Diagnostic Tools

Diffusion Tensor Weighted Imaging

DTI measures the diffusion of water molecules and their vectors/direction

along white matter tracts, using MR techniques. Disruption of white matter
tracts, as is typically seen in the context of diffuse axonal injury (DAI), is
more dramatically visualized with DTI.

Functional MR Imaging

fMRI measures changes in blood oxygenation levels in specific volumes

(voxels) of the brain. The brain rapidly changes its blood flow/oxygen delivery
to parts of the brain as they become metabolically more or less 160
Moderate to Severe TBI active.

Positron Emission Tomography

PET utilizes positron-emitting radiopharmaceuticals to map the physiology,

biochemistry, and hemodynamics of the brain. 2-Deoxy-2-[18F] fluoro-d-
Glucose (FDG) is the most common radiopharmaceutical used in PET to
measure regional glucose metabolism in the brain. A variety of other
substrates and radiolabeled compounds can be injected and a cross-sectional
map of the brain shows the quantitative distribution, utilization, or binding of
these substrates in the brain. The radiation exposure from a PET scan is
about the same as a CT.

Single Photon Emission Computerized Tomography

SPECT is a nuclear medicine tomographic imaging technique using rays

and a camera. A common -emitting isotope used in SPECT, 99mTcHMPAO
(technetium 99m-hexamethylpropylene amine oxime), is useful in the
detection of regional cerebral blood flow. SPECT is uncommonly used in TBI
and its clinical value is limited.

Angiography

Angiography defines the intra- and extracranial circulation to the brain.

Catheter cerebral angiogram is the definitive test for visualization of the
vasculature, but is invasive and uncommonly used in TBI unless an
underlying aneurysm or arteriovenous malformation (AVM) is suspected.
Noninvasive tests such as CTa are very good for visualizing these same
structures. If venous thrombosis is suspected, MRV is a useful and sensitive
test.
PHARMACOLOGICAL TREATMENT OF SPECIFIC POST-TBI DISORDERS

a. Cognitive Impairment

Cholinesterase inhibitorsCholinergic augmentation with cholinesterase

inhibitors is a reasonable first-line treatment for memory impairment. In particular,
donepezil has been studied for impairments in both memory and attention in
moderate to severe TBI.

Noradrenergic agonistsNoradrenergic agonist agents, which increase

norepinephrine (and to a lesser extent, dopamine) availability, are the mainstay of
treatment for impaired attention and processing speed. These agents may also
enhance learning and memory. Methylphenidate has been studied extensively in
moderate to severe TBI.

Dopaminergic agentsBromocriptine and amantadine can be used to treat

executive dysfunction. Amantadine is not only a dopaminergic agent but also a
partial N-methyl-d-aspartate (NMDA) antagonist and a noradrenergic agent. These
agents also have beneficial effects on attention and general cognitive functioning.
Amantadine is one of the most extensively studied neurostimulant medications in
TBI. It is of particular interest because, in addition to its dopaminergic properties, it
possesses noradrenergic properties, and therefore has the potential to influence
multiple cognitive domains simultaneously.

b. Depression

Selective serotonin reuptake inhibitors (SSRIs)SSRIs are the first-line

treatment for post-TBI depression because of their safety and tolerability as
compared with tricyclic antidepressants (TCAs). Sertraline, the most dopaminergic
of the SSRIs, has the best evidence supporting its use and is the authors preferred
SSRI. Other commonly used SSRIs include citalopram and escitalopram.

TCAsTCAs, which block reuptake of norepinephrine and serotonin, can be quite

effective for depression in some TBI patients. Although amitriptyline is
recommended by certain groups [8], the authors prefer nortriptyline and
desipramine because they are the least anticholinergic. Because of their
unfavorable side effect profile, most clinicians use TCAs only if an initial trial of
SSRIs has been unsuccessful.

Serotonin/norepinephrine reuptake inhibitors (SNRIs)SNRIs, dual reuptake

inhibitors of both serotonin and norepinephrine (e.g., venlafaxine), may also be
effective.

MirtazapineMirtazapine, a presynaptic -2 adrenergic and serotonin receptor

antagonist, can be especially useful when insomnia and/or anorexia are presenting
comorbid symptoms.
NeurolepticsIn cases of major depression with psychotic features, or in cases of
depression with severe agitation or aggression, atypical antipsychotics (also called
second generation antipsychotics; e.g., risperidone, olanzapine) at a standard dose
may be used in conjunction with antidepressants. First generation antipsychotics
such as haloperidol should be avoided as animal studies reveal that they can
increase neuronal toxicity and impede neural plasticity .

CautionBupropion, which facilitates dopamine transmission and has effects on

norepinephrine, is known to lower the seizure threshold. When it must be used, the
long-acting XL form is preferred with a daily dosage not to exceed 300 mg.

c. Mania

AnticonvulsantsAnticonvulsants, such as valproate , are the firstline treatment

for post-TBI mania and bipolar disorder. Close monitoring of serum levels, liver
function, and blood counts is recommended.

LithiumAnecdotal reports and animal studies suggest the effectiveness of

lithium but clinical trials are needed. Because TBI patients are particularly prone to
its neurotoxic side effects, lithium should be used with caution and is usually
reserved for patients with a prior history of mania. Serum levels should be
monitored.

NeurolepticsAtypical antipsychotics (e.g., risperidone and olanzapine) may be

preferred when psychosis, agitation, and/or restlessness are present.

Anxiety

SSRIsTreatment of persistent anxiety often includes the use of SSRIs, for

example, sertraline, at doses that are similar to or sometimes higher than those
used for major depression.

SNRIsSNRIs may also be a good option for anxiety in TBI patients.

BuspironeBuspirone, a serotonergic and weakly dopaminergic agent, can be

used safely as an anxiolytic in patients with TBI. Although it has a slower onset of
action than benzodiazepines, buspirone can be considered as a first-line agent
because of its benign side effect profile and lack of significant drug-drug
interactions.

d. Psychosis

NeurolepticsAtypical antipsychotics are the drugs of choice for psychosis

following TBI. They are preferred over the older typical antipsychotics because of
their lower incidence of neurological side effects such as extrapyramidal side effects
(EPS) and because they do not inhibit dopamine release to the same degree.
Risperidone is a good first-line agent and the one that the authors prefer because of
its favorable risk to benefit ratio. Olanzapine is recommended by the
Neurobehavioral Guidelines Working Group on the basis of case reports supporting
its effectiveness; however, metabolic side effects such as weight gain may limit its
long-term use. Other atypical antipsychotics may also be reasonable option.

AnticonvulsantsIf there is no improvement on neuroleptics, anticonvulsants can

be tried. Anticonvulsants can be useful for associated agitation.

CautionClozapine should be avoided because of its potential to induce

seizures.

Behavioral Dyscontrol

AntidepressantsIn general, the authors tend to use low-dose SSRIs as a first-line

treatment for chronic agitation and aggression, especially if comorbid depressive
symptoms exist. Antidepressants have also been shown to be effective in cases of
affective lability and syndromes of impulsivity and/or disinhibition related to TBI,
such as pathological laughter and crying (formerly referred to as pseudobulbar
affect or emotional incontinence).

Mood stabilizersMood stabilizers such as anticonvulsants are routinely used in

the treatment of post-TBI lability, impulsivity, and/or disinhibition.

-BlockersSmall randomized controlled trials have demonstrated the efficacy of

-adrenergic receptor blocker agents for the treatment of post-TBI aggression and
guidelines have been established for their use [8]. -Blockers selective for the -1
subtype (e.g., metoprolol) are generally preferred because they tend to result in less
CNS depression.

NeurolepticsAcutely, if the patient is getting increasingly agitated, lowdose

atypical antipsychotics can be used. Note, however, that antipsychotic medications
do not help with chronic nonpsychotic aggression.

OtherNoradrenergic agonists and dopaminergics may be useful for impulsivity

and disinhibition.

e. Apathy

Noradrenergic agonists (e.g., methylphenidate) and dopaminergic agents

(e.g., amantadine) may be beneficial in the treatment of post-TBI apathy.
Cholinesterase inhibitors may also be useful if there is an associated post-TBI
dementia. A note of caution: SSRIs, especially in high doses, can worsen apathy and
amotivational syndromes.