Textbook of Traumatic Brain Injury - part 10 pps

Altern Med Rev 4:438–441, 1999 Arciniegas DB: Traumatic brain injury and cognitive impair- ment: the cholinergic hypothesis.. Cascade of secondary damaging events in experimental traumat

B-vitamin supplement at double the usual adult dose, was

given to 75 patients age 55–85 years with mild dementia in

a 3-month DBRPC trial The placebo group deteriorated

In contrast, the Bio-Strath group showed improvement in

short-term memory with physical and emotional benefits

at 3 months (Pelka and Leuchtgens 1995) The

relation-ship between B vitamins and cognitive function persuades

us to treat brain-injured patients with B vitamins

Homeopathy

A pilot study (at Spaulding Rehabilitation Hospital in

Boston) of 50 patients with mild TBI found that

homeo-pathic treatment significantly reduced the intensity of

patients’ symptoms (P=0.01) and reduced difficulty tioning (P=0.0008) (Chapman et al 1999) Limitations of

func-this study include the small number of patients, the ety of symptoms, duration of treatment, the use of differ-ent combinations of multiple homeopathic preparations

vari-in different patients, and questions about the validity andreliability of the measures used (Chapman 2001) Never-theless, the finding of statistically significant differences

in this PC study is intriguing The investigators edged the need for a larger collaborative MC study to val-idate these findings, but such a study has not been funded

acknowl-as of this date It is not possible to place this study within

T A B L E 3 8 – 3 How to obtain quality alternative compounds

Galantamine/Rhodiola A/P Formula/Ameriden 888-405-3336; http://www.ameriden.com

Huperzine-A GNC (General Nutrition Centers) http://www.gnc.com

Centrophenoxine Lucidril/International Antiaging Systems (IAS) http://www.antiaging-systems.com; Fax:

011-44-870-151-4145 Acetyl- L -carnitine Life Extension Foundation (LEF) 800-544-4440; http://www.lef.org

Citicholine Smart Nutrition (SN); LEF http://www.smart-nutrition.net

S-adenosylmethionine Donnamet/IAS See above

NatureMade (tosylate and butanedisulfonate) http://www.naturemade.com, pharmacies, chain

stores, buyer’s clubs, Costco, BJs

Idebenone SN; Thorne Research 800-932-2953 (Thorne)

Vinpocetine LEF; SN; Intensive Nutrition See above

Rhodiola rosea Rosavin/Ameriden 888-405-3336; http://www.ameriden.com

Energy Kare/Kare-N-Herbs http://www.Kare=N-herbs.com

Rhodiola Force/New Chapter Health food stores or online Ginkgo Ginkgold/Nature’s Way Health food stores, pharmacies

Ginkoba/Pharmaton Ginseng (Panax/

L -Deprenyl Jumex tabs, Cyprenil (liquid)/IAS

Deprenyl, Selegiline, Eldepryl By prescription from U.S pharmacies

B vitamins Bio-Strath/Nature’s Answer 800-681-7099 or health food stores

Note. This list of specific brands is not comprehensive It simply represents easily available brands that we have used and found to be consistently of good quality Because brands and companies may change, the physician should reevaluate each product over time See Table 38–4 for independent evaluations of many brands and check www.consumerlab.com or www.supplementwatch.com.

the framework of the other treatments in this chapter

because the pathophysiological basis of homeopathy is

unproven Biological effects are inferred from

observa-tions of change after treatment is administered For a

dis-cussion of the state of homeopathic research, we refer the

reader to Alternative and Complementary Treatment in

Neu-rological Illness (Weintraub 2001).

Summary

Doctors and consumers are concerned about the quality

of herbs and nutrients Advances in biochemistry have

improved the purity and stability of many products

(Wag-ner 1999) Although the publication of specific brands is

not the norm in a text of this kind, in the field of

alterna-tive medicine it is particularly important to choose

prod-ucts that have proven to be of good quality To help

clini-cians find their way through the morass of unreliable,

ineffective lookalikes, Table 38–3 lists brands that we have

investigated The following compounds in the brands we

have listed are pharmaceutical grade, regulated by

Euro-pean governmental agencies: centrophenoxine, acetyl-L

-carnitine, citicholine, S-adenosylmethionine (SAMe),

Picamilon, pyritinol, idebenone, vinpocetine, racetams,

and L-deprenyl The brands of the herbs, ginkgo, andginseng have been assessed by independent laboratories

as reported by ConsumerLab.com The authors have

per-sonally contacted the manufacturers of Rhodiola rosea,

gal-antamine, and SAMe to obtain adequate informationregarding standardization, content, purity, and batch test-ing procedures (including shelf life) to be reasonablyassured of the quality and reliability of these products.Invariably, some products and companies will changeover time Physicians should stay current by using unbi-ased sources of product evaluation and rigorous studies.Table 38–4 provides resources for those interested in reli-able information on alternative compounds Anyoneinterested in an alternative product may contact the man-ufacturer and request information about content, purity,testing, and quality control, as well as consulting indepen-dent sources of evaluation when available

Alternative compounds can offer significant benefitswith few side effects in some patients with TBI Certainagents may help repair the nervous system and enhanceplasticity In practice, it often requires several attempts todesign an effective combination of treatments Many pa-tients and families can participate in the development of

an alternative treatment regimen

References

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Prevention

HAVE classified traumatic brain injury (TBI) as either

focal or diffuse (Graham et al 1995) Although focal

in-juries most often involve contusions and lacerations

ac-companied by hematoma (Gennarelli 1994), diffuse

brain swelling, ischemic brain damage, and diffuse

ax-onal injury are also considered to be major components

of the diffuse injury profile (Adams et al 1989; Graham

et al 1995; Maxwell et al 1997) All TBIs can be further

stratified into primary injury (encompassing the

imme-diate, nonreversible mechanical damage to the brain),

and secondary or delayed injury, which represents a

po-tentially reversible process with a time of onset ranging

from hours to days after injury that progresses for weeks

or months (Graham et al 1995) This secondary injury

process is a complex and poorly understood cascade of

interacting functional, structural, cellular, and

molecu-lar changes, including, but not limited to, impairment of

energy metabolism, ionic dysregulation, breakdown of

the blood–brain barrier (BBB), edema formation,

activa-tion and/or release of autodestructive neurochemicals

and enzymes, changes in cerebral perfusion and

intra-cranial pressure (ICP), inflammation, and pathologic/

protective changes in intracellular genes and proteins

(Figure 39–1) Although these events may lead to

layed cell death and/or neurological dysfunction, the

de-layed onset and reversibility of secondary damage offer

a unique opportunity for targeted therapeutic

pharma-cological intervention to attenuate cellular damage and

functional recovery during the chronic phase of the jury (McIntosh et al 1998)

in-It is now well established that several clinically relevantexperimental TBI models mimic many aspects of behav-ioral impairment and histopathological damage reportedafter human brain injury (for review see Laurer et al 2000).Moreover, these experimental models provide us with theunique opportunity to both identify and investigate thepathophysiological changes triggered by TBI and targetthese pathways using new pharmacological strategies Asthe pathophysiological sequelae of TBI are multifactorial,the development and characterization of new compoundsremains extremely challenging This chapter reviews some

of the more promising neuroprotective strategies studied

to date in clinical and preclinical settings

Excitatory Amino Acid Antagonists

Pathologic release of the excitatory amino acid (EAA)neurotransmitters glutamate and aspartate and subse-quent activation of specific glutamate receptors result inincreased neuronal influx of cations (sodium and calcium)into the cell (Figure 39–2) This ionic influx may damage

or destroy cells (i.e., excitotoxicity) through direct orindirect pathways (Olney et al 1971) Both experimentaland clinical brain injury induce an acute and potentiallyneurotoxic increase in extracellular glutamate concentra-tions (Faden et al 1989; Globus et al 1995; Katayama et

al 1989, 1990; Nilsson et al 1990; Palmer et al 1993;

Panter et al 1992) Although most experimental studies

have suggested that the posttraumatic rise in extracellular

glutamate is of short duration, clinical studies have

reported that glutamate concentrations are significantly

elevated in the cerebrospinal fluid (CSF) of brain-injured

patients for several days or perhaps weeks (Baker et al.1993; Palmer et al 1994)

Regional distribution of both N-methyl-D-aspartate(NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazole-propionate/kainic acid (AMPA/KA) receptors has been di-rectly related to the selective vulnerability of specific brainregions caused by CNS injury (for review see Choi 1990).Miller et al (1990) reported an acute decrease in NMDA butnot AMPA/KA receptor binding in the hippocampal CA1stratum radiatum, the molecular layer of the dentate gyrus,and the outer (1–3) and inner (5–6) layers of the neocortexwithin 3 hours after TBI in the rat The hippocampus, whichplays a prominent role in learning and memory, possesses ahigh density of glutamate receptors (Monaghan and Cot-man 1986) Cognitive dysfunction, including a suppression

of long-term potentiation and deficits in learning and ory, has been reported after TBI (for review see Albensi2001) Sun and Faden (1995b) demonstrated that pretreat-ment with antisense oligodeoxynucleotides directed againstthe NMDA-R1 receptor subunit enhances survival and neu-rological motor recovery after TBI in rats These studies un-

mem-F I G U R E 3 9 – 1 Cascade of secondary damaging

events in experimental traumatic brain injury.

F I G U R E 3 9 – 2 Glutamate receptor subtypes: N-methyl-D -aspartate (NMDA) and

α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA)/kainate.

APV=2-amino-5-phosphovaleric acid; CPP=3-(2-carboxypiperizin-4yl)-propyl-1-phosphonic acid; I2CA=indole-2-carboxylic acid.

derscore the potentially important role of the NMDA

re-ceptor in mediating part of the pathological response to

brain trauma (Table 39–1)

Although competitive NMDA receptor antagonists

are logical candidates for the treatment of traumatic CNS

injury, most of the early-generation compounds such as

2-amino-5-phosphovaleric acid (APV) and

3-(2-carbox-ypiperizin-4yl)-propyl-1-phosphonic acid (CPP) were

strongly lipophobic and possessed poor BBB

permeabil-ity, resulting in the necessity for direct CNS

administra-tion Intracerebral administration of CPP was shown to

improve neurological outcome (Faden et al 1989), and

intracerebroventricular APV administration was reported

to reverse hypermetabolism after TBI in rats (Kawamata

et al 1992) In addition, CPP has recently been shown to

increase apoptotic damage despite its ability to decrease

excitotoxic cell damage in a model of TBI in the

develop-ing rat (Pohl et al 1999)

More recently developed competitive NMDA

antag-onists such as Selfotel (CGS-19755 or

cis-4-[phospho-methyl]-2-piperidine carboxylic acid), LY233053

([1]-[2SR,4RS]-4-[1H-tetrazol-5-ylmethyl]

piperidine-2-car-boxylic acid), and CP101,606 ([1S,

29]-1-[4-hydroxyphe-nyl]-2-[hydroxy-4-phenylpiperidino]-1-propanol), an

NR2B-selective NMDA receptor antagonist, have been

shown to have greater BBB permeability than earlier

gen-erations of similar compounds (Menniti et al 1995)

Although Selfotel has shown no beneficial effects on

behavioral outcome, administration of this antagonist has

been reported to reduce trauma-induced extracellular

glutamate release in rats (Panter and Faden 1992) On the

basis of this and other published data from experimental

models of ischemia, a multicenter trial of Selfotel was

ini-tiated in the United States and Europe but was

prema-turely terminated because of side effects associated with

competitive NMDA antagonism (Bullock 1995)

Admin-istration of CP101,606 and its stereoisomers has been

shown to attenuate both cognitive dysfunction and

re-gional cerebral edema in TBI in the rat (Okiyama et al

1997, 1998) The CP101,606 compound is currently in

Phase II trials in the United States and in Phase I trials in

Japan for the potential treatment of brain injury and has

been shown to be well tolerated and able to penetrate

CSF and brain (Bullock et al 1999; Merchant et al 1999)

In the initial pilot studies, mild to moderately

head-in-jured patients did not exhibit differences in performance

on the Neurobehavioral Rating Scale or Kurtzke Scoring

(Merchant et al 1999), whereas severely head-injured

pa-tients who were treated with the CP101,606 compound

presented with, on average, better Glasgow Outcome

Scores (Bullock et al 1999)

Noncompetitive NMDA receptor antagonists also pear to have efficacy in the treatment of TBI Hayes et al.(1988) first reported that pretreatment with the dissocia-tive anesthetic and noncompetitive NMDA antagonistphencyclidine (PCP) attenuated neurological motor defi-cits after TBI in rats Similar results were obtained withprophylactic treatment using dizocilpine (MK-801)(McIntosh et al 1990) Treatment with MK-801 afterTBI in rats also improved brain metabolic function andrestored magnesium homeostasis (McIntosh et al 1990),and administration of higher doses improved neurologicalmotor deficits and reduced regional cerebral edema (Sha-pira et al 1990) Pretreatment with MK-801 was found toattenuate the extracellular rise in glutamate associatedwith closed head injury followed by hypoxia in rats (Katoh

ap-et al 1997) and enhance the recovery of spatial memoryperformance in animals subjected to combined TBI andentorhinal cortical lesions (Phillips et al 1997) Adminis-tration of the noncompetitive NMDA antagonists dextro-phan and dextromethorphan improved brain metabolicstate, attenuated neurological motor deficits, and reducedthe postinjury decline in brain magnesium concentrationsobserved after TBI in rats (Faden et al 1989) Goldingand Vink (1995) reported that dextromethorphan im-proved brain bioenergetic state and restored brain magne-sium homeostasis after TBI in rats Dextrophan also im-proved neurologic motor function and reduced edema afterTBI in rats (Shohami et al 1993) The NMDA-associatedchannel blocker ketamine has also been shown to improveposttraumatic cognitive outcome (Smith et al 1993a),maintain both calcium and magnesium homeostasis (Sha-pira et al 1993), and reduce expression of several immedi-ate early genes (IEGs) induced in cerebral cortex and hip-pocampal dentate gyrus after TBI in rats (Belluardo et al.1995) Gacyclidine, a more recently discovered phencyc-lidine derivative that acts as a noncompetitive NMDA an-tagonist (Hirbec et al 2000), reduced lesion volume andimproved neuronal survival and motor function when ad-ministered intraparenchymally after TBI (Smith et al.2000) Although administration of the high-affinity,noncompetitive NMDA receptor antagonist CNS1102(Aptiganel or Cerestat) was shown to attenuate contu-sion volume and hemispheric swelling after TBI in rats(Kroppenstedt et al 1998), a clinical trial of this drug wasprematurely terminated because of high mortality rates in

an associated stroke trial Although few studies have uated the potential neuroprotective effects of noncompet-itive NMDA antagonists in models of brain trauma, Smith

eval-et al (1997) reported that the NMDA receptor-associated

ionophore blocker remacemide

(2-amino-N-[1-methyl-1,2-diphenylethyl] acetamide hydrochloride) also

signifi-T A B L E 3 9 – 1 Excitatory amino acid antagonists and agonists classified according to binding site

Compound

Type of research Outcome References

NMDA antagonist

Competitive APV e ↓ glucose utilization Kawamata et al 1992

CPP e ↑ motor function, apoptotic

damage; ↓ necrosis

Faden et al 1989; Pohl et al 1999

Selfotel e,c ↑ bioenergetic state, Mg 2+

homeostasis

Bullock 1995; Juul et al 2000; Morris et al 1998; Panter et al 1992

CP101,606 e,c ↑ cognitive function; ↓ cell

death, edema

Bullock et al 1999; Merchant et al 1999; Okiyama et al 1997, 1998 Noncompetitive Phencyclidine e ↑ motor function Hayes et al 1988

↓ immediate early genes

Belluardo et al 1995; Shapira et al 1993; Smith et al 1993a

Gancyclidine e ↑ motor function; ↓ cell death,

lesion volume

Hirbec et al 2001; Smith et al 2000

Cerestat e,c ↓ edema, lesion volume;

↑ psychomotor side effect

Kroppenstedt et al 1998; Muir et

al 1995 Remacemide

hydrochloride

e ↓ lesion volume Smith et al 1997

NMDA glycine site I2CA e ↑ motor/cognitive function;

al 2001; Smith et al 1993a MgSO4 e ↑ motor/cognitive function;

↓ edema

Heath and Vink 1998; McIntosh

et al 1988 NMDA polyamine site Ifenprodil e ↓ edema, BBB breakdown Okiyama et al 1998

Eliprodil e ↑ cognitive function; ↓ lesion

mGluR1 antagonist AIDA e ↑ motor/cognitive function;

↓ cell death, lesion volume

Faden et al 2001; Lyeth et al 2001

cantly reduced posttraumatic cortical lesion volume after

TBI in rats

The magnesium ion functions as a key endogenous

modulator of the NMDA receptor, and its essential roles

in many bioenergetic and cellular metabolic and genomic

processes makes it an attractive candidate for use in the

treatment of TBI The loss of intracellular magnesium

concentrations after experimental TBI (Shohami et al

1993; Vink et al 1996) suggests that replacement therapy

using this ionic salt may have therapeutic value Both

pre-and postinjury treatment with magnesium salts (MgCl2 or

MgSO4) has been demonstrated to improve neurological

motor and cognitive deficits and decrease regional

cere-bral edema formation (Bareyre et al 2000; McIntosh et al

1988, 1989; Okiyama et al 1995; Saatman et al 2001;

Shapira et al 1993; Smith et al 1993a) Because of this

documented efficacy in experimental trauma models, a

single-center National Institutes of Health–sponsored

clinical trial in severely injured TBI patients has been tiated in the United States

ini-Other strategies to block NMDA-receptor associatedneurotoxicity involve blockade or modulation of theNMDA receptor–associated glycine sites and/orpolyamine binding sites One selective glycine site antago-nist, indole-2-carboxylic acid (I2CA), has been shown toimprove behavioral outcome and reduce edema after TBI

in rats (Smith et al 1993b) Two broad-spectrum glutamateantagonists, kynurenate (KYNA) and 6-cyano-7-nitroqui-noxaline-2,3-dione (CNQX), which antagonize both theglycine site and AMPA/KA receptors with varying affinity,have also been shown to be efficacious in reducing post-traumatic metabolic and neurobehavioral dysfunction inexperimental TBI (Kawamata et al 1992; Smith et al.1993b) Postinjury administration of KYNA reduced theposttraumatic loss of hippocampal neurons after TBI in therat (Hicks et al 1994) Inhibition of the ornithine decar-

mGluR1/2 antagonist MCPG e ↓ cell death Gong et al 1995; Mukhin et al

1996 mGluR2 agonist LY354740 e ↑ motor function Allen et al 1999

mGluR5 antagonist MPEP e ↑ motor/cognitive function;

619C89 e,c ↑ motor/cognitive function;

↓ cell death, gliosis

Sun et al 1995; Voddi et al 1995

Riluzole e ↑ motor/cognitive function;

↓ edema, lesion volume, glutamate release

Bareyre et al 1997; McIntosh et al 1996; Stover et al 2000; Wahl et

al 1997; Zhang et al 1998 AMPA/KA antagonist KYNA e ↑ cognitive function; ↓ cell

death, edema

Hicks et al 1994; Smith et al 1993b

Competitive CNQX e ↓ glucose utilization Kawamata et al 1990, 1992

Ikonomidou and Turski 1996; Ikonomodou et al 1996, 2000 Noncompetitive GYKI-52466 e ↑ cognitive function; ↓ cell

death

Hylton et al 1995 Talampanel e ↓ cell death Belayev et al 2001

Note BBB=blood–brain barrier; c=clinical trial; e=experimental study; NMDA = N-methyl-D -aspartate.

T A B L E 3 9 – 1 Excitatory amino acid antagonists and agonists classified according to binding site (continued)

Compound

Type of research Outcome References

boxylase (ODC) enzyme using difluoromethylornithine

(DFMO) has been shown to reduce regional cerebral

edema after TBI in rats (Baskaya et al 1996), and

compet-itive antagonism of the NMDA-associated polyamine

binding site by ifenprodil and its derivative eliprodil (SL

82.0715) has also been reported to exert beneficial effects

after experimental TBI (Toulmond et al 1993)

Although the NMDA receptor is implicated as

play-ing an important role in mediatplay-ing part of the

pathologi-cal response to brain trauma, AMPA antagonists have also

been used therapeutically with some success

Administra-tion of 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(f

)qui-noxaline (NBQX) has been shown to prevent

hippocam-pal cell loss after brain trauma in adult but not immature

rats (Bernert and Turski 1996; Ikonomidou and Turski

1996; Ikonomidou et al 1996) The compound

GYKI-52466

(1-[4-aminophenyl]-4-methyl-7,8-methylenedio-ixy-5H-2,3-benzodiazepine), a noncompetitive AMPA/

KA antagonist, markedly improved cognitive function

af-ter TBI in the rat (Hylton et al 1995) More recently, an

orally active, noncompetitive AMPA antagonist,

(R)-7-

acetyl-5-(4-aminophenyl)-8,9-dihydro-8-methyl-7H-1,3-dioxolo(4,5-h)(2,3) benzodiazepine (Talampanel) has

also been shown to significantly attenuate neuronal CA1

cell loss when administered after TBI (Belayev et al

2001)

Elevated concentrations of extracellular glutamate

af-ter TBI activate metabotropic receptors (mGluRs), in

ad-dition to ionotropic receptors, and a number of recent

studies implicate activation of mGluRs in acute TBI

path-ology (Faden et al 1997; Gong et al 1995, 1999; Mukhin

et al 1996, 1997) Eight mGluR subtypes have been

clas-sified, and these have been divided into three major

classes on the basis of sequence homology, signal

trans-duction pathways, and pharmacological sensitivity (Pin

and Duvoisin 1995; Schoepp et al 1999) A differential

role for the different subgroups of mGluRs in

posttrau-matic cell death and survival has been proposed, and the

blockade of group I or the activation of group II or group

III receptors seems to be a beneficial strategy after TBI

On the basis of the use of antisense oligonucleotides and

less selective group I antagonists such as (S)-

α-methyl-4-carboxyphenylglycine (MCPG), a drug that acts as both a

group I and group II antagonist, it has been suggested

that mGluR1 activation contributes to traumatic cell

death (Gong et al 1995; Mukhin et al 1996)

Administra-tion of (R,S)-1-aminoindan-1,5-dicarboxylic acid

(AIDA), a selective mGluR1 antagonist, resulted in

sig-nificant improvement in motor and cognitive function

and reduction in the numbers of degenerating neurons

and in lesion volume when administered after TBI (Faden

et al 2001; Lyeth et al 2001) Although comparable

re-sults were obtained with administration of (2-phenylethenyl)-pyridine (MPEP), a specific mGluR5antagonist, it was suggested that the therapeutic utility ofthis drug may reflect its ability to modulate NMDA re-ceptor activity rather than its ability to act as an mGluR5agonist (Movsesyan et al 2001) A number of laboratorieshave recently produced evidence that activation of group

2-methyl-6-I mGluRs may reduce apoptotic cell death in models hibiting neuronal apoptosis but increase necrotic celldeath in vitro (Allen et al 2000) The mechanism under-lying the apparent dual neurotoxic/neuroprotective ef-fects of group I mGluR activation remains unidentified.With respect to group II and III mGluRs, postinjuryadministration of LY354740, a specific group II mGluRagonist, significantly improved neurological outcome af-ter TBI in experimental animals with apparently fewerside effects and better tolerance than those associatedwith NMDA receptor antagonists (Allen et al 1999) Ad-ministration of the group II mGluR2 agonist 2-(2',3')-dicarboxycyclopropylglycine (DCG-IV) directly into thehippocampus after TBI in rats resulted in a decrease inthe number of degenerating neurons in the CA2 and CA3regions (Zwienenberg et al 2001), although hippocampal

Given the apparent failure of postsynaptic glutamateantagonist clinical trials, one novel strategy to attenuateglutamatergic neurotoxicity after brain trauma may be touse pharmacological agents that function presynaptically

to inhibit glutamate release The compound lamotrigine(3,5-diamino-6-[2,3-dichlorophenyl]-1,2,4-triazine) andits derivatives BW 1003C87 (5-[2,3,5-trichlorophenyl]pyrimidine-2,4-diamine ethane sulphonate), 619C89 (4-amino-2-[4-methyl-1-piperazinyl]-5-[2,3,5-trichlo-rophenyl] pyrimidine mesylate monohydrate), and rilu-zole all inhibit veratrine- but not potassium-stimulatedglutamate release, presumably by reducing ion fluxthrough voltage-gated sodium channels with subsequentattenuation of glutamate release (Miller et al 1986) Pre-injury treatment with 619C89 has been shown to reduceneuronal loss in CA1 and CA3 hippocampal pyramidalcells after TBI in rats (Sun and Faden 1995a), whereaspostinjury treatment with BW1003C87 can attenuate re-

gional cerebral edema and improve neurobehavioral

function (Okiyama et al 1995; Voddi et al 1995)

Treat-ment with riluzole after TBI significantly attenuated both

cognitive and motor deficits (McIntosh et al 1996),

re-duced cerebral edema (Bareyre et al 1997; Stover et al

2000a), and reduced posttraumatic lesion volume (Wahl

et al 1997; C Zhang et al 1998) The use of presynaptic

inhibitors of glutamate release, such as riluzole, in clinical

brain injury may present a possible alternative to the use

of postsynaptic glutamate antagonists, which are known

to be associated with neurotoxicity and psychomimetic

side effects

Inhibition of Lipid Peroxidation

Oxidative damage has been implicated in many of the

pathological changes that occur after TBI (Ercan et al

2001; Hsiang et al 1997) Oxidative damage in the CNS

manifests itself primarily as lipid peroxidation because the

brain is rich in peroxidizable fatty acids and possesses

rel-atively few antioxidant defense systems (for review see

Floyd 1999) After TBI, alterations in regional cerebral

blood flow (CBF) and reductions in substrate delivery

likely combine to produce intracellular arachidonic acid

cascade metabolites and reactive oxygen species (ROS)

(Ikeda and Long 1990; Kontos and Povlishock 1986)

The genesis of ROS after TBI has also been related to

nonischemic events, including the increase in

intracellu-lar calcium concentrations that induces ROS release from

mitochondria (Tymianski and Tator 1996) Other

endog-enous ROS also occur from enzymatic processes,

mono-amine oxidase, cyclooxygenase (COX), nitric oxide

syn-thase (NOS), and nicotine adenine dinucleotide

phosphate oxidase, as well as macrophages and

neutro-phils Excessive glutamate release can also generate high

levels of ROS (Dugan and Choi 1994) These ROS cause

peroxidative destruction of the lipid bilayer cell

mem-brane, oxidize cellular proteins and nucleic acids, and

attack the cerebrovasculature, thereby affecting the BBB

integrity and/or vascular reactivity Several regulatory

mechanisms can be affected by ROS, including activation

of cytokine or growth factor–mediated signal

transduc-tion pathways, inductransduc-tion of IEGs, and disruptransduc-tion of

cal-modulin-regulated gene transcription (Yao et al 1996)

Free reactive iron, a catalyst for the formation of ROS,

may also be involved in trauma-induced peroxidative

tis-sue damage

Several studies have indirectly demonstrated the early

generation of superoxide radicals in injured brains, which

subsequently resulted in secondary damage to the brain

microvasculature (Povlishock and Kontos 1992) Some

investigators have used spin trap probes of salicylate ping methods to demonstrate an early posttraumatic for-mation of hydroxyl radicals in injured brains (Hall et al.1993) that also correlated with the development of BBBdisruption (Smith et al 1994) Still others have used cy-clic-voltammetry techniques to measure the production

trap-of low-molecular-weight antioxidants (LMWAs) by theinjured brain as another indirect indication of ROS pro-duction after brain trauma (Beit-Yannai et al 1997; Sho-hami et al 1997b) These studies suggest that LMWAsare mobilized from brain cells to the extracellular space(Moor et al 2001) More stable molecules such as 3,4-dihydroxybenzoic acid (3,4-DHBA) have been used to de-tect an increase in ROS with microdialysis after TBI(Marklund et al 2001a) Recently, isoprostanes have beenused as specific markers to detect lipid peroxidation afterTBI (Tyurin et al 2000); in one study, 8,12-iso-IPF2α-VIlevels increased in brain and blood between 1 and 24hours after TBI (Pratico et al 2002)

Posttraumatic alterations in intracellular calcium cipitate an attack on the cellular cytoarchitecture via acti-vation of calpains and lipases and also induce the formation

pre-of ROS that attack the cell membrane Trauma-inducedactivation of phospholipases A2 (PLA2) and C (PLC) re-sults in the release of free fatty acids, diacylglycerol(DAG), thromboxane B2, and leukotrienes, whereas accu-mulation of free arachidonic acid itself may affect mem-brane permeability (for a review see Bazan et al 1995).TBI-induced DAG formation is associated with posttrau-matic cerebral edema (Dhillon et al 1994, 1995), andDAG activates protein kinase C, which may modulateother signal transduction pathways Protein kinase C in-creases over time in the cortex and hippocampus afterTBI in the rat (Sun and Faden 1994) Homayoun et al.(1997) reported that TBI in rats induces a delayed andsustained activation of phospholipase-mediated signalingpathways, leading to membrane phospholipid degrada-tion that targets docosahexaenoyl phospholipid-enrichedmembranes

Compounds that block various steps in the nate cascade have been shown to be somewhat effective inexperimental models of TBI (Table 39–2) The nonselec-tive COX inhibitors ibuprofen and indomethacin havebeen shown to improve neurologic function and to de-crease mortality after TBI (Hall 1985; Kim et al 1989).Head-injured patients who have received intravenous in-domethacin present with reduced ICP and CBF and in-creased cerebral perfusion pressure (Slavik and Rhoney1999) COX-2 levels have been shown to be elevated ininjured cortex and in the ipsilateral hippocampus afterexperimental TBI in rats (Dash et al 2000) Althoughadministration of selective COX-2 inhibitors 4-(5-[4-

arachido-T A B L E 3 9 – 2 Antioxidant, antiinflammatory, and neurotrophic factors

Type of agent Compound

Type of research Outcome References

COX inhibitor Indomethacin e,c ↓ ICP Slavik et al 1999

COX-2 inhibitor Celecoxib e ↑ cognitive function; ↓ motor

function

Dash et al 2001 Nimesulide e ↑ motor/cognitive function Cernak et al 2001

SC 58125 e ↓ antioxidants Tyurin et al 2000 Iron chelator Deferoxamine e ↑ motor function; ↓ tissue SOD Panter et al 1992

Desferal e ↑ motor/cognitive function;

↓ edema

Ikeda et al 1989; Zhang et al

1998 Antioxidant U-101033E e ↓ mitochondria dysfunction Xiong et al 1997

PEG-SOD e,c ↑ motor function, BBB

penetration; ↓ ARDS

Hamm et al 1996; Muizelaar

et al 1993; Young et al 1996

PBN e ↑ cognitive function; ↓ lesion

volume, tissue loss

Marklund et al 2001

LY341122 e ↓ cell death, lesion volume Wada et al 1999 21-aminosteroid Freedox e ↑ motor function, metabolism;

↓ edema, mortality

Hall et al 1988, 1994; McIntosh et al 1992; Sanada et al 1993 U-743896 e ↓ axonal injury Marion and White 1996 NOS inhibitor BN 80933 e ↑ sensory/motor function Chabrier et al 1999

Leukocyte adherence inhibition Prostacyclin e ↓ cell death Allan et al 2001

death

Knoblach et al 2000; Sanderson et al 1999; Toulmond et al 1995 Tetracycline Minocycline e ↑ motor function; ↓ lesion

Kallikrein-kinin CP-0127 e,c ↑ GCS; ↓ edema, mortality Marmarou et al 1999;

Narotam et al 1998;

B2 receptor antagonist Lf-16-068Ms e ↓ edema Stover et al 2000a, 2000b

Neutrophic factors NGF e ↑ cognitive function,

cholinergic reinnervation;

↓ cell death

Philips et al 2001

benzenesulfonamide (celecoxib) and nimesulide was

shown to improve cognitive function after TBI, its effect

on motor function remains controversial (Hurley et al

2002) The COX-2 inhibitor SC 58125 prevented

deple-tion of antioxidants after TBI in rats (Tyurin et al 2000)

Although COX-2 induction after TBI may result in

selec-tive beneficial responses, chronic COX-2 production may

actually potentiate free radical–mediated cellular damage,

vascular dysfunction, and alterations in cellular

metabo-lism (Strauss et al 2000)

Experimental work suggests that ROS scavengers may

confer some neuroprotection in experimental models of

TBI (Hensley et al 1997; Shohami et al 1997a)

Antiox-idants such as α-tocopherol (vitamin E) have been shown

to be beneficial in TBI (Clifton et al 1989; Stein et al

1991; Conte et al 2004) Conversely, Stoffel and

col-leagues (1997) have reported that increasing plasma

vita-min E levels had no effect on posttraumatic vasogenic

brain edema It has been reported that systemic levels of

two major antioxidants, vitamin E and ascorbic acid

(vita-min C), were significantly reduced in injured rats after

TBI and that these reductions inversely correlated with

isoprostane levels (Pratico et al 2002)

Panter et al (1992) reported that administration of

the iron chelator dextran-deferoxamine, which protects

brain tissue by terminating radical-chain reactions and

re-moving intracellular superoxide, improved neurological

impairment after TBI in mice, suggesting that brain

in-jury is associated with significant iron-dependent

ROS-induced lipid peroxidation Desferal, another potent

che-lator of redox-active metals, has been shown to attenuate

brain edema and improve neurological recovery after TBI

in rats (Ikeda et al 1989; R Zhang et al 1998) tration of the novel antioxidant pyrolopyrimidine (U-101033E) after TBI in the rat was also shown to reducemitochondrial dysfunction

Adminis-The use of stable nitroxide radicals as antioxidanttherapy in CNS injury has also been attempted Nitrox-ides, which are cell-permeable, nontoxic, stable radicals,have been shown to prevent ROS-induced lipid peroxida-tion (Krishna et al 1996; Pogrebniak et al 1991) Admin-istration of these compounds markedly improved neuro-logical recovery, reduced edema, and protected theimpaired BBB after TBI in rats (Beit-Yannai et al 1996).Administration of nitrone radical scavengers, anotherclass of potent ROS, has been evaluated for neuroprotec-tive efficacy after TBI Administration of α-phenyl-tert- N-butyl nitrone (PBN) or 2-sulfo-phenyl-N-tert-butyl

nitrone (S-PBN) in rats significantly reduced ROS mation, cognitive impairment, and lesion volume afterTBI (Marklund et al 2001b, 2001c, 2001d) Other ROSscavengers that recently have been demonstrated to exertneuroprotective effects in experimental TBI include thesecond-generation azulenyl nitrone stilbazulenyl nitrone(STAZN) (Belayev et al 2002), melatonin (Sarrafzadeh et

for-al 2000), a superoxide radical scavenger (OPC-14117)

(Aoyama et al 2002; Mori et al 1998)

2-(3,5-di-t-butyl-phenyloxy]ethyl)oxazole LY341122 (Wada et al 1999),and citicoline, an endogenous intermediate of phosphati-dylcholine synthesis reported to stabilize the cell mem-brane integrity and free fatty acid formation (Baskaya et

4-hydroxyphenyl)-4-(2-[4-methylethylaminomethyl-al 2000)

GDNF e ↓ cell death, lesion volume Hermann et al 2001; Kim et

al 2001 bFGF e ↑ cognitive function; ↓ cell

death

Dietrich et al 1996;

McDermott et al 1997; Yang et al 2000 IGF-1 e,c ↑ motor/cognitive function Hatton et al 1997; Saatman

et al 1997

Note. ARDS=adult respiratory distress syndrome; BBB=blood–brain barrier; BDNF=brain-derived neurotrophic factor; bFGF=basic fibroblast growth factor; c=clinical trial; COX=cyclooxygenase; CPP=cerebral perfusion pressure; e=experimental study; FGF= fibroblast growth factor; GDNF=glial cell-line–derived neurotrophic factor; ICAM-1=intercellular adhesion molecule-1; ICP=intracranial pressure; IGF=insulin-like growth factor; IL=interleukin; NGF=nerve growth factor; NOS=nitric oxide synthase; PC-SOD=lecithinized superoxide dismutase; PEG- SOD=polyethylene glycol superoxide dismutase; SOD = superoxide dismutase; TNF = tumor necrosis factor.

T A B L E 3 9 – 2 Antioxidant, antiinflammatory, and neurotrophic factors (continued)

Type of agent Compound

Type of research Outcome References

Administration of the antioxidant enzyme SOD was

reported to have beneficial effects on survival and

neuro-logical recovery (Shohami et al 1997a) The conjugation

of polyethylene glycol to SOD (PEG-SOD, Dismutec),

thereby improving BBB penetration and increasing

SOD’s plasma half-life, has been shown to reduce motor

deficits (Hamm et al 1996) DeWitt et al (1997) have

shown that PEG-SOD administration reverses cerebral

hypoperfusion after TBI in rats, and others have reported

that administration of lecithinized SOD (PC-SOD)

re-duced brain edema after weight-drop brain injury in rats

(Yunoki et al 1997) A multicenter clinical trial of

Dis-mutec was conducted in the United States Although

ini-tial Phase II studies were compelling (Muizelaar et al

1993), the results of the larger Phase III trials in severely

head-injured patients were disappointing (Muizelaar et al

1995; Young et al 1996)

High-dose glucocorticoids stabilize membranes and

also reduce ROS-induced lipid peroxidative injury

(Braughler et al 1987; Hall et al 1987) Although many

early clinical studies reported that high-dose steroid

treatment is without effect in TBI (Braakman et al 1983;

Cooper et al 1979; Gudeman et al 1979), a few

tantaliz-ingly positive studies have been published Giannotta et

al (1984) reported that high-dose methylprednisolone

significantly reduced mortality in severely head-injured

patients In a multicenter trial conducted in Germany,

treatment of severely head-injured patients with the

syn-thetic corticosteroid triamcinolone significantly reduced

mortality and improved long-term neurological outcome

(Grumme et al 1995) The CRASH (Corticosteroid

Ran-domization After Significant Head Injury) trial has been

designed to determine the effects of short-term steroid

treatment on death and disability after severe brain injury

in more than 7,000 patients in the United Kingdom

(Roberts 2001)

A group of 21-aminosteroid compounds have been

developed that lack true glucocorticoid activity while

maintaining the ability to scavenge ROS and inhibit lipid

peroxidation (Braughler and Pregenzer 1989) The most

widely evaluated member of this group of compounds,

ti-rilazad mesylate (Freedox), has been shown to enhance

neurological recovery and survival (Hall et al 1988),

at-tenuate posttraumatic edema, reduce mortality

(McIn-tosh et al 1992), improve motor function (Sanada et al

1993), and increase metabolism of nonedematous tissue

adjacent to contusion (Hall et al 1994) after experimental

TBI in rodents Freedox appears to exert its antilipid

per-oxidative action through two mechanisms: free radical

scavenging and membrane stabilization (Fernandez et al

1997; Kavanagh and Kam 2001) Treatment of TBI with

the Freedox-like 21-aminosteroid U-743896, or

moder-ate hypothermia, or a combination of both significantlyreduces axonal injury, although the 21-aminosteroid ther-apy was more effective when treatment was initiated 40minutes after injury (Knoblach et al 1999) The lipophi-licity of these 21-aminosteroids, coupled with their po-tent inhibition of lipid peroxidation over a wide dose-response range and the positive data collected from a widevariety of animal models of CNS injury generated mo-mentum to launch a multicenter clinical trial of Freedox

in the treatment of severely brain-injured patients in theUnited States and Europe However, the results of thesestudies were largely negative (Marshall and Marshall1995) Future studies enrolling patients with mild andmoderate severity of brain trauma may demonstrate clin-ical use of this class of compounds

An overproduction of the free radical nitric oxide (NO)and its derivative anion peroxynitrite is also thought to play

an active role in the pathophysiology of TBI Althoughpharmacological intervention with both nonselective in-hibitors of NOS and selective inhibitors of neuronal andinducible NOS isoforms have proven effective in experi-mental TBI (Gahm et al 2002; Khaldi et al 2002), furtherpreclinical work is necessary to clarify the therapeutic po-tential of these compounds, particularly because NO can

be either neuroprotective or destructive, depending on itsspatiotemporal distribution and concentration A novelagent linking an antioxidant to a selective inhibitor of neu-ronal NOS (BN 80933) has been shown to be neuroprotec-tive in models of both TBI and cerebral ischemia (Chabrier

et al 1999) The inhibition of NOS-induced cellular age may confer neuroprotection to the injured brain, andfuture studies should emphasize the evaluation and devel-opment of pathway-specific compounds

dam-Anti-Inflammatory Strategies

Although CNS inflammation was long believed to be acatastrophic event leading to sustained functional impair-ment and even death, there is increasing evidence thatinflammatory pathways may be of importance for initia-tion of regenerative response Posttraumatic edema for-mation is associated with complex cytotoxic events andvascular leakage after the breakdown of the BBB (Baskaya

et al 1997; Unterberg et al 1997), and a profound tion of the BBB has been observed in a variety of experi-mental TBI models (Barzo et al 1996; Fukuda et al 1995;Soares et al 1992) as well as in human TBI (Csuka et al.1999; Morganti-Kossmann et al 1999; Pleines et al.1998) As such, infiltration and accumulation of polymor-phonuclear leukocytes into brain parenchyma occurs inthe acute posttraumatic period, reaching a peak by 24

disrup-hours postinjury (Soares et al 1995; Stahel et al 2000b).

Alterations in bloodborne immunocompetent cells have

been described in head-injured patients (Hoyt et al 1990;

Piek et al 1992; Quattrocchi et al 1992)

Immunocy-tochemical studies have further demonstrated the

pres-ence of macrophages, natural killer cells, helper T cells,

and T cytotoxic suppressor cells as early as 2 days

postin-jury (Holmin et al 1995) The entry of macrophages into

brain parenchyma has been shown to be maximal by 24–

48 hours after TBI in rats and humans (Holmin et al

1995, 1998; Soares et al 1995) A recent study of severe

TBI patients suggested that the activated cell population

after CNS trauma appears to be composed predominantly

of the macrophage/microglia lineage, as opposed to the

T-cell lineage (Lenzlinger et al 2001) Both macrophages

and microglia have been proposed as key cellular

ele-ments in the progressive tissue necrosis—presumably

associated with the release of cytotoxic molecules that

may be involved in mediating the local inflammatory

response to trauma and the phagocytosis of debris from

dying cells—that occurs after CNS trauma

(Morganti-Kossmann et al 2001)

Zhuang et al (1993) have suggested a relationship

be-tween cortical polymorphonuclear leukocyte

accumula-tion and secondary brain injury, including lowered CBF,

increased edema, and elevated ICP The migration of

leu-kocytes into damaged tissue typically requires the

adhe-sion of these cells to the endothelium, which is mediated

by the expression of the intercellular adhesion

molecule-1 (ICAM-molecule-1) An upregulation of ICAM-molecule-1 has been

de-scribed in a variety of experimental TBI models (Carlos et

al 1997; Isaksson et al 1997; Rancan et al 2001),

suggest-ing a role for leukocyte adhesion in the pathobiology of

posttraumatic cell infiltration in the brain In humans,

soluble ICAM-1 (sICAM-1) in CSF has been associated

with the breakdown of the BBB after severe TBI (Pleines

et al 1998) However, treatment with the anti-ICAM-1

antibody 1A29 failed to significantly improve the learning

deficits or histopathological damage after severe TBI in

rats (Isaksson et al 2001) (see Table 39–2) Recently,

pros-tacyclin, which is known to inhibit leukocyte adherence

and aggregation and platelet aggregation, was shown to

reduce neocortical neuronal death in rats after TBI

(Bentzer et al 2001) Besides the expression of adhesion

molecules, leukocyte transmigration appears to require

the production of chemokines that activate and guide

leu-kocytes to the injured area

The specific cytokines and growth factors that have

been implicated in the posttraumatic inflammatory

cas-cade include the interleukin (IL) and tumor necrosis

fac-tor (TNFα) families of peptides (for review see Allan and

Rothwell 2001) Alterations in systemic and intrathecal

concentrations of these cytokines have been reported tooccur in human patients after severe brain injury, and re-gional mRNA and protein concentrations have beenshown to increase markedly in the acute posttraumaticperiod after experimental brain trauma in the rat (Allanand Rothwell 2001) IL-1α and IL-1β, two IL-1 agonists,and IL-1 receptor antagonist (IL-1ra), a naturally occur-ring physiological IL-1 antagonist, are produced as precur-sors While pro-IL-1α and pro-IL-1ra are active, pro-IL-1β

is activated when it is cleaved by IL-1 converting enzyme(ICE or caspase-1) IL-1 has been implicated in an array

of pathological and nonpathological processes, includingapoptotic cell death (Friedlander et al 1996), leukocyte–endothelial adhesion (Bevilacqua et al 1985), BBB dis-ruption (Quagliarello et al 1991), edema (Yamasaki et al.1992), astrogliosis and neovascularization (Giulian et al.1988), and synthesis of neurotrophic factors (DeKosky et

al 1996) IL-1, in turn, stimulates other inflammatorymediators, such as phospholipase A2, COX-2, prostaglan-dins, NO, and matrix metalloproteinases (Basu et al.2002; Rothwell and Luheshi 2000) A significant increase

in pro-IL-1β mRNA in the injured hemisphere as early as

1 hour and remaining up to 6 hours postinjury has beenreported after experimental TBI (Fan et al 1995) A sim-ilar acute increase in IL-1 activity and mature IL-1β pro-tein levels after TBI has been reported (Taupin et al.1993), which can be directly correlated to the severity ofinjury in experimental models of TBI (Kinoshita et al.2002)

Caspase-1 mRNA is increased in ipsilateral cortex andhippocampus between 24 and 72 hours after TBI in rats(Sullivan et al 2002; Yakovlev et al 1997) although in-creased cleavage of caspase-1 is observed after humanbrain injury (Clark et al 1999) Intracerebroventricularadministration of IL-1ra results in improved cognitivefunction without motor improvement (Sanderson et al.1999), and administration of recombinant IL1-ra resulted

in reduced neuronal damage after TBI in rodents mond and Rothwell 1995) Despite the inability to readilydetect caspase-1 activity in the injured rat brain, adminis-tration of a selective inhibitor of caspase-1 (e.g., acetyl-Tyr-Val-Ala-Asp-chloromethyl-ketone [AcYVAD-cmk]

(Toul-or the tetracycline derivative minocycline) bef(Toul-ore TBIsignificantly reduces lesion volume and attenuates motordeficits (Fink et al 1999; Sanchez Mejia et al 2001).The pleiotropic cytokine IL-6 has been implicated in avariety of physiological as well as pathological processes in-cluding induction of nerve growth factor (NGF) expres-sion (Frei et al 1989; Gruol and Nelson 1997; Marz et al.1999; Nieto-Sampedro et al 1982) Elevated levels of IL-6have been detected in the CSF and the serum of patientswith severe TBI over a period of up to 3 weeks after trauma

(Hans et al 1999a; Kossmann et al 1995) The higher

con-centration of IL-6 reported in the CSF of TBI patients

suggests an intrathecal production of this factor, which has

been reported to occur in several models of experimental

TBI (Woodroofe et al 1991) Hans and coworkers (1999b)

demonstrated that IL-6 mRNA was upregulated in cortical

and thalamic neurons as well as in infiltrating macrophages

as early as 1 hour postinjury, whereas IL-6

immunoreactiv-ity and protein levels in rat CSF peaked within the first 24

hours after TBI In a study by Kossmann et al (1996), a

temporal relationship between high CSF concentrations of

IL-6 and the detection of NGF in CSF was noted in

brain-injured patients In vitro experiments using CSF from

these patients showed that IL-6 stimulated cultured

pri-mary mouse astrocytes to produce NGF, an effect which

could be significantly attenuated by preincubation with

anti-IL-6 antibodies (Kossmann et al 1996) IL-6 released

in the CNS has also been shown to be associated with the

systemic acute phase response after severe TBI in humans

(Kossmann et al 1995), indicating that centrally released

immune mediators may evoke a substantial systemic

re-sponse to trauma, with profound implications for the

out-come of TBI patients

In a study subjecting IL-6 knockout mice and their

wild-type (WT) littermates to a cortical freeze lesion,

Penkowa and colleagues (1999) found that the lack of

IL-6 greatly reduced reactive astrogliosis and the appearance

of brain macrophages around the lesion site IL-6

defi-ciency also caused greater lesion-induced neuronal cell

loss These observations highlight the dual role that this

pleiotropic cytokine may play in the posttraumatic

cas-cade Conversely, a recent study using IL-6 knockout

mice subjected to TBI showed that these animals were

not significantly different from their WT littermates in

their response to TBI in several outcome measures, such

as neurologic motor function, BBB permeability,

intrace-rebral neutrophil infiltration, and neuronal cell loss

(Sta-hel et al 2000b) Therefore, IL-6 appears to promote an

inflammatory response to trauma but at the same time

also seems to enhance neuronal survival The exact

na-ture, severity, and type of the CNS injury as well as the

timing of IL-6 release may be decisive for either a

detri-mental or a beneficial effect of this factor after TBI

IL-10 is an anti-inflammatory cytokine that inhibits a

variety of macrophage responses and is also a potent

sup-pressor of T-cell proliferation and cytokine response by

blocking expression of TNF and IL-1 (Benveniste et al

1995; Chao et al 1995) and enhancing synthesis and

se-cretion of their endogenous antagonists (Cassatella et al

1994; Joyce et al 1994) IL-10 also reduces leukocyte–

endothelial interactions that promote procoagulation

(Jungi et al 1994) and extravasation of blood cells (Krakauer

1995; Perretti et al 1995) Subcutaneous or intravenousadministration of IL-10 before or after TBI in rats signif-icantly reduced TNF expression in the injured cortex andenhanced neurological recovery (Knoblach and Faden1998) Although a combination of IL-10 systemic admin-istration and hypothermia was expected to exhibit in-creased neuroprotection after TBI, this combinationtherapy resulted in adverse effects when compared withhypothermia alone after TBI (Kline et al 2002)

TNF-α, a proinflammatory cytokine with cytotoxicproperties, has been detected in the CSF and the serum ofpatients with TBI (Goodman et al 1990; Ross et al.1994) Csuka and coworkers (1999) found increased pat-terns of TNF-α concentrations among 28 TBI patientsover a 3-week study period These observations togetherwith the detection of TNF-α mRNA and protein in theinjured rodent brain suggest that this cytokine is mark-edly and acutely unregulated in brain tissue after TBI(Fan et al 1996; Shohami et al 1994) Increases in TNF-

α expression were immunohistochemically localizedprimarily to neurons and to a much lesser extent to astro-cytes after TBI in rats (Knoblach et al 1999) The upreg-ulation of TNF-α therefore appears to be an endogenousresponse of the brain parenchyma to trauma, as opposed

to being the result of a nonspecific invasion of the brain

by peripheral blood leukocytes TNF-α may mediate ondary damage after TBI through several different mech-anisms (for a review see Shohami et al 1999) This cyto-kine is known to affect BBB integrity, leading to cerebraledema and infiltration of blood leukocytes, and it hasbeen shown to induce expression of the receptor for thepotent secondary inflammatory mediator anaphylatoxin(or C5a) on neurons (Stahel et al 2000a) Furthermore,TNF can induce both apoptosis and necrosis via intracell-ular signaling pathways (Reid et al 1989)

sec-On the basis of the above evidence, it is not surprisingthat both direct and indirect inhibition of TNF-α activityhas been shown to be beneficial in experimental TBIstudies Administration of the immunosuppressive pen-toxifylline as well as of TNF-α binding protein, a physio-logical inhibitor of TNF-α activity, has been shown tosignificantly diminish edema formation and enhance mo-tor function recovery after experimental TBI (Shohami et

al 1996) These studies suggest a detrimental effect ofTNF-α in the sequelae of TBI However, more recent in-vestigations in genetically engineered animals point againtoward a dual role of this cytokine after TBI Mice defi-cient in both subtypes of TNF receptors have been shown

to be more vulnerable to TBI than WT animals, ing a neuroprotective role for TNF-α in the pathologicalsequelae of brain injury (Sullivan et al 1999) Moreover,brain-injured TNF-deficient (–/–) mice show an early

suggest-benefit from the lack of TNF, with neurologic motor

scores initially better than brain-injured WT controls

However, this trend is reversed from 1–4 weeks after

in-jury: the injured WT animals recover while the TNF –/–

mice do not (Scherbel et al 1999) Taken together, these

data suggest that a differential role of this cytokine may be

dependent on the temporal profile of its release within the

posttraumatic cytokine cascade These data suggest that

antagonism of TNF activity may be beneficial for the

in-jured brain in the acute posttraumatic period but may

prove deleterious if extended into the chronic phase,

when it may be essential for initiating a regenerative

re-sponse Alternatively, another possibility allows that the

expression of TNF receptor subtypes may change over

the acute and chronic postinjury phases, and recent

evi-dence suggests that neuronal death or survival in response

to TNF-α may depend on the particular subtype that is

predominantly expressed (Yang et al 2002)

The role of the kallikrein–kinin system in

inflamma-tion and pain has led to the development of bradykinin B2

receptor antagonists In a multicenter clinical trial,

Bradycor (CP-0127) was found to be neuroprotective in

severely brain-injured patients (Marmarou et al 1999),

and a recently developed nonpeptide B2 receptor

antago-nist (LF-16–0687Ms) was shown to reduce TBI-induced

brain vasogenic edema in rats (Stover et al 2000b)

Inhi-bition of the posttraumatic inflammatory cascade

contin-ues to be a viable avenue of development of

neuroprotec-tive compounds

Recently, several groups have implicated modulation

of the endocannabinoid system, including the

arachi-donoylethanolamide (anandamide), 2-arachidonyl

glyc-eryl ether, and 2-arachidonoyl glycerol (2-AG) ligands

and their cognate CB1 and CB2 receptors, as a possible

therapeutic paradigm after TBI Cannabinoid receptor

agonists have been shown to inhibit glutamatergic

synap-tic transmission (Shen et al 1996) and protect neurons

from excitotoxicity in vitro (Shen and Thayer 1998) It

has also been suggested that cannabinoid receptor

ago-nists can counteract the vasoconstrictory effects of

endo-thelin-1 (Chen and Buck 2000), a molecule that may play

a role in TBI-induced ischemia Gallily et al (2000) have

reported that 2-AG suppresses formation of ROS and

have noted lower levels of TNF-α in the serum of

LPS-treated mice after administration of 2-AG (Gallily et al

2000) Most recently, it has been demonstrated that levels

of anandamide (Hansen et al 2001; Panikashvili et al

2001) and 2-AG (Panikashvili et al 2001) are significantly

elevated after TBI, and if this response is further

aug-mented by administration of synthetic 2-AG, injured

an-imals exhibit a significant reduction in brain edema,

re-duced lesion volume, and quicker recovery of neurological

function (Panikashvili et al 2001) Collectively, these dataprovide a rationale for the use of cannabinoids in thetreatment of TBI Indeed, dexanabinol (HU-211), a non-psychotropic cannabinoid, has been reported to have asignificant neuroprotective role after TBI In a random-ized, placebo-controlled Phase II clinical trial, patientswith severe closed head injury receiving an intravenousinjection of dexanabinol showed significantly better ICP,cerebral perfusion pressure, and clinical outcome (Knol-ler et al 2002)

Neurotrophic Factors

The peptide growth factors, including NGF, basic blast growth factor (bFGF), ciliary neurotrophic factor(CNTF), brain-derived neurotrophic factor (BDNF), in-sulinlike growth factor (IGF-1), neurotrophin-3 (NT-3),neurotrophin-4/5 (NT-4/5), and glial-derived neu-rotrophic factor (GDNF), all function in the normalbrain to support neuronal survival, induce sprouting ofneurites (neuronal plasticity), and facilitate the guidance

fibro-of neurons to their proper target sites during ment (for a review see Huang and Reichardt 2001) (Fig-ure 39–3) Several recent studies suggest that some ofthese neurotrophic factors are altered after brain injury,perhaps as a response designed to facilitate neuronal re-pair and reestablish functional connections in the injuredbrain DeKosky and colleagues (1994) observed a markedincrease in NGF mRNA and protein expression in theacute posttraumatic period after both weight-drop andTBI in rats, whereas a significant reduction in NGFp75NTR receptor was observed in the chronic postinjuryperiod after TBI in rats (Leonard et al 1994) Goss et al.(1997) observed an increase in the antioxidant enzymeglutathione peroxidase and catalase concentrations over atime course that reflected the temporal increase in NGFand hypothesized that the upregulation of NGF after TBIserves as a mediator of oxidative homeostasis by inducingthe production of ROS The same authors suggested thatastrocytes are the major source of NGF upregulation af-ter TBI in the rat (Goss et al 1998) Using models of TBI,several laboratories reported that intraparenchymal ad-ministration of NGF can attenuate cognitive but not neu-robehavioral motor deficits or hippocampal cell loss afterTBI in rats (Dixon et al 1997; Sinson et al 1995, 1996)(see Table 39–2) Follow-up studies demonstrated thatcentral NGF administration can reduce the extent of apo-ptotic cell death in septal cholinergic neurons after TBI(Sinson et al 1997) and can reverse the trauma-induced re-ductions in scopolamine-evoked acetylcholine release(Dixon et al 1997) Recently, both rat- and hippocampal-

develop-derived precursor (HiB5) cells and human NT2M

neu-rons, transfected to express NGF and transplanted into the

injured cortex, have been shown to improve cognitive and

neurological motor function and reduce CA3 neuronal cell

death when transplanted into the injured cortex at 24 hours

after TBI in rats (Longhi et al., in press; Philips et al 2001)

BDNF, a member of the neurotrophin family of

trophic factors, has almost 50% homology with NGF

(Leibrock et al 1989), although BDNF is more abundant

in the adult brain than NGF (Maisonpierre et al 1990)

BDNF has two receptors: the high-affinity receptor TrkB

and the low-affinity receptor p75NTR (Table 39–3) A

sec-ond ligand, NT-4/5, also binds to TrkB with high affinity

and is expressed ubiquitously within the adult rodent

brain (Timmusk et al 1993); however, changes in

NT-4/5 expression have not been evaluated to date in an perimental model of TBI, nor has its therapeutic value af-ter TBI been evaluated and documented BDNF and itsprimary receptor, the TrkB tyrosine kinase, are found inmany areas of the brain, including the hippocampal CA3and the dentate hilus regions (Nawa et al 1995; Yan et al.1997a, 1997b) (see Table 39–3) BDNF regulates the gen-eration and differentiation of neurons during develop-ment, axon growth and growth cone mobility, and synap-tic plasticity (Lu and Chow 1999; McAllister et al 1999;Schinder and Poo 2000), and it was recently shown topromote neurogenesis from adult stem cells in vivo (Ben-raiss et al 2001; Pencea et al 2001)

ex-Initial observations suggested that a rapid increase inBDNF mRNA levels occurs in injured brain as early as 1

F I G U R E 3 9 – 3 Growth factors and their cognate receptors

BDNF = brain-derived neurotrophic factor; bFGF = basic fibroblast growth factor; FGFR = FGF receptor; GDNF = glial-derived neurotrophic factor; GFR = GDNF family receptor; IGF = insulin-like growth factor; IGFBR= IGF receptor; NGF = nerve growth factor; NT-3 = neurotrophin-3; VEGF = vascular endothelial growth factor.

hour after TBI and persists for days (Griesbach et al.

2002; Hicks et al 1997; Oyesiku et al 1999; Truettner et

al 1999) with a concomitant acute increase in trkB

mRNA levels within the hippocampus (Hicks et al 1998;

Mudo et al 1993) Animals in which milder injuries are

induced exhibit unilateral, rather than bilateral, increases

in BDNF and trkB mRNA levels (Hicks et al 1999b)

Another study reported significantly decreased levels of

BDNF mRNA in the injured cortex at 72 hours and

in-creased levels in other adjacent cortical areas from 3–24

hours postinjury (Hicks et al 1999a) This apparent

dis-crepancy in observations could be a function of

differ-ence of injury models, the time points chosen for

obser-vation if expression levels prove to be biphasic, or

differences in the sensitivity of assays used to measure the

reported changes In one of the few treatment studies,

administration of BDNF directly into injured brain

pa-renchyma failed to attenuate behavioral deficits or

histo-logical damage after TBI in rats (Blaha et al 2000)

Al-though there are many possible explanations of why

BDNF administration failed to confer neuroprotection

after TBI, one interesting possibility is that injury

selec-tively upregulated the truncated form of trkB rather than

the full-length form

The neurotrophic factors GDNF, neurturin,

per-sephin, and artemin are included among the TGF-β

super-family (for a review see Airaksinen et al 1999) (see Table

39–3) The GDNF family ligands signal via a

two-compo-nent receptor complex that includes c-Ret, a

protoonco-gene and tyrosine kinase receptor (Durbec et al 1996;

Trupp et al 1996), and GDNF family receptor-α

(GFR-α), a glycosyl-phosphatidylinositol-anchored protein that

is devoid of an associated kinase activity (Baloh et al 1997;Jing et al 1996) (see Table 39–3) The GDNF transcripthas been detected in all major brain regions (Schaar et al.1993), including those regions vulnerable to TBI, andGDNF and neurturin exert neurotrophic effects in a widespectrum of neuronal populations (Arenas et al 1995;Henderson et al 1994; Kotzbauer et al 1996; Lin et al.1993; Mount et al 1995) GDNF appears to reduceNMDA-induced calcium influx via the activation of themitogen-activated protein kinase pathway and as a resultattenuates NMDA-induced excitotoxic cell death (Nicole

et al 2001) Such activity suggests that GDNF may be anespecially attractive candidate for reducing excitotoxicneuronal death after TBI if administered at acute timepoints when excitotoxicity is predominant (see above)

To date, little evidence exists documenting changes inexpression of GDNF or its receptors after TBI A singlepreliminary report suggests that GDNF protein levels, asmeasured by quantitative enzyme-linked immunosorbentassay (ELISA), increase approximately 2.5 times in the in-jured cortex after TBI in rats (Shimizu et al 2002) WhenGDNF or artificial CSF is infused continuously for 7 daysinto the lateral ventricle after TBI in rats, a significant de-crease was observed in injury-induced CA2 and CA3 cellloss (Kim et al 2001) Likewise, when an adenovirus engi-neered to confer GDNF expression was injected into thesensorimotor cortex 24 hours before freeze-lesion injury inrats, a significant reduction in lesion volume and the num-ber of cells immunopositive for iNOS, activated caspase-3,and TUNEL was observed (Hermann et al 2001).The polypeptide FGF-2 (also known as bFGF) is amember of the FGF family, which currently includes sevenmembers (for a review see Gimenez-Gallego and Cuevas1994), all of which possess the ability to stimulate fibroblastgrowth with the notable exception of FGF-7 FGF-2 binds

to four cell surface receptors that are expressed as a number

of splice variants (for a review see Nugent and Iozzo 2000),

of which FGFR1 is the high-affinity receptor (for a reviewsee (Stachowiak et al 1997) (see Table 39–3) FGF-2 andFGFR1 proteins, as well as their mRNAs, have been dem-onstrated to be expressed in both the developing and theadult brain (for a review see Unsicker et al 1991) FGF-2has been implicated as a neurotrophin, a neurite branchingfactor, an enhancer of synaptic transmission, and a neuralinducer (Abe and Saito 2001)

Initial reports demonstrated an increase in FGF-2protein after TBI at the lesion periphery in cells withmorphological features consistent with reactive astro-cytes (Finklestein et al 1988) Further analysis resulted

in the observation that FGF-2 mRNA, FGF-2 protein,FGFR1 mRNA, and FGFR1 protein were increased as

T A B L E 3 9 – 3 Neurotrophic receptor families and

endogenous ligands in the central nervous system

Types of receptors

and neurotrophic

factor family

Neurotrophic factors as ligand

Tyrosine kinase receptors —

NGF receptor family Neurotrophins (NGF, BDNF,

NT-3, NT-4/5) FGF receptor family FGF-2

Ret receptor family GDNF, neurturin, artemin,

persephin Insulin receptor family Insulin, IGF-1

VEGF receptor family —

Note BDNF=brain-derived neurotrophic factor; FGF =fibroblast growth

factor; GDNF=glial cell-line–derived neurotrophic factor;

IGF=insulin-like growth factor; NGF=nerve growth factor; 3=neurotrophin 3;

NT-4/5= neurotrophin 4/5; VEGF=vascular endothelial growth factor.

early as hours postinjury and persisted for at least 2 weeks

postinjury (Frank and Ragel 1995; Reilly and Kumari

1996; Yang and Cui 1998) Furthermore, at acute time

points, FGF-2 co-localized with MAC-1

immunoposi-tive microglial/macrophages, whereas at later time

points FGF-2 co-localized with reactive astrocytes

(Frautschy et al 1991; Reilly and Kumari 1996), neurons,

and vascular endothelial cells (Logan et al 1992; Yang

and Cui 1998) Given the early expression patterns and

the localization of the FGF-2 ligand and its receptors,

these data collectively suggest that one of the roles of

FGF-2 induction after TBI may be in stimulating

astro-gliosis Additionally, recent evidence suggests that

FGF-2 is necessary and sufficient to stimulate proliferation and

differentiation of neuroprogenitor cells in the adult

hip-pocampus after various brain insults (Yoshimura et al

2001) and may regulate postlesional sprouting (Ramirez

et al 1999) Dietrich et al (1996) reported that acute

ad-ministration of FGF-2 could attenuate cortical cell loss

after TBI in rats, whereas McDermott et al (1997)

dem-onstrated that delayed intraparenchymal administration

of FGF-2, beginning 24 hours after TBI, can

signifi-cantly improve posttraumatic cognitive deficits in the rat

Exogenous FGF-2 was also shown to reduce

hippocam-pal cell death after diffuse brain injury (Yang and Cui

2000) Furthermore, the combination of FGF with

hypo-thermia (Yan et al 2000) may increase the magnitude of

the protective effect

IGF-I is polypeptide hormone that shares several

structural features with insulin (Isaksson et al 1991) and

is produced in many tissues in the body including the

brain (Bondy and Lee 1993; Rotwein et al 1988; Werther

et al 1990) In rodents, expression of mRNA for IGF-I is

highest during the development of the nervous system,

but it is also expressed in many regions of the adult rat

brain (Bondy and Lee 1993) IGF-I readily crosses the

BBB and as a result the brain is influenced by the

concen-tration of circulating IGF-I (Armstrong et al 2000; Carro

et al 2000; Pulford and Ishii 2001) IGF-I exerts its

ac-tions primarily via the type I IGF receptor, although

in-teractions with the insulin receptor have been reported

(Butler et al 1998; Lamothe et al 1998) (see Table 39–3)

IGF binding proteins (IGFBPs) modulate the interaction

of IGF-I with its receptor (Ocrant et al 1990) IGFBP-2,

IGFBP-4, and IGFBP-5 are the predominant binding

proteins in the brain and can bind IGF-I, thus rendering

it biologically inactive (Dore et al 2000) However, there

is also evidence suggesting that some IGFBPs potentiate

the effect of IGF-I, possibly by presenting IGF-I more

ef-ficiently to its receptor, protecting IGF-I from

degrada-tion, or transporting IGF-I to regions of injury (Beilharz

et al 1998; Guan et al 2000)

Initial reports of IGF-I expression after TBI ized expression to reactive astrocytes from acute timepoints to 1 month after injury (Garcia-Estrada et al.1992) In a different model of TBI, a dramatic increase

local-in the expression of IGFBP-2 and IGFBP-4 mRNAwas observed between 24 hours and 7 days within in-jured cortex, whereas increased expression of IGF-1mRNA peaked at 3 days postinjury (Sandberg Nor-dqvist et al 1996) This increase in IGFBP-4 mRNA iscompletely blocked by administration of the NMDA an-tagonist MK-801, and injury-induced IGF-1 mRNA ex-pression is blocked by both MK-801 and the AMPA an-tagonist CNQX (Nordqvist et al 1997), suggestingthat activation of glutamatergic systems may influenceIGF expression or function in the setting of brain in-jury In contrast, another study provided evidence thatMK-801 reversed a measured decrease in IGF-IImRNA levels after injury (Giannakopoulou et al.2000) Further studies using IGFBP-1 overexpressingtransgenic mice observed that reactive astrogliosis, re-flected by morphology and glial fibrillary acidic proteinexpression in astrocytes in response to a mechanical le-sion, was substantially less in transgenic compared with

WT mice (Ni et al 1997), suggesting that IGF-I mayplay a role in astrogliosis

Saatman and colleagues (1997) showed that ous subcutaneous administration of IGF-I for 7 daysdramatically accelerated neurological motor recoveryand attenuated cognitive deficits after TBI in rats APhase II clinical trial demonstrated that continuous in-travenous IGF-I in moderate to severe TBI patients re-sulted in greater weight gain, higher glucose concentra-tions and nitrogen outputs, and moderate to goodGlasgow Outcome Scale scores at 6 months (Hatton et

continu-al 1997) Taken together, the above data suggest thatsystemic IGF-I therapy should be further evaluated as apotential candidate for neuroprotection after clinicalbrain injury

The VEGF family currently includes six knownmembers VEGF, or VEGF-A as it is now designated,was the first member of the VEGF family to be discov-ered and is also the best-characterized member (for areview see Neufeld et al 1999) VEGF-A is established

as a major inducer of endothelial cell proliferation, gration, sprouting, neural tube formation, and perme-ability during embryonic vasculogenesis and in physio-logical and pathological angiogenesis These effects aremediated mainly by the VEGF receptor VEGFR-2 (seeTable 39–3) More recently, VEGFR-1 was suggested

mi-to be an important mediami-tor of stem cell recruitment(Eriksson and Alitalo 2002; Jin et al 2002) A role ofVEGF in BBB breakdown and angiogenesis/repair has

7 2 7

40 Prevention

Elie Elovic, M.D.

Ross Zafonte, D.O.

PREVENTABLE INJURY IS one of the most

signifi-cant health care issues in the United States Estimates

place the annual cost in the United States to be $260

bil-lion, and 30% of all life years lost before age 75 years are

a result of injury The Centers for Disease Control and

Prevention (CDC) estimates that during 1995, 2.6

mil-lion hospital discharges and more than 36 milmil-lion

emer-gency department visits occurred as a result of injury

(Centers for Disease Control and Prevention 2001) At

the more serious end of the spectrum, injury is the cause

of 150,000 deaths every year and is the leading source of

death for Americans ages 1–44 years (Nguyen et al 2001)

Looking specifically at traumatic brain injury (TBI),

the figures are only slightly less daunting, with TBI one of

the leading causes of death and disability for children and

young adults in the United States The CDC estimates

that in the United States between 1 million and 1.5 million

people seek medical attention secondary to TBI In

addi-tion, there are 230,000 hospitalizations and 80,000–

90,000 people who develop disability secondary to TBI

every year (Centers for Disease Control and Prevention

2001; McDeavitt 2001; Thurman et al 1999) TBI also

ac-counts for more than 50,000 deaths annually, which

con-stitutes one-third of all injury-related deaths Current

es-timates place the number of Americans who have some

disability as a result of TBI at roughly 5.3 million (Centers

for Disease Control and Prevention 2001) Schootman

and Fuortes (2000) reported that during the years 1994–

1997, 1.4 million people in the United States sought care

either at a doctor’s office or the emergency department

secondary to TBI, whereas Guerro et al (2000) reported

TBI incidence between 392 and 444 per 100,000

popula-tion when emergency department visits are included

These numbers suggest a much higher incidence of TBI

than those based on deaths and hospital admissions

Looking at deaths and hospital admissions, TBI dence is close to 100 per 100,000 (Thurman et al 1999).This is a drop of 50% from previous reports of rates of 200per 100,000 during the 1970s and 1980s (Annegers et al.1980; Centers for Disease Control and Prevention 2001;Jagger et al 1984; Kraus et al 1984) The decrease may inpart be a result of insurance’s influence on admission deci-sions, in addition to prevention efforts This is in contrast

inci-to TBI mortality, because a reduction in the incidence ismore likely a result of prevention efforts In 1980, the rate

of TBI-related mortality in the United States was 24.7 per100,000 This had fallen 20% by 1994 to a rate of 19.8.Motor vehicle–related mortality showed the greatest de-cline With the advent of air bags, seat belts, and childsafety seats, mortality dropped 38% from 11.1 to 6.9 per100,000 between 1980 and 1994 (Thurman et al 1999)

TBI Versus Other Disabling Conditions

TBI has often been called the silent or invisible epidemic(Centers for Disease Control and Prevention 2001), thestepchild that has only received minimal public awarenessand dedication of financial resources to its treatment andprevention To obtain a better perspective on this state-ment, one can compare TBI incidence to other conditionsthat have greater notoriety despite a lower incidence TheBrain Injury Association of America has made substantialeffort to spread the word and inform the lay and scientificpublic about TBI incidence The association has a Web sitethat actively deals with the issue (Brain Injury Association

of America 2001b) At this time, the annual incidence ofTBI is greater than that of the more widely known condi-tions of spinal cord injury, breast cancer, multiple sclerosis,and human immunodeficiency virus (HIV) (Figure 40–1)

The magnitude of TBI-related mortality as compared

with these other conditions is quite striking As compared

with the 50,000 deaths that occur each year as a result of

TBI, the number of HIV-related deaths during 1999 was

16,273 (U.S Department of Health and Human Services

2001), whereas 43,700 people died during 1999 from

breast cancer (American Cancer Society 2001) What may

be most striking for HIV information is that the mortality

rate in 1999 is a substantial drop from the 1995 high of

50,610 HIV-related deaths (U.S Department of Health

and Human Services 2001) With dedication to

preven-tion, treatment, and increased public awareness, a similar

drop in the personal suffering and economic loss of TBI

may also be possible

Economics of TBI and Its Prevention

Because TBI often occurs in the very young, the cost to

society in lost years of productivity and years of dependent

care can be enormous Estimates of work years lost because

of TBI run as high as 2.6 million, which accounts for 58%

of all injury-related losses reported (McDeavitt 2001) Max

et al (1991) reported that the cost associated with TBI in

1988 dollars was $44 billion With the enormous personal

suffering, loss of life, and economic hardship on society, the

fact that many of these often catastrophic events are

pre-ventable only compounds this tragedy

With the competition for dollars in today’s world, the

cost-benefit ratio of preventive efforts is an issue of some

importance Some prevention techniques are widely cepted in society today, such as childhood vaccinations and

ac-flu vaccine, as they have proven to be efficacious both nancially and as a vehicle for health maintenance This hasbeen proven to be true with injury prevention as well Pe-diatricians who administer injury prevention counseling tofamilies with children younger than 4 years have demon-strated a 13 to 1 benefit to cost ratio (Miller and Galbraith1995) Bicycle helmets for children ages 4–15 years havealso shown great benefit For every $1 spent on bicycle hel-mets, society saves $2 in direct medical costs, $6 in futureearnings, and $17 in quality of life The use of child safetyseats for children younger than 4 years has also proven to

fi-be of substantial fi-benefit to society If child safety seats areused, the savings in direct medical costs, future earnings,and quality of life are $2, $6, and $25, respectively (Miller

et al 2000) Finally, Graham et al (1997) demonstratedthat the use of seat belts and air bags demonstrated a costeffectiveness that matched any other prevention effort thataddressed any medical or public health issues

What Is Prevention?

People use the word prevention for many activities Speed

limits, highway barriers, and highway designs to lessen thenumber of motor vehicle accidents (MVAs) are clearly aimed

at injury prevention So too are seat belts and air bags, forthough they do not play a major role in accident prevention,they minimize personal injury to passengers in the car once

an accident occurs The development of advanced traumacare to mitigate further injury is also a form of prevention.Although all three of these examples are geared towardinjury prevention, they clearly have differences As a result,the distinction between primary, secondary, and tertiary pre-vention has been made Primary prevention efforts aredirected to prevent the injury from occurring Other exam-ples of primary prevention include fall-proofing homes, traf-

fic laws and their enforcement, salting of ice-covered roads,and education about drinking and driving In contrast, sec-ondary efforts lessen an injury’s effect once it has occurred,with helmets, automobile design, and air bags examples ofsecondary prevention Development of advanced traumacare and emergency management services are examples oftertiary prevention (Nguyen et al 2001)

Injury Control Theory

Originally, the general belief was that TBI was a result ofaccidents, which implied that all persons had equal prob-ability of sustaining injury (Elovic and Antoinette 1996;

F I G U R E 4 0 – 1 A comparison of traumatic brain

injury and leading injuries or diseases: annual

incidence.

AIDS=acquired immunodeficiency syndrome; HIV=human

im-munodeficiency virus.

Source. Brain Injury Association of America, March 2001.

Available at: http://www.biausa.org/word.files.to.pdf/good.pdfs/

2002.Fact.Sheet.tbi.incidence.pdf Accessed March 22, 2004.

Used with permission.

Traumatic brain injuries 1,500,000

Breast cancer 176,300 HIV/AIDS

43,681 Spinal cord injuries 11,000

Multiple sclerosis 10,400

Guyer and Gallagher 1985) Any discussion of TBI

epide-miology, such as the one in Chapter 1, Epideepide-miology,

clearly demonstrates the fallacy of this position There are

certain people who are at higher risk of sustaining injury

As a result, there has been substantial work devoted to the

identification of people at risk and to developing effective

preventive countermeasures (Elovic et al 1996; Teutsch

1992), with a substantial increase in the science of injury

control theory since the 1950s

The relationship between infectious pathogens and

their related illness has been investigated since the time of

Louis Pasteur, more than 100 years ago More than 50

years ago, Gordon first raised the idea that injury can be

studied in the same fashion as infectious illness (Gielen

and Girasek 2001) In 1961, James Gibson introduced the

idea that the energy that induced injury could be studied

as a causative agent similar to an infectious agent (Gielen

and Girasek 2001) Baker (1975) compared the concept of

the epidemiologic model of injury to that of illness by

de-scribing the etiologic agent as one that demonstrates a

negative effect on a host in a particular environment

Haddon Matrix

Further work on the study of injury prevention was carried

out by Haddon, resulting in the construction of the Haddon

Matrix (Haddon 1968) With this model, injury is divided

into three separate areas First is the host; the second is the

vector, or injuring agent; and the third is the environment

that the first two interact within The environment is further

divided into two separate components, physical and social

In addition, the matrix model divides the injury using

tem-poral factors; preinjury, injury, and postinjury This is

com-parable to the primary, secondary, and tertiary prevention

efforts mentioned in the section What Is Prevention?

(Nguyen et al 2001) Using these sets of variables, a table

can be created in which each cell represents an area and a

temporal component All factors related to injury can be

placed into one of the table’s cells An example of this would

be the decreased balance and vision of an elderly person who

sustained a fall In the Haddon Matrix, these items would be

placed in the host, preinjury cell The contribution of the

shag rug that caused the fall would be classified as preinjury,

physical environment The vector in falls is the energy that

is transmitted to the brain tissue Head height is a source of

potential injury before an event Clearly, by standing on a

ladder there is greater potential energy, which places the

host at greater risk The energy is converted to kinetic

energy during a fall that is transmitted to the brain tissue at

impact The distortion of brain tissue and bleeding that

result from the energy transfer can be considered the

postin-jury vector component

Passive Versus Active Strategies

There are two general approaches to the promotion ofinjury prevention, passive and active A passive strategy isone that the host takes no action to use (Gielen et al.2001) and may as a result be more effective than activeinterventions By nature, passive strategies offer protec-tion to a larger percentage of the population (Karlson1992) Some examples of these include air bags, road bar-riers, fingerprint-based gun locks, and car safety engi-neering A system that would not let a driver start his orher car if he or she could not pass a Breathalyzer test isanother example of a passive strategy that would preventthe host from driving while intoxicated Active strategiesare ones that require some action on the host’s part Thedonning of a seat belt, avoiding driving when under theinfluence, motorcycle helmet usage, and car seats are justsome examples of active prevention Although these itemsmay be more effective than passive approaches, their dis-tinct disadvantage is that somehow society must convincethe host to use them

As a result, there is some controversy as to how injuryprevention resources should be applied It is generalknowledge that changing human behavior is a challeng-ing endeavor, and passive interventions aimed at the vec-tor and environment may be the most effective in reduc-ing death and injury (Haddon 1970) That does notnegate the potential benefit of using a combined ap-proach, because the use of one method does not excludethe use of another An example of this is, of course, the use

of seat belts in combination with air bags Each tion method has shown its benefit; however, using bothtogether has been shown to be more effective than eitherone by itself As a result, there is evidence that a combinedapproach of active and passive interventions should beused in a comprehensive approach

preven-Facilitating Active Strategies to Develop Comprehensive Injury Control

How can society develop a comprehensive approach toinjury control? Also, how can society influence the hostthat can be potentially injured to act according to itswishes? These important questions must be answered tomaximize the benefit of an injury control program.The first of these questions can only be answered onceone defines what components are critical to the develop-ment of a comprehensive program Clearly, engineeringsolutions are important components of passive interven-tions such as energy-absorbing car bodies, road barriers,and air bags What methods should be used for the active

strategies? Education is an important component, both at

the individual and community level (Nguyen et al 2001)

However, there is a problem if education is performed

alone without giving the listener some incentive to

change his or her behavior on the basis of the information

presented An example of this was the early public service

announcements that used fear as a potential motivator for

increased seat belt usage, but they were largely ineffective

(Roberston et al 1974) Education prevention counseling

by health care professionals in a clinical setting has been

proven to be much more effective DiGuiseppi and

Rob-erts (2000), after reviewing many clinical trials, reported

that education counseling was effective in encouraging

the use of automobile restraints

A method to facilitate a host’s compliance with safer

behaviors is to connect them to incentives This can be

accomplished with legislative intervention and

appropri-ate enforcement Community-based intervention

pro-grams combining education with legislative options has

been shown to be effective in increasing bicycle helmet

usage (Klassen et al 2000) Work performed in three

sep-arate Maryland counties explored the issue of children’s

bicycle helmet usage under three separate conditions In

one county, legislation and education were undertaken,

and helmet use increased from 4% to 47% Another

county used education alone and experienced a small,

sta-tistically insignificant increase in usage from 8% to 19%

The third county, which did nothing, actually

demon-strated a decreased rate of helmet usage from 19% to 4%

The third piece of the puzzle to facilitate active

inter-ventions is enforcement of legislation Passing laws

with-out proper enforcement leads to only minimal benefits,

with seat belts being an example By 1984, all passenger

cars were required to have seat belts However, rates of

usage were only 15% This rate increased to 42% by 1987

with a combination of educative efforts and seat belt

leg-islation By 1992, when secondary enforcement laws were

enacted for nonuse of seat belts, usage increased to 62%

A secondary enforcement law is one that allows the giving

of a citation when the driver has been pulled over for

an-other traffic offense This 62% usage rate persisted

through 1998 in the states that used secondary

ment laws In states that have enacted primary

enforce-ment legislation, which allowed ticketing when seat belt

nonuse was the only infraction, usage rates increased to

79% (National Highway Traffic Safety Administration

1999) In summary, facilitation of active prevention

re-quires a combination approach Education, both at a

community and individual level, must be included with

appropriate legislation and its enforcement Standing in

the way of many of these changes is the idea that

preven-tive legislation infringes on personal freedoms The

op-position to gun control by the National Rifle Associationand to helmet laws by motorcycle clubs are just two exam-ples of this problem However, with the great cost to so-ciety, both financially and emotionally, of TBI the gov-ernment has not only the right, but also the obligation, todeal effectively with these issues

TBI Prevention and Motor Vehicles

As the discussion is turned to more specific issues of TBIprevention, it is appropriate to begin with efforts thatinvolve motor vehicles The reasons for this are twofold.First, MVAs are the leading cause of TBI in the UnitedStates (Centers for Disease Control and Prevention2001), with data from state registries reporting that trans-portation accounted for 48.9% of TBIs reported (Thur-man et al 1999) Second, there is evidence that preven-tion efforts aimed at reduction of transportation-relatedmortality have been efficacious There was a 38%decrease in motor vehicle–related deaths from 1980 to

1994 (Centers for Disease Control and Prevention 2001).Transportation-related TBI prevention efforts can beapproached by looking at both passive and active meth-ods, as well as using the Haddon Matrix discussed in anearlier section

Air Bags and Seat Belts

Air bags are a classic example of passive prevention thatexerts its influence at the time of incident Jagger (1992)has strongly advocated their use and has stated thatinstalling them as standard equipment in the front seats ofpassenger cars would have a greater effect on TBI thanany other prevention method She estimated that 25% ofpatients admitted to a hospital secondary to TBI had sus-tained an injury that air bags are designed to protectagainst

Air bags are automatic protection systems that are signed to protect during a frontal collision They are de-signed to deploy when a car hits a similarly sized vehicle

de-at 20–30 miles an hour, or a brick wall de-at 15 miles an hour.They provide a protective cushion between occupantsand the car’s interior, slowing the energy transfer that oc-curs at impact This occurs within 1/20 of a second afterimpact, and deflation begins within 4/20 of a second, withthe entire cycle completed within 1 second This allowsthe driver to maintain control of the car and avoids trap-ping of passengers (National Highway Traffic Safety Ad-ministration 2002)

With the exception of some recently designed impact bags, air bags have not been engineered to protectthe occupants from side impact, rear, or rollover events One

side-of the major sources side-of crash mortality is ejection from the

vehicle, and this is another event that air bags are not

de-signed to protect against In addition, during a rollover, car

occupants can be thrown against hard objects such as the

steering wheel that can cause further injury Instead, it is the

seat belt that is most protective for these events, and air bags

should not be considered as a solo item, but should be used

in conjunction with seat belts The combined utilization of

seatbelts and air bags has been proven to be the most

protec-tive In the National Highway Safety Administration’s Third

Report to Congress in 1996, air bags were reported to

re-duce fatalities in pure frontal crashes, excluding rollovers, by

34% and 18% in near-frontal collisions In this analysis, the

fatality rate using air bags alone ws reduced by 13%, taking

all crashes into consideration This is in comparison with a

45% reduction rate using lap-shoulder belts alone and a

50% reduction using both modalities (National Highway

Traffic Safety Administration 2002)

The information gathered by the National Highway

Traffic Safety Administration’s National Accident Sampling

System’s Crashworthiness Data System regarding the effect

of air bag and seat belt use on moderate and severe injuries

is eye opening (National Highway Traffic Safety

Adminis-tration 2002) A moderate injury was defined as having a

Maximum Abbreviated Injury Score of 2 or greater, and a

severe injury was defined as one with a Maximum

Abbrevi-ated Injury Score of 3 or greater On the basis of

informa-tion collected on two car crashes, the effect of air bags alone

was not statistically significant, with a reported reduction of

18% and 7% in moderate and severe injuries, respectively

In contrast, the use of a lap-shoulder belt system alone

re-sulted in a 49% and 59% reduction in moderate and severe

injuries, respectively A 60% reduction was found when

used in combination Before one draws the incorrect

con-clusion that air bags have little value, one must remember

that all body systems are not equally important when

dis-cussing injury severity Gennarelli et al (1989) reported that

TBI is the major source of mortality in multiple trauma

pa-tients Therefore, a system that has its greatest effect on

head and brain injury may play an important role The

combination of manual lap-shoulder belt and air bag

duced moderate and severe brain injuries 83% and 75%,

re-spectively This compares to 59% and 38% reductions in

moderate and severe brain injuries, respectively, when a

lap-shoulder belt was used alone Although the data suggest that

lap-shoulder belts provide a greater level of protection than

air bags, the reader must of course be aware that the key

phrase is “when used”; the passive nature of the air bag

sys-tem clearly underscores its importance, whereas the greater

protection afforded by the lap-shoulder belt means society

must encourage its use

Although both air bags and seat belts have a net

posi-tive benefit from an injury prevention standpoint, there

are problems associated with their use Seat belts havebeen associated with various injuries, especially whenused improperly Some of the injuries reported includespinal injuries; brachial plexopathy; liver lacerations;small bowel tears; traumatic hernias; aortic and other vas-cular, ocular, and facial injuries; neck sprains; cardiac in-juries; kidney injuries; neck injuries; sternal fracture; lungperforation; chest injuries; and placental and fetal injury(Agran et al 1987; Appleby and Nagy 1989; Arajarvi et al.1987; Blacksin 1993; Bourbeau et al 1993; Chandler et al.1997; Hall et al 2001; Holbrook and Bennett 1990; Im-mega 1995; Johnson and Falci 1990; Kaplan and Cowley1991; Lubbers 1977; May et al 1995; Restifo and Kelen1994; Santavirta and Arajarvi 1992; Shoemaker and Ose1997; Verdant 1988; Warrian et al 1988; Yarbrough andHendey 1990) In particular, injuries to children haveprompted development of car seats and booster seats thatare discussed in the section Car Seats and Air Bags Likeseat belts, air bags have also been shown to be a potentialsource of injury Problems with air bags have includedskull fracture and facial injury (Bandstra and Carbone2001; Murphy et al 2000; Rozner 1996), ocular trauma(Ghafouri et al 1997; Lueder 2000; Ruiz-Moreno 1998;Stein et al 1999; Zabriskie et al 1997), burn injuries(Conover 1992; Ulrich et al 2001; White et al 1995), ex-tremity fracture (Kirchhoff and Rasmussen 1995; Ongand Kumar 1998), chest injuries, spinal injury (Giguere et

al 1998; Traynelis and Gold 1993), ear injury and ing loss (Beckerman and Elberger 1991; Kramer et al.1997; Morris and Borja 1998), and reflex sympathetic dys-trophy (Guarino 1998; Shah and Weinstein 1997) Chil-dren, in particular, are at greatest risk of injury from airbag deployment (“Air-bag-associated” 1995; From theCenters for Disease Control and Prevention 1995; “Up-date” 1996; From the Centers for Disease Control andPrevention 1997; Giguere et al 1998; Marshall et al.1998; McCaffrey et al 1999; Totten et al 1998) Properlyand improperly positioned children have sustained severeand sometimes fatal injuries from air bag deployment(Angel and Ehlers 2001; “Air-bag-associated” 1995; fromthe Centers for Disease Control and Prevention 1995;

hear-“Update” 1996; from the Centers for Disease Controland Prevention 1997; Giguere et al 1998; Lueder 2000;Marshall et al 1998; McCaffrey et al 1999; Morrison et

al 1998; Willis et al 1996) As a result, special effortshave been directed to ensure the safe coexistence of chil-dren and air bags

Motorcycles

Motorcycles account for 6% of all transportation dents in the United States, but may be the most danger-ous form of transportation (Flint 2001) From 1979

acci-through 1986, more than 15,000 motorcycle deaths were

associated with brain injury (Elovic et al 1996), and from

1989 through 1991, almost 10,000 people died in the

United States as a result of a motorcycle accident (“Head

injuries” 1994) This is also true in New Zealand as

doc-umented by Begg et al (1994) who reported that between

1978 and 1987 the incidence of motorcycle-related injury

hospitalization was 80.4 per 100,000 whereas the

mortal-ity rate was 3.6 per 100,000 A study from Connecticut

(Braddock et al 1992) reported a lower fatality rate of 1.2

per 100,000 and a hospitalization rate of 24.7 per

100,000, with 22% of those injuries occurring in the

head, brain, or spinal area

In 1994, some of the factors that were linked to

mo-torcycle-related fatal trauma included driver error (76%),

with excessive speed found commonly (Elovic et al 1996),

and elevated blood alcohol levels and a failure to use a

hel-met Alcohol is a major problem, and the highest rate of

alcohol use among all methods of transportation is in

mo-torcycle drivers (Peek-Asa and Kraus 1996) who also have

the highest rate of legal intoxication of any group

Helmet usage is another critical item that plays a major

part in brain injury and mortality prevention In 1982,

Heilman et al reported that helmetless riders were 2.3

times as likely to have a head, neck, or facial injury than

those wearing a helmet, and they were also 3.19 times as

likely to have a fatal injury Bachulis et al (1988) reported

similar results, with the rate of brain injury twice as likely

and severe brain injury six times more likely when helmets

were not worn Reporting on data from Colorado, Gabella

et al (1995) reported that the risk of brain injury was 2.5

times as high when helmets were not worn Ferrando et

al (2000) demonstrated a 25% reduction in

motorcycle-related fatalities after implementation of a mandatory

hel-met law in Spain, whereas Chiu et al (2000) reported a

33% reduction in brain injuries, better outcomes, shorter

hospital lengths of stay, as well as decease in injury severity

in Taiwan after implementation of a mandatory helmet law

Many other investigators around the world have

demon-strated similar results after the implementation of

manda-tory helmet laws The rate of overall fatalities, TBI-related

fatalities, overall TBI injury severity (Chiu et al 2000;

Fer-rando et al 2000; Fleming and Becker 1992; Kraus et al

1994; Muelleman et al 1992; Rowland et al 1996; Sosin et

al 1990; Tsai and Hemenway 1999), length of

hospitaliza-tion (Muelleman et al 1992; Rowland et al 1996), and

overall cost to society (Muelleman et al 1992; Rowland et

al 1996; Vaca and Berns 2001) are all decreased as a result

of helmet law legislation

Despite the strength of the evidence, motorcycle

hel-met laws are not pervasive in the United States As of

No-vember 2000, only 20 states had legislation that required

all motorcycle riders to wear helmets, whereas another 27states had laws that required them for teenagers Threestates had no legislation at all (Vaca and Berns 2001) This

is a step backward from the 1970s

In 1967, the federal government through the ment of Transportation required that all states pass a mo-torcycle helmet law If a state did not comply, it would bepunished by a loss of federal safety funds As a result, by

Depart-1975 47 states had mandatory helmet laws However, in

1975 Congress rescinded the requirement Within 3years, more than one-half of the states with mandatoryhelmet laws repealed them (Vaca et al 2001) Opponentsargued that adults have the right of choice in this country,and the government has no right to interfere, but the sim-ple facts do not support this position First, helmet use hasbeen shown to decrease with the abolition of mandatoryhelmet laws In Texas and Arkansas, where the helmet ratewas at 97% before legislation repeal, usage rate dropped

to 66% and 52%, respectively, within 9 months of the peal Data from the Arkansas Trauma Registry demon-strated that there was also an increase in overall injuriesand brain injuries, and a larger proportion of motorcy-clists injured had brain injuries (Vaca et al 2001) Recentwork from Miami Dade County by Hotz et al (2002)demonstrated decreased helmet use and increased inci-dence of brain injury and lethality post repeal of manda-tory helmet laws The authors noted that helmet usedropped from 83% to 56%, whereas the number of fatal-ities and brain injuries increased substantially

re-There is also the financial cost that is borne by societywhen helmet laws are repealed In Texas, as a result of therepeal of the motorcycle helmet laws, the cost of motor-cycle-related TBI increased 75% to more than $32,000,whereas the median cost increased 300% to $22,531.These numbers are greater than the required insurancecoverage of the majority of these riders, and therefore so-ciety has been forced to pick up this cost (National High-way Traffic Safety Administration 2000) The riders’freedom to choose has resulted in increased cost borne bythe society in general

Finally, the issue of alcohol and motorcycle driving is

an important one Alcohol has a tremendous effect on allmotor vehicle–related trauma This may be even truer formotorcycle-related trauma because the handling of a mo-torcycle requires greater coordination and judgment thandriving a car Sun et al (1998) demonstrated that al-though many of the drivers of both cars and motorcyclesbrought into the trauma center are under the influence,motorcyclists have a lower level as compared with otherdrivers As a result, it may be warranted to set an evenlower level for acceptable blood alcohol levels for motor-cycle drivers

Falls have been identified as the second most common

source of TBI in numerous studies (Annegers et al 1980;

Cooper et al 1983; Jagger et al 1984; Kraus et al 1984;

Sosin et al 1989; Tiret et al 1990; Whitman et al 1984)

The greatest number of falls occurs in young children

younger than age 5 years and in the elderly (Elovic et al

1996) A survey from Switzerland (Addor and

Santos-Eggimann 1996) demonstrated that 66% of all injuries

that occurred to preschoolers were as a result of a fall,

whereas the work of Benoit et al (2000) demonstrated

that falls accounted for 41% of admissions to a suburban

hospital for children ages 0–14 years Among older adults,

more than 60% of fall-related deaths occur in people

older than 75 years (National Center for Injury

Preven-tion and Control 2002) A study from New Zealand

dem-onstrated that falls were far more likely to be the cause of

injury for elderly patients admitted to the intensive care

unit as compared with young patients (Safih et al 1999)

Fatalities as a result of TBI are most common in those

older than age 75 years, and falls are the number one

cause of TBI in the elderly (Centers for Disease Control

and Prevention 2001) Overall, the economic impact of

falls can be enormous In 1994, the estimated cost in the

United States from falls approached $20.2 billion

(Koplan and Thacker 2000)

Efforts at fall prevention are clearly critical and have

shown efficacy in Sweden (Bjerre and Schelp 2000) as

well as in an American urban neighborhood (Davidson

et al 1994; Durkin et al 1998) Because the pattern of

those injured secondary to fall is bimodal, so must be the

prevention efforts For children, issues such as

protec-tive surfaces on playgrounds (Consumer Product Safety

Commission 2001a); having a safe, 12-inch border of a

soft material such as wood chips, sand, or rubber around

play areas (Consumer Product Safety Commission

2001b); adult supervision; and equipment maintenance

and age appropriateness are beneficial (“Playground

Safety” 1999) Educational efforts directed at both

chil-dren and communities have also shown possible benefits

(Gresham et al 2001; Jeffs et al 1993) Certainly, with

falls from windows accounting for 11% of falls in a

sub-urban neighborhood (Benoit et al 2000), safety devices

can be helpful

Falls involving the elderly require different solutions

Miller et al (2000) mentioned four common issues that

have been implicated in an increased risk of falls in the

el-derly They are 1) postural hypotension, 2) gait and

bal-ance instability, 3) polypharmacy, and 4) the use of

sedat-ing medications Other host-related factors that have

been associated with falls in the elderly include

musculo-skeletal or neurological abnormalities, visual bances, dementia (National Center for Injury Preventionand Control 2001), and frailty (Speechley and Tinetti1991) The environment plays an important part in falls

distur-of the elderly The National Bureau distur-of Standards has timated that 18%–50% of falls are a result of highlywaxed floors, loose rugs, sharp furniture, poor lighting, orproblems with tubs and showers (Elovic et al 1996).Some of the fall-prevention ideas for the elderly becomequite obvious The elderly should work on areas of phys-ical conditioning; review medications with their pharma-cist or physicians; wear comfortable, gripping shoes; andmodify their environment (Brain Injury Association ofAmerica 2001a) A study by Plautz et al (1996) demon-strated that 10 hours of nonskilled time and $93 of sup-plies per person were all that was needed to make an el-derly person’s environment substantially safer When theenvironment was modified, the rate of falls decreased by60%, from an annual rate of 0.81 falls per person per year

es-to just 0.33 falls

Sports and Recreational Injury

Recreation and sports are an important part of many ple’s lives; however, they can also be a significant cause ofinjury, including TBI (Annegers et al 1980; Elovic et al.1996; Kraus et al 1984; Whitman et al 1984) Themajority of these injuries are, of course, concussions.Unlike musculoskeletal events, the brain cannot be con-ditioned to withstand the energy assault that is the cause

peo-of concussion (Johnston et al 2001) Therefore, theemphasis must instead be directed at efforts to designequipment and structure the individual sports to mini-mize the likelihood of sustaining a TBI This includesproper equipment design such as helmets for contactsports, sport rules that discourage dangerous activities,and training and educational efforts for coaches andparticipants

The importance of dealing with the issue of related trauma and TBI becomes obvious once one looks

bicycle-at the stbicycle-atistics In 1996, more than 500,000 visits to theemergency department were as a result of bicycle-relatedinjuries; almost three-fourths of those injured wereyounger than 21 years In 1997, 817 people riding bicy-cles were killed in an accident between them and a motorvehicle Almost one-third of them were children youngerthan 16 years, and only 3% of those killed were wearing abicycle helmet (Koplan et al 2000) In patients admitted

to a hospital secondary to a brain injury, the risk of death

is 20 times higher for those who did not wear a helmet(Think First Foundation 2004) The use of helmets wouldreduce fatalities by more than 500 and reduce the number