Textbook of Traumatic Brain Injury - part 9 potx

6 1 2 TEXTBOOK OF TRAUMATIC BRAIN INJURYBaclofen Usually after sudden withdrawal Ketamine Also produces hallucinations, crying, changes in body image, and delirium Levodopa Often after

6 1 2 TEXTBOOK OF TRAUMATIC BRAIN INJURY

Baclofen Usually after sudden withdrawal Ketamine Also produces hallucinations, crying, changes in body image, and

delirium Levodopa Often after dosage increase Pentazocine During treatment

Propranolol See above a

Digitalis See above a

Paranoia Asparaginase May be common

Bromocriptine Not dose related Corticosteroids, ACTH See above a

Amphetamines Even at low doses Indomethacin Especially in elderly patients Propranolol At any dose

Sulindac Reported in a few patients Aggression Bromocriptine Not dose related; may persist

Tranquilizers and hypnotics A release phenomenon Levodopa See above a

Phenelzine May be separate from mania Digitalis See above a

Carbamazepine In children and adolescents

Note. ACTH=adrenocorticotropic hormone.

a Same comments apply as for previous reactions on this drug.

Source Reprinted from Dubovsky SL: “Psychopharmacological Treatment in Neuropsychiatry,” in The American Psychiatric Press Textbook of

Neu-ropsychiatry, 2nd Edition Washington, DC, American Psychiatric Press, 1991, pp 694–695 Used with permission.

T A B L E 3 4 – 2 General principles of pharmacotherapy for patients with traumatic brain injuries

Start low, go slow Initiate treatment at doses lower than those used in patients without brain injuries, and raise doses more

slowly than in patients without brain injuries.

Adequate therapeutic

trial

Although patients with brain injuries may be more sensitive to the side effects of many medications, standard doses of such medication may be needed to treat adequately the neuropsychiatric problems of these patients Continuous

reassessment

The need for continued treatment should be reassessed in an ongoing fashion, and dose reduction or medication discontinuation should be attempted after achieving remission of target symptoms Spontaneous recovery occurs, and in such circumstances continued pharmacotherapy is unnecessary.

Monitor drug–drug

interactions

Because patients with brain injuries are often sensitive to medication side effects and because they may require treatment with several medications, it is essential to be aware of and to monitor these patients for possible drug–drug interactions.

Augmentation A patient experiencing a partial response to treatment with a single agent may benefit from augmentation of

that treatment with a second agent that has a different mechanism of action Augmentation of partial responses is preferable to switching to an agent with the same pharmacological profile as that producing the partial response.

Symptom

intensification

If targeted psychiatric symptoms worsen soon after initiation of pharmacotherapy, lower the dose of the medication; if symptom intensification persists, discontinue the medication entirely.

T A B L E 3 4 – 1 Psychiatric side effects of neurological drugs (continued)

multiple anticonvulsants Additionally, alterations of

pharmacodynamics may develop during the

administra-tion of medicaadministra-tions with additive or synergistic clinical

ef-fects (i.e., increased sedative efef-fects when several sedating

medications are administered simultaneously)

If a patient does not respond favorably to the initial

medication prescribed, several alternatives are available If

there has been no response, changing to a medication with

a different mechanism of action is suggested, much as is

done in the treatment of depressed patients without brain

injury If there has been a partial response to the initial

medication, addition of another medication may be useful

The selection of a second supplementary or augmenting

medication should be based on consideration of the

possi-ble complementary or contrary mechanisms of action of

such agents, the individual and combined side-effect

pro-files of the initial and secondary agents, and their potential

pharmacokinetic and pharmacodynamic interactions

Although individuals after TBI may experience

multi-ple concurrent neuropsychiatric symptoms (i.e., depressed

mood, irritability, poor attention, fatigue, and sleep

distur-bances), suggesting a single psychiatric diagnosis such as

major depression, we have found that some of these

symp-toms often persist despite treatment of the apparent

“diag-nosis.” In other words, diagnostic parsimony should be

sought but may not always be the best or most accurate

di-agnostic approach in this population For this reason, the

neuropsychiatric approach of evaluating and monitoring

individual symptoms is necessary and differs from the usual

syndromal approach of the present conventional

psychiat-ric paradigm Several medications may be required to

alle-viate several distinct symptoms after TBI, although it is

prudent to initiate such treatments one at a time to

deter-mine the efficacy and side effects of each prescribed drug

Studies of the effects of psychotropic medications in

patients with TBI are few, and rigorous double-blind

placebo-controlled studies are rare (see Arciniegas et al

2000b) The recommendations contained in this chapter

represent a synthesis of the available treatment literature

in TBI, extensions of the known uses of these medications

in phenotypically similar non–brain-injured psychiatric

populations of patients with other types of brain injuries

(e.g., stroke and multiple sclerosis), and the opinion of the

authors of this chapter We recognize that the

pathophys-iology of these symptoms may differ in patients with TBI,

and, thus, generalization of response to treatment seen in

the context of other forms of brain dysfunction (e.g.,

stroke and Alzheimer’s disease) to TBI may not always be

valid Where there are treatment studies in the TBI

pop-ulation to offer guidance regarding medication

treat-ments, these are noted and referenced for further

consid-eration by interested readers

Neurotransmitter Changes After TBI

Neuropsychiatric symptoms arising from penetrating orfocal trauma, or both, are often understandable given thefunctions known to be subserved by the site of injury (e.g.,behavioral disinhibition and aggression after bilateral orb-itofrontal contusion), but the etiology of cognitive impair-ments after nonpenetrating (or “nonfocal”) injuries is rela-tively less well understood Cytotoxic processes such ascalcium and magnesium dysregulation, free radical–induced injury, neurotransmitter (especially glutamateand cholinergic) excitotoxicity, and diffuse axonal injurybecause of straining and shearing biomechanical forcesmay be produced by nonpenetrating injuries (see Chapter

2, Neuropathology, and Chapter 39, Pharmacotherapy ofPrevention, as well as McIntosh et al 1999 and Halliday

1999 for review) These processes functionally and turally disrupt the neural networks, subserving many crit-ical neuropsychiatric functions (i.e., cognition, emotion,and behavior) Although TBI-induced glutamatergic dis-turbances are almost certainly important in the genesis ofinjury to areas critical to neuropsychiatric function (seeObrenovitch and Urenjak 1997 for review), there are atpresent no therapies available to directly ameliorate neu-ropsychiatric problems predicated on disturbances in thissystem Several studies of neurochemical changes subse-quent to TBI suggest that alterations in neurotransmitterproduction or delivery, or both, occur within these net-works both acutely and chronically and may thereforeplay a role in the development of neuropsychiatric prob-lems after TBI These studies have shown that neu-rotransmitter systems, including norepinephrine, seroto-nin, dopamine, and acetylcholine, are altered by TBI,although the timing of such effects after TBI is important

struc-to consider Multiple pharmacotherapies are available struc-tomodify the function of these neurotransmitter systemsand the neuropsychiatric problems arising from distur-bances within them

In this chapter, we focus on TBI-induced mitter disturbances that are both related to neuropsychi-atric functioning and amenable to modification usingagents presently available These two limits focus thisportion of the discussion on disturbances in dopamine,norepinephrine, serotonin, and acetylcholine

neurotrans-CatecholaminesDiscrete lesions to ascending monoaminergic projectionsmay interfere with the function of systems dependent onsuch afferent pathways (Morrison et al 1979) Monoam-inergic afferents course from the brainstem anteriorly,

6 1 4 TEXTBOOK OF TRAUMATIC BRAIN INJURY

curving around the hypothalamus, the basal ganglia, and

the frontal cortex, placing them in anatomical areas that

are especially vulnerable to the effects of TBI

Two studies found markedly elevated plasma

norepi-nephrine levels after acute brain injury (Clifton et al

1981; Hamill et al 1987) However, most of the studies in

this area suggest only that acute elevations of striatal

do-pamine are predictive of poor recovery from TBI

(Don-nemiller et al 2000; Hamill et al 1987; Woolf et al

1987) Only the study of Tang et al (1997) related

alter-ations in dopamine function to cognitive performance,

and their findings suggest that dopamine antagonism, but

not agonism, may improve performance speed on the

wa-ter maze task in experimentally injured mice The

ob-served pairing of striatal hyperdopaminergia with

post-TBI memory deficits in mice is puzzling in light of the

long-standing inference of reduced dopamine function

after TBI in humans It is noteworthy that this inference

is drawn from the observation of cognitive benefits after

augmentation of dopaminergic function in persons with

TBI, an observation for which several hypotheses (e.g.,

correction of primary dopamine deficiency or correction

of secondary dopamine dysfunction because of

dysregula-tion in complementary neurotransmitter systems) may be

generated Few other experimental injury studies

(Egh-wrudjakpor et al 1991; Kmeciak-Kolada et al 1987;

Tang et al 1997) offer support for the hypothesis that

ce-rebral catecholamine levels are chronically altered by

TBI No human studies have demonstrated a clear

rela-tionship between in vivo markers of dopaminergic

func-tion and long-term cognitive deficits in traumatically

brain-injured humans Thus, the extent of dopaminergic

and noradrenergic dysfunction in the late period after

TBI remains uncertain, and the implications of such

find-ings with respect to long-term neuropsychiatric

distur-bances require further study Nonetheless, the

observa-tion of cognitive improvements (e.g., arousal, speed of

processing, attention, and, perhaps, memory) among

some persons with TBIs during treatment with agents

that increase dopaminergic neurotransmission suggests

that dopamine dysfunction (primary, secondary, or both)

may play an important role in the genesis of cognitive

im-pairment after TBI

Serotonin

Serotonergic projections to the frontal cortical areas are

susceptible to biomechanical injury, and both diffuse

axonal injury and contusions may produce dysfunction in

this neurotransmitter system Secondary neurotoxicity

that is caused by excitotoxins and lipid peroxidation may

also damage the neuronal systems that mediate serotonin

(Karakucuk et al 1997) and perhaps also norepinephrine.Studies of serotonin activity after TBI are somewhat vari-able in their findings, although differences in the method-ology (especially location of cerebrospinal fluid [CSF]sampling) appear to account for many of the differences

in study findings Pappius (1989) demonstrated spread increases in hemispheric serotonin levels afterexperimentally induced brain injury in rats and noted thatincreases in serotonin appeared to produce decreases incerebral glucose utilization Busto et al (1997) found aprompt increase in the extracellular levels of serotonin incortical regions adjacent to the impact site in an experi-mental injury study in rats Tsuiki et al (1995) demon-strated in an experimental injury paradigm that serotoninsynthesis was significantly increased in cortical areasthroughout the injured hemisphere, and particularly inthe dorsal hippocampus and area CA3, the medial genic-ulate, and the dorsal raphe, concurrent to a depression incortical glucose use Eghwrudjakpor et al (1991) demon-strated a rapid increase in hemispheric concentration ofserotonin, dopamine, and norepinephrine shortly afterexperimentally induced TBI in rats, with continuedincreases to three to four times control levels by 24–48hours postinjury These authors also reported significantregional differences in serotonin levels after experimentalTBI, with increases in the hemispheres but decreases inthe spinal cord

wide-This may offer some explanation for the discrepancy

of findings related to CSF serotonin, norepinephrine, anddopamine metabolites after TBI in humans; namely, thatthe site from which samples are obtained may yield sub-stantially different findings Consistent with this experi-mental observation, Vecht et al (1975) and Bareggi et al.(1975) found that lumbar CSF 5-hydroxyindoleaceticacid (5-HIAA) was below normal in conscious patientsand normal in patients who were unconscious DecreasedCSF levels of serotonin were reported by Karakucuk et al.(1997) in 45 adults undergoing minor surgery with spinalanesthesia within 24 hours of TBI However, Porta et al.(1975) demonstrated elevated ventricular CSF 5-HIAAlevels in patients within days of severe TBI Additionally,focal and diffuse lesions may result in differences with re-spect to monoaminergic alterations after TBI For exam-ple, Van Woerkom et al (1977) investigated patients withfrontotemporal contusions and those with diffuse contu-sions They documented decreased levels of 5-HIAA inpatients with frontotemporal contusions but increased 5-HIAA levels in those with more diffuse contusions Insummary, the animal and human studies suggest acute in-creases in hemispheric serotonin levels after TBI and sug-gest that such increases are associated with decreased glu-cose utilization Whether or to what extent similar

changes persist into the late period after TBI remains

un-certain, as does the role of such changes in the genesis of

neuropsychiatric symptoms after TBI

Acetylcholine

Findings from both basic and clinical neuroscience

sug-gest both acute and long-term alterations in cortical

cho-linergic function develop after TBI Multiple animal

studies (Ciallella et al 1998; DeAngelis et al 1994; Dixon

et al 1994a, 1994b, 1997a, 1997b; Saija et al 1988)

dem-onstrate both acute and chronic alterations in

hippocam-pal cholinergic function after experimentally induced

TBI as well as a robust relationship between such

alter-ations in cholinergic function and persistent cognitive

impairments, including memory dysfunction One of the

most compelling demonstrations of relatively selective

cholinergic injury after TBI is the report of Schmidt and

Grady (1995) They induced a fluid-percussion brain

injury sufficient to cause a 13- to 14-minute loss of

right-ing reflex in rats anesthetized with halothane Rats with

experimentally induced midline injury had significant

bilateral reductions in cholinergic neurons, including

reductions in area Ch1 (medial septal nucleus; 36%), Ch2

(nucleus of the diagonal band of Broca; 44%), and Ch4

(nucleus basalis of Meynert; 41%) In animals with

later-alized injuries, similarly severe losses of cholinergic

neu-rons were observed ipsilaterally and lesser (11%–28%)

losses were observed contralateral to the injury site The

authors noted that these losses did not extend to

brain-stem cholinergic nuclei (Ch5 and Ch6), and there were no

observable effects on forebrain dopaminergic or

norad-renergic innervation These findings suggest that

cholin-ergic losses may exceed those of other neurotransmitter

afferents

TBI appears to produce an acute increase in

cholin-ergic neurotransmission followed by chronic reductions

in neurotransmitter function and cholinergic afferents

Consistent with observations in experimental injury

stud-ies, Grossman et al (1975) demonstrated that patients

with TBI had elevated acetylcholine levels in fluid

ob-tained from intraventricular catheters or lumbar puncture

in the acute period after TBI Dewar and Graham (1996)

and Murdoch et al (1998) demonstrated cortical

cholin-ergic dysfunction (loss of cortical cholincholin-ergic afferents

with concurrent preservation of postsynaptic muscarinic

and nicotinic receptors) weeks after severe TBI

Arcinie-gas et al (1999, 2000a, 2001), using the hippocampally

mediated cholinergically dependent P50-evoked

wave-form response to paired auditory stimuli, demonstrated

electrophysiological abnormalities consistent with

re-duced hippocampal cholinergic function in patients with

chronic symptoms of impaired auditory gating, attention,and memory in the late (longer than 1 year) period afterTBI (see Chapter 7, Electrophysiological Techniques)

Pharmacological Treatment of Specific Neuropsychiatric Syndromes

Neuropsychiatric symptoms resulting from the rotransmitter disturbances produced by TBI are amenable

neu-to treatment with a variety of medications Where possible,selection of these medications should be guided by anunderstanding of the relationship between the neurochem-istry most likely related to the symptom, the injury location

in the patient with that symptom, or (preferably) both Inthis section, we review the major neuropsychiatric symp-toms and syndromes after TBI that may respond to medi-cations We also present recommendations for the use ofpsychotropic medications to treat these syndromes as well

as review their significant side effects

Emotional DisturbancesEmotional disturbances, including mood disorders anddisorders of affect regulation, are common conse-quences of TBI and may be detrimental to a patient’srehabilitation and socialization (for reviews on theseissues, see Arciniegas and Topkoff 2000; Arciniegas et

al 2000b; Hurley and Taber 2002; Silver et al 1990,1991) The literature regarding treatment of these con-ditions after TBI is limited when compared with that forphenotypically similar primary psychiatric disorders but

is actively developing

Depression

Depression after TBI can be responsive to macologic treatment Because of the safety profile, selec-tive serotonin reuptake inhibitors (SSRIs) are the pre-ferred medications Cassidy (1989) conducted an opentrial using fluoxetine for eight patients with severe TBIand associated depression He found that two had markedimprovement and three had moderate improvement.One-half of the patients experienced sedative side effects,and three out of the eight patients reported an increase inanxiety Bessette and Peterson (1992) reported the case of

psychophar-a 41-yepsychophar-ar-old wompsychophar-an who experienced psychophar-an episode ofmajor depression after a mild brain injury and respondedfavorably to treatment with fluoxetine, 20 mg/day Wrob-lewski et al (1992a) reported a case in which improve-ment in depression after treatment with fluoxetine, 20mg/day, after treatment with desipramine alleviated

6 1 6 TEXTBOOK OF TRAUMATIC BRAIN INJURY

depressive symptoms but also precipitated posttraumatic

seizures; however, this patient developed seizures while

on fluoxetine as well, prompting the addition of

pheny-toin It is difficult to reach conclusions regarding the

safety (or efficacy) of a medication based on single case

reports Thus, we remain circumspect with regard to the

potential for fluoxetine to lower significantly the seizure

threshold among patients with posttraumatic epilepsy

Nonetheless, the published observation of precipitation

of posttraumatic seizures with both of these generally

well-tolerated agents suggests that the possibility of

alter-ing seizure threshold by their administration should not

be dismissed offhandedly Additionally, the observation

supports the suggestion that this possibility should be

dis-cussed during the process of providing informed consent

to treatment with these (or almost any) antidepressant

agents in this population

Fann et al (2000) described improvement in

depres-sion secondary to mild TBI using sertraline (dose range,

25–200 mg by end of study) in an 8-week,

nonrandom-ized, single-blind, placebo run-in trial conducted on 15

patients diagnosed with major depression between 3 and

24 months after a mild TBI Thirteen (87%) had a

de-crease in Hamilton Rating Scale for Depression score of

50% or more (“response”), and 10 (67%) achieved a score

of 7 (“remission”) or less by treatment week 8 Significant

improvements were also observed in ratings of

psycho-logical distress, anger and aggression, functioning, and

postconcussive symptoms during treatment, and only one

patient discontinued treatment because of side effects In

a subsequent report, Fann et al (2001) described

im-provements in psychomotor speed, recent verbal

mem-ory, recent visual memmem-ory, and general cognitive

effi-ciency as well as improvements in patient perception of

cognitive symptoms as an effect of treatment of post-TBI

depression with sertraline

Turner-Stokes et al (2002) performed an open-label

trial of sertraline for depression after brain injuries,

in-cluding TBI, in 21 adult patients They reported clinical

improvement as assessed by DSM-IV (American

Psychi-atric Association 1994) criteria in all of these patients

Among the 17 patients able to complete the Beck

De-pression Inventory before and after treatment,

signifi-cant decreases in depressive symptoms were associated

with treatment in this group Of these, 11 had failed

pre-vious treatment with a different selective serotonin

reup-take inhibitor

However, Meythaler et al (2001) performed a

pla-cebo-controlled trial of sertraline for arousal and

atten-tional impairments in 11 subjects with severe TBI in the

acute rehabilitation setting and failed to find a statistically

significant treatment effect on these cognitive functions

Horsfield et al (2002) performed an 8-month label study of the effects of fluoxetine, 20–60 mg/day infive patients with TBI and varying levels of depression todetermine whether this medication conferred mood and/

open-or cognitive benefits They observed improvements inmood as well as improvement on several measures of at-tention, processing speed, and working memory in thissmall group of patients They suggested that fluoxetine’sability to stimulate expression of brain-derived neu-rotrophic factor and its specific tyrosine kinase receptor,which has in rodents been demonstrated to produce neu-ritic elongation and increased dendritic branching density

of some hippocampal neurons, may explain the apparentbenefits of this agent on posttraumatic cognitive impair-ments Although their suggestion is intriguing, supportfor it in experimental injury models is lacking For thepresent, it is simpler to interpret their findings as reflect-ing the well-known activating effects of fluoxetine.Kant et al (1998) reported that sertraline may also re-duce irritability and aggression (as assessed using theOvert Aggression Scale—Modified for outpatients) anddepressive symptoms (as assessed using the Beck Depres-sion Inventory) after TBI at doses of 50 mg or greater.Notably, in this study, sertraline appeared to have a morerobust effect on irritability and aggression than on de-pressive symptoms

Although Khouzam and Donnelly (1998) reported areduction in TBI-induced compulsive behavior in re-sponse to treatment with venlafaxine, there are at the time

of this writing no reports offering support for the use ofnewer antidepressants such as venlafaxine or mirtazapine

in the treatment of depression after TBI Common cal experience suggests that many of these agents may beuseful in the treatment of depression after TBI, but theiruse must be undertaken knowing that there has been nopublished information in this population to assist clini-cians in ascertaining the likelihood of benefit and the risk

clini-of adverse consequences Because clini-of the concern abouthepatotoxicity with nefazodone, we would consider thismedication only for individuals who have not been re-sponsive or tolerant to other antidepressants

When using the SSRIs, we would start at equivalentdosages of sertraline, 25 mg, or citalopram, 10 mg, andgradually increase the dose on a weekly basis (i.e., sertra-line, 50 mg for 1 week, then 100 mg, or increase citalo-pram to 20 mg after 1 week) Usual antidepressant dos-ages may be required

Tricyclic antidepressants (TCAs) may not be as tive a treatment for depression after TBI as for primarymajor depressive episodes, and they are associated withincreased risks of adverse events in patients with TBI Sa-ran (1985) conducted a crossover study of phenelzine and

effec-amitriptyline administered at therapeutic doses to 10

pa-tients with “minor brain injury” and 12 papa-tients with

ma-jor depression without TBI All of the patients with mama-jor

depression improved after 4 weeks of amitriptyline, but

none of the TBI patients improved Of note, however, the

patients were reported to be the “melancholic” subtype,

but they did not have significant weight loss or difficulty

sleeping, which are typical symptoms of melancholic

de-pression; therefore, the diagnostic categorization of these

patients must be questioned A subsequent study by

Var-ney et al (1987) found that 82% of 51 patients with major

depressive disorder and TBI who received treatment with

either TCAs or carbamazepine reported at least moderate

relief of depressive symptoms However, Dinan and

Mobayed (1992) subsequently reported 85% of patients

with major depressive disorder responded to

amitrip-tyline, whereas only 31% of similarly depressed TBI

pa-tients responded to this treatment

Nortriptyline and desipramine are used commonly in

clinical practice, but there remains less evidence to guide

their use and with which to assess the risks entailed by their

use in persons with TBI than in other populations

Wrob-lewski et al (1996) performed a modified, blinded, placebo

lead-in treatment study of 10 patients with depression after

severe TBI using desipramine and demonstrated

improve-ment in six of seven patients (86%) able to complete the

study However, three patients (30%) discontinued the

study, including one who developed seizures and one who

developed mania during treatment An additional patient

experienced a seizure during treatment with desipramine

but continued treatment with this medication nonetheless

In a study comparing nortriptyline versus fluoxetine in

poststroke depression, nortriptyline was superior in

effi-cacy to fluoxetine, and fluoxetine demonstrated no benefit

above placebo (Robinson et al 2000) Stroke is not

patho-physiologically equivalent to TBI, and the studies

compar-ing antidepressant efficacy may not be equally applicable to

both populations Both stroke and TBI may produce

dis-crete white matter lesions that interrupt catecholaminergic

or serotonergic pathways (source, projection, or target),

and mood disorders after such injuries may result from

dys-function in these neurotransmitter systems Many persons

with TBI may not have discrete lesions to these systems but

may instead experience diffuse axonal injuries; such injuries

may modestly affect ascending catecholaminergic or

sero-tonergic pathways and also glutmatergically dependent

systems, cholinergic projections, and a host of other

cor-tico-cortico or cortico-subcortical pathways and cortical

and/or subcortical structures Additionally, TBI, but not

stroke, produces bihemispheric injury in this manner

Therefore, the neuroanatomical and neurochemical

conse-quences of TBI may not be the same as those resulting

from stroke That being so, there is reason to predict andalso to explain observed differences in treatment effectsand side effects in these two populations The publishedtreatment data for these two populations suggest the possi-bility that there are differences in TCA efficacy in thesetwo populations (more effective in stroke than in TBI) andalso that there may be a greater risk of adverse effect in TBIpatients

If a heterocyclic antidepressant is chosen, we suggestnortriptyline (initial doses of 10 mg/day), or desipramine(initial doses of 25 mg/day), and a careful plasma moni-toring to achieve plasma levels in the therapeutic rangefor the parent compound and its major metabolites (e.g.,nortriptyline levels 50–150 ng/mL; desipramine levelsgreater than 125 ng/mL) Should the patient become se-dated, confused, or severely hypotensive, the dosage ofthese drugs should be reduced

Depressed mood because of TBI may respond totreatment with methylphenidate Gualtieri and Evans(1988) reported significant improvement on ratings ofmood and cognitive performance among 15 patients withTBI after treatment with methylphenidate using a double-blind, placebo-controlled crossover design study Al-though these results were modest and suggestive of a pos-sible role for methylphenidate in the treatment of themood and cognitive disturbances after TBI, they have of-ten been interpreted as strong evidence of a role for thismedication in the treatment of neuropsychiatric sequelae

of TBI Although other studies offer support for the role

of methylphenidate in the treatment of cognitive ment after TBI (discussed in the section Cognitive Im-pairment), it is not clear if or for how long such benefits

impair-on either mood or cognitiimpair-on might be sustained by thistreatment Common clinical experience suggests thatdextroamphetamine may be similar in its effects on moodand cognition after TBI, but no reports document a clearrole for this medication in the treatment of depression af-ter TBI

Monoamine oxidase inhibitors (MAOIs) are not oftenused in persons with depression after TBI This may re-flect the high likelihood of difficulties with compliance tothe complex dietary restrictions required during use ofthese medications given the cognitive impairments expe-rienced by many TBI patients Additionally, the literatureoffers little support for the effectiveness of these medica-tions in the TBI population In the studies by Saran(1985) and Dinan and Mobayed (1992) noted above,phenelzine was tried unsuccessfully in patients who haddepression after TBI, even among those failing to re-spond to amitriptyline Moclobemide, a selective MAO-

A inhibitor, afforded improvement in 23 of 26 patients(88%) with depression after TBI (Newburn et al 1999)

6 1 8 TEXTBOOK OF TRAUMATIC BRAIN INJURY

Because moclobemide does not affect the isoenzyme

MAO-B, its use does not entail the dietary restrictions

as-sociated with other MAOIs However, moclobemide is

not available in the United States

Electroconvulsive therapy (ECT) remains a highly

ef-fective and underused modality for the treatment of

de-pression in general, and it appears to be an effective

treat-ment of depression after acute TBI (Crow et al 1996;

Ruedrich et al 1983; Zwil et al 1992) Kant et al (1999)

re-ported on the safety and efficacy of ECT in patients with

brain injury in a retrospective review of 11 patients

hospi-talized as a result of neuropsychiatric problems after TBI

Of these subjects, 9 experienced a major depression or

other mood disorder because of TBI All of the patients

with neuropsychiatric problems because of TBI responded

favorably to ECT, as assessed by the Montgomery-Åsberg

Rating Scale for Depression and Global Assessment Scale,

and did so without significant adverse cognitive or physical

sequelae Functional improvement occurred irrespective of

baseline cognitive functioning or severity of injury These

studies suggest that ECT may be a safe treatment for

chronic and severe neuropsychiatric disorders because of

TBI When ECT is used, we recommend treatment with

the lowest possible energy levels that will generate a seizure

of adequate duration (longer than 20 seconds), using

pulsa-tile currents, increased spacing of treatments (2–5 days

be-tween treatments), and fewer treatments in an entire

course (four to six) If the patient also has significant

cogni-tive (especially memory) impairments because of TBI,

nondominant unilateral ECT may be the preferable

tech-nique if this treatment is used in this population

Adverse effects of antidepressants. The most common

and disabling side effects of antidepressants in patients

with neurological disorders are those associated with the

anticholinergic properties of these medications, which

can impair attention, concentration, and memory For

example, patients with Parkinson’s disease have shown

increased confusion when treated with anticholinergic

medications (De Smet et al 1982; Dubois et al 1990)

Experimental evidence in traumatically brain-injured rats

supports this observation (Dixon et al 1994b, 1995), as

does common clinical experience in the treatment of

patients with TBI Such observations are consistent with

the observed effects of both experimental and human TBI

on cortical cholinergic function noted in the section

Ace-tylcholine The antidepressants amitriptyline,

trimip-ramine, doxepin, and protriptyline have high affinities

for the muscarinic receptors; given their strong

anticho-linergic properties, these medications should be

pre-scribed only after careful consideration of alternative

medications

The choice of SSRI may require similar ation; Schmitt et al (2001) demonstrated that healthymiddle-aged adults experienced significantly greater im-pairments of delayed recall in a word learning test duringtreatment with paroxetine, 20–40 mg/day, than duringtreatment with placebo, an effect attributed to paroxe-tine’s nontrivial antimuscarinic properties This study alsodemonstrated significant improvements in verbal fluencyamong healthy middle-aged adults treated with sertraline,50–100 mg, when compared with treatment with placebo,

consider-an effect attributed to sertraline’s dopamine reuptake hibition Whether similar differences in cognitive profilesdistinguish between these and other SSRIs in the TBIpopulation is not yet clear Nonetheless, observations ofdistinct cognitive profiles among these agents may meritconsideration when selecting an agent in this population.Additionally, many antidepressants (e.g., doxepin, am-itriptyline, trimipramine, imipramine, maprotiline, andtrazodone) are highly sedating, resulting in significantproblems of arousal in the TBI patient Again, these med-ications should be prescribed only after careful consider-ation of other therapies

in-TCAs may be associated with nontrivial rates of verse events, particularly seizures Wroblewski et al.(1990) reviewed the records of 68 patients with TBI whoreceived antidepressant and, predominantly, TCA treat-ment for at least 3 months The frequency of seizures wascompared for the 3 months before treatment, duringtreatment, and after treatment Seizures occurred among

ad-6 patients during the baseline period, 1ad-6 during pressant treatment, and 4 after treatment was discontin-ued Fourteen patients (20%) had seizures shortly afterthe initiation of treatment For 12 of these patients, noseizures occurred after treatment with the antidepressantwas discontinued Importantly, 7 of these patients werereceiving anticonvulsant medication before and duringantidepressant treatment Also, the occurrence of seizureswas related to greater severity of brain injury Wroblewski

antide-et al (1992a) also observed seizures in a patient receivingfluoxetine for depression after TBI, suggesting that thismedication, and perhaps other SSRIs, may be associatedwith an increased risk of seizures during antidepressanttherapy after TBI In addition to the TCAs, maprotilineand bupropion are often suggested to be associated with ahigher incidence of seizures in otherwise healthy psychi-atric patients (Davidson 1989; Pinder et al 1977) Suchsuggestions prompt caution before prescribing theseagents in patients with depression after TBI However,Johnston et al (1991), in a 102-site study of 1,986 patientstreated with bupropion for depression, reported seizurerates of 0.24%–0.40%, and, among those receiving 300–

450 mg/day, the cumulative rate of seizure was 0.36%

This large data set suggests that bupropion may not be

more likely to reduce seizure threshold than other

antide-pressants Whether the same is true of bupropion’s effects

on seizure threshold after TBI is not clear at present, nor

are there any data with which to assess the likelihood of

similar problems during treatment with maprotiline in

this population

Among patients with established epilepsy, Ojemann et

al (1987) found that seizure control does not appear to

worsen if psychotropic medication is introduced cautiously

and if the patient is on an effective anticonvulsant regimen

There are, at present, no indications that treatment of

de-pression in patients with posttraumatic epilepsy differs

from that in patients with epilepsy of other etiologies

Al-though we conclude that antidepressants can be used safely

and effectively in patients with TBI, including patients

with posttraumatic epilepsy, we recommend that these

agents be prescribed with caution and that treatment with

them should include assiduous monitoring for adverse

ef-fects, including change in seizure frequency

There are several important drug interactions that

may occur among antidepressants and other drugs

com-monly prescribed for neurological conditions (Dubovsky

1992) Many antiparkinsonian drugs and neuroleptics

have anticholinergic effects that are additive to those of

the antidepressants Antidepressant levels are likely to be

decreased—often below therapeutic range—by the

anti-convulsants phenytoin, carbamazepine, and

phenobar-bital Similarly, antidepressants such as fluoxetine may

raise the plasma levels of the anticonvulsants phenytoin

(Jalil 1992), valproate (Sovner and Davis 1991), and

car-bamazepine (Grimsley et al 1991) Carcar-bamazepine

in-duces the metabolism of sertraline Therefore, patients

receiving treatment with medications that require

ther-apeutic blood level monitoring should have more

fre-quent monitoring when antidepressants are

adminis-tered Although they may be highly efficacious drugs in

patients with primary major depression, MAOIs should

be less frequently prescribed for the treatment of

de-pression in patients with TBI and particularly among

those who are also taking other drugs that affect the

cen-tral nervous system (CNS) For example, interactions

with stimulants such as dextroamphetamine and with

le-vodopa may result in lethal hypertensive reactions (For

a review of the safe use of MAOIs, see Marangell et al

2003.)

Mania

Mania and bipolar disorder are less common

conse-quences of TBI, although we believe they have been

underdiagnosed in these individuals (see Chapter 10,

Mood Disorders, and Hurley and Taber 2002 for review)

Several small case series suggest that lithium carbonatemay be useful for the treatment of mania after TBI,although partial response, relapse of symptoms, or needfor a second mood stabilizer is often observed (Bamrahand Johnson 1991; Parmalee and O’Shanick 1988; Stark-stein et al 1988, 1990; Stewart and Hemsath 1988; Zwil

et al 1993) Lithium has been reported to aggravate fusion in patients with brain damage (Schiff et al 1982)and may relatively easily produce nausea, tremor, ataxia,and lethargy in persons with neurological disorders Inaddition, lithium may lower seizure threshold (Masseyand Folger 1984) Hornstein and Seliger (1989) reported

con-a pcon-atient with preexisting bipolcon-ar disorder who enced a recurrence of mania after closed head injury Thispatient’s mania, before injury, was controlled with lithiumcarbonate without side effects However, subsequent tobrain injury, dysfunctions of attention and concentrationemerged that reversed when the lithium dosage was low-ered Because lithium carbonate may exacerbate cognitiveimpairments or cause confusion, especially in combina-tion antidepressants, anticonvulsants, and antipsychoticmedications, we suggest limiting the use of lithium inpatients with TBI to those with mania or recurrentdepressive illness that preceded their brain damage andwho previously responded well to this treatment Fur-thermore, and to minimize lithium-related side effects,

experi-we begin with low doses (300 mg/day) Patients withmania after TBI may respond to treatment with lithiumdespite relatively low blood levels (e.g., 0.2–0.5 mEq/L),highlighting the need for a “start low, go slow” approach

to the care of these patients

Manic episodes occurring after TBI may also respond

to carbamazepine (Nizamie et al 1988; Stewart and sath 1988), although often only after addition of lithium(Stewart and Hemsath 1988) or antipsychotics (Sayal et al.2000; Starkstein et al 1988) For patients with mania sub-sequent to TBI, carbamazepine should be initiated at adosage of 200 mg bid and adjusted to obtain plasma levels

Hem-of 8–12 µg/mL Because carbamazepine may produce orexacerbate cognitive impairments (Massagli 1991), moni-toring for this effect when using this agent in patients withTBI is suggested Brain damage appears to increase suscep-tibility to neurotoxicity induced by combination therapywith carbamazepine and lithium (Parmelee and O’Shanick1988) As is true for patients without histories of TBI, cli-nicians should be aware of the potential risks associatedwith carbamazepine treatment, particularly bone marrowsuppression (including aplastic anemia) and hepatotoxicity.Complete blood cell counts and liver function tests should

be regularly monitored (Marangell et al 1999) The mostcommon signs of carbamazepine-induced neurotoxicity in-clude lethargy, confusion, drowsiness, weakness, ataxia,

6 2 0 TEXTBOOK OF TRAUMATIC BRAIN INJURY

nystagmus, and increased seizures Pleak et al (1988)

de-scribed the development of mania, irritability, and

aggres-sion with carbamazepine treatment; however, in our

expe-rience, this reaction is unusual

Pope et al (1988) suggested that sodium valproate

may be a useful mood stabilizer for patients with

symp-toms of bipolar disorder after TBI, and Monji et al (1999)

suggested that this benefit may extend to patients with

rapid cycling mood disorders after TBI In Monji et al.’s

retrospective report, patients with such symptoms after

TBI appeared to respond more robustly than those with

similar symptoms in the absence of TBI (88% vs 46%)

The small sample sizes in this study do not permit

extrap-olation of this observation to TBI patients more

gener-ally, but are nonetheless encouraging of the use of this

medication in the TBI population As with

carbamaz-epine, valproate may exacerbate cognitive impairments

(Massagli 1991), and its use should include ongoing

as-sessment of cognition in persons with TBI Valproate is

begun at a dosage of 250 mg bid and gradually increased

to obtain plasma levels of 50–100 µg/mL Tremor and

weight gain are common side effects Hepatotoxicity is

rare and usually occurs in children who are treated with

multiple anticonvulsants (Dreifuss et al 1987)

For mania or manic-like syndromes after TBI that do

not respond to conventional mood-stabilizing therapies,

relatively more novel approaches may be useful to

con-sider Bakchine et al (1989) described a manic-like state

in a 44-year-old right-handed woman with bilateral

or-bitofrontal and right temporoparietal traumatic

contu-sions that responded to clonidine after her behavior failed

to respond to carbamazepine and worsened with

levo-dopa Dubovsky et al (1987), Levy and Janicak (2000),

and others have suggested that verapamil may be a useful

agent for the treatment of mania alone or in combination

with other mood stabilizers To date, there are no studies

of verapamil for the treatment of mania after TBI, but

this agent might be worth considering when other

con-ventional treatments fail or produce intolerable side

ef-fects Clark and Davison (1987) also reported that ECT

effected improvement in manic symptoms after

nonpen-etrating trauma, and the authors suggested that this

ther-apy may be valuable to consider in such cases

Lamotrig-ine, oxcarbazepLamotrig-ine, and gabapentin are other options,

although evidence as to efficacy in individuals with TBI is

not presently available

Affective Dysregulation (Affective Lability and

Pathological Crying/Laughing)

In contrast to mood disorders, conditions in which the

base-line emotional state is pervasively disturbed over a relatively

long period (i.e., weeks), disorders of affect denote

condi-tions in which the more moment-to-moment variation andregulation of emotion is disturbed The classic disorder ofaffective dysregulation is pathological laughing and/or cry-

ing (PLC), also sometimes referred to as emotional nence or pseudobulbar affect Patients with this condition expe-

inconti-rience episodes of involuntary crying and/or laughing thatmay occur many times per day, often provoked by trivial (i.e.,not sentimental) stimuli, are quite stereotyped in their pre-sentation, are uncontrollable, do not evoke a concordantsubjective affective experience, and do not produce a persis-tent change in the prevailing mood (Poeck 1985) In thisclassic presentation, PLC appears to be a relatively infre-quent (5.3%) consequence of TBI (Zeilig et al 1996) Affec-tive lability differs from PLC in that both affective expres-sion and experience are episodically dysregulated, theinciting stimulus may be relatively minor but is often some-what sentimental, and the episodes are somewhat more ame-nable to voluntary control and are less stereotyped How-ever, these episodes do not produce a persistent change inmood and are often sources of significant distress andembarrassment to patients who otherwise (quite correctly)report their mood as “fine” (euthymic) The prevalence ofaffective lability after TBI is not clear, although Jorge andRobinson (2003) suggested a 1-year prevalence of approxi-mately 12% among persons with TBI

Although the neurobiology of mood and affect lation overlap, the treatment of affective dysregulation inpatients with brain injury overlaps but is not identicalwith the treatment of “uncomplicated” depression afterTBI (Lauterbach and Schweri 1991; Panzer and Mellow1992; Schiffer et al 1985; Seliger et al 1992; Sloan et al.1992) The treatment literature overwhelmingly supportsthe use and effectiveness of relatively low doses (belowtypical antidepressant doses) of serotonergically and nor-adrenergically active antidepressants (Andersen et al.1993; Lawson et al 1969; Robinson et al 1993; Schiffer

regu-et al 1985) and to a lesser extent dopaminergic (Udaka regu-et

al 1984) and noradrenergic (Evans et al 1987; Sandykand Gillman 1985) agents for the treatment of PLC andaffective lability Whether the lack of distinct therapiesfor these two disorders of affect reflects inseparable com-monalities in their neurobiology or is instead an artifact ofthe diagnostic heterogeneity of patients included in theavailable treatment reports is unclear (Arciniegas andTopkoff 2000) It is noteworthy that the majority of treat-ment studies of these problems derives from the stroke,and not TBI, literature Nonetheless, similar findings inmultiple case series support the benefit of these agents foraffective lability and PLC after TBI

There are multiple reports of the beneficial effects offluoxetine for “emotional incontinence” secondary to neu-rological disorders (Panzer and Mellow 1992; Seliger et al

1992), including TBI (Nahas et al 1998; Sloan et al 1992).

Brown et al (1998) treated 20 patients with poststroke

“emotionalism” (either PLC or affective lability) with

flu-oxetine in a double-blind placebo-controlled study Those

individuals receiving fluoxetine exhibited statistically and

clinically significant improvement In general, these

inves-tigators began treatment with 20 mg/day of fluoxetine, and

patients often exhibited response within 5 days We have

had similar success with fluoxetine raised to higher doses

(40–80 mg/day) and with sertraline, often starting and

re-maining at 25 mg/day and occasionally increasing

gradu-ally to 100 mg/day A single-case report (Breen and

Gold-man 1997) and a small open-label trial (Muller et al 1999)

demonstrated reductions in affective lability during

treat-ment with paroxetine; the latter of these two reports also

compared the effectiveness of paroxetine and citalopram

for the treatment of affective lability after brain injury and

found both medications effective and citalopram somewhat

better tolerated Although only 2 of 26 patients included in

the series described by Muller et al (1999) were patients

with TBI (the remainder being patients with strokes), both

remained successfully treated for 1 year with paroxetine

and relapsed after drug discontinuation Andersen et al

(1999) also describe improvement in episodic crying after

TBI in a 6-year-old child with citalopram, 2.5 mg daily As

is often seen in the treatment of affective lability, treatment

response occurred within 2 days of beginning treatment, a

response more rapid than that usually encountered in the

treatment of depressed mood or major depressive episode

TCAs may also be effective for affective lability and

PLC Allman (1992) described a marked decrease in

patho-logical laughter in a patient treated with imipramine, 150

mg/day, with improvement occurring by the second week

of treatment Common clinical practice using TCA for

PLC and affective lability after stroke (Robinson et al

1993) suggests that nortriptyline may be of considerable

benefit to patients with these conditions, and often at doses

lower than those generally used to treat major depressive

episodes However, we emphasize that for many patients it

may be necessary to administer these medications at

stan-dard antidepressant dosages to obtain full therapeutic

ef-fects, even when patients begin responding within days of

initiating treatment at relatively low doses

Although psychostimulants and dopaminergic agents

are used most often for the treatment of cognitive

impair-ments or diminished motivation, or both, after TBI, they

may also offer some relief from affective lability during

treatment of these other problems as well Evans et al

(1987) reported reduced affective lability as well as

cogni-tive improvements in a young man treated with

methyl-phenidate or dextroamphetamine during a single-case,

double-blind, placebo-controlled, dose-response study

Gualtieri et al (1989) described a sustained reduction ofagitation and aggression, decreased distractibility, andimprovement in affective stability among 19 of 30 TBIpatients taking amantadine, 50 to 400 mg/day (averagedose of 290 mg/day) Udaka et al (1984) also reported re-ductions of PLC in response to amantadine or levodopa

in approximately 50% of stroke or TBI patients Whenpatients present with affective lability or PLC in addition

to cognitive and/or motivational impairments, phenidate, dextroamphetamine, amantadine, or levodopamay offer some relief from both sets of problems

methyl-In the event that the first-line therapies (i.e., ergically and/or dopaminergically active agents) do notprovide adequate relief from affective lability after TBI,particularly if affective lability is comorbid with posttrau-matic aggression, treatment with mood-stabilizing agentsmay be necessary and of some benefit Glenn et al (1989)described an open-label trial of lithium carbonate for thetreatment of affective instability and aggressive behavior

seroton-in 10 patients (8 TBI and 2 stroke) The patients’ toms included episodic aggressive or self-destructive be-havior, “mood swings,” tearfulness, and euphoria Six ofthese patients demonstrated marked or moderate im-provement in these target symptoms, one improved tran-siently, one failed to respond, and two patients worsenedwith this treatment Three patients were on concomitantneuroleptic therapy and experienced neurotoxic side ef-fects that prompted discontinuation of the lithium Addi-tionally, one patient experienced decreased attentiveness,and one patient experienced a seizure during this treat-ment Lithium levels associated with clinical improve-ment ranged between 0.5 and 1.4 mEq/L

symp-Lewin and Sumners (1992) described a single case port of carbamazepine treatment of posttraumatic “epi-sodic dyscontrol,” a term used in their report to denoteuncontrolled disproportionate episodic violence, depres-sion, tearfulness, and irritability toward and intolerance

re-of others Treatment with carbamazepine, 200 mg/day,produced a good response, with no violent outbursts overthe 12-month period of observation

Both of these reports suggest possible benefit ofmood-stabilizing agents for the treatment of some forms

of affective lability after TBI, especially when mixed withirritability, aggression, or both However, and as notedbefore, a cautious approach to dosing and continuous re-assessment of benefit and adverse effects is needed in thispopulation when using such agents

Cognitive ImpairmentMedication treatments for cognitive impairments afterTBI follow one or both of two major neuropharmacolog-

6 2 2 TEXTBOOK OF TRAUMATIC BRAIN INJURY

ical themes: dopaminergic augmentation or cholinergic

augmentation Because agents augmenting either of these

neurotransmitter systems may improve several types of

cognitive impairments (e.g., impaired attention, speed of

processing, memory, and executive function), this section

is organized by medication type rather than by type of

cognitive impairment The types of cognitive impairments

responsive to each medication are discussed within these

sections accordingly

Methylphenidate and Related Psychostimulants

Psychostimulants, such as dextroamphetamine and

meth-ylphenidate, and dopaminergically active agents, such as

amantadine and bromocriptine, may be useful for the

treatment of diminished arousal, slowed speed of

cogni-tive processing, attentional impairments, apathy,

irritabil-ity, impulsivirritabil-ity, and fatigue after TBI (Table 34–3) (Evans

et al 1987; Glenn 1998; Kraus 1995; Lipper and

Tuch-man 1976; Marin et al 1995; Weinstein and Wells 1981)

and may afford such benefits in both the acute inpatient

rehabilitation and also outpatient settings Stimulants

may also increase neuronal recovery after brain injury

by a variety of dopaminergically mediated mechanisms

(Crisostomo et al 1988)

Stimulant medications act on central monoaminergic

systems in a variety of complex and often reciprocally

in-teractive ways Methylphenidate and dextroamphetamine

increase the release of dopamine and norepinephrine and,

at higher doses, block the reuptake of these monoamines

These agents also appear to inhibit monoamine oxidase,

which, in combination with these other effects, facilitates

increased monoaminergic neurotransmission The effect

of such increases in the ascending reticular activating

sys-tem, the striatum, and the several cortical-subcortical

cir-cuits in which these areas are involved appears to be an

in-crease in arousal, speed of processing, and attention

Kaelin et al (1996) described the effect of phenidate, 15 mg twice daily, on the course of recovery in

methyl-11 patients with TBI during an acute inpatient tion setting Using an A-A-B-A design, they demon-strated that methylphenidate significantly improved at-tention as measured by performance on digit span andsymbol search tasks and was associated with improvedDisability Rating Scale scores Although one subject waswithdrawn from the study because of tachycardia, meth-ylphenidate was generally well tolerated Plenger et al.(1996) demonstrated a significant effect of methylpheni-date on attention, Disability Rating Scale scores, and mo-tor performance during subacute recovery from TBI in arandomized, double-blind, placebo-controlled study.They found that attention and performance were signifi-cantly improved by treatment with methylphenidate atday 30, but were not different from placebo treatment atday 90 In this study, although methylphenidate treat-ment did not affect the ultimate level of recovery on thesemeasures, it did improve the rate of recovery Both studiessuggest that methylphenidate may be used during thepostacute recovery period after TBI to increase the rate ofrecovery, an effect that may facilitate increased involve-ment and compliance with acute rehabilitation and per-haps also permit earlier hospital discharge

rehabilita-Similarly, Gualtieri and Evans (1988) reported icant improvement on ratings of mood and performanceamong 15 patients with TBI after treatment with methyl-phenidate using a double-blind, placebo-controlled,crossover design study Although these results were mod-est and suggestive of a possible role for methylphenidate

signif-in the treatment of the neurobehavioral sequelae of TBI,they have often been interpreted as strong evidence for arole for this medication However, in a similarly designedstudy performed several years later, Speech et al (1993)found no effect of methylphenidate on attention, learn-ing, processing speed, or social interaction in a group of

12 brain-injured patients treated a year or more after theirinjuries More recently, Whyte et al (1997) performed arandomized, double-blind, placebo-controlled, repeatedcrossover design study to assess the effect of methylphen-idate on attention in TBI patients referred for treatment

of attentional impairment In this study, methylphenidatehad no significant effect on any aspect of attention but didsignificantly improve speed of processing

Dextroamphetamine is frequently used in the ment of attention and memory impairment after TBI and

treat-is thought to have additional beneficial effects on sion, anergia, and impaired motivation However, a thor-

depres-ough MEDLINE-based literature search undertaken at the

time of this writing yielded only two reports to support itsuse in this population The first report (Evans and Gual-

T A B L E 3 4 – 3 Medications to treat impaired

cognition and arousal

Drug

Initial dose

Maximum dose

Methylphenidate 2.5 mg bid 20 mg tid

Dextroamphetamine 2.5 mg bid 20 mg tid

Amantadine 100 mg qam 200 mg bid

Bromocriptine 2.5 mg qam 20 mg tid

Sinemet (levodopa/carbidopa) 10/100 tid 25/250 qid

Modafinil 100 mg qam 200 mg bid

Donepezil 5 mg qd 10 mg qd

tieri 1987) described improvement in verbal memory and

learning skills in response to treatment with either this

agent or methylphenidate in a single adult male treated in

the late postinjury period The second report (Hornstein et

al 1996) reviewed the use of dextroamphetamine in the

treatment of individuals during acute rehabilitation after

TBI Of the 27 patients so treated, 15 appeared to benefit

from treatment with dextroamphetamine as measured by

the Glasgow Outcome Scale

Protriptyline, a secondary amine tricyclic agent, has

also been suggested to have sufficient psychostimulant

properties to permit its use for anergia and diminished

mo-tivation in TBI patients (Wroblewski et al 1993) Reinhard

et al (1996) administered amitriptyline (one patient) and

desipramine (two patients) and found improvement in

arousal and initiation after TBI They hypothesized that

this effect resulted from the noradrenergic effects of the

TCA Showalter and Kimmel (2000) reported

better-than-expected improvements in level of arousal in 9 of 13 severe

(Rancho Los Amigos Scale I–III) TBI patients taking

lam-otrigine during the postacute recovery period (up to 10

months) They suggested that lamotrigine’s ability to block

sodium channels and inhibit glutamate release may prevent

or facilitate recovery from injury; although not directly

ac-tivating, lamotrigine may permit more rapid emergence

from deeper stages of diminished arousal after TBI than

might occur spontaneously Pachet et al (2003) also

re-ported improvements in cognition and other

neurobehav-ioral functions (as assessed by the Functional

Indepen-dence Measure) in a single case study in a 40-year-old man

with severe TBI treated with lamotrigine for

approxi-mately 4 months in the late (1.0–1.5 years) period after his

injury Additional studies are needed to ascertain the

valid-ity of this suggestion

The published literature is quite variable with regard to

the beneficial effects of psychostimulants on cognitive

im-pairments after TBI In light of the lack of in vivo evidence

of long-term dopaminergic or noradrenergic dysfunction

after TBI, the variability of benefit in the published reports

is not surprising At present, it appears that some patients

may experience cognitive improvements during treatment

with psychostimulants To the extent that improved arousal

or speed and efficiency of information processing can

im-prove attention and memory, methylphenidate and related

psychostimulants may be of benefit to some cognitively

im-paired TBI patients However, additional studies are

needed to clarify the role of these agents in the treatment

of cognitive impairment after TBI before formal guidelines

can be offered regarding their use

Unlike most other medications, stimulants begin to take

effect within a relatively short time (0.5–1.0 hour) and lose

effect after a few hours Thus, the goal is to first determine

the effective dosage and then determine the frequency ofdosing Many individuals need repeat dosing every 3–4hours We suggest using an initial dosage of methylpheni-date, 5 mg, or dextroamphetamine, 5 mg There are nowavailable multiple formulations of longer acting methyl-phenidate or dextroamphetamine preparations (such asAdderall, Concerta, and Metadate) Although no studieshave been conducted on these formulations, some individu-als may experience longer duration of response

In clinical practice, careful assessment of arousal, speed

of processing, and attention should be undertaken beforeand serially during treatment with these agents Althoughsuch assessments may be difficult (Whyte 1992), they areimportant to perform to determine whether these medica-tions impart sufficient benefit to merit their continued use

in a given patient Assessment with appropriate chological tests may be particularly helpful in determiningresponse to treatment with these agents

neuropsy-Other Dopaminergically Active Agents

Lal et al (1988) reported on the use of dopa (Sinemet) in the treatment of 12 patients with braininjury (including anoxic damage) Levodopa is a dopa-mine precursor that, when coupled with carbidopa todecrease the extent of its metabolism in the periphery,increases dopamine levels in the CNS With treatment,patients exhibited 1) improved alertness and concentra-tion; 2) decreased fatigue, hypomania, and sialorrhea; and3) improved memory, mobility, posture, and speech Dos-age administered was 10/100 mg to 25/250 mg qid.Bromocriptine is sometimes used as a psychostimu-lant in light of its effects on dopamine function when used

levodopa/carbi-at higher doses At such doses, it appears to act directly onpostsynaptic dopamine receptors—particularly dopaminetype 2 (D2) receptors—and serves as an agonist in dopa-minergically mediated systems At low doses, bromocrip-tine acts as a presynaptic D2 agonist and thereby reducesdopaminergic release and function in dopaminergicallymediated systems Its net effect at midrange doses appears

to be that of dopamine agonism (Berg et al 1987) Eames(1989) suggested that bromocriptine may be useful intreating cognitive initiation problems of brain injury pa-tients who are at least 1 year subsequent to injury He rec-ommended starting at 2.5 mg/day with treatment for atleast 2 months at the highest dose tolerated (up to 100mg/day) Other investigators found that patients withnonfluent aphasia (Gupta and Mlcoch 1992), akineticmutism (Echiverri et al 1988), and apathy (Catsman-Berrevoets and Harskamp 1988) improved after treat-ment with bromocriptine Parks et al (1992) suggestedthat bromocriptine exerts specific effects on the frontallobe, thus increasing goal-directed behaviors In the larg-

6 2 4 TEXTBOOK OF TRAUMATIC BRAIN INJURY

est study of bromocriptine in this population, McDowell

et al (1998) studied 24 subjects using a counterbalanced,

double-blind, placebo-controlled crossover design

Bro-mocriptine improved performance on some frontally

me-diated tasks such as executive function and dual-task

per-formance but did not improve working memory No

other effects on cognition were demonstrated Unlike the

other psychostimulants, bromocriptine has not been

demonstrated to have a consistent effect on affective

labil-ity or mood disorders because of TBI

Amantadine may be beneficial in the treatment of

an-ergia, abulia, mutism, and anhedonia subsequent to brain

injury (Chandler et al 1988; Gualtieri et al 1989; Nickels

et al 1994; Van Reekum et al 1995) Kraus and Maki

(1997) administered amantadine, 400 mg/day, to six

pa-tients with TBI Improvement was found in motivation,

attention and alertness, as well as executive function

These authors also reported that amantadine reduced

im-pulsivity and emotional (affective) lability The

mecha-nism of action of amantadine is not entirely clear but may

involve increased dopamine release, decreased

presynap-tic dopamine reuptake, stimulation of the dopamine

re-ceptors, and/or enhancement of postsynaptic dopamine

receptor sensitivity In addition, amantadine is an

N-methyl-D-aspartate glutamate receptor antagonist (Weller

and Kornhuber 1992) As such, amantadine may inhibit

N-methyl-D-aspartate receptor–mediated stimulation of

striatal acetylcholine release Although amantadine does

not possess direct anticholinergic activity per se at

con-ventional therapeutic doses, it is not uncommon for

pa-tients treated with this agent to develop

anticholinergic-like symptoms Amantadine is often started at a dose of 50

mg bid and increased every week by 100 mg/day to either

symptomatic improvement or medication intolerance In

our experience, amantadine, 100 mg twice daily, is often

sufficient to impart maximal benefit without undue side

effects When higher doses are necessary, the maximum

dosage of amantadine should not exceed 400 mg/day

Adverse effects of psychostimulants and dopaminergic

agents. Adverse reactions to psychostimulants and

dopaminergic agents are most often related to increases in

dopamine activity Dextroamphetamine and

methylpheni-date have the potential to produce paranoia, dysphoria,

agi-tation, and irritability, although these adverse effects are in

practice uncommon at the doses typically used to treat

cog-nitive impairment after TBI Side effects of bromocriptine

include sedation, nausea, psychosis, headaches, and

delir-ium Amantadine may cause confusion, hallucinations,

edema, and hypotension; these reactions occur more often

in elderly patients than in younger patients Because

depressed mood and increased fatigue may develop after

dis-continuation of psychostimulants and other activatingagents, these medications should be discontinued gradually.Clinicians are sometimes reluctant to make use of psy-chostimulants out of concern that they might lower seizurethreshold in patients with TBI, because at least a subgroup

of this population appears to be at increased risk for traumatic seizures (see Chapter 16, Seizures) Wroblewski

post-et al (1992b) examined changes in seizure frequency afterinitiation of methylphenidate among 30 patients with bothsevere brain injury and posttraumatic seizures The seizurefrequency was monitored for 3 months before treatmentwith methylphenidate, 3 months during treatment, and 3months after treatment was discontinued They found thatwhereas only 4 patients experienced more seizures duringmethylphenidate treatment, 26 had either fewer or thesame number of seizures during treatment Although manypatients in this study were treated concomitantly with an-ticonvulsant medications that may have conferred someprotection against the development of seizures, 13 patientsnonetheless experienced fewer seizures when treated withmethylphenidate The authors of this study concluded thatthere was no increased risk of lowering seizure thresholdduring methylphenidate treatment even in this group ofTBI patients at high risk for seizures

Similarly, in a double-blind, placebo-controlled study ofthe effects of methylphenidate (0.3 mg/kg body weight bid)

in 10 children with well-controlled seizures and deficit disorder, no seizures occurred during the 4 weeks oftreatment with either active drug or placebo (Feldman et al.1989) Dextroamphetamine has been used adjunctively inthe treatment of refractory seizures (Livingston and Pauli1975), and bromocriptine may also have some anticonvul-sant properties (Rothman et al 1990) It seems, therefore,that this class of medications is generally well tolerated withrespect to its effects on seizure frequency and may in somepatients be associated with reduced seizure frequency Oneexception to this generality is amantadine, which may lowerseizure threshold (Gualtieri et al 1989); we also have ob-served several patients who had not experienced seizures formonths before the administration of amantadine but whohad a seizure within weeks after its prescription Althoughamantadine may be of benefit for diminished arousal, atten-tion, and executive function for some TBI patients, caution

attention-is indicated in patients with a hattention-istory of pre- or posttraumaticepilepsy or among patients at high risk for this latter condi-tion (see Chapter 16, Seizures, for a discussion of risk factorsfor posttraumatic epilepsy)

Ace-tylcholine, both animal and human studies support this

suggestion Additionally, the susceptibility of TBI

patients to exacerbation of cognitive impairments during

treatment with anticholinergic medications also suggests

that these patients may have a relatively reduced reserve

of cholinergic function Several reports describe cognitive

improvements after administration of physostigmine,

both in the acute (Bogndanovitch et al 1975) and

post-acute (Eames and Sutton 1995; Goldberg et al 1982)

injury period Levin et al (1986) performed a

double-blind, placebo-controlled study of combined oral

physo-stigmine and lecithin in 16 patients with cognitive

impair-ment after moderate to severe TBI Sustained attention

on the continuous performance test was more efficient

under physostigmine than placebo, and lecithin did not

appear to increase this effect Cardenas et al (1994), in a

double-blind, placebo-controlled, crossover design study

of physostigmine, placebo, and scopolamine (a

cholin-ergic antagonist) in 36 males with memory impairment of

at least 3 months’ duration after TBI demonstrated

improved memory scores on the long-term storage

com-ponent of the Selective Reminding Test in 44% of

sub-jects during treatment with oral physostigmine but not

placebo or scopolamine Although physostigmine may be

of benefit to cognitively impaired TBI survivors, the

sys-temic toxicity associated with this medication limits its

acceptability as a treatment in this population; we do not

recommend using physostigmine for the treatment of

cognitive impairment after TBI

The second-generation cholinesterase inhibitors

(e.g., tacrine, donepezil, rivastigmine, and galantamine)

may be similarly useful, but donepezil is the only agent for

which there are published reports supporting use in the

TBI population Taverni et al (1998) described

improve-ments in refractory memory impairimprove-ments on the

River-mead Behavioral Memory Test and Ross Immediate

Pro-cessing Assessment in the late postinjury period in two

traumatically brain-injured patients; these benefits were

apparent after approximately 3 weeks of treatment with

donepezil, 5 mg/day Whelan et al (2000) performed an

open-label study of donepezil in 53 outpatients receiving

care for long-term cognitive and neuropsychiatric

prob-lems after TBI Patients treated with donepezil, 5–10 mg

daily, for an average of 12 months were rated by clinicians

as improved A subset (22) of these patients were assessed

with the Wechsler Adult Intelligence Scale—Revised and

demonstrated improvements in full-scale IQ Although

these improvements occurred well after the period during

which spontaneous recovery and “practice effects” might

offer better explanations for them, the design of the study

offers only suggestion of benefit with this treatment

Masanic et al (2001) described significant improvements

in learning and short- and long-term recall on the ReyAuditory Verbal Learning Test and the complex figuretest, and a trend toward improvements in behavior as as-sessed using the Neuropsychiatric Inventory, in four pa-tients treated with donepezil, 5–10 mg daily

Kaye et al (2003) performed an 8-week, open-labelstudy of 10 persons with remote (1–5 years; mean = 1.2years) TBI in an outpatient setting using a forced titrationprotocol of donepezil (5 mg/day for 4 weeks followed by

10 mg/day for 4 weeks) Subjects ranged in age from 26 to

60 years (mean age=41 years), and included six with mild,one with moderate, and three with severe TBI Eight sub-jects completed the study; one subject was dropped fromthe study due to treatment noncompliance, and one sub-ject discontinued treatment due to intolerable gas-trointestinal side effects Among those completing thestudy, ratings of Clinical Global Impression improved, al-though not necessarily as a function of improvements inmemory The authors reported that Clinical Global Im-pression improvements instead appeared to reflect thesubject reports of improvements in “focus, attention, andclarity of thought.” They noted that several subjects re-ported being better able “to keep multiple ideas in mindsimultaneously,” and that subjects’ family members fre-quently described “improved socialization.”

Morey et al (2003) studied the effectiveness of donepezilfor the treatment of chronic memory impairments in agroup of seven patients with TBI Subjects were on average

33 months postinjury (range=20–65 months) and mean agewas 31 years (range=19–51 years) All subjects were withoutother medical, psychiatric, or physical problems that couldhave interfered with ability to participate in neuropsycho-logical assessment, and none was taking medications withanticholinergic properties Measures of cognitive functionincluded the Brief Visual Memory Test—Revised, HopkinsVerbal Learning Test, Digit Span, and Letter-Number Se-quence subtests of the Wechsler Adult Intelligence Scale—Revised, Controlled Oral Word Association Test, and theMemory Functioning Questionnaire, all of which were ad-ministered pre- and posttreatment during the two treatmentphases of the study These phases included donepezil, 5 mgdaily for 1 month, followed by donepezil, 10 mg daily for anadditional 5 months; after a 6-week washout period, patientswere treated for an additional 6 months with donepezil, 5

mg daily Treatment-emergent side effects (lethargy andsomnolence) were observed in two subjects, prompting theirremoval from the study Improvements in immediate anddelayed memory as assessed by the Brief Visual MemoryTest—Revised were reported as a function of treatment withdonepezil, 10 mg/day, but not 5 mg/day No other signifi-cant effects on cognition were observed during treatmentwith donepezil at either dose

6 2 6 TEXTBOOK OF TRAUMATIC BRAIN INJURY

More recently, Zhang et al (2004) reported findings

from a 24-week, randomized, placebo-controlled,

double-blind crossover trial of donepezil, 10 mg daily, in 18

sub-jects with TBI seen in two university-based hospitals They

had impairment on tests of attention or short-term

mem-ory and could not have a number of co-occurring

condi-tions, including depression and epilepsy, or be treated with

psychotropic medications Donepezil and placebo were

given in a randomized, double-blind, placebo-controlled

crossover study, with 10 weeks on one treatment, a 4-week

washout, and crossover to 10 weeks on the second

treat-ment phase When compared with baseline scores on the

Wechsler Memory Scale Auditory and Visual Immediate

Indices and the Paced Auditory Serial Addition Task,

sig-nificant improvement was seen after treatment with

do-nepezil For those individuals who received donepezil first,

no deterioration was seen after the 4-week washout and 10

weeks of placebo This controlled trial in a subacute TBI

population (average, 4–5 months post-TBI), demonstrated

efficacy of donepezil Limitations impair generalization to

broader clinical populations because these individuals did

not have co-occurring psychiatric disorders (which are very

common) or were receiving other psychotropic

medica-tions Whether this improvement would apply for those

with a more remote history of TBI was not studied The

presence of a possible carryover effect is intriguing

Cer-tainly, this at least is a caution for crossover studies and

sug-gests that short-term treatment may have prolonged

ef-fects Nonetheless, this study offers reasonably strong

evidence that donepezil improves attention and memory

impairments in the postacute injury period

Although individuals with TBI may have difficulty

maintaining attention on single tasks, many also experience

difficulty mounting robust selective attention in the face of

multiple competing stimuli (Arciniegas et al 1999) This

latter problem is referred to as impaired sensory gating, and

it is experienced by so-affected individuals as difficulty

fo-cusing on any of several competing stimuli such that the

stimuli become “blurred together” and “overwhelming.”

Many of these patients endorse the experience of impaired

sensory gating as analogous to listening to a radio receiving

two stations on the same frequency such that one is aware

that there are two sources of information but is unable to

clearly discern the content of one from the other Impaired

auditory gating can be distinguished clinically from

dis-tractibility, which refers to difficulty with sustained (but

not selective) attention that results in brief but robust

shift-ing of attention between competshift-ing stimuli Impaired

au-ditory gating is associated with abnormal middle latency

(50 milliseconds) electrophysiological responses to closely

paired (500-millisecond interstimulus interval) auditory

stimuli, and this abnormal response is referred to as P50

nonsuppression (Arciniegas et al 1999, 2000a; see Chapter

4) Importantly, distractibility (as may be seen in adultswith attention-deficit/hyperactivity disorder) is associatedwith normal P50 suppression (Olincy et al 2000), suggest-ing that the experience of impaired sensory gating reflects

a physiological process distinct from that underlying tractibility Arciniegas et al (2002) reported normalization

dis-of P50 physiology during treatment with donepezil, 5 mg/day, in 10 patients with impaired auditory sensory gating inthe late period after TBI in a randomized, double-blind,placebo-controlled, crossover design study Notably, sub-jects in this study did not maintain normalized P50 physi-ology during treatment with donepezil, 10 mg/day, or ei-ther placebo condition, suggesting that there may be atherapeutic window for response of impaired sensory gat-ing using cholinesterase inhibitors This and the previouslynoted studies suggest that there may be a role for cholines-terase inhibitors in the treatment of impaired memory andimpaired sensory gating after TBI

Cytidine 5'-Diphosphocholine

Cytidine 5'-diphosphocholine (CDP-choline or citicoline)

is an essential intermediate in the biosynthetic pathway ofphospholipids incorporated into cell membranes thatappears to activate the biosynthesis of structural phospholip-ids in neuronal membranes, increase cerebral metabolism,and enhance activity of dopamine, norepinephrine, and ace-tylcholine (Dixon et al 1997a; Secades and Frontera 1995)

A single-blind, randomized study of 216 patients with severe

or moderate TBI demonstrated improved motor, cognitive,and psychiatric function during treatment with CDP-choline, and this treatment decreased length of stay in thehospital (Calatayud et al 1991) Levin (1991) performed adouble-blind, placebo-controlled study of 14 patients toevaluate the efficacy of CDP-choline (1 g/day) for the treat-ment of postconcussional symptoms in the first month aftermild to moderate TBI This treatment reduced the severity

of postconcussional symptoms and improved recognitionmemory for designs but did not influence other aspects ofneuropsychological performance CDP-choline is availableonly as an over-the-counter agent; because content, purity,and effective dose may be difficult to predict in present for-mulations, patients electing to undertake treatment withCDP-choline should be cautioned about these potentialproblems and monitored carefully for both benefit andadverse reactions during its use

ApathyStates of diminished motivation, or apathy, are commonconsequences of TBI (see Chapter 18, Disorders of Dimin-ished Motivation) Diminished motivation or apathy

denotes a neuropsychiatric syndrome in which there is a

clinically significant decrease in goal-directed cognition,

emotion, and/or behavior Apathetic states occur on a

con-tinuum of severity, with states of mildly diminished

motiva-tion at one end of that continuum and akinetic mutism at the

other end Determining whether an individual patient’s

apa-thy is a symptom of another neuropsychiatric condition such

as depression or is instead an independent syndrome is

imperative before undertaking treatment When apathy is a

feature of depression, treatment of the underlying

depres-sion with agents such as the SSRIs may relieve both mood

and apathy symptoms However, when apathy occurs as an

independent problem, the SSRIs are unlikely to improve the

apathy and may actually worsen this problem Complicating

matters, apathy not uncommonly co-occurs with behavioral

dyscontrol (i.e., disinhibition, impulsivity, and aggression)

This seemingly odd combination of behavioral problems

may occur in the setting of injury to both the anterior

cingu-late-subcortical circuits (resulting in apathy) and lateral

orbitofrontal-subcortical circuits (resulting in a behavioral

dyscontrol syndrome) In such circumstances, patients

appear apathetic at baseline and demonstrate episodic

behav-ioral dyscontrol when an environmental or somatic stimulus

produces automatic (and often aggressive or appetitive)

behaviors This combination of apathy and behavioral

dys-control presents substantial challenges to clinicians

attempt-ing to treat such problems because the therapies to improve

apathy may worsen behavioral dyscontrol and the therapies

for behavioral dyscontrol may worsen apathy If clinicians

select apathy as the target of treatment, psychostimulants and

other dopaminergically active medications are the principal

pharmacotherapies Because these drugs are also used for the

treatment of cognitive dysfunction, the reader is referred to

the section Cognitive Impairment for guidelines on use

Fatigue

Stimulants (methylphenidate and dextroamphetamine)

and amantadine can diminish the profound daytime

fatigue experienced by patients with TBI Dosages utilized

would be similar to those used for treatment of diminished

arousal and concentration These medications may be of

particular benefit in patients with apparent depression

after TBI in whom fatigue persists despite improvement in

mood during treatment with antidepressants

Modafinil, a medication recently approved for the

treat-ment of excessive daytime somnolence in patients with

nar-colepsy, also may have a role in treatment of post-TBI

fa-tigue Although the exact mechanism of action of modafinil

is not known, animal studies suggest that its promotion of

wakefulness may result from an indirect, dose-dependent

re-duction of the release of γ-aminobutyric acid (GABA) in the

cerebral cortex, medial preoptic area, and posterior thalamus (Ferraro et al 1996, 1997b); activation of hypocre-tin (Orexin) neurons in the lateral hypothalamus (Chemelli

hypo-et al 1999); and dose-dependent increases in glutamate lease in the ventrolateral and the ventromedial thalamus(Ferraro et al 1997a) Some combination of these mecha-nisms in humans may increase arousal via activation in re-gions critical to this purpose, either directly via glutamater-gic thalamic activation, indirectly via reduction of GABAfunction, or through the secondary effects of lateral hypo-thalamic projections to regions involved in control of arousaland the sleep-wake cycle (the tuberomammillary nucleusand the locus ceruleus) (Lin et al 1999)

re-Studies of the effect of modafinil on fatigue and sive sleepiness in patients with multiple sclerosis (Rammo-han et al 2002; Zifko et al 2002) and Parkinson’s disease(Nieves and Lang 2002) suggest benefit Elovic (2000) hassuggested that modafinil may be of similar benefit in pa-tients with TBI Teitelman (2001) described his use ofmodafinil among 10 outpatients with nonpenetrating TBIand functionally significant excessive daytime sleepinessand in two patients with somnolence because of sedatingpsychiatric medications The patients included in his re-port were between the ages of 42 and 72 years, all were out-patients, and were treated in an open-label fashion Doses

exces-of modafinil ranged between 100 mg and 400 mg takenonce each morning Nine of these patients reportedmarked improvements in excessive daytime sleepiness, andthree reported moderate improvements Some patients re-ported subjective improvements in attention as well asother cognitive benefits Although this medication wasgenerally well tolerated, Teitelman also described treat-ment intolerance because of increased “emotional instabil-ity” in two women with brain injury complicated by multi-ple other medical conditions and receiving multipleadditional medications At the time of this writing, thereare no published clinical studies with which to evaluate theeffectiveness or tolerability of modafinil for posttraumatichypersomnolence or fatigue If modafinil is used in thispopulation, dosages should start with 100 mg in the morn-ing and can be increased to up to 400 mg/day administered

in either a single daily dose or two divided doses (i.e., 200

mg in the morning and 200 mg in the afternoon) Higherdoses (up to 600 mg/day) are sometimes used, but there is

no evidence in any patient population that such doses offerbenefit beyond that achieved with 400 mg/day

ColdnessComplaints of feeling cold, without actual alteration inbody temperature, are occasionally seen in patients whohave experienced brain injury This feeling can be distress-

6 2 8 TEXTBOOK OF TRAUMATIC BRAIN INJURY

ing to those who experience it Patients may wear excessive

amounts of clothing and adjust the thermostat so that other

members of the family are uncomfortable Although this is

not a commonly reported symptom of TBI, Hibbard et al

(1998) have found that in a sample of 331 individuals with

TBI, 27.9% complained of changes in body temperature

and 13% persistently felt cold Eames (1997), while

con-ducting a study of the cognitive effects of vasopressin

(DDAVP) nasal spray in patients with TBI, reported

inci-dentally that 13 patients had the persistent feeling of

cold-ness, despite normal sublingual temperature All were

treated with nasal DDAVP spray for 1 month Eleven of

these patients stopped complaining of feeling cold after 1

month of treatment, and one other patient had

improve-ment in the symptom, without complete relief

Silver and Anderson (1999) performed a pilot study of

the effects of intranasal DDAVP twice daily for 1 month

among six patients who complained of persisting coldness

after brain injury Five of the six patients had a dramatic

response to DDAVP—some as soon as 1 week after

initi-ating treatment—and no longer complained of feeling

cold This response persisted even after discontinuation

of treatment Patients denied any side effects from

treat-ment with this agent The authors of this study suggested

that DDAVP may reverse physiological effects of a

rela-tive deficit in DDAVP in the hypothalamus caused by

in-jury to the DDAVP precursor, producing cells in the

an-terior hypothalamus, and may thereby correct an internal

temperature set-point disrupted by the brain injury

Psychosis

Antipsychotic and Neuroleptic Medications

Typical antipsychotic medications are used commonly to

control agitation and psychosis after TBI but are not benign

treatments in this population Side effects such as

hypoten-sion, sedation, and confusion are common Patients with

brain injury are particularly subject to dystonias, akathisias,

and other parkinsonian side effects—even when relatively

low doses of antipsychotic medications are prescribed (Wolf

et al 1989) Stanislav (1997) demonstrated improvement in

cognitive performance in brain-injured patients after

dis-continuation of antipsychotic medications, the magnitude of

which appeared to be greater after discontinuation of

thior-idazine (Mellaril) than of haloperidol (Haldol) Although

both medications appeared to negatively affect cognitive

performance, Stanislav suggested that the greater

improve-ment observed after discontinuation of thioridazine is

attrib-utable to the brain-injured patients’ reduced tolerance to the

anticholinergic properties of this agent Similarly, Sandel et

al (1993) observed new-onset delusions in a TBI patient

receiving chlorpromazine for the treatment of agitation after

TBI, an effect that may also be attributable to the significantanticholinergic properties of this agent Antipsychotic med-ications have also been reported to delay neuronal recoveryafter brain injury (Feeney et al 1982) Consistent with thisobservation, Rao et al (1985) found that patients treatedwith haloperidol in the acute period after TBI experiencedsignificantly longer periods of posttraumatic amnesia,although the acute rehabilitation outcome did not differfrom those not treated with this medication Consistent withtheir greater sensitivity to medications affecting the CNS,patients with brain injury are more sensitive to the develop-ment of extrapyramidal side effects during treatment withtypical antipsychotic medications (Rosebush and Stewart1989; Vincent et al 1986; Wolf et al 1989; Yassa et al.1984a, 1984b)

Given this literature and the availability of several cal antipsychotic medications, we strongly discourage theuse of typical and, particularly, the low-potency typical anti-psychotic medications among persons with TBI However,there is at present a dearth of reports to guide selectionamong the atypical antipsychotic agents in this population.Michals et al (1993) used clozapine (Clozaril) to treat ninebrain-injured patients with psychotic symptoms or outbursts

atypi-of rage and aggression that had failed to respond to othermedications Three of these patients demonstrated markedimprovements in aggression and/or psychosis, three demon-strated decreased agitation and auditory hallucinations, and

an adequate duration of treatment was not achieved in threepatients Two of the nine patients experienced seizures dur-ing treatment Burke et al (1999) also reported improve-ment in refractory psychotic symptoms after TBI duringtreatment with clozapine These reports suggest that cloza-pine may be useful in the treatment of psychosis and aggres-sive behavior after brain injury, but this treatment carries arelatively high risk of adverse effects, including seizures.Whether clozapine may also exacerbate cognitive impair-ments given its substantial anticholinergic properties is notclear but seems likely in light of the effects of other low-potency antipsychotic agents

Schreiber et al (1998) reported a case in which done (Risperdal) treated delusions and sleep disturbanceafter TBI effectively One of us (D.A.) has used this med-ication in two patients who developed psychosis (paranoiddelusions, auditory hallucinations) after TBI in the acuterehabilitation setting Each patient responded with de-creasing psychotic symptoms with risperidone, 4 mg/day,and without significant adverse effect The second of thesepatients was treated in an A-B-A-B fashion, and psychosisrecurred during each reduction of risperidone below 3mg/day There are, to date, no studies reporting improve-ment in psychosis after TBI during treatment with olanza-pine, quetiapine, aripiprazole (Abilify), or ziprasidone

risperi-Each of these medications may be of benefit in this

popu-lation, but specific benefits and side-effect profiles

rele-vant to their use in TBI remain to be determined

Special Consideration in the

Use of Antipsychotic Agents

Neuroleptic malignant syndrome is a potentially

life-threat-ening disorder that may emerge after the use of any

antipsy-chotic agent and has been reported among patients receiving

haloperidol after TBI (Vincent et al 1986; Wilkinson et al

1999) Patients experiencing neuroleptic malignant

syn-drome become severely rigid and occasionally catatonic

Fever, elevated white blood cell count, tachycardia,

abnor-mal blood pressure fluctuations, tachypnea, and diaphoresis

occur Although medications such as bromocriptine and

dantrolene sodium have been suggested to treat neuroleptic

malignant syndrome, the most important therapeutic

inter-ventions are discontinuation of antipsychotic medications,

treatment of any underlying infections or other concurrent

medical illnesses, and symptomatic treatment of fever and

hypertension (Rosebush et al 1991)

Many psychotropic medications affect seizure

thresh-old This is of particular concern in this population given

the risk of posttraumatic seizures after TBI Among all the

first-generation antipsychotic drugs, molindone and

fluphenazine have consistently demonstrated the lowest

po-tential for lowering the seizure threshold (Marangell et al

1999; Oliver et al 1982) Clozapine treatment is associated

with a significant dose-related incidence of seizures

(rang-ing from 1% to 2% of patients who receive doses below 300

mg/day, and 5% of patients who receive 600–900 mg/day)

(Lieberman et al 1989) The observations of Michals et al

(1993) suggest that this risk may be increased in patients

with TBI; if this agent is prescribed at all in these patients,

its use should be undertaken with extreme caution and only

for the relief of refractory psychotic symptoms

Anxiety Disorders and

Posttraumatic Stress Disorder

Because of the side effects and danger of dependence

associ-ated with benzodiazepine use, we generally prefer to treat

complaints of anxiety in brain injury patients with supportive

psychotherapy and social interventions TBI is highly

asso-ciated with alcoholism and drug dependency (see Chapter

29, Alcohol and Drug Disorders), which further increases

our caution in prescribing benzodiazepines for these

patients However, when the symptoms are so severe that

they require pharmacological intervention, treatment with

SSRIs, buspirone, or benzodiazepines may be considered

Benzodiazepines may produce sedation and impair

memory and motor function In some instances, sedation

may be the desired effect of benzodiazepines, but this sideeffect poses risk for further impairing the patient’s cogni-tive and physical functioning These drugs can produceamnesia (Angus and Romney 1984; Lucki et al 1986;Roth et al 1980) and will worsen preexisting memory dif-ficulties Problems with balance, ataxia, and coordinationthat occur subsequent to brain injury are likely to be ex-acerbated by benzodiazepines Walburga et al (1992) ex-amined the effects of anxiolytic medications (buspironeand diazepam) on driving performance of outpatientswith generalized anxiety disorder who had no neurologi-cal impairment Each week, the subjects were tested fordriving ability by a 100-kilometer on-the-road drivingtest The diazepam-treated group showed significantlyimpaired performance in the first, second, and thirdweeks No impairment was detected in the subjects whoreceived buspirone Importantly, these effects were dem-onstrated in subjects without neuropsychiatric impair-ments before the study The likelihood of similar or worseeffects among TBI patients is not trivial and poses seriousconcerns with respect to the effect of benzodiazepines onboth everyday function and potentially risky endeavorssuch as driving or operating heavy machinery This con-stellation of adverse effects make the use of benzodiaz-epines for the treatment of anxiety in patients with braininjury undesirable, and their use as first-line treatmentsfor anxiety after TBI is not encouraged

Buspirone may be less deleterious with respect to tive functioning in patients with TBI than benzodiazepines,and the former is not associated with dependency Bu-spirone’s therapeutic effects may occur after a latency of sev-eral weeks Gualtieri (1991a, 1991b) found that four out ofseven patients with “postconcussion syndrome” experienced

cogni-“decreased anxiety, depression, irritability, somatic pation, inattention, and distractibility” after treatment withbuspirone Side effects from buspirone are dizziness, light-headedness, and, paradoxically, increased anxiety

preoccu-Patients with brain injury also may develop other iety disorders, such as panic disorder, obsessive-compul-sive disorder, posttraumatic stress disorder (PTSD), andphobias The most important step in the treatment of thepatient with PTSD is the careful assessment and diagno-sis of comorbid DSM-IV-TR Axis I or II conditions(American Psychiatric Association 2000a) When no per-vasive comorbid condition is diagnosed, antidepressantmedications should be the initial pharmacological treat-ment Serotonergically active antidepressants are themedications initially indicated for the treatment of PTSDand other posttraumatic anxiety disorders

anx-The positive symptoms of PTSD, including encing of the event and increased arousal, often improvewith medication The negative symptoms of avoidance

reexperi-6 3 0 TEXTBOOK OF TRAUMATIC BRAIN INJURY

and withdrawal usually respond poorly to

pharmacother-apy and may require additional treatment with

psycho-therapy targeting reductions of these symptoms

Sleep

Sleep patterns of patients with brain damage are often

disordered (see Chapter 20, Fatigue and Sleep Problems),

with impaired rapid eye movement recovery and multiple

nocturnal awakenings (Prigatano et al 1982)

Hypersom-nia that occurs after severe penetrating brain injury most

often resolves within the first year after injury, whereas

insomnia that occurs in patients with long periods of

coma and diffuse injury has a more chronic course

(Aske-nasy et al 1989) Barbiturates and long-acting

benzodiaz-epines should probably be avoided in this population, and

if prescribed at all, they should be used with great caution

These drugs interfere with rapid eye movement and stage

4 sleep patterns and may contribute to persistent

insom-nia (Buysse and Reynolds 1990) Clinicians should warn

patients of the dangers of using over-the-counter

prepa-rations for sleeping and for colds because of the

promi-nent anticholinergic side effects of these agents

Trazodone, a sedating antidepressant medication that

is devoid of anticholinergic side effects, may be used for

nighttime sedation A dose of 50 mg should be

adminis-tered initially; if ineffective, doses up to 150 mg may be

prescribed Nonpharmacological approaches should be

considered, including minimizing daytime naps,

main-taining regular sleep onset times, and engaging in regular

physical activity during the day

Aggression and Agitation

We suggest using the framework provided by the Expert

Consensus Panel for Agitation in Dementia (1998) when

addressing aggression and agitation in persons with TBI

After appropriate assessment of possible etiologies of

these behaviors, treatment is focused on the occurrence ofcomorbid neuropsychiatric conditions (e.g., depression,psychosis, insomnia, anxiety, and delirium), whether thetreatment is being undertaken in the acute phase (hours

to days) or the chronic phase (weeks to months), and theseverity of the behavior (mild to severe) The pharmaco-therapy of aggression and agitation is summarized inTable 34–4 and reviewed in detail in Chapter 14, Aggres-sive Disorders

Concerns Regarding PharmacotherapyThere has been a bias held by patients, families, and,often, treatment centers against the use of medicationsfor the treatment of neuropsychiatric disorders inpatients with brain injury The issue is important, becausethe neuropsychiatrist is often faced with resistance frompatients, families, and staff about the use of medications.The bias against the use of psychiatric medications mayhave several sources, including the stigma associated withmental illness and psychiatric treatment and, in somecases, the patient’s previous suboptimal experience withpsychotropic medications Stigma may relate to the viewthat psychiatric symptoms are signs of weakness, indo-lence, or even moral decline We have suggested that theneuropsychiatric paradigm—one that rejects the mis-leading demarcation between “brain” and “mind” andemphasizes the neurobiological bases of all cognitive,emotional, and behavioral problems regardless of therelationship of such problems to brain injury—as ourstrongest weapon against stigma (Arciniegas and Beres-ford 2001; Yudofsky and Hales 1989) Patients struggling

to accept treatment in the face of old stigmas may benefitfrom an explanation of symptoms as the products of alter-ations in neurotransmitters, brain structures, brain net-works, or some combination of these and presentation oftreatments as designed to alleviate or compensate forsuch brain dysfunctions

T A B L E 3 4 – 4 Psychopharmacological treatment of chronic aggression

Antipsychotics Psychotic symptoms Oversedation and multiple side effects Benzodiazepines Anxiety symptoms Paradoxical rage

Anticonvulsants: carbamazepine

(CBZ), valproic acid (VPA)

Seizure disorder Bone marrow suppression (CBZ) and

hepatotoxicity (CBZ and VPA) Lithium Manic excitement or bipolar disorder Neurotoxicity and confusion

Buspirone Persistent, underlying anxiety and/or depression Delayed onset of action

Propranolol and other β-blockers Chronic or recurrent aggression Latency of 4–6 weeks

Antidepressants Depression or mood lability with irritability May need usual clinical doses

However, particularly for patients with TBI, the use

of psychotropic medications indeed has often been a

neg-ative one Antipsychotic medications, and particularly

typical antipsychotics, are widely misused as a general

“tranquilizer” to sedate patients agitated after TBI, with

resulting impairment in alertness, cognition, and

initia-tion, and the producinitia-tion, over time, of severe

extrapyra-midal side effects For example, we evaluated in

consulta-tion one patient who had been treated with low-dose

fluphenazine to control agitated behavior One month

later, the staff and family complained that she was

“under-aroused.” On our examination, the patient had severe

cogwheel rigidity that had not been diagnosed previously

One hour after administration of benztropine, 1 mg, she

was “active” again

Another fear about medication is that it will interfere

with a “natural healing process” that occurs after TBI

Evidence obtained from animal models suggests that

cer-tain drugs, particularly agents that potently antagonize

D2 receptors, may interfere with recovery after

neuro-nal injury Feeney et al (1982) studied the effect of D

-amphetamine on recovery from hemiplegia after

abla-tion of the sensorimotor cortex in rats They found that

D-amphetamine accelerated the rate of recovery and that

this effect was blocked by haloperidol In addition,

halo-peridol, when administered alone, resulted in delayed

re-covery Importantly, recovery was affected only when the

animal was allowed to move during drug administration

This implies that haloperidol delays the recovery process

during active rehabilitation rather than interfering with

spontaneous recovery per se In another model, Hovda et

al (1985) found that haloperidol blocked the positive

ef-fect of D-amphetamine on recovery of depth perception

after visual cortex injury

It has been suggested that the mechanism of action of

haloperidol in delaying recovery also operates through its

effects as an α-adrenergic antagonist (Sutton et al 1987)

Clonidine, an α2-adrenergic agonist, and prazosin, an α1

-adrenergic antagonist, reinstate deficits after

sensorimo-tor cortex ablation (Sutton and Feeney 1987), an effect

not seen with propranolol (Boyeson and Feeney 1984)

Other studies have demonstrated that clonidine has

dele-terious effects on recovery (Feeney and Westerberg 1990;

Goldstein and Davis 1990) It should be noted that these

experimental methods in animals do not produce the

same neuropathological findings as contusions or diffuse

axonal injury in humans, and, therefore, may not apply

fully to many patients with TBI

In animal studies involving the neurotransmitter

GABA, increased GABA function has been associated

with greater neuromotor deficits and poorer recovery

(Boyeson 1991) Increased production of GABA

associ-ated with benzodiazepine administration may result ingreater glutamate neurotoxicity (Simantov 1990) Diaz-epam has been found to block recovery of sensory deficitsafter rat neocortex ablation (Schallert et al 1986).The preceding studies relating psychotropic use toimpaired neuronal recovery after laboratory-inducedbrain injury have all used animal models The study byRao et al (1985) appears to offer support for the notion

of delayed recovery after administration of haloperidol byvirtue of its demonstration of increased duration of post-traumatic amnesia among patients receiving this medica-tion However, there have been no carefully controlledclinical trials of this important relationship in humans.When the medical records of recovering stroke patientswere reviewed, the use of antihypertensive medications orhaloperidol was associated with poorer recovery (Porch et

al 1985) Goldstein and Davis (1990) found that when tients who had had ischemic strokes were administeredphenytoin, benzodiazepines, dopamine receptor antago-nists, clonidine, or prazosin, they showed poorer sen-sorimotor function and lower activities of daily livingthan stroke patients who did not receive those drugs.Many patients are prescribed anticonvulsant drugs(ACDs) after TBI and may still be receiving them at thetime of neuropsychiatric consultation in the period afteracute rehabilitation It is important, as discussed in Chap-ter 16, to ascertain whether such agents were prescribedfor the treatment of active seizures, for seizure prophy-laxis, or for the treatment of another neuropsychiatricproblem

pa-ACDs can result in cognitive and emotional symptoms(Reynolds and Trimble 1985; Rivinus 1982; Smith 1991).Phenytoin has more profound effects on cognition thandoes carbamazepine (Gallassi et al 1988) Dikmen et al.(1991) described greater cognitive impairment duringtreatment with phenytoin for prophylaxis of posttraumaticseizures when compared with placebo in a study of 244 pa-tients with TBI Intellectual deterioration in children onchronic treatment with phenytoin or phenobarbital alsohas been documented (Corbett et al 1985) Dikmen et al.(2000) found no adverse cognitive effects of valproate whenadministered for 12 months after TBI In a double-blind,placebo-controlled study of the cognitive and emotionaleffects of phenytoin (40 patients) and carbamazepine (42patients) in TBI patients being treated with these medica-tions for seizure prophylaxis, Smith et al (1994) noted thatboth of these medications (but particularly carbamazepine)produced significantly more cognitive and motor slowingthan did placebo They found that both phenytoin and car-bamazepine had negative effects on cognitive performance,especially those that involved motor and speed perfor-mance Although in the patient group as a whole the effects

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6 4 1

35 Psychotherapy

Irwin W Pollack, M.D., M.A.

THERE CONTINUES TO be some disagreement among

mental health professionals about whether the use of

psy-chotherapeutic techniques in cases of depression and

schizophrenia adds significantly to the known therapeutic

effects of selected pharmacological agents However, in the

case of patients who have sustained traumatic brain injuries

(TBIs), there is no doubt that drug treatment, although

im-portant in many cases, is not sufficient alone to bring about

meaningful improvement in patients’ life situations Every

TBI of any consequence causes some disturbance in a

number of systems integral to the individual, including

those responsible for motor, cognitive, and emotional

function For this reason, no single approach to treatment

is sufficient During the course of rehabilitation, a range of

treatment approaches must be used, and among these,

psy-chotherapy should be included to assist the patient with his

or her efforts to reestablish an acceptable sense of self

De-spite this need for a range of approaches, for the most part

psychiatrists have limited their transactions with patients

who have sustained TBIs to the prescription and

manage-ment of medications There are several factors that may be

contributing to this state of affairs

Possibly because in most medical schools little time

and attention are devoted to the study of TBIs, many

psy-chiatrists trained in these institutions are reluctant to

ac-cept a person with a history of brain injury for

psycho-therapy Indeed, possibly because of their limited

exposure to persons with TBI during the course of their

training, many psychiatrists see no role in the

rehabilita-tion process for psychotherapy, at least as it has been

tra-ditionally practiced

Certainly, people with significant brain injuries do not fit

the usual image of an appropriate candidate for this form of

treatment The traditional approach to psychotherapy is

based on the assumption that the primary source of a

per-son’s emotional problems resides within that person and not

in the outside world Provided that a person possesses

cer-tain abilities, it is assumed that he or she has the potential tofunction more effectively and to gain greater satisfactionfrom life––a potential that can be actualized through thetherapeutic process A list of those requisite abilities includesthe capacity for abstract thinking, a degree of self-awarenessand the ability to self-monitor, the ability to tolerate frustra-tion and anxiety, memory that is intact enough to recall sig-nificant information both within and across therapy sessions,and the ability to transfer what is learned in the treatmentenvironment to other life situations These abilities arerarely found in people with significant brain injuries (Ben-nett 1989; Ludwig 1980; Miller 1991) Rather, far morecommonly, these individuals may be impulsive, emotionallylabile, and only minimally able to tolerate anxiety and frus-tration They may be unable to assume an abstract attitudeand may have a limited ability to profit from experience.They may not self-monitor effectively and as a result mayfail to recognize the existence of significant problems, evenwhen those problems are quite obvious to others (Conboy et

al 1986; Eames 1988; Goldstein 1952; Prigatano 1987).When one contrasts this list of deficits with the aforemen-tioned list of abilities that are assumed to be necessary for asuccessful psychotherapeutic experience, the reasons for thelingering doubts regarding the use of psychotherapy withTBI patients are better understood

But the life experiences of persons with brain injuriesare not so different from those of noninjured persons tojustify limiting their treatment options on an a priori ba-sis After their accidents, people with brain injuries, likenoninjured persons, may struggle with unresolved inter-nalized conflicts; operate on irrational assumptions aboutthemselves and their world; demonstrate anxiety, depres-sion, phobias, and obsessions; feel alienated and devoid offeeling; and face confrontation by environmental circum-stances that threaten to overwhelm them All of theseconditions are known to respond to psychotherapeutic in-tervention Within limits, the fact that a person has sus-

6 4 2 TEXTBOOK OF TRAUMATIC BRAIN INJURY

tained a TBI should not change this assessment The

problem is not that persons who have sustained brain

in-juries do not respond to psychotherapy but rather that

ev-ery aspect of their being and their sense of self has been

affected in ways that cannot be managed successfully by

any single approach to therapy (Fordyce 1983; Weddell

et al 1980)

The Psychotherapeutic Process

The primary goal of psychotherapy in the treatment of a

person with a brain injury is the same as that of the other

therapeutic modalities involved in the rehabilitation

pro-cess: to enable the injured person to reestablish an

accept-able sense of self (Banja 1988; Condeluci and

Gretz-Lasky 1987; Pollack 1994)

To accomplish this goal, the downhill course leading to

social isolation and loneliness must be stopped and then

re-versed; however, all too often the physical, cognitive, and

emotional residuals of the brain injury and their social

con-sequences compromise the injured person’s ability to

re-gain the initiative without professional help This is no less

the case for many people who have sustained mild brain

in-juries who, over time, have become too bewildered and

de-moralized to put their lives back together without help

Starting Point

To enable patients with brain injuries to breach the walls of

their isolation and to begin to relate to other people

effec-tively again, therapists and their patients must find areas of

shared meaning (Stuewe-Portnoff 1988) The therapist

and the patient must come to share an understanding of the

nature of the problem as it is experienced by the patient

(Cicerone 1989; Pollack 1989; Prigatano 1989) Prigatano

(1989) expressed the view that a therapist working with an

individual who has sustained a brain injury needs symbols,

concepts, or analogies that adequately represent––for both

the therapist and the patient––what it is like to have a

dam-aged brain The model thus developed provides a base

from which a series of other shared experiences can evolve,

eventually culminating in the reestablishment of the

injured person’s sense of self In most cases, initially it is the

therapist who must provide a rationale for what has

hap-pened to the patient as a result of his or her injury

If the patient is competent enough to understand, he

or she should be reassured that it is the brain injury, not a

neurotic or psychotic process, that is causing his or her

disturbances As much as possible, specific complaints

should be taken up and their relationship to the injury

should be explained in nontechnical language The

pa-tient should be told that although the final outcome of theinjuries is not wholly predictable, some improvement inphysical and cognitive abilities is to be expected, and thedegree of this improvement often can be enhancedthrough rehabilitation activities The patient should beforewarned that his or her efforts will be of the greatestimportance because therapy of any kind will not be fruit-ful without this active participation, and that even underthe best of circumstances, positive changes will be slow incoming, so great patience will be required The patientshould be discouraged from returning to his or her regu-lar routine prematurely—that is, before relevant abilitieshave progressed to the point at which success can be rea-sonably expected It is extremely important to avoid un-necessary failures and the demoralization that results

In the case of a severely impaired person, the tion of the effects of brain injury should be brief, con-crete, and directed specifically at clarifying the most sig-nificant of the patient’s complaints

explana-Importance of a Historical PerspectiveAlthough the importance of obtaining an adequate history

is emphasized in all areas of medical practice, in therapeuticwork with people who have sustained a brain injury, it is thesine qua non Not only must the therapist acquire in-depthinformation about the circumstances surrounding theinjury and the patient’s preinjury personality and postinjurysymptoms, abilities, and behaviors, but the therapist mustalso know about that person’s preinjury level of physicaland social development, interests and values, school andwork experiences, cultural background, and friendshipsand family relationships as they existed both before andafter the brain injury (Cicerone 1989; Ellis 1989; Prigatano1989) Events surrounding the injury can have far-reachingexperiential and symbolic significance for the injured per-son, and the disinhibition that frequently follows as a con-sequence of brain injury can result in the reemergence ofpreviously resolved psychological issues dating back tochildhood (Bennett 1989; Silver et al 1992) These factorsall contribute to an injured person’s vulnerabilities and pre-dispositions; therefore, it is important to distinguish symp-toms that are associated with one or another of these fac-tors from those associated with the brain injury itself,because these distinctions affect the therapeutic approach(Prigatano 1989)

Patient Changeability: The Need for Therapist Flexibility

To paraphrase Heraclitus, for the therapist in the earlystages of his or her attempts to understand the patient’s

postinjury behaviors, the only unchanging characteristic

is change itself As noted by Gardner (1976),

I have never seen a brain damaged individual, with

the possible exception of those either completely

demented or virtually recovered, who did not

dis-play sizable variations in performance from day to

day, if not across hours or minutes No skill

seems to be completely destroyed or wholly intact;

rather, each seems to be in a partial state of

disre-pair, and, depending upon such factors as the

sur-rounding conditions, the extent of fatigue, the

events of the preceding minutes, motivation at the

given moment, the degree of alertness or

atten-tiveness, the patient may succeed strikingly or fail

dismally on a given set of tasks This variability is

all important because it precludes a ready

fool-proof description of the patient—as most

consult-ing physicians soon learn, one must speak of the

patient at-a-given-moment-in-time, or in

particu-lar circumstances, rather than as a fixed set of

mechanized routines always performing at the

same level (p 431)

Not only their behaviors but the entire beings of people

with brain injuries are in a state of flux Most are rather

young when they are injured––in their adolescence or early

adulthood––and still in the process of evolving both

physi-cally and psychosocially (Lewis and Rosenberg 1990)

Ad-ditionally, over time, people with brain injuries usually

show a progressive improvement in their physical and

cog-nitive capacities, thereby enhancing their ability to analyze

and comprehend the significance of their subjective

expe-riences (Stein 1988) Successful psychotherapeutic work

with people who have experienced a TBI usually requires

that the therapist use several different approaches to

ment It is most common for a therapist to begin the

treat-ment process with an approach that is almost entirely

un-der his or her control: taking a medical and social history,

educating the patient and family members about the effects

of a brain injury, and consulting with other members of the

rehabilitation team, employers and teachers, and the staff

of involved social agencies

After arriving at a mutual understanding of what has

happened to the patient as a result of the brain injury,

therapeutic efforts should focus on selected concrete

problems Preferably, these issues should be raised by the

client and pursued even if they are not considered to be

important by the therapist The patient should be assisted

in attaining a clear picture of the problem as it affects both

the patient and the family At first, therapeutic efforts

should be focused on the here and now, even when it is

clear that the patient’s preinjury personality is playing asignificant role Therapist and patient together shoulddetermine how best to modify ineffectual responses, al-though at times, direct suggestions and advice are neces-sary Often, a second or even a third approach to treat-ment is indicated, such as the addition of behavioral,group, or family therapy In addition, environmental ma-nipulation may be indicated, and for this reason the fam-ily, employer, and/or friends may need to be brought intothe therapeutic situation

The psychiatrist should emphasize the patient’s maining assets and help the patient see how these can beused to manage present problems Success should be re-warded with acknowledgment and praise; failure should

re-be addressed with acknowledgment and support sis should be placed on what the patient can learn fromeach experience, and the therapist must recognize that,for the most part, it is the process that is therapeutic, notthe patient’s insights

Empha-As the therapeutic relationship develops and the tient makes additional gains in cognitive abilities, the ap-proach to therapy should gradually shift to one that placesgreater demands on the patient (e.g., rational or eveninsight-oriented therapy) However, as noted earlier inthis section, because of the patient’s extreme changeabil-ity, the psychiatrist may need to shift the approach fromtreatment session to treatment session or even within asingle treatment session

pa-Because a truly empathic relationship between thetherapist and his or her TBI patient is often impossible toachieve, psychodynamic interpretations should be maderarely and, even then, tentatively On the other hand, de-cisiveness is most appropriate when offering guidance.Cicerone (1989) suggests that interpretations should beused to make explicit connections that the patient hasbeen unable to make

The need for therapist flexibility is clear, because nosingle therapeutic approach suffices The psychiatristmust be prepared to shift tactics as dictated by the pa-tient’s change in state and/or by the behaviors present atthe moment; only through these measures can the ensu-ing transactions between therapist and patient be effective

in promoting further recovery

The therapist must be aware that if a patient with abrain injury is placed in a demanding situation in whichinformation or concepts are presented too rapidly or aretoo complex for him or her to process effectively, a cata-strophic response may be precipitated, thereby causingthe patient to leave the therapeutic situation

The course of recovery from even a mild brain injury

is slow and uneven, whereas the impact on the life of theinjured person and family and friends is immediate Be-

6 4 4 TEXTBOOK OF TRAUMATIC BRAIN INJURY

cause loss of morale and increased anxiety and depression

are continuing threats to each patient’s successful

rehabil-itation, the psychotherapist must make every effort to

still hope in the patient and the family without making

in-substantial predictions of a successful rehabilitation

outcome (Prigatano 1986) Moreover, implicit in all

con-tacts with even a moderately impaired person is a quality

of uncertainty that tends to engender a level of anxiety in

anyone (e.g., family and friends) who desires or needs to

maintain a close relationship with the injured individual

A therapist can allay this anxiety most effectively through

the sharing of information about the nature of the brain

injury, the problems that can be expected, and the

progress that the injured person is making in his or her

therapy

Goal-Directed Activities: Vehicles for

Reconstituting a Sense of Self

The rebuilding of an acceptable sense of self cannot be

achieved through talk alone It requires action both by the

members of the therapeutic team and the injured person

Only through the patient’s actions that lead to a desired

effect can a new sense of self begin to be acquired Often,

the most effective staff members in this patient–staff joint

effort are those who are activity oriented (e.g.,

occupa-tional therapists, recreation specialists, dancers and

movement specialists, actors and drama specialists, artists

and art therapists) (McKenna and Haste 1999; Stensrud

et al 1987) Unfortunately, for the most part, the

thera-peutic activities of this group of therapists are not

consid-ered to be significant enough to warrant reimbursement

by patients’ insurance carriers

The therapeutic tactics described in the preceding

sections are summarized in Table 35–1

Treatment Goals and

Outcome Measures

Most individuals who have sustained more than a mild TBI

neither die nor fully recover They are left with some

degree of impairment, most often involving several areas of

function As a result, they are less effective in dealing with

the everyday demands of the world around them Many

people who were employed before they were injured will

never again be able to perform satisfactorily in the same

position, regardless of the progress that they make in their

rehabilitation programs Although a significantly injured

person may voice some concern about his or her financial

future, this concern, when examined closely, appears to be

contributing relatively little to the intensity of that person’sdistress This is understandable when one considers thedegree of concern and anxiety that the individual feelsabout confronting the many other more pressing issues ofimmediate significance, not the least of which is the task ofreestablishing a workable and acceptable sense of self Onthe other hand, people with less significant brain injuries

do appear to feel great concern and anxiety about the sibility that they will no longer be able to perform satisfac-torily in the positions that they held before their injuries.Often, after treatment is concluded, many of these lessimpaired individuals are able to return to their preinjuryjobs, and others are able to work successfully in new andless-challenging positions

pos-In both of the above cases, it appears that concernabout the loss of income is less significant to a person with

a brain injury than is the loss of the status and identity thatare associated with having a job The question “Who areyou?” most often is answered by naming one’s occupation(e.g., “I am a plumber,” [or a physician, a housewife, ahouse painter, an actor, etc.]) To have no occupation is tohave a hole in one’s identity––a further assault on the in-jured person’s sense of self

When we consider that even after participating in anexcellent rehabilitation program, many patients are stillleft with some permanent disability, agreement aboutwhat constitutes a satisfactory treatment outcome be-comes even more important Indeed, in the case of pa-tients who have sustained a TBI, there is a lack of agree-ment among the experts over what outcome to measure(Rice-Oxley and Turner-Stokes 1999)

An often-used outcome measure is improvement inneuropsychological test performance But improved testscores may have little or no relationship with a person’sability to manage real-life challenges successfully.Two other measures often used by researchers to de-scribe a satisfactory treatment outcome are “independentliving” (McColl et al 1999) and “community reentry.”But both of these “measures” are poorly defined For ex-

ample, independent is defined in Merriam-Webster’s giate Dictionary as “not requiring or relying on something

Colle-else not requiring or relying on others (as for care orlivelihood).” But no one lives or can live without relying,

at least to some degree, on someone else Nor would that

be a desirable condition, even if it were possible So if tal independence is neither possible nor desirable, whatdegree of independence is enough to be considered a sat-isfactory treatment outcome?

to-In considering community reentry as an outcomemeasure, we are left with the problem of deciding whichcommunity we are considering Is it an inner-city com-munity, a suburban community, a rural community, a con-

servative community, a liberal community, a large

com-munity, a small comcom-munity, a poor comcom-munity, a wealthy

community, a supportive community, a remote

commu-nity, a community with many resources, or a community

with few resources? In addition, we need to know whether

the patient will be living with family, with friends, with

some sort of organized support, or unsupported and

alone Clearly, the level of competence that is required of

a patient is related directly to the amount and nature ofthe resources and support that are available and accessible

T A B L E 3 5 – 1 Suggested tactics for the psychotherapeutic process

Find areas of shared

meaning.

Determine what having a brain injury means to the patient and how he or she perceives its effects

At first, the psychiatrist may have to take the initiative, explaining the mechanism of traumatic brain injury in simple terms, relating the patient’s difficulties to the injury, and describing the problems, events, and so on that can be expected in the future.

Encourage the patient to

take the lead.

Concentrate on the concrete “real life” difficulties that the injury has caused the patient Early

in treatment, focus on the “here and now,” avoid discussing the past (it requires good memory, and it is over), avoid discussing the future (it requires the ability to abstract, and at this point it

is beyond comprehension).

Help the patient develop

simple coping strategies.

For example, suggest that the patient keep a notebook, follow a sequence of predetermined steps, rest before becoming too fatigued, request that a confusing message be repeated slowly and in simpler terms, set up priorities for a series of necessary tasks.

Manipulate aspects of the

environment to enable the

patient to function more

effectively.

For example, suggest organizing household equipment, utensils, dishes, and so on in a systematic fashion; labeling drawers and closets; using an alarm or calendar watch.

Mobilize assistance Mobilize the assistance of family members, employers, teachers, and friends to help keep the

social and work demands as noncomplex and as manageable as possible.

Build on the patient’s assets Build on the patient’s remaining assets and avoid focusing on the residual deficits Do not make

every task seem like a test.

Engage the patient in

meaningful goal-directed

activities.

Use members of professional groups that are action oriented such as actors, dancers, and artists

in addition to the more traditional rehabilitation staff.

Recognize that the patient’s

world may differ from that

of the psychiatrist.

Interpret the meaning of behavior with caution Provide guidance to improve inappropriate behavior with authority.

Maintain flexibility Many patients are adolescents or young adults in various stages of development; for most of these

patients, some improvement in physical condition and cognitive function can be expected over time Remember that a patient’s abilities and emotional state can vary from moment to moment depending on preceding events, the character of the task, the degree of alertness and motivation, and the environmental conditions.

The approach to therapy

should change as the patient

changes.

This should happen both within and across treatment sessions Ideally, the treatment approach should move gradually from one that is concerned primarily with the management of concrete, here-and-now, practical problems to one that places greater demands on the patient to consider psychodynamic issues.

Instill hope Instill hope in the patient and family without expressing unwarranted optimism.

6 4 6 TEXTBOOK OF TRAUMATIC BRAIN INJURY

provement resulting from the treatment program should

make possible a lifestyle that is both acceptable to the

pa-tient and manageable without undue stress on the

re-sources, both human and material, that are available to

him or her That is the only reasonable measure of a

suc-cessful treatment outcome

Mild Brain Injury

A number of animal and human studies have

demon-strated that there is a continuum of neurological damage

and functional impairment from mild to severe brain

injury (Eisenberg and Levin 1989; Genarelli 1981;

Ruth-erford 1989) The cognitive impairments that result from

mild brain injuries are essentially the same as many of

those that are seen after major brain trauma, although

they are more subtle, at times becoming obvious only on

neuropsychological testing Commonly, these

impair-ments include decreimpair-ments in attention, concentration,

short-term memory, and rapid and/or complex mental

processing (Conboy et al 1986; Rimel et al 1981) For

some individuals, the overall impact of these seemingly

low-level deficits can be devastating, in large part because

the quality of their combined effect is difficult to define

and almost impossible to communicate effectively As a

result, the person with a mild brain injury often is seen as

overreacting and neurotic In such circumstances the

individual, feeling misunderstood, maligned, and without

support, can become confused, frightened, and angry

Lezak, calling on her extensive experience in

evaluat-ing and treatevaluat-ing patients with mild brain injuries,

de-scribed a triad of subtle sequelae: perplexity,

distractibil-ity, and fatigue (Lezak 1978, 1989) Perplexity is reflected

in the individual’s distrust of his or her own abilities and

in doubts regarding the validity of his or her thought

pro-cesses In interpersonal situations, perplexity is expressed

as confusion, uncertainty, and self-doubt (Piotrowski

1937) Distractibility results when an individual cannot

screen out unwanted or irrelevant stimulation Because of

the subtlety of this problem, it is quite common for the

in-dividual not to recognize that it exists He or she is aware

only of feeling uncomfortable when in contact with

groups of people and of an intolerance of noise and

ran-dom activity

Unusual fatigability is found routinely after any brain

injury The injured person tires more easily, probably

be-cause formerly automatic activities and functions now

re-quire concentrated and sustained effort

These subtle consequences of mild head injury, which

are difficult to recognize and even more difficult to

com-prehend, can engender secondary feelings of confusion,

anxiety, anger, and depression in both the injured personand members of his or her family These painful emotionstend to cause the person with mild brain injury to overesti-mate the degree of his or her cognitive and physical impair-ments Unlike many persons with profound brain injurieswho do not complain, tending rather to deny the serious-ness of their deficits, individuals who have experienced amild brain injury frequently complain of their symptomsand mourn the loss of their former competencies

Although some subtle impairments may be lifelong,most people who have experienced mild brain injuries areable to resume the key aspects of their lives within a pe-riod of 3–6 months Symptoms that persist beyond 6months usually are fueled by an interplay of the neurolog-ical damage, the person’s premorbid personality traits,and his or her psychological response to the trauma(Levin et al 1989) Lishman (1973) reported that psycho-logical difficulties are more likely to follow mild brain in-juries when the premorbid personality was characterized

by insecurity and feelings of inadequacy

Case Example

Mrs D, a 40-year-old married bank officer, wasseen for neuropsychiatric evaluation 3 years aftershe had been involved in a minor automobile acci-dent At the time, she experienced a very brief loss

of consciousness, no more than 1 or 2 minutes induration A neurological evaluation done in thelocal hospital emergency room was described asessentially normal, and Mrs D was discharged toher home after being advised to return if any one

of a prescribed list of symptoms should appear.Over the next several months, Mrs D began tonotice difficulties in a number of areas of functionthat tended to reduce her effectiveness both athome and at work She noticed that her short-term memory and her ability to concentrate haddeteriorated, and she described having problemsfinding the appropriate words to express herthoughts She frequently became distracted dur-ing business discussions and often felt so fatiguedwhen she arrived home in the evening that she wasunable to meet her family obligations

Over the next 3 years, Mrs D was evaluated by

a number of physicians whom she saw either at herown initiative or at the request of her insurancecompany The various consultants, most of whomwere neurologists or psychiatrists, agreed on twopoints: first, there was no evidence of residual neu-rological damage; and second, Mrs D appeared to

be overreacting to ordinary life stresses In Mrs

D’s opinion, she had received neither

understand-ing nor relief as a result of her various contacts

with members of the medical profession As time

passed, Mrs D became increasingly confused and

overwhelmed by her continuing problems The

quality of her work at the bank slipped badly, and

her position there was in jeopardy At home, the

quality of her interactions with her husband and

children deteriorated so far that she feared that

her husband was about to leave her

During our initial meeting, Mrs D described

the effect of her brain injury in the following

man-ner: “Since my injury, I feel that there is not

enough of me to cope Everywhere I look I have a

sense of ‘not me.’ It seems like I’ve been fractured

internally [pointing to her head] I have panic

at-tacks! Something is terribly wrong!”

After completing the remainder of the

evalua-tion, Mrs D was assured that her complaints were

those that typically follow a mild brain injury A

simplified explanation of what occurs in the brain

when the head is forcefully impacted was

pre-sented to her, and some strategies that could help

her manage her workload more effectively were

suggested

When Mrs D returned the following week

for her second appointment, she reported that

the strategies had worked and that she was feeling

less anxious and confused and more in control

than at any time since her accident Obviously,

this was not the end of Mrs D’s problems, but an

alliance had been forged that would support her

further recovery

In every case of mild brain injury, the best treatment

is prevention––prevention of the secondary troubled

emotional responses that are most disabling The injured

person and that person’s family should be warned that the

aftereffects of even a mild brain injury take time to clear

To prevent unnecessary and demoralizing failures during

the early recovery period, the injured person’s activities

should be limited, the immediate environment should be

structured and predictable, and the demands on his or her

time and effort should be minimal

As soon as possible after the injury, both the injured

person and the family should be made aware of the nature

of the problems that frequently follow a mild brain injury,

and a simple explanation of the pathophysiology involved

should be presented Strategies to reduce stress and

in-crease coping ability should be developed cooperatively

with the participation of the injured person, that person’s

family, and the injured person’s employer or teachers

when indicated (Conboy et al 1986) Frequently, thesepreventive measures are sufficient to ensure an uneventfulrecovery When the expected progress fails to occur, moreformal psychotherapeutic intervention is indicated

Special Therapeutic Problems

Transference and Countertransference Issues

Any significant threat to the integrity of a person’s sense

of self, whether caused by brain injury, abnormal brainchemistry, or some catastrophic environmental or humanevent, precipitates anxiety In an effort to alleviate thisanxiety, a person with a brain injury who has a compro-mised ability to adapt may attempt to modify or structureelements in the surrounding physical environment toincrease its orderliness and therefore its predictability,thus reducing the probability that unexpected and/orunmanageable demands will arise

For the same reason––that is, to reduce terpersonal transactions may be managed, manipulated,interpreted, and evaluated in terms of the level of emo-tional stress that they provoke or alleviate Under thesecircumstances, the brain-injured patient’s evaluation ofothers’ behavior during interpersonal transactions will bealmost entirely based on the level of comfort that is expe-rienced by the patient at that moment rather than reflec-tive of the true character and motives of the other person

anxiety––in-or persons involved in these transactions Accanxiety––in-ordingly, itshould be expected that the injured person’s specific atti-tudes and responses will stem, in most part, from earlierinterpersonal experiences—that is, transference phenom-ena—rather than from the present circumstances Be-cause people who have survived a significant brain injuryfrequently have limited self-awareness and impaired self-monitoring abilities, potentially orienting and correctiveinterpersonal experiences may not be attended to or may

be misinterpreted and discounted

Psychotherapists who work with people who have had

a brain injury must be alert to the fact that ference forces, both positive and negative, lie just belowthe surface of every encounter (Goldstein 1952) Suchforces can lead a therapist to underestimate the severity ofthe patient’s disabilities and overestimate the degree of re-covery that reasonably can be expected after treatment

countertrans-As a result, a therapist may encourage his or her patient toincorporate impossible personal goals and adopt socialvalues that are in conflict with those of the community towhich the patient eventually must return, thereby settingthe stage for the patient’s eventual failure

6 4 8 TEXTBOOK OF TRAUMATIC BRAIN INJURY

Although it is common for the positive changes that

result from any psychotherapeutic process to be slow in

coming, an unusual level of patience is required of the

psychotherapist in the treatment of patients with brain

in-juries because of their memory problems, inflexibility,

and impaired comprehension

Not infrequently, a patient appears to comprehend

the relevance of a therapeutic exchange, but because of

frontal cortex damage, he or she fails to initiate an

appro-priate action or, indeed, any action at all Because the

pa-tient initially appeared to understand that there was a

need to act and had repeatedly expressed his or her good

intentions, inactivity and/or other “inappropriate”

behav-iors may be interpreted by the therapist as a lack of

moti-vation or even as an act of rebelliousness and sabotage

When the patient does not meet the therapist’s

expecta-tions, feelings of frustration and anger emerge and the

quality of the therapeutic alliance begins to deteriorate

When the therapist gradually becomes aware of the wish

to abandon the patient, feelings of guilt become the only

“glue that”––for a short period––prevents the

relation-ship from coming apart

At the same time, the patient, as might be expected, is

feeling hurt and confused If expressions of pain and

an-ger fail to communicate to the psychiatrist the depth of

the patient’s despair, and no improvement in the quality

of the relationship is forthcoming, the patient’s angry

feelings can change to hate Hate directed toward the

therapist can serve as evidence for the patient that some

sort of relationship continues to exist, thereby defending

the patient against the possibility that he or she actually is

alone (Gan 1983)

Unless the therapist can clarify what has been

tran-spiring and can begin to redirect the process, the alliance

inevitably dissolves To avoid this state of affairs, the

psychiatrist, from the very first, must work to moderate

the transference–countertransference effects Positive

aspects of the transference relationship may be

nur-tured, but the boundaries between patient and therapist

must be kept well defined The negative aspects of both

transference and countertransference reactions must be

confronted and tested against reality to preserve the

therapeutic alliance

Denial

Perhaps the most striking of the many phenomena

asso-ciated with brain injury is the capacity of many seriously

impaired people to deny the existence of their

impair-ments In almost every case, several interacting factors

contribute to the patient’s distorted view of his or her

abilities and limitations

It is widely recognized that denial can be the direct sult of brain injury In this instance, denial is characterized

re-by a lack of awareness or recognition of the presence and/

or significance of functional impairments This enon, termed anosognosia by Babinski (1914), is reportedmost frequently in stroke patients who appear to be un-aware of their hemiplegia and/or hemianopsia Denialalso is found in patients with cortical blindness and peoplewith amnestic conditions (Heilman et al 1985; McGlynnand Schacter 1989)

phenom-Many people who have experienced a TBI deny theirmemory deficits and the changes in their personalities(Bond 1984) In fact, people with brain injuries frequentlyexhibit some awareness of their physical and intellectualdeficits while at the same time denying the existence ofthe changes in their temperament that are described byrelatives and friends (Cicerone 1989; Fahy et al 1967;Thomsen 1974) It is important to recognize that organi-cally mediated denial is not motivated and serves noknown defensive purpose for the injured person On theother hand, so-called psychological denial is known to oc-cur in the absence of brain injury This kind of denial ismobilized either consciously or unconsciously in an effort

to allay anxiety and/or other unpleasant affects that canarise when an individual’s integrity is threatened (Beisser1979; Cicerone 1989; Rosen 1986; Weinstein and Kahn1955) It is probable that motivated unawareness (psycho-logical denial) always plays some role in a patient’s effort

to cope with the effects of brain injury

Although at times denial may disrupt the treatmentprocess, several investigators have pointed out that fre-quently there are discrepancies between what patients sayand what they do Despite verbally denying the signifi-cance of their deficits, many patients continue to partici-pate appropriately in prescribed treatment activities(Fordyce 1983; Tyerman and Humphrey 1984)

It is important for the therapist to distinguish betweenthe neurogenic and psychogenic aspects of the patient’sdenial, and in this way to discriminate between thosecomponents that the patient is unable to change fromthose that he or she is unwilling to change The manage-ment of denial is one of the most difficult problems con-fronting a psychiatrist who is working with TBI patients

As a rule, direct confrontation of the patient’s denial is effective and may negatively affect the therapeutic rela-tionship Beisser (1979) advised that “if the physiciantakes an adversary stance to the patient’s view, there is arisk either of the patient’s compliance at the risk of his orher own integrity or opposition in the service of main-taining his or her integrity” (p 1029) Modification of thetherapeutic environment so that it supports reality in aconsistent but nonthreatening manner is perhaps the

in-most effective intervention in a situation where denial is

hampering a patient’s progress (Cicerone 1989; Rosen

1986)

When denial is not an immediate impediment to the

patient’s progress, therapy should concentrate on

en-abling the patient to recognize and strengthen his or her

preserved assets When the patient’s sense of competence

increases and self-esteem improves, the need for the

pro-tection afforded by denial will be reduced and perhaps

eventually may even be eliminated Beisser (1979) noted

that “if the integrity of the person is respected, the person

is more likely to move toward those aspects of reality

which will serve his or her needs” (p 1029)

Catastrophic Conditions

A person who has had a significant brain injury tends to

limit both the range of his or her activities and the

physi-cal and social situations in which these activities are

car-ried out for the purpose of keeping them manageable If

for any reason the individual’s efforts to keep the elements

of his or her world contained are not successful and a task

must be confronted that is beyond his or her present

capabilities, a catastrophic condition occurs (Goldstein

1952; Miller 1991; Prigatano 1988) The catastrophic

condition was described by Goldstein (1952) in the

fol-lowing way:

When the patient is unable to fulfill a task set

before him the overt behaviors [that result]

appear very much the same as [they do in] a person

in a state of anxiety In the catastrophic

condi-tion, the patient not only is incapable of

perform-ing a task which exceeds his impaired capacity but

he also fails for a longer or shorter period in

per-formances which he is able to carry out in the

ordered state (p 255)

By a process of selective modification of behaviors and

routines, people with TBI may be able to eliminate, or at

least to decrease, the number of catastrophic episodes that

they experience For example, when they are threatened

with the possibility of being overwhelmed, they may

withdraw to reduce the number and intensity of stimuli

affecting them, show a lack of interest or involvement in

the task at hand or deny its relevance to their situation,

question the competence and/or motives of a therapist,

and ridicule other patients who have willingly worked on

the same task Usually, an injured person’s defensive

ma-neuvers are confined to words and avoidance behaviors

but can escalate to physical assault if other tactics fail to

reduce the stress Therefore, as a first priority,

psycho-therapists working with this exceedingly vulnerable group

of patients must strive to avoid precipitating a strophic condition In particular, open-ended, anxiety-provoking comments and questions must be avoided.New concepts should be introduced gradually and in assimple a form as possible so they can be processed effec-tively It is most important to avoid presenting each newtask as though it constitutes another test of the injuredperson’s abilities If the onset of a catastrophic conditionappears to be imminent, active manipulation of one ormore aspects of the therapeutic situation many avert a cri-sis For example, the psychiatrist can rephrase a question

cata-or a comment and/cata-or give additional infcata-ormation to ther clarify and simplify the patient’s task Or the patientcan be presented with several possible solutions or alter-native strategies that would permit the given task to bepursued more effectively At times, it can be useful for thepsychiatrist to acknowledge to the patient that explana-tions may have been unclear or expectations may havebeen unreasonably high for that point in the recoveryprocess Obviously, the therapist should not assume re-sponsibility for the patient’s growing anxiety unless he orshe actually believes this to be the case Ultimately, thebest way to manage a catastrophic condition is to prevent

fur-it in the first place, because patients have few assets able to assist them in reestablishing their equilibriumonce it has been disturbed

avail-Guilt, Shame, and Punishment

It is not uncommon for a person who survives significantbrain trauma to experience distressing feelings of guiltand shame If that person was the driver of a vehicleinvolved in a collision, and especially if he or she wasdrinking beforehand, the occurrence of these feelings isquite understandable If a passenger in the vehicle wasseriously injured or killed as a result of that collision,these feelings certainly are appropriate Often, however,even when an injury is caused by a series of unavoidableevents, intense feelings of guilt and shame add theirweight to the injured person’s already-heavy burden.Robert Murphy, an anthropologist who was pro-foundly impaired as the result of a spinal cord tumor,wrote about guilt, shame, and punishment as they are ex-perienced by seriously disabled people What he has tosay applies as well to persons who have had a significantTBI:

The usual formula is that a wrongful act leads to aguilty conscience; if the guilt becomes publiclyknown, then shame must be added to the sequence,followed by punishment A fascinating aspect of

6 5 0 TEXTBOOK OF TRAUMATIC BRAIN INJURY

disability is that it dramatically and completely

reverses the progression, while preserving every

step The sequence of the person damaged in body

goes from punishment (the impairments) to

shame, to guilt and finally to the crime This is not

a real crime but a self-delusion that lurks in our

fears and fantasies; in the never articulated

ques-tion, “What did I do to deserve this?” (Murphy

1987, p 93)

This pressing question deserves a meaningful answer––

one that is possible for the patient to find through the

process of psychotherapy

Stigmatization and Marginality: Society’s

Response to Disability

The classic model of psychotherapy starts with the

assumption that the patient’s problems arise from early

life experiences and that, within limits, the character of

the current outside world has limited impact on the

patient’s potential for recovery This certainly is not the

case for people who have been disabled by a TBI They do

not have a benign or even a neutral physical and social

environment with which to contend during their struggle

toward recovery In effect, TBI, at one and the same time,

is a condition of the injured person’s body and an aspect

of his or her social identity The process is set in motion

by the physical insult but is given definition and meaning

by society (Murphy 1987; Thomsen 1984; Weddell et al

1980) In fact, “very often, social relations between

[peo-ple with brain injuries] and their non-injured peers are

tense, awkward and problematic” (Murphy 1987, p 86)

In our society, brain injury is a condition that is deeply

discrediting and stigmatizing (Goffman 1963) “By

defi-nition, the person with stigma is not quite human [and] on

this assumption all varieties of discrimination are

prac-ticed through which the [injured] person’s life choices are

effectively reduced” (Murphy 1987, p 6) Survivors of

brain injuries may be treated as incompetent, stupid, or

crazy Frequently, they are held responsible for their

con-ditions, for example, “He drove too fast,” “She wasn’t

paying attention to the road conditions,” or “He should

have known that it is dangerous to drink and drive.” In

fact, many persons who have had a brain injury exist in a

kind of marginal state––neither in society nor fully out of

it, not sick nor entirely well—a fact that is reflected in the

confusion over how they should be categorized: patient,

client, or survivor? People who cannot be categorized

neatly and whose behaviors are therefore not predictable

tend to provoke anxiety in others (Murphy 1987; Murphy

et al 1988) Both of these qualities—not being easily

cat-egorized and being unpredictable—frequently cause ple with brain injuries to be demeaned or ignored This is

peo-an inescapable fact of life for a person with a brain injury,and its significance must not be excluded from the psy-chotherapeutic process

LonelinessAlmost every person who survives a TBI, including manywhose injuries are characterized as “mild,” experiencesperiods of significant loneliness This is not the sort ofloneliness that is brought on by the breakup of a marriage,the absence of friends, or the unavailability of rewardingsocial activities, although certainly these situations occurwith dismaying frequency after brain injury Rather, thecondition of loneliness considered here has a far more pro-found impact on the injured person and his or her familyand friends After a TBI, impaired cognitive function andalterations in emotional responsiveness can interfere withthe injured person’s ability to interact empathically withothers As a result, the injured person begins to experiencethe world in ways that are significantly different from those

of other people With the continued loss of meaningfulinterpersonal relationships, the individual begins to losefaith in the validity of his or her sense of self In fact, thecondition of intense loneliness is tantamount to a suspen-sion in the very fashioning of identity (Becker 1962) In anunderstandable effort to maintain consistency in theirworld as well as control over it, exceedingly lonely people,brain injury survivors included, attempt to construct plau-sible explanations for their unhappy lives In these efforts,there is a tendency to develop inaccurate or distorted stan-dards for acceptable social relationships that are impossiblefor others to meet in a consistent fashion (Peplau et al.1982) Then, to explain the reasons for the recurring disap-pointments while denying the possible sources in them-selves, lonely individuals tend to evaluate the motives ofothers negatively, and from this paranoid thinking can fol-low Psychiatrists working with survivors of a TBI whohave become socially isolated should keep in mind that asense of profound loneliness cannot be communicated ver-bally Fromm-Reichmann (1959) related that “unlike othernon-communicable emotional experiences, it [loneliness]cannot even be shared empathetically perhaps because theother person’s empathetic abilities are obstructed by theanxiety arousing quality of its emanations” (p 5) Lonelypeople, especially those who have had a brain injury, cancommunicate and be communicated with only in the mostconcrete terms; therefore, at least in its earliest phase, psy-chotherapy should emphasize behavior rather than words.Meaningful communication with a lonely brain injurypatient is not possible at all until some degree of that pa-

tient’s isolation is breached This may be accomplished by

the psychiatrist’s mere presence in the room without

mak-ing demands, expectmak-ing nothmak-ing more than to be

eventu-ally accepted as a person who is there To progress from

that point, because the sense of profound loneliness is so

difficult for the patient to communicate, it may be

neces-sary for the psychiatrist to take the initiative and open the

discussion about it (Fromm-Reichmann 1959)

The special therapeutic problems and the suggested

therapist responses that were discussed in the preceding

sections are summarized in Table 35–2

Further Suggestions for

Effective Psychotherapy

The psychotherapist must be responsive An effective

therapeu-tic relationship is one in which the patient’s words and

actions elicit appropriate and overt responses There is no

place for therapeutic passivity, open-ended questions, or

nondirective comments in the treatment of individuals

who have experienced significant brain injuries; nor is

there room for intrusiveness or authoritarianism

Psychia-trists must be careful not to force their values and life goals

on patients who, threatened as they are with further

disrup-tion of their identities, are quite vulnerable and therefore

more likely to accept the therapist’s values, no matter how

inappropriate they may be

The patient must be encouraged to lead the way Whenever

possible, the therapeutic endeavor should be guided by the

present concerns of the patient and by what he or she

be-lieves is relevant or can accept as relevant, not by what the

therapist thinks will be of greater significance for the

pa-tient at some future date For most people, whether they

have a brain injury or not, the ability to sustain attention is

limited when they feel forced to attend to tasks that conflict

with their present intentions in order to secure some future

goal (Lichtenberg and Norton 1970) In the words of one

of my own patients, “I hate it when I hear, ‘It’s for your own

good!’” In treating patients who have experienced a brain

injury, psychotherapists are limited in their ability to “tune

in” fully to or empathize deeply with their patients because

psychotherapists experience the world differently from

their patients For these reasons, therapists must follow the

leads of their patients; only in this way can they come to

understand the world in which their patients exist

The need to follow the patient’s lead applies also to

practical issues such as the frequency and duration of

ther-apy sessions and the length of the total psychotherapeutic

endeavor For example, many patients cannot attend

effec-tively for more than 15 or 20 minutes As the informationthat they must process increases, they become more andmore confused and fatigued In these circumstances, pa-tients absorb very little at best, and at worst, they may bethreatened with the onset of a catastrophic condition Usu-ally, with improvement in their cognitive abilities, patientsare able to work productively for longer periods However,the psychiatrist must be aware of the possibility that a shift

in topic or even termination of a treatment session may benecessary if such is indicated by the moment-to-momentevaluation of the patient’s ability to cope

The frequency of therapy sessions should be mined not only by the psychiatrist’s appraisal of the emer-gent nature of the patient’s problems but also by an eval-uation of the patient’s new learning ability A patient withsignificant short-term memory difficulties may initiallyhave to be scheduled on a daily basis to ensure carryoverfrom treatment session to treatment session

deter-The length of the total therapeutic endeavor depends

in large part on the patient’s goals Indeed, a significantpart of the treatment involves helping the patient set ap-propriate goals––goals that are fashioned after the patienthas become aware of both strengths and liabilities and hasaccepted and incorporated a new sense of self

Group experiences are important Every treatment program

for TBI patients should include both formal and informalgroup experiences in addition to individual psychotherapy,because “the real world” with which they hope to reengage

is composed of groups—large groups, small groups, tets, triads, and pairs In “the real world,” no one functions

quar-in isolation; there are always others present, if only quar-in one’smemory and imagination (Pollack 1989)

People who have experienced significant brain ries process information slowly and have difficulty attend-ing to more than one thing at a time; consequently, highlevels of anxiety can be generated when they engage ingroup activities To avoid the onset of a catastrophic con-dition, the injured person may withdraw from the group

inju-or, if that is not possible, may express distress in an moderate fashion Controlled and graduated group expe-riences can assist patients with brain injuries in expressingtheir feelings appropriately and communicating theirideas effectively

im-Family members should be involved in the patient’s treatment In

every case of brain injury, the impact of the injury is tious.” It affects not only the patient but also the patient’sfamily, disrupting its integrity, disturbing the interrelated-ness of its members, and tending to isolate them from eachother as well as from the community at large (Brooks 1991;Lezak 1986; Thomsen 1984)