's office with a reported head injury or high likelihood of a head injury. Loss of consciousness or amnesia may be an important determining factor for ordering a radiograph. In addition, deep scalp lacerations, persistent headache and/or vomiting, a violent mode of injury, or maxillofacial injuries also warrant radiographic evaluation.

 Anyone with a moderate or low rating on the Glasgow Coma Scale should be evaluated with CT. The same holds for patients whose radiographic findings show CNS injury.

 Patients with milder injuries may not need scans

; however, some patients are alert and able to speak coherently when they present to the emergency room, only to suffer deterioration later.

 recommend that a CT scan be obtained immediately after the injury. If the results of the CT scan do not clarify the clinical observations, an MRI scan should be obtained.

A recent report, delivered at the American Institute of Ultrasound in Medicine, found that elevated intracranial pressure, which may result from contusions, lacerations, hematomas, or brain swelling, may be diagnosed in unconscious patients by using ultrasonographic measurement of optic nerve sheath diameter.

 Tolias C, Sgouros S, Dulebohn SC, et al. Initial evaluation and management of CNS injury. Emedicine. Available at: http://www.emedicine.com/med/topic3216.htm. Accessed July 18, 2005.

 Brain Trauma Foundation Inc. Part 2: Early indicators of prognosis in severe traumatic brain injury. Brief summary. Available at: http://www.guideline.gov/summary/summary.aspx?doc_id=3122&nbr=2348&string= Coma. Accessed July 18, 2005.

 Besenski N, Saini R, Selby JB Jr. CT and MRI detect brain damage after trauma. 

 Besenski N. Traumatic injuries: imaging of head injuries. 

Tayal VS, Neulander M, Norton H, Blaivas M. Use of emergency department sonographic measurement of optic nerve sheath diameter to detect CT findings of increased ICP in adult head injury patients. Presented at: the 2005 annual meeting of the American Institute of Ultrasound in Medicine; June 19-22, 2005; Orlando, FL.

traumaticbraininjury,behavioralneurology,generalneurology,neuropsychiatry

Traumatic Brain Injury: A Public Health Epidemic?

www.sci-illinois.org/factsheets/funcelec.htm

www.spinalcord.org/html/factsheets/estimul.php

Until recently, physicians assumed that any recovery from spinal cord injury (SCI) was limited to the first few months to a year after the injury occurred. In children, this window of opportunity for recovery could last about 2 years. Certainly, no one expected any significant recovery in any person with a chronic SCI or other condition that causes SCIs, such as a stroke, blood clots, or arteriovenous malformation affecting the spinal cord.

However, John W. McDonald, MD, PhD, director of the International Center for Spinal Cord Injury (ICSCI) at the Kennedy Krieger Institute in Baltimore, said that this cutoff date for recovery doesn't apply to all patients. McDonald worked with the late Christopher Reeve, who was showing small gains in neuromuscular control years after his injury. For Reeve, McDonald prescribed activity-based therapies that mobilize the body. Such exercises, noted McDonald, can result in some long-term recovery.

On June 14, Kennedy Krieger opened the ICSCI. Although it is touted as a pediatric center, according to McDonald, "The center will serve both children and adults. The big new focus--the first for the country--is that we're providing restorative applications to all ages of children living with paralysis, not just SCI." Although most of the patients he's been treating at Kennedy Krieger suffer from traumatic or nontraumatic SCI, others have leukodystrophies (biochemical defects that may lead to abnormalities in myelinization or in nerve cells), transverse myelitis (inflammation of the spinal cord), Friedreich ataxia (a degenerative disease of the spinal cord), pediatric disorders equivalent to amyotrophic lateral sclerosis, and neurodevelopmental disorders.

McDonald has found that, although many of his patients are almost totally immobilized, his program of exercise stimulates endogenous neural stem cells within the nervous system to begin to repair the damage, leading to neuronal regeneration and acquisition of motor activity that had disappeared because of the injury. Functional electrical stimulation (FES) of muscles and nerves in patients with SCI is not new; the technique has been cited in the medical literature since at least the mid-1980s, and it probably dates back 2 more decades. However, bringing patients into a coordinated, wide-ranging program that uses various pieces of equipment, along with exercises, to stimulate muscle cell regrowth and neuronal repair is relatively new. It was widely publicized by Reeve and his family, although Reeve, according to McDonald, is an "extreme example" of the recovery that occurred in someone who "should never recover."

McDonald also cited the case of a 7-year-old girl who suffered a nervous system injury at birth that resulted in paralysis from the shoulders down. With FES and a regimen of therapy, "now she's walking without braces," said McDonald. FES has such a long history of research that commercially manufactured FES bicycles are available, and some models are small enough for a patient to use in the home.

People with SCIs can only do a limited amount of exercise; the amount depends on the level and completeness of the injury. Immobility leads to skin breakdown and pressure sores, osteoporosis, muscle atrophy, respiratory and cardiovascular problems, urinary tract infections, and many other life-threatening comorbidities (see Spinal Cord Injury: Dealing With More Than Inability to Move, 

 January 2005, pp 32-34). However, explained McDonald, exercises such as riding an FES bicycle can lead to buildup of muscle mass and even repair of damaged neurons. Riding an FES bicycle stimulates the muscles and nerves locally with electrical impulses so that the patients, as McDonald said, can "ride on their bike even though their brains aren't running it."

Even if the muscle or nerve recovery is negligible, McDonald noted that "everyone can benefit" from such an exercise plan because "everyone who is living with immobility or disability doesn't get adequate exercise." Recovery, however, depends on the individual, he said.

The ICSCI offers its services to any patient who can come to the Baltimore site for an initial evaluation, said McDonald. An evaluation may take anywhere from an afternoon to a 2-week stay at the center. The ICSCI physicians will prescribe a home-based rehabilitation regimen and will train family members to assist the patient. They also will educate the patient's home physician, "partnering with their caregivers in their town," stated McDonald. After the patient is sent home, he or she will be monitored by the local physician and will return to Kennedy Krieger for a 6-month follow-up, and once a year thereafter. Most important, stated McDonald, "Many aspects of this are already covered by insurance, or we work to get it covered."

McDonald explained that this type of regimen is "more doable with children." He referred to them as being not as "gravitationally challenged" as adults. He added that they also do not accept that something is impossible. This type of exercise program is not short-term. It will extend throughout the patient's lifetime, but it can greatly decrease health problems related to the SCI.

The Kennedy Krieger Institute is at 707 N. Broadway, Baltimore, MD 21205. Referral numbers are 888-554-2080 or, locally, 443-923-9400; online access is at www.kennedykrieger.org.	*

New Spinal Cord Center Offers More Than Local Services

It almost looks like a younger sibling of the Alzheimer Disease Neuroimaging Initiative (see box, plus Advances in Imaging for Diagnosis of Alzheimer Disease, 

May 2005, page 19) of the NIH. The program, emerging from Sweden's Karolinska Institute, is seeking international research partners to participate in an Alzheimer disease (AD) project that begins this month. The project is part of a larger neurosciences program called Swedish Brain Power, which is an interdisciplinary network for research, diagnosis, and therapeutics.

The entire project, which is run by Bengt Winblad, MD, PhD, a professor in the Department of Clinical Neuroscience and Family Medicine and director of the Alzheimer Center at the Karolinska University Hospital in Huddinge, began with SEK 100 million in funding (approximately USD 14 million), to be apportioned over 5 years and shared among its major programs. The program that most resembles ADNI focuses specifically on familial Alzheimer disease as a model for common forms of AD.

Sweden is in a unique position to carry out such research. Since 1947, all Swedes have been given a permanent personal identity number (PIN) that is associated with all their records. Because medical care in Sweden is under government aegis, medical records are attached to the PIN; thus, complete records are available on every citizen and legal resident. Furthermore, Sweden maintains many health-related registries; a Swedish twin registry is maintained at the Karolinska Institute, which includes data on 80,000 pairs of twins, and a familial dementia registry is maintained at the Karolinska University Hospital's Department of Geriatric Medicine. Furthermore, aside from the fact that various entities maintain health records, the Swedish population is willing to participate in scientific studies, said Harriet Wallberg-Henriksson, MD, PhD, president of the Karolinska Institute.

Samuel Gandy, MD, PhD, head of the Farber Institute for Neurosciences at Thomas Jefferson University in Philadelphia, explained what makes such a study so valuable: "The Nordic countries have the records--complete records going back for hundreds of years--and we don't have that sort of record-keeping in any accessible form in this country."

In fact, according to Caroline Graff, MD, PhD, a researcher at the Karolinska Institute in Huddinge and director of the AD program under Swedish Brain Power, the national familial dementia registry contains medical and genealogic data for more than 300 families. Furthermore, church records dating back to the 1800s may give clues to the cognitive status of forebears of these persons. How? Persons were tested on their knowledge of Christianity, and these notes in the church records may provide clues about whether an individual suffered from a cognitive impairment, explained Graff.

The project's goal is to identify early diagnostic markers that will differentiate between normal cognitive function and dementia so that the plunge into dementia can be prevented. Graff explained that this is a prospective study to aid in determining when a person carrying a gene for AD will become clinically demented. The dementia database at the Karolinska Institute already contains data on 4 families with mutations that are known to be associated with AD. One of these families has a unique mutation called the "Swedish mutation."

A great deal already is known about the Swedish mutation, which "has been used in a large number of experimental systems for AD, such as cell studies, mouse models," commented Graff. But the question to be solved is what diagnosable markers indicate that a person carrying this or another mutation associated with AD is beginning to show signs of Alzheimer dementia. Graff noted that the study will "gather data on biochemical, cognitive and physiological parameters in humans carrying this mutation."

The study will recruit asymptomatic individuals from families that are included in the dementia database and from families that have a history of dementia but are not in the database. The study will include individuals from families with known mutations, along with individuals who have a family history of dementia and were referred to any of 3 clinics: the clinic at Karolinska Hospital, the University Hospital in Malmö, or the Sahlgrenska University Hospital in Gothenburg.

Because the researchers already know the average age at onset of dementia within the families, they expect to be able to recruit asymptomatic participants from these families who are 10 years younger than the families' average age at AD onset. This should give researchers sufficient time to discover the types of subtle biochemical, physiologic, and behavioral changes that mark the onset of AD.

The current plan is to examine these persons every other year and collect a vast amount of data during each examination. Investigators plan to use imaging modalities, including MRI, single photon emission computed tomography , and photon emission tomography. They also will do neuropsychological testing and will take samples of cerebrospinal fluid (CSF), plasma, serum, DNA, RNA, and fibroblasts. They specifically plan to screen for mutations associated with AD in 3 genes: 

Graff noted that CSF samples are rarely taken in screening for AD. Thomas Jefferson University's Gandy explained, "Since there's nothing definitive in spinal fluid at the moment to make the diagnosis, and it's not something people enjoy having [done], spinal taps and lumbar punctures are often not done in this country anymore for evaluating someone for dementia unless there's a specific indication." But, he added, his group had just been invited to join the NIH's ADNI study, and "we had to agree that we would get a certain quota of CSF tests done in order to participate." Graff said that membrane dysfunction could be identified through CSF sample testing.

Because funding for the Karolinska study is being provided for 5 years only, Graff plans to analyze data on persons from families with known mutations years before they are clinically diagnosed with dementia. "We know who are mutation carriers and, thus, we know who inevitably will develop the diseases." Gandy noted that neuroimaging data should make it possible to quantify the volume and size of the person's brain and to follow these changes. "What you don't want is for the brain to shrink," he added. Developing biochemical and physiological markers may predict--and prevent--the disease long before there is irreversible neurologic damage.

The familial AD genetics study portion of the Swedish Brain Power Study is actively seeking international collaborators. "We are a member of the European Alzheimer's Disease Consortium, which meets on a regular basis several times per year, and this is a natural ground for establishing further collaborations," Graff said. They also have begun discussions with the German National Initiative on Dementia and with 2 laboratories in the United States. Researchers interested in participating in the program should contact Graff by e-mail at Caroline.Graff@neurotec.ki.se. *

he Alzheimer's Disease Neuroimaging Initiative (ADNI) was set to begin recruiting this month for its clinical trial (www.alzheimers.org/clintrials/fullrec.asp?PrimaryKey=208) that will study how brain imaging technology can help measure the progression of mild cognitve impairment (MCI) and early Alzheimer disease (AD). A spokesperson for the National Institute on Aging (NIA), the lead agency in the multiple-sponsor initiative, said in late May that the 55 trial sites in the United States and the 5 Canadian sites will each begin recruitment as soon as they receive approvals from their respective institutional review boards.

ADNI's purpose is to test whether the combination of serial MRI scans, positron emission tomography scans, other biological markers, and clinical and neuropsychological assessment can measure the progression of MCI and early AD, according to the October 13, 2004, announcement of the program's establishment. Possible outcomes could be development of new treatments and a method of monitoring their effectiveness, plus shorter time periods and lower costs for future clinical trials. Investigators will seek to recruit a total of about 800 patients, aged 55 to 90, for the trial. They expect to observe 200 cognitively normal persons for 3 years, 400 patients with MCI for 3 years, and 200 patients with early AD for 2 years.

In addition to NIA, federal sponsors include the National Institute of Biomedical Imaging and Bioengineering and the FDA. The Foundation for NIH is managing the corporate and other private participation. The Alzheimer's Disease Education and Referral Center is serving as a central information center and can provide up-to-date information on the status of the trial through its toll-free number, 800-438-4380, or Web site, www.alzheimers.org. Principal investigator for the clinical trial is Michael W. Weiner, MD, director of the Brain Imaging Center at San Francisco Veterans Affairs Medical Center and the University of California at San Francisco.

The Alzheimer's Disease Neuroimaging Initiative (ADNI) was set to begin recruiting this month for its clinical trial (www.alzheimers.org/clintrials/fullrec.asp?PrimaryKey=208) that will study how brain imaging technology can help measure the progression of mild cognitve impairment (MCI) and early Alzheimer disease (AD).

Swedish Brain Power Seeks Partners to Study Genetic Basis of Alzheimer Disease

 Christopher Reeve's death this past October from cardiac complications after infection resulting from pressure ulcers is a reminder that patients with spinal cord injury (SCI) are more than their motility impairments. According to the Annual Statistical Report of the National Spinal Cord Injury Statistical Center (NSCISC), published last June, of 3312 patients for whom the cause of death was known, nearly 22% died of respiratory system diseases, 9% of infective and parasitic diseases, 8% of hypertensive and ischemic heart diseases, and 13% of other heart disease.1  Suzanne Groah, MD, MSPH, director of the National Rehabilitation Hospital's Rehabilitation Research and Training Center on Secondary Conditions After Spinal Cord Injury in Washington, DC, noted that the NSCISC database represents only 12% to 15% of all persons with SCI in the United States; however, she said, "It's the best database we have."  Secondary health problems depend on the level of the spinal cord that sustained the injury and the degree of injury. The patient's age and the time since the injury occurred also have an impact. Among the secondary health effects of the immobility resulting from SCI are pressure sores and their sequelae; respiratory complications; cardiovascular disease; hyperlipidemia; metabolic syndrome; chronic pain; osteoporosis; joint and muscular injury; urinary tract infections; bowel control problems; muscle spasticity; and emotional problems, such as depression, alcoholism, drug abuse, and suicide.2-7  Groah pointed out that as medical care for patients with SCI improves, "people are living to older ages, and we're beginning to see [increasing] chronic diseases." These patients, she explained, show accelerated aging, with diseases of aging appearing in them at younger ages than in the rest of the population. It's possible that the person would never have had any of these diseases without the SCI, but when diseases such as coronary artery disease and diabetes occur, they are more aggressive or may be at a more advanced stage at diagnosis than they usually are in patients without SCI.  Part of the problem in diagnosing secondary diseases is that a quadriplegic person may not perceive chest pain, so he cannot report the signs of cardiovascular disease to his physician. Thus, the patient with SCI must be screened more often than other patients for signs of cardiovascular disease; this screening is usually done by the primary care physician. Alberto Martinez-Arizala, MD, chief of the Spinal Cord Injury Service at the Miami Veterans Administration Hospital, warned that physicians "must be aware that the typical sensory signals . . . in these patients are al- tered." This, he added, means that symptoms of myocardial infarction are different, as are symptoms of a pathologic process in the GI tract. A patient with SCI who also has a serious physical disorder may experience dystonia, sweating spells, or symptoms that are out of the ordinary but are not the same as the kinds of symptoms a physician would see in a patient with an intact spinal cord.2  Furthermore, noted Groah, immobility results in a loss of muscle mass and an increase in fat mass, leading the body to act as if it's obese. This puts the patient at greater risk for metabolic syndrome, which includes insulin resistance and may result in diabetes and heart disease.  EXAMINATIONS MORE COMPLICATED  Groah explained that a standard physical examination is more difficult to carry out on a patient who is immobile. "Checking someone's weight doesn't get done with the same frequency." This is because physicians don't usually have scales that can handle wheelchairbound patients. "Colonoscopies don't get done; mammograms don't get done like they should; Pap smears don't get done like they should," she continued.  One of the most prevalent complications--in some studies, reported to affect nearly 40% of patients with SCI--is pressure sores.2,3 These sores, according to newspaper reports, led to septicemia that eventually claimed Reeve's life. But according to Jung Ahn, MD, clinical professor at New York University's Rusk Rehabilitation Institute, pressure sores usually are preventable. He explained that there are 2 theories on how these sores develop. One is that the skin, especially over the bony prominences, is irritated by the patient's lying on a mattress or sitting all day in one position in a wheelchair. According to this theory, pressure sores begin superficially and, without proper care, go deeper, eventually affecting the underlying muscle and even the bone. The second theory is that the bone is pressing the muscle into the skin and ischemic changes in the muscle start the process, with the sore beginning internally and then spreading superficially.  No matter how they begin, Ahn said, "Pressure sores in spinal cord injury are, as far as I'm concerned, preventable." The way to prevent the sores is to train patients and their families to inspect the patient's skin each morning after hours of bed rest and again in the evening, after the patient has spent the day sitting in a wheelchair. If a sore begins to develop, especially if it is caused by the wheelchair, Ahn may put a patient on bed rest until the sore is completely healed. But to prevent sores, paraplegic patients are told to do sit-ups or weight shifts in the wheelchair. Ahn stated that paraplegic persons could do sit-ups every half hour and lift their buttocks off the seat every half hour. Quadriplegic patients can learn how to shift their weight, leaning to one side of the chair to eliminate pressure.  Good nutrition is essential in preventing pressure sores: a diet high in protein and vitamin C prevents skin breakdown. Once pressure sores develop, zinc sulfate is added to the patient's diet. It's important that skin remains dry. Fecal or urinary incontinence should be prevented or actively managed. If the patient does have a bowel or urinary accident, he should be cleaned up immediately.  Bladder control is a major problem for patients with SCI.2 Although some patients are able to void urine on their own, others, Groah said, may require an indwelling catheter, such as a Foley or superpubic catheter; still others may use an external condom urine collector. Groah has been studying the relationship of indwelling urinary catheters to bladder cancer. She has found that even adjusting for other risk factors, a patient with SCI who has an indwelling catheter has a 5-fold greater risk of bladder cancer developing than does someone with an intact spinal cord. She explained, "The risk of mortality due to bladder cancer is 3.2/100,000 person-years in the non-SCI population. The age-adjusted mortality due to bladder cancer in those with SCI using indwelling catheters is 52/100,000 person-years." Also, Groah said, patients with SCI will have more aggressive bladder cancer, such as squamous cell carcinoma, than do persons with intact spinal cords, who tend to have transitional cell carcinoma. She continued, "The increased risk of bladder cancer occurs mainly when people are in their 40s--as opposed to after 60 in non-SCI [patients]--although a few cases in people in their early 30s have been reported."  Long-term use of an indwelling catheter seems to predispose patients to kidney and bladder stones and pyelonephritis, she explained. At present, physicians do not know whether the greater risk of bladder cancer is related to the catheter itself or to the increased risk of infection and stone development from having a catheter. Nevertheless, Groah suggested that patients who have had indwelling catheters for 10 years or more should be more aggressively screened for bladder cancer. Martinez-Arizala said that kidney and urinary tract function should be monitored annually.  Groah also explained that pulmonary problems, such as pneumonia, have been one of the major causes of morbidity and mortality in patients with SCI. The higher up the spinal cord the injury is, the greater the risk, and the longer the period of survival after the injury-- especially if someone was injured 10 to 15 years before and is now in his 40s or 50s--the greater the risk of pulmonary conditions. Said Martinez-Arizala, "These patients have impaired cough mechanisms so they don't clear their airways as they should." Monitoring these patients and giving them annual influenza vaccinations and pneumococcal vaccination every 5 years can help.  WIDESPREAD CHRONIC PAIN  Chronic pain is a major problem for about 75% of patients with SCI, said Eva Widerstrm-Noga, DDS, PhD, research assistant professor at the Miami Project to Cure Paralysis.4-7 Paraplegic patients may suffer from nociceptive pain--true pain sensations, often in the back and shoulder, resulting from wheeling around in a wheelchair. Neuropathic pain, often described by the patient as a burning, electric, or stabbing sensation, derives from the areas of the body with absent or impaired sensation. Pain also may be referred to visceral organs. This latter type of pain is especially difficult to treat and to endure, said Widerstrm- Noga. Neuropathic pain may be treated with anticonvulsant or antidepressant medications, she said, but there have been few studies on patient response to these medications. In some patients, pain may be alleviated by massage therapy or relaxation methods, Widerstrm-Noga noted.  Muscle spasticity may occur after the acute stage of the injury.2 "It could be a lifelong problem for that patient," said Martinez-Arizala. But newer drugs and drug delivery methods make it possible to control severe spasticity in some patients.  The lesion itself may change character. Progressive syringomyelia or progressive post-traumatic cavitation of the spinal cord may occur with or without tethered cord syndrome, a condition in which the spinal cord builds up scar tissue that prevents the flow of cerebrospinal fluid through and around the spinal cord. The patient will present with new loss of function and new neurologic symptoms that were not present before, said Martinez-Arizala. This condition may be corrected with surgery.  Patients with SCI also may have sexual dysfunction. 2,8,9 Men may have erectile dysfunction, and they are likely not to be able to ejaculate even if they can maintain an erection.2,8 Women may not be able to reach orgasm.9 There are treatments that allow sexual activity in both men and women with SCI, and with some medical intervention, men can even father children.  The hope, of course, is the one Reeve maintained: that someday there will be a way for damaged spinal tissue to regenerate. A study published in the November 10, 2004, issue of the Journal of Neuroscience showed that mice lacking a molecule that guides axons in the spinal cord during development will regenerate axons and will recover spinal cord function.10 This leaves the tantalizing possibility that by blocking this molecule, damaged human spinal cord tissue can regenerate. But right now, medicine is many years away from such a cure, and patients with SCIs remain at risk for numerous secondary effects of the injury. ?  REFERENCES   1. National Spinal Cord Injury Statistical Center. The 2004 Annual Statistical Report for the Model Spinal Cord Injury Care Systems. Birmingham, Ala: University of Alabama at Birmingham; June 2004. 2. Ahn JH. General considerations of rehabilitation of spinal cord injured patients. In: Errico T, Bauer RD, Waugh T, eds. Spinal Trauma. Philadelphia: JB Lippincott; 1991:627-643. 3. Garber SL, Rintala DH. Pressure ulcers in veterans with spinal cord injury: a retrospective study. J Rehabil Res Dev. 2003;40:433-442. 4. Widerstrm-Noga EG, Felipe-Cuervo E, Broton JG, et al. Perceived difficulty in dealing with consequences of spinal cord injury. Arch Phys Med Rehabil. 1999;80:580-586. 5. Widerstrm-Noga EG, Felipe-Cuervo E, Yezierski RP. Chronic pain after spinal injury: interference with sleep and daily activities. Arch Phys Med Rehabil. 2001;82:1571-1577. 6.Widerstrm-Noga EG, Felipe-Cuervo E, Yezierski RP. Relationships among clinical characteristics of chronic pain after spinal cord injury. Arch Phys Med Rehabil. 2001;82:1191-1197. 7. Widerstrm-Noga EG, Turk DC. Types and effectiveness of treatments used by people with chronic pain associated with spinal cord injuries: influence of pain and psychosocial characteristics. Spinal Cord. 2003;41:600-609. 8. Amador MJ, Lynne CM, Brackett NL. A Guide and Resource Directory to Male Fertility Following Spinal Cord Injury/dysfunction. Miami: Miami Project to Cure Paralysis; 2000. 9. Sipski ML, Alexander CJ, Rosen R. Sexual arousal and orgasm in women: effects of spinal cord injury. Ann Neurol. 2001;49:35-44. 10. Goldshmit Y, Galea MP, Wise G, et al. Axonal regeneration and lack of astrocytic gliosis in EphA4-deficient mice. J Neurosci. 2004;24:10064-10073. 

Christopher Reeve’s death this past October from cardiac complications after infection resulting from pressure ulcers is a reminder that patients with spinal cord injury (SCI) are more than their motility impairments. According to the Annual Statistical Report of the National Spinal Cord Injury Statistical Center (NSCISC), published last June, of 3312 patients for whom the cause of death was known, nearly 22% died of respiratory system diseases, 9% of infective and parasitic diseases, 8% of hypertensive and ischemic heart diseases, and 13% of other heart disease.

Author | Myrna E. Watanabe, PhD

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