Traumatic Brain Injury - Denver, · PDF fileTraumatic Brain Injury: ... University of Colorado School of Medicine. ... At the conclusion of this lecture, participants will: 1

Traumatic Brain Injury:A Neuropsychiatric Perspective

David B Arciniegas MD FANPA CBISTDavid B. Arciniegas, MD, FANPA, CBISTMichael K. Cooper Professor of Neurocognitive Disease

Director, Neurobehavioral Disorders ProgramAssociate Professor of Psychiatry and Neurology

University of Colorado School of MedicineUniversity of Colorado School of Medicine

G l d Obj tiGoals and Objectives

At the conclusion of this lecture participants will:At the conclusion of this lecture, participants will:

1. Understand the diagnostic criteria for traumatic brain injury (TBI)injury (TBI)

2. Identify variables that affect outcome following TBI

3. Recognize the common neuropsychiatric symptoms that follow TBI

4. Be able to apply treatments for the neuropsychiatric sequelae of TBI

Case Example ‐ 1• Ms A. is a previously healthy 34‐year old, right‐handed woman who

sustained a mild TBI (duration of post‐traumatic amnesia of ~ 2 hours) in a motor vehicle accident 2 years prior to consultation. Her Glasgow Coma Score (GCS) = 15 in the ED. She was evaluated and released intoComa Score (GCS) 15 in the ED. She was evaluated and released into the care of her husband on the day of injury.

• Since the accident she has experienced impairment in attention and memory, and has not able to work full‐time as a result of these yproblems.

• Additionally, developed problems with impulse control and affect regulation (brief paroxysms of crying and irritability).

• She was prescribed buspirone 10 mg twice daily by her psychiatrist to improve impulsivity and affective liability, which she describes as moderately effective.

Case Example ‐ 1• On interview, she describes her attention problems as most evident in

her difficulty completing tasks at both work and home, such as reading lengthy pieces of information or writing notes, learning new information such as names or telephone numbers and followinginformation such as names or telephone numbers, and following conversations. These problems were especially evident (and made much worse by) noisy environments.

• Neurological examination was normal.Neurological examination was normal.

• MMSE score was 30/30.

• On neuropsychological testing, she demonstrated slow but errorless f th T il M ki T t P t B d f fperformance on the Trail Making Test – Part B and a few errors of

omission on the Digit Vigilance task.

• Magnetic resonance imaging of the brain (clinical study) was read as “normal for age ”normal for age.

Case Example ‐ 2• Ms C. is a previously healthy 45‐year old, right‐handed woman who

sustained a mild TBI (duration of post‐traumatic amnesia of ~15 minutes) 9 years prior to this evaluation. GCS = 15 in the ED. She was evaluated and released into the care of her husband on the day of injury.released into the care of her husband on the day of injury.

• Since the accident, she described impairments in attention and memory. She has returned to partial employment despite these deficits.

dd ll h ff d d h ( )• Additionally, she suffered L5‐S1 disc herniation (requiring surgery), developed chronic mild neck pain and occipital headaches, and irritability/rage with trivial provocation.

Sh i tl b i t t d ith NSAID f i d th l h id t• She is presently being treated with NSAIDs for pain and methylphenidate 7.5 mg twice daily to improve attention and decrease irritability/rage. She describes these treatments as moderately effective.

Case Example ‐ 2• On interview, she describes her attention problems as most evident in

difficulty staying on task with her reading, writing, and conversations, a tendency to `easy mental fatigue’, impairment in learning new information such as names and appointments; and inability toinformation such as names and appointments; and inability to concentrate in any noisy environment, especially those with `white noise’ such as fans.

• Neurological examination was normal.Neurological examination was normal.

• MMSE score was 30/30.

• On neuropsychological testing, her performance on both the Digit Vi il d Di it S b l t k l d t th f lVigilance and Digit Symbol tasks was slow and noteworthy for several errors on each test.

• Magnetic resonance imaging of the brain (clinical study) was read as “normal for age ”normal for age.

Case Example ‐ 3p• A 22 year old man with no known medical, neurological, or

psychiatric problems is brought to the emergency room after a motor vehicle accidentmotor vehicle accident.

• Paramedics report that at the scene of the accident, the patient had a Glasgow Coma Scale (GCS) score of 11, but that en route t th h it l h h d d t i t d idl f iti dto the hospital he had deteriorated rapidly from a cognitive and behavioral standpoint.

• His GCS is now 5, and his blood alcohol level is found to be above the legal limit.

• There is no other evidence of skull fracture, significant facial injury, or multitrauma, although he has a few rib fractures. He isinjury, or multitrauma, although he has a few rib fractures. He is intubated upon arrival to the emergency room.

Case Example Case Example ‐‐ 33• A CT scan of the brain is performed immediately upon his arrival• A CT scan of the brain is performed immediately upon his arrival,

and demonstrates a large left frontotemporal epidural hematoma, bilateral frontal and anterior temporal cortical contusions and punctate hemorrhages at the gray‐white junctions, and hypodensities in the frontal white matter bilaterallybilaterally.

• The epidural hematoma is evacuated by the neurosurgeons within the first hour of hospitalization, but the patient remains in coma for the next seven days (day 7 GCS = 6).days (day 7 GCS 6).

• He gradually emerges from coma over the following seven days (day 14 GCS = 13), although his Galveston Orientation and Amnesia Test (GOAT) scores remain in the 30‐40 range. g

• He is evaluated by a rehabilitation team, and transferred to a neurorehabilitation unit approximately three weeks after his injury, at which time his GOAT scores remain in the 30‐40 range.

• At one‐year post‐TBI, he remains severely impaired cognitively, has frequent episodes of agitation/aggression, and experiences once‐monthly partial complex seizures that intermittently generalize. He has not been able to

k d i i i f hi f hi hreturn to work, and requires supervision from his parents for most higher‐level activities of daily living.

General Definition of TBI• Application to the brain of an external physical force or

rapid acceleration and/or deceleration forces

– not due to congenital, degenerative, vascular, hypoxic‐ischemic, neoplastic, toxic‐metabolic, infectious, or other causes

d d l h l l• Produces an immediately apparent physiological disruption of brain function manifested by cognitive or neurological impairments

• Results in partial or total functional disability (regardless of the duration of such disability)

(TBI Act of 1992, House Resolution 5907; Kay and Harrington 1993;TBI Act of 1996, Public Law 104-166; Marr and Coronado 2002)

American Congress of Rehabilitation MedicineAmerican Congress of Rehabilitation Medicine Definition Definition of Mild TBI:of Mild TBI:

• A traumatically induced physiological disruption of brain function, as manifested by at least one of the following:

– any period of loss of consciousness (LOC)

– any loss of memory for events immediately before or after the accident (posttraumatic amnesia, PTA)

– any alteration in mental state at the time of the accident (e.g., feeling dazed, disoriented, or confused)

– focal neurologic deficit(s) that may or may not be transientfocal neurologic deficit(s) that may or may not be transient

Kay, T., Harrington, D. E., Adams, R. E., Anderson, T. W., Berrol, S., Cicerone, K., Dahlberg, C., Gerber, D., Goka, R. S., Harley, J. P., Hilt, J., Horn, L.J., Lehmkuhl, D., & Malec, J. (1993). Definition of mild traumatic brain injury: Report from the Mild Traumatic Brain Injury Committee of the Head InjuryInterdisciplinary Special Interest Group of the American Congress of Rehabilitation Medicine. Journal of Head Trauma Rehabilitation, 8(3), 86-87.

American Congress of Rehabilitation MedicineAmerican Congress of Rehabilitation Medicine Definition Definition of Mild TBI:of Mild TBI:

• The severity of the injury does not exceed the y j yfollowing:

– LOC ≤ 30 minutes

– after 30 minutes, Glasgow Coma Scale = 13‐15

– PTA ≤ 24 hours

• TBI producing disturbances that exceed these criteria is classified as moderate or severe

Kay, T., Harrington, D. E., Adams, R. E., Anderson, T. W., Berrol, S., Cicerone, K., Dahlberg, C., Gerber, D., Goka, R. S., Harley, J. P., Hilt, J., Horn, L.J., Lehmkuhl, D., & Malec, J. (1993). Definition of mild traumatic brain injury: Report from the Mild Traumatic Brain Injury Committee of the Head InjuryInterdisciplinary Special Interest Group of the American Congress of Rehabilitation Medicine. Journal of Head Trauma Rehabilitation, 8(3), 86-87.

Self‐diagnosis of TBISelf diagnosis of TBI

• Diagnosis of TBI based on unsubstantiated claims of• Diagnosis of TBI based on unsubstantiated claims of injury must be regarded with caution

– under‐reporting vs. over‐reporting

– poor understanding of TBI

– misunderstanding symptoms as reflective of TBI when other diagnoses offer better explanations

– stigma vs. secondary gains

Powell et al. 2008Powell et al. 2008 (Arch Phys Med Rehabil)

• Used CDC/ACRM definition of mild TBI to screen• Used CDC/ACRM definition of mild TBI to screen 197 patients presenting to the ED with history or event suggestive of mild TBI

• 56% percent of mild TBI cases identified by study personnel did not have a documented mild TBIpersonnel did not have a documented mild TBI‐related diagnosis in the ED record

l k d t d di i d it ti t ti– lack documented diagnosis despite patients reporting findings consistent with a mild TBI diagnosis when interviewed by study personnel

Self‐diagnosis of TBI• Claims of mild TBI without evidence in the medical

record require careful evaluation of the history and other available evidenceavailable evidence– use ACRM definition of mild TBI as an anchor for the clinical

history

– interview witnesses, if any, to the purported injury

– review medical, neurological, and neuropsychological evaluations (including comparison to pre‐injury whenever such d b b i d)data can be obtained)

– review (by visual inspection, not just reports) any structural neuroimaging (CT, MRI) for findings consistent with traumaticb i i jbrain injury

TBI: The Scope of the Problem• Conservative estimate: 240,000 new TBI per year

– based on CDC surveillance of TBIs resulting in hospital stay 24 hours

– only 1 in 5 patients experiencing a mild TBI are hospitalized 24 hours

• Estimated actual frequencies of between 1 and 2 million new injuries per year

• 3.17 million Americans (1.1% of the US population) currently live with disabilities resulting from TBI

(Thurman et al. 1999; Thurman and Guerrero 1999; Marr and Coronado 2002; Zaloshnja et al. 2008)

Annual Costs of TBI• 50,000 people in the U.S. die each year as a result of TBI

• Every year, at least 80,000 people in the U.S. develop permanent functional disabilities as a p presult of TBI

• Total direct cost for TBI at all levels of severity is yestimated at $48.3 billion annually– indirect costs (eg, lost wages by survivor and family) additive

hto these costs

(CDC 2001; Kraus and Sorenson 1994, Max et al. 1991)

I d t d t d th ff t f b iIn order to understand the effects of braininjury, we must undertake full study of thei di id l’ tit ti I th d it i tindividual’s constitution. In other words, it is notjust the kind of injury that matters, but the kindof brain that is inj redof brain that is injured.

Sir Charles Symonds, c. 1937

Influences on Neurobehavioral Outcome after TBIInfluences on Neurobehavioral Outcome after TBI

Disturbed ConsciousnessDisturbed ConsciousnessImpaired AttentionSlowed Processing

Working Memory ProblemsMemory Disturbance

CognitiveDisturbance

Pre-InjuryFactors Memory Disturbance

Functional Communication Impairments

Executive DysfunctionDepression

Disturbance

Emotional

Factors

Traumatic Brain Injury

DepressionAnxiety

Irritability/LabilityRage

Agitation

EmotionalDisturbance

Brain Injury AgitationAggressionDisinhibition

ApathySleep Disturbance

BehavioralDisturbance

Sleep DisturbanceHeadaches

PainVisual ProblemsDizziness/Vertigo

PhysicalDisturbancePost-Injury

(Adapted from Silver and Arciniegas 2006)

Dizziness/VertigoSeizures

PsychosocialFactors

Pre‐Injury FactorsPre‐Injury Factorsj yj y

• Age and gender

• Baseline intellectual function

• Psychiatric problems & substance abuse

• Sociopathy

• “Risk‐taking” and “novelty‐seeking” behavior

• Premorbid behavioral problems

• Social circumstances and SES

• Neurogenetic (ie, APOE‐4, COMT, ?other)

(Rates of TBI-related hospitalization and death by age group as reported through the CDC TBI surveillance program in 1994 by AZ, CO, MN, MO, NY (excluding NYC), OK, and SC. Source: Thurman et al. 1999)

Pre injury FactorsPre injury FactorsPre‐injury FactorsPre‐injury Factors

• Pre‐injury psychiatric problemsPre injury psychiatric problems

Pre TBIPre TBI11 Post TBIPost TBI11 CommunityCommunity22

Major Dep.Major Dep. 17%17% 58%58% 6%6%Major Dep.Major Dep. 17%17% 58%58% 6%6%

S/U DisorderS/U Disorder 38%38% 16%16% 17% 17%

PTSDPTSD 6%6% 18%18% 8%8%

OCDOCD 1%1% 14%14% 3%3%

Panic Panic 4% 11%4% 11% 2%2%

GADGAD 1%1% 8%8% 4%4%

PhobiasPhobias 4%4% 6%6% 13%13%

((11Hibbard, Silver, et al. 2001;Hibbard, Silver, et al. 2001; 22Bourdon et al. 1992)Bourdon et al. 1992)

Pre injury FactorsPre injury FactorsPre‐injury FactorsPre‐injury Factors• Pre‐injury sociopathy

• “Risk‐taking” and “novelty‐seeking” behavior

• Pre‐injury behavioral problems (children)Pre injury behavioral problems (children)

– all are complex issues with respect to outcome

• Simplistically, if one has impaired impulse control, a tendency to aggression or socially inappropriate behavior or other severe behavioral disturbances TBIbehavior, or other severe behavioral disturbances, TBI will rarely result in improvement in those problems

NeurogeneticsNeurogenetics• A new approach to understanding TBI outcome

• The apolipoprotein E (APOE) genes appear to stronglyThe apolipoprotein E (APOE) genes appear to strongly influence recovery following TBI at all levels of severity

– the APOE‐4 gene negatively affects cognitive, motor, and functional outcome after TBI

• Genes that affect the metabolism of neurotransmitters in the brain and/or neuronal plasticity may influencethe brain and/or neuronal plasticity may influence cognitive and behavioral outcome after TBI– catechol‐O‐methyltransferase (COMT), dopamine receptor type 2

(DRD2), Taq1, ? others

(Roberts et al. 1994, Nicoll et al. 1995; Sorbi et al. 1995; Graham et al. 1996; Jordan et al. 1997; Friedman et al. 1999; Ramassamy et al. 1999; Kutner et al. 2000; Lichtman et al. 2000; White et al. 2001; Crawford et al. 2002; Liaquat et al. 2002; Lieberman et al. 2002; Lynch et al. 2002; Lynch et al. 2003; Diaz-

Arrastia et al. 2003; Kerr et al. 2003; Lipsy et al. 2005; McAllister et al. 2004; Zhou et al. 2008)

Injury Factors• Biomechanical Injury

– acceleration/decelerationl i l/ i l

• Secondary Injury – traumatic hematomas

– translational/rotational– angular acceleration/deceleration– cavitation (“microexplosive”)

diff l i j (DAI)

– cerebral edema– hydrocephalus– increased intracranial– diffuse axonal injury (DAI)

• Cytotoxic Injury– cytoskeletal & axonal injury

increased intracranial pressure (ICP)

– systemic complications• hypoxia/hypercapnia– cytoskeletal & axonal injury

– disturbance of cell metabolism– Ca++ and Mg++ dysregulation– free radical release

hypoxia/hypercapnia• anemia• electrolyte disturbance• infectionfree radical release

– neurotransmitter excitotoxicity

(Reviewed in: Meythaler et al. 2001; Nuwer 2005; Povlishock and Katz 2005; Bigler 2007)

Rotational force

Inertial Forces:Inertial Forces:force vector Translation, Rotation, and Angular Translation, Rotation, and Angular

Acceleration ForcesAcceleration Forces

Translational force vector

(Figure adapted from Arciniegas and Beresford 2001)

Center of mass

Cytotoxic Cascadey

Contact Forces

Injury Factors: Neurotransmitter ExcitotoxicityNeurotransmitter Excitotoxicity

• Biomechanical forces strain axons1,2,3,4

– within the brainstem and ventral forebrain

– along septohippocampal pathway (retro‐forniceal projections)

– projecting through anterior and midline cerebral areas to cortical targetsto cortical targets

• Mechanical deformation of axons results in stretch‐induced action potentials5 and the release of potentially neurotoxic excesses of cerebral neurotransmitters1,6

(Reviewed in: 1. Arciniegas and Silver 2006; 2. Bigler 2007; 3. Povlishock and Katz 2005; 4. Meythaler et al. 2003; 5. Julian and Goldman 1962; 6. Shaw 2002)

Adapted from anatomic illustrations in Gilman and Newman 1987

Injury Factors: Neurochemistryj y y• Neurotransmitter “storm” at time of TBI

i i l (1 5) d i (6 7)– acute increases in glutamate(1‐5), dopamine(6,7), norepinephrine(6,7), serotonin(6‐9), and acetylcholine(10) are reported from CSF samples in the acute post‐injury period among persons with severe TBI

– these acute neurotransmitter excesses are functionally disruptive

– among those who survive their injuries, cerebral glutamate, dopamine, norepinephrine, and serotonin levels appear to normalize in the days to weeks following TBI (6; 11‐13)TBI

(1. Wagner et al. 2005; 2. Kerr et al. 2003; 3. Yamamoto et al. 1999; 4. Alessandri et al. 1999; 5. Koura et al. 1998; 6. Markianos et al. 1996; 7. Markianos et al. 1992; 8. Porta et al. 1975; 10. Grossman et al. 1975; 11. Obrenovitch and Urenjak 1997; 12. Matsushita et al. 2000; 13. Goodman et al. 1996; )

Injury Factors: Neurochemistryj y y• Persistent damage in and dysfunction of areas with

dense glutamate and acetylcholine inputsdense glutamate and acetylcholine inputs

• Chronic primary cortical cholinergic dysfunction

– damage to cerebral cholinergic nuclei (1‐3)

– loss of cholinergic afferents (3,4)

– dysfunction of cholinergically‐dependent information processing circuits (5‐8)

P ibl h i i d d f ti i• Possible chronic primary or secondary dysfunction in serotonin‐, dopamine‐, norepinephrine‐dependent neuropsychiatric functions (9)neuropsychiatric functions

(1. Dewar and Graham 1996; 2. Murdoch et al. 2002; 3. Salmond et al. 2005; 4. Murdoch et al. 1998; 5. Arciniegas et al. 1999; 6. Arciniegas et al. 2000; 7. Arciniegas et al. 2001; 8. Arciniegas et al. 2004. 9. In: Arciniegas and Silver 2006)

Injury Factors• Biomechanical Injury

– acceleration/deceleration

• Secondary Injury – traumatic hematomas/

– translational/rotational

– cavitation (“microexplosive”)

diffuse axonal injury (DAI)

traumatic hematomas

– cerebral edema

– hydrocephalus– diffuse axonal injury (DAI)

• Cytotoxic Injury– increased intracranial pressure (ICP)

l– cytoskeletal & axonal injury

– disturbance of cell metabolism

– Ca++ and Mg++ dysregulation

– systemic complications• hypoxia/hypercapnia

• anemia– free radical release

– neurotransmitter excitotoxicity• electrolyte disturbance

• infection

(Reviewed in: Meythaler et al. 2001; Nuwer 2005; Povlishock and Katz 2005; Bigler 2007)

Regional Vulnerability to TBI

Yeates et al. 2007 Salmond et al. 2005 Kraus et al. 2007

Regional Vulnerability to TBIand Brain‐Behavior Relationshipsp

(Figure adapted from Arciniegas and Beresford 2001)

Selective Distributed Networks Subserving Selective Distributed Networks Subserving Executive Executive FunctionFunction,, ComportmentComportment,, MotivationMotivation,, andand EmEmototioionn

Dorsolateral Prefrontal

CortexAnterior Cingulate Posterior Cingulate

Dorsolateral Prefrontal

CortexAnterior Cingulate Posterior Cingulate

Infracallosal CingulateInfracallosal Cingulate

(Lateral)

Orbitofrontal

StriatumMultimodal

Sensory Information

(Lateral)

Orbitofrontal

StriatumMultimodal

Sensory Information

Orbitofrontal Cortex(Medial)

GPe GPi

STn

ThalamusNuc. Acc.

Orbitofrontal Cortex(Medial)

GPe GPi

STn

ThalamusNuc. Acc.

HiA d l HiA d l

(Mega and Cummings 1994; Mayberg 1997; Arciniegas and Topkoff 2000; figure adapted from Arciniegas and Beresford 2001)

HippocampusAmygdalaHypothalamusHippocampusAmygdalaHypothalamus

Post‐injury Factors• Untoward medical complications

• Failure to receive timely medical, neurological, psychiatric, or y , g , p y ,other needed rehabilitative services– early engagement in neurorehabilitation is associated with improved

functional outcomes

• Lack of education regarding the course of recovery and interpretation of symptoms

• Lack of family, friends, or resources to support recovery

• Premature return to work/school with ensuing failure to perform d l lat expected levels

• Poor adjustment to or coping with disability by injured person or familyfamily

• Litigation or other legal entanglements

Courses of Recovery after TBICourses of Recovery after TBIop

athy

c E

ncep

halo

sttra

umat

icS

tage

of P

os

Glu, DA, NE, 5HT, GABA

ACh

Adapted from Arciniegas et al. 2010 and Arciniegas and McAllister 2008

S

Rancho Los Amigos Scale ‐ Revised• Level I ‐ No Response: Total Assistance

• Level II ‐ Generalized Response: Total Assistance

• Level III ‐ Localized Response: Total Assistance

• Level IV ‐ Confused/Agitated: Maximal Assistance

• Level V ‐ Confused, Inappropriate Non‐Agitated: Maximal Assistance

• Level VI ‐ Confused, Appropriate: Moderate Assistance

• Level VII ‐ Automatic, Appropriate: Minimal Assistance

• Level VIII ‐ Purposeful, Appropriate: Stand‐By Assistance

• Level IX ‐ Purposeful, Appropriate: Stand‐By Assistance on Request

• Level X ‐ Purposeful, Appropriate: Modified Independent

(Hagen 1997)

Recovery from M d S TBIModerate‐to‐Severe TBI

• About 35 60% of persons with moderate to• About 35‐60% of persons with moderate to severe TBI will develop chronic neurobehavioral and/or physical symptoms related to TBIand/or physical symptoms related to T I

– more severe initial injury increases the likelihood of incomplete neurological, neurobehavioral, and p g , ,functional recovery

• Successful return to work and/or school is• Successful return to work and/or school is inversely related to the severity of persistent neurobehavioral and physical symptomsneurobehavioral and physical symptoms

Recovery from Mild TBIRecovery from Mild TBI• 1st week post‐TBI: 90% (or more) endorse p ( )postconcussive symptoms

• 1 month post TBI: ~50% are recovered fully• 1 month post‐TBI: 50% are recovered fully

• 3 months post‐TBI: ~66% are recovered fully

• 6‐12 months post‐TBI: ~10% still symptomatic

• Those who remain symptomatic at 12 months are likely to continue experiencing postconcussive

h fsymptoms thereafter

Recovery from Mild TBIRecovery from Mild TBI• Persistent symptoms following mild TBI are more

h i j i i fcommon among persons whose injuries are in fact not “mild” at all

– mild TBI (GCS 13‐15) with skull fracture, cerebral contusion, or intracranial hemorrhage (“complicated mild TBI”)

ild TBI ith ti ti f t (APOE 4)– mild TBI with negative neurogenetic factors (APOE‐4)

• Persistent symptoms following mild TBI are also more i di id l i h h i ificommon among individuals with other significant pre‐

injury vulnerabilities or post‐injury medical or psychosocial complicationspsychosocial complications








Disturbance

Emotional

Factors


DepressionAnxiety


Agitation










PsychosocialFactors

Pre‐Treatment AssessmentPre Treatment Assessment

• Reevaluate current treatment– Other treatments not properly applied

– Misdiagnosisg

– Poor communication among professionals

• Key issuesKey issues– Indications of all drugs

Are they still necessary?– Are they still necessary?

– Potential side effects of medications

Pre‐Treatment Assessment• Eliminate or at least reduce doses of neurobehaviorally problematic medications

– neuroleptics/typical antipsychotics

– benzodiazepinesp

– strongly anticholinergic medications

• including some tricyclic antidepressants and paroxetineincluding some tricyclic antidepressants and paroxetine

– phenytoin and carbamazepine

– 2 agonists (e g clonidine)– 2 agonists (e.g., clonidine)

– high‐dose opiates

alcohol and other substances of abuse– alcohol and other substances of abuse(Goldstein 1999; Goldstein 2003; Stanislav 1997; Rao et al. 1985; Riches and Brown 1986; Brailowsky et al. 1986; Schallert 1986; Buffett-Jerrot and Stewart

2002; Bleigberg et al. 1993; Dixon et al. 1994; Dixon et al. 1995; Saija et al. 1988; Smith et al. 1994; Dikmen 1991; Dikmen et al. 2000; Schierhout and Roberts 2001; Marion et al. 2006; reviewed in Arciniegas and Silver 2006)

Dopamine and Norepinephrine AntagonismDopamine and Norepinephrine Antagonism

• In animal models, dopamine and norepinephrine antagonists delay neuronal recovery and neural plasticity1,2

• Among humans, typical antipsychotics exacerbate cognitive i i t ith TBI2 3impairments among persons with TBI2,3

– haloperidol increases duration of PTA following severe TBI in humans4

and in animals5

– risperidone increases duration of PTA and motor impairments in animals5

• TBI increases the risk for haloperidol induced NMS especially• TBI increases the risk for haloperidol‐induced NMS, especially with high‐dose parental administration6

(1. Goldstein 1999; 2. Goldstein 2003; 3. Stanislav 1997; 4. Rao et al. 1985; 5. Hoffman et al. 2008; 6. Bellamy et al. 2009)

Benzodiazepinesp

• In animal models, administration of benzodiazepines suppresses induction of LTP (neural mechanism for new learning) and increases motor and sensory impairments1,2,3

• Among humans, benzodiazepines worsen motor and memory function amongmotor and memory function among healthy individuals4 and persons with TBI5

(1. Riches and Brown 1986; 2. Brailowsky et al. 1986; 3. Schallert 1986; 4. Buffett-Jerrot and Stewart 2002; 5. Bleigberg et al. 1993)

Anticholinergic AgentsAnticholinergic Agents

• In animal models of TBI, administration of scopolamine impairs memory function, even in animals with apparently recovered f ti 1 2 3function1,2,3

• Among humans with TBI, anticholinergic g gagents (including antidepressants with potent anticholinergic properties) impair

d h h l llmemory and other cholinergically‐dependent neurobehavioral functions4

(1. Dixon et al. 1994; 2. Dixon et al. 1995; 3. Saija et al. 1988; 4. Reviewed in Arciniegas and Silver 2006)

Anticonvulsants• Double‐blind, placebo‐controlled trials of phenytoin1,2,3, carbamazepine2, and valproate3, p e yto , ca ba a ep e , a d a p oate ,among persons with TBI demonstrate:

– impaired cognitionimpaired cognition

– impaired motor function

no benefit on the pre ention of late sei res (i e– no benefit on the prevention of late seizures (i.e., seizures occurring after the first week post‐injury)1‐5

– if an anticonvulsant must be used valproate appears to– if an anticonvulsant must be used, valproate appears to preferable to phenytoin or carbamazepine with respect to its effects on cognition

(1. Smith et al. 1994; 2. Dikmen 1991; 3. Dikmen et al. 2000; 4. Schierhout and Roberts 2001; 4. Marion et al. 2006)

Pre‐Treatment Assessment• Neuroimaging evaluation may be a helpful guide to

treatment selection and response expectations

– severe focal cortical and white matter damage bodes poorly for response to treatments attempting to remediate neurobehavioral deficits served by the damaged area(s)

– diffuse axonal injury is a better prognostic finding with respect to the potential benefits of treatment

l h h " l" i l i i di d– although "normal" conventional neuroimaging studies do not indicate that the brain is in fact uninjured, they do suggest that underlying injury may be of a sufficiently mild severity to bode well for treatment response

Treatment of Neuropsychiatric Sequelae of TBITreatment of Neuropsychiatric Sequelae of TBI• Acute management focuses on reduction of symptoms

interfering with rehabilitation or posing risk of harminterfering with rehabilitation or posing risk of harm

– reduce risk of re‐injury (setting, medications, assistive devices, etc.)

• Select patients for formal rehabilitation

– evaluation of functional deficits and development ofevaluation of functional deficits and development of compensatory strategies to promote independence

• Family counselingFamily counseling

• Non‐pharmacologic + pharmacologic treatment of acute and chronic posttraumatic neuropsychiatric problemsand chronic posttraumatic neuropsychiatric problems

Nonpharmacological TreatmentNonpharmacological Treatment

• Environmental management– reduce overstimulation

– facilitate adaptive engagement with the environment

t i ti t th d h i l– support existing strengths and psychosocial resources

• Educational interventions for person with TBI and their families

• Symptom targeted physical therapy occupational• Symptom‐targeted physical therapy, occupational therapy, speech therapy, and neuropsychological treatments (cognitive rehabilitation)1,2ea e s (cog e e ab a o )

(1. Cicerone et al. 2000; 2. Cicerone et al. 2005)

Principles of TBI PharmacotherapyPrinciples of TBI Pharmacotherapy

• Define target symptoms clearly

• Therapeutic trial of all medications (pre‐set dose and duration of treatment)

• Monitor side effects

i f i• Duration of maintenance treatment

• Ease of use

• Monitor drug‐drug interactions

A t ti l h• Augment partial responses when necessary

Posttraumatic Cognitive Impairmentsg p• In the acute and late periods following TBI, the

domains of cognition most commonly affected by TBI include:

– arousal/disturbances of consciousness

– processing speed/reaction time

– attention (selective, sustained, alternating, divided)( , , g, )

– working memory

memory (new learning retrieval or [usually] both)– memory (new learning, retrieval, or [usually] both)

– functional communication (use of language)

i f i– executive function

(Reviewed in: Bigler 2007; Arciniegas and Silver 2006; Nuwer 2005; Meythaler et al. 2001)

RRxx of Posttraumatic Cognitive Impairmentsof Posttraumatic Cognitive ImpairmentsRRxx of Posttraumatic Cognitive Impairmentsof Posttraumatic Cognitive Impairments

• Catecholaminergic augmentation

– target symptoms: arousal, speed of processing, and sustained attention/vigilance

– emerging evidence (McAllister et al. 2004) of differential effects of DA and NE on posttraumatic working memory impairments

– additional evidence (Lipsky et al. 2002; McAllister et al. 2004) demonstrating differences in cognitive profiles and treatment response to catecholaminergic agents may be influenced by p g g y ygenetic polymorphisms relevant to these neurotransmitters

• COMT, DRD2, Taq1, others?q

Catecholamine AugmentationCatecholamine Augmentation• Dopaminergic • Indirect dopaminergic

ff t i– bromocriptine

– carbidopa/levodopa

effects via:– uncompetitive NMDA

receptor antagonism

• Mixed dopaminergic and noradrenergic

receptor antagonism

• Amantadine

• Memantineg– methylphenidate

– dextroamphetamine

– ? Modafinil

– ? lamotriginep

– other amphetamine salts

(Eames 1989; Powell et al. 1996; Passler et al. 2001; McDowell et al. 1998; Lal et al. 1988;Whyte et al. 1997; Whyte et al. 2004; Worzniak et al. 1997; Evans et al. 1987; Gualtieri and Evans 1988; Speech et al. 1993; Plenger et al. 1996; Kaelin et al. 1996; Tiberti et al. 1998; Evans et al. 1987; Hornstein et al. 1996; Gualtieri T et al. 1989; Kraus MF and Maki PM 1997; Van Reekum R et al. 1995; Nickels JL et al. 1994; Meythaler et al. 2002; Schneider et al. 1999; Elovic 2000; Teitelman 2001; Showalter and Kimmel 2000; Pachet et al. 2003)

Cholinergic Augmentationg g• Target symptoms: memory (encoding, retrieval, or both)

and sustained attention

– in principle, arousal would be a reasonable target symptom as well

– however, the response of hypoarousal to cholinergic augmentation has not been studied in this population

• Present evidence suggests that patients with posttraumatic memory impairments are most likely to b fi f hi fbenefit from this type of treatment

– among those with memory impairments who respond to cholinergic augmentation attention and executive function maycholinergic augmentation, attention and executive function may also improve

Cholinergic Augmentation: Acetylcholinesterase InhibitorsCholinergic Augmentation: Acetylcholinesterase Inhibitors

• Agents in this class of medication that have been• Agents in this class of medication that have been used to treat posttraumatic cognitive impairments include:impairments include:

– physostigmine

– donepezil

– rivastigminerivastigmine

– galantamine

(Bogdanovitch et al. 1975; Eames and Sutton 1995; Goldberg et al. 1982; Levin et al. 1986; Cardenas et al. 1994; Taverni et al. 1998; Whelan et al. 2000; Masanic et al. 2001; Bourgeois et al. 2002; Morey et al. 2003; Kaye et al. 2003; Walker et al. 2004; Zhang et al. 2004; Khateb et al. 2005; Tenovuo 2005; Trovato et al. 2006; Foster and Spiegel 2008; Tenovuo 2006; Silver et al. 2006 )

RRxx of Posttraumatic Cognitive Impairmentsof Posttraumatic Cognitive ImpairmentsRRxx of Posttraumatic Cognitive Impairmentsof Posttraumatic Cognitive Impairments

• Catecholamine augmentation for problems with l d f i d harousal, speed of processing, and perhaps

sustained attention

• Cholinergic augmentation when impaired memory is the most prominent symptom

– attention and executive function may also respond among persons with prominent memory impairments

• Both for patients inadequately responsive to either approach aloneeither approach alone

Common Posttraumatic Emotional d B h i l P bland Behavioral Problems

• Depression

• Mania

• Pathological Laughing and Crying

• Anxiety

• Irritability or loss of temper (“rage episodes”)

• Disinhibition

• Agitation/Aggression (“socially inappropriate behavior”)

• Apathy (loss of drive to think, feel, and/or behave)

• Psychosisy

• Sleep disturbance

Depression after TBI: Epidemiology

M i d• Most common posttraumatic mood disturbance

• Incidence: 10‐77%

b t t di t f 25 50%– best studies suggest a range of 25‐50%

– highest rates of depression in the 1st year post‐TBI

(Reviewed in Alderfer et al. 2005)

Psychiatric Diagnoses after TBIPsychiatric Diagnoses after TBIPsychiatric Diagnoses after TBIPsychiatric Diagnoses after TBI Not controlling for alcohol abuse Controlling for alcohol abuse Odds ratio 95% CI Odds ratio 95% CI Major depression 2.4 1.7-3.4 2.3 1.6-3.2 Dysthymia 2.0 1.2-3.1 1.7 1.1-2.7 Bipolar disorder 1.4 0.6-3.0 1.1 0.5-2.5Bipolar disorder 1.4 0.6 3.0 1.1 0.5 2.5Obsessive-compulsive disorder 2.1 1.3-3.4 2.0 1.2-3.2 Panic disorder 2.8 1.5-5.2 2.5 1.3-4.6 Any phobia 1.7 1.3-2.4 1.6 1.2-2.3 D b /d d 1 8 1 2 2 5 1 5 1 0 2 1Drug abuse/dependence 1.8 1.2-2.5 1.5 1.0-2.1Alcohol abuse/dependence 2.2 1.7-2.8 Schizophrenia 1.8 1.0-3.3 1.7 0.9-3.0 Suicide attempt 5.7 3.7-8.7 4.5 2.8-7.1

Table 4. The association between psychiatric disorders and TBI after controlling for sociodemographic variables (age, sex, marital status, and SES) and quality of life variables. From the New Have Epidemiologic Catchment Area Study (n=5034). Adapted from Silver et al. (2001).

(Adapted from Silver et al., 2001)

Risk Factors for Depression after TBIRisk Factors for Depression after TBI

• Risk for post‐TBI depression is associated with pre‐d finjury, injury, and post‐injury factors

• Pre‐injury risk factors:j y– poor pre‐injury occupational status

– poor pre‐morbid social function and/or poverty

– history of psychiatric diagnosis or brain injury

– alcohol abuse

– fewer years of formal education

– female gender

a tendency to experience high levels of stress– a tendency to experience high levels of stress



• Injury factors:

– laterality of injury (left)• decreased left prefrontal gray matter

• left dorsolateral frontal and/or left basal ganglia lesions

i it f i j t th l ft f t l l i di tl• proximity of injury to the left frontal pole is directly proportional to the severity of depression

serotonergic dysfunction– serotonergic dysfunction

– injury severityh h f d f ld• higher rates of depression after mild TBI

(Lispey et al. 1983; Mobayed and Dinan 1990; Jorge et al. 1993; Glenn et al. 2001; Rapoport et al. 2002; Dikmen et al. 2004; Robinson et al. 2004)


• Post‐injury factorsj y– Changes in autonomy

– Altered self‐image

– Changes in close relationships (social isolation)

– Poor psychosocial support

• Depression is also common (as high as 47%), in caregivers of persons with TBI and exposes the person with the injury to greater risk (Gillen et al. 1998)


Effects of Depression on Outcome after TBIEffects of Depression on Outcome after TBI• Posttraumatic depression is associated with other problems after TBI:problems after TBI:

– increased suicidality

d f– cognitive dysfunction

– anxiety

– aggressive behavior

– poor psychosocial outcome

– increased psychosocial distress

– greater number and perceived severity of post‐g p y pconcussive symptoms


Effects of Depression on Outcome after TBIEffects of Depression on Outcome after TBI• Depression interferes with physical and cognitive rehabilitationrehabilitation

• Effective treatment of depression after TBI:

– improves depressive symptoms

– facilitates cognitive function

– reduces the number of other postconcussive symptoms

– decreases the perceived severity of remaining postconcussive symptoms


RRxx of Depression after TBI: SSRIsof Depression after TBI: SSRIsRRxx of Depression after TBI: SSRIsof Depression after TBI: SSRIs• Selective‐serotonin reuptake inhibitors (SSRIs) are highly

effective and well tolerated treatment for depressioneffective and well tolerated treatment for depression following TBI:

t lit t i t t f t li– present literature is strongest for sertraline

– citalopram appears to be effective and safeb t i d i ti it l i i il l ff ti• by extension, and in practice, escitalopram is similarly effective

– extended half‐life of fluoxetine’s primary metabolite, norfluoxetine, may present problems when side effects developnorfluoxetine, may present problems when side effects develop

– anticholinergic effects of paroxetine may be problematic

(Cassidy 1989; Bessette and Peterson 1992; Wroblewski et al. 1992; Breen et al. 1997; Kant et al. 1998; Fann et al. 2000; Fann et al. 2001; Perino et al. 2001; Lee et al. 2005; Rapoport et al. 2007)

RRxx of Depression after TBI: TCAsof Depression after TBI: TCAsxx pp• Response to tricyclic and heterocyclic antidepressants is highly variable in the TBI p g ypopulation

– less effective in this population vs. among persons withless effective in this population vs. among persons with idiopathic (primary) major depressive disorder

– seizures in as many as 20% of patients treated with sei ures in as many as 0% of patients treated withTCAs in the acute rehabilitation setting

– increased risk for cognitive impairment with higher g p ganticholinergic load

– nonetheless, for some patients, they may be useful and reasonably well‐tolerated treatments

(Saran 1985; Varney et al. 1987; Wroblewski et al. 1990; Dinan and Mobayed 1992;. Wroblewski et al. 1996)

RR of Depression after TBI: Stimulantsof Depression after TBI: StimulantsRRx x of Depression after TBI: Stimulantsof Depression after TBI: Stimulants

• Methylphenidate or dextroamphetamine may improve mood disturbances after TBI

B t d d dj ti t t t• Best regarded as adjunctive treatments or pre‐treatment to standard antidepressants

• Response of depression to a stimulant may be not only helpful symptomatically but also presage response to standard antidepressant

(Lipper and Tuchman 1976; Gualtieri and Evans 1988; Whyte et al. 1997; Lee et al. 2005 )

RRxx of Depression after TBI:of Depression after TBI:Other AntidepressantsOther Antidepressants

• No published evidence to support the use ofNo published evidence to support the use of bupropion, venlafaxine, mirtazapine, duloxetine, or other newer antidepressants for posttraumatic ddepression

• Common clinical experience suggests that some of these agents may be useful

• Use with caution in persons with TBI given theUse with caution in persons with TBI given the current lack of information

– dose‐related seizure risk with bupropion merits particular concern in this population

RRxx of Depression after TBI: ECTof Depression after TBI: ECTx x pp• Electroconvulsive therapy (ECT) appears to be a safe

and effective treatment for severe and/or refractoryand effective treatment for severe and/or refractory post‐TBI depression

– may also be useful for post‐TBI mania agitation delirium ormay also be useful for post TBI mania, agitation, delirium, or psychosis

– rare increase in confusion/worsening of cognition/ g g

– no reported increase in post‐traumatic seizures

• Probably best reserved for use after multiple medication failures or in cases of severe, refractory, or life threatening depressionlife‐threatening depression

(Ruedrich et al. 1983; Zwil et al. 1992; Crow et al. 1996; Kant et al. 1999)

RRx x of Depression after TBI: of Depression after TBI: Psychosocial InterventionsPsychosocial Interventions

• Paucity of data on this aspect of treatmentPaucity of data on this aspect of treatment

• Focus on education of the injured person and his or her familyher family

– peer support groups increased knowledge about TBI, helped persons cope with depression better, and improved

l f l f ( bb d l )quality of life (Hibbard et al. 2002)

• A formal coping skills group intervention in a wait‐list control design ( f )control design (Anson and Ponsford 2006)

– improvement on the Coping Scale for Adults

i ifi t h i i t d i lf t– no significant changes in anxiety, depression, self‐esteem and psychosocial function

Posttraumatic Mania: EpidemiologyPosttraumatic Mania: Epidemiology

• Prevalence of posttraumatic mania: 2‐9%

– highest risk in the first several months post‐injury

although the occurrence of a single manic episode– although the occurrence of a single manic episode merits a DSM‐IV‐TR bipolar disorder diagnosis, this method of diagnosis works poorly in this g p ypopulation

• Prevalence of posttraumatic bipolar disorderPrevalence of posttraumatic bipolar disorder (true bi‐polar presentations): uncertain, but probably <1%p y

P tt ti M i E id i lPosttraumatic Mania: Epidemiology

• TBI may increase the relative risk (RR) for bipolarTBI may increase the relative risk (RR) for bipolar disorder (general population prevalence = 0.8%)

– Van Reekum et al. (2000): 4.2% lifetime risk (RR=5)

– Hibbard et al. (1998): 1.6% lifetime prevalence (RR=2)

– Silver et al. (2001): Odds ratio equal in persons with and without TBI

Psychiatric Diagnoses after TBIPsychiatric Diagnoses after TBIPsychiatric Diagnoses after TBIPsychiatric Diagnoses after TBI

Not controlling for alcohol abuse Controlling for alcohol abuse Odds ratio 95% CI Odds ratio 95% CI Major depression 2.4 1.7-3.4 2.3 1.6-3.2 Dysthymia 2.0 1.2-3.1 1.7 1.1-2.7 Bipolar disorder 1.4 0.6-3.0 1.1 0.5-2.5Bipolar disorder 1.4 0.6 3.0 1.1 0.5 2.5Obsessive-compulsive disorder 2.1 1.3-3.4 2.0 1.2-3.2 Panic disorder 2.8 1.5-5.2 2.5 1.3-4.6 Any phobia 1.7 1.3-2.4 1.6 1.2-2.3 D b /d d 1 8 1 2 2 5 1 5 1 0 2 1Drug abuse/dependence 1.8 1.2-2.5 1.5 1.0-2.1Alcohol abuse/dependence 2.2 1.7-2.8 Schizophrenia 1.8 1.0-3.3 1.7 0.9-3.0 Suicide attempt 5.7 3.7-8.7 4.5 2.8-7.1

Table 4. The association between psychiatric disorders and TBI after controlling for sociodemographic variables (age, sex, marital status, and SES) and quality of life variables. From the New Have Epidemiologic Catchment Area Study (n=5034). Adapted from Silver et al. (2001).

(Adapted from Silver et al., 2001)

Mania after TBI: PresentationMania after TBI: Presentation

• The majority (>80%) of posttraumatic maniasThe majority (>80%) of posttraumatic manias begin in the first 3 months post‐TBI

A d ti f f ll t ti i d f• Average duration of fully symptomatic episodes of posttraumatic mania is 2 months

– euphoric/expansive mood may persist for as long as 6 months

• Recurrence of posttraumatic mania (and development of true bi‐polarity) is unusual

(Jorge et al. 1993)

Mania after TBI: Risk FactorsMania after TBI: Risk Factors

• Risk is not clearly related to:Risk is not clearly related to:

– type or severity of brain injury

– degree of physical or intellectual impairment

– level of social functioning

f il / l hi f hi i di d– family/personal history of psychiatric disorder

(Jorge et al. 1993)

f kMania after TBI: Risk Factors• Risk of posttraumatic mania increased with• Risk of posttraumatic mania increased with injury to:

– basopolar temporal lesions

i ht li bi th li bi i ti– right limbic pathways or paralimbic association cortices lesions

• Unclear association with posttraumatic seizures

(Jorge et al. 1993; Starkstein et al. 1987, 1988; Robinson et al. 1988)

RRxx of Mania after TBI: Treatmentof Mania after TBI: TreatmentRRx x of Mania after TBI: Treatmentof Mania after TBI: Treatment• Very limited literature

– case reports, case series, all open‐label

• Beneficial effects reported usingBeneficial effects reported using

– lithium (1,2)

carbamazepine (2 3)– carbamazepine (2,3)

– valproate (4‐7)

– haloperidol (with or without benzodiazepines) (8)– haloperidol (with or without benzodiazepines) (8)

– quetiapine (9,10)

– combinations of agents (3 11)combinations of agents (3,11)

(1. Starkstein et al. 1987; 2. Stewart et al. 1988; 3. Bouvy et al. 1988;4. Kim et al. 2002; 5. Pope et al. 1988; 6. Monji et al. 1999; 7. Yassa et al. 1994; 8. Mustafa et al. 2005; 9. Oster et al. 2007; 10. Daniels and Felde 2008; 11. Murai et al. 2003)

RRxx of Mania after TBI: Treatmentof Mania after TBI: TreatmentRRx x of Mania after TBI: Treatmentof Mania after TBI: Treatment• Problems with many currently available agents when

used among persons with TBIused among persons with TBI

– lithium and carbamazepine impair cognitive and motor performance among person with TBI (1‐4)

– lithium lowers seizure threshold (2)

– haloperidol (and all D2 antagonists) interfere with neuronalhaloperidol (and all D2 antagonists) interfere with neuronal recovery (5), cognition and motor function (6‐8), and are

particularly problematic when administered chronically (9)

– benzodiazepines impair cognitive and motor performance (10)

(1. Smith et al. 1994; 2. Hornstein and Seliger 1989; 3. Massagli et al. 1991; 4. Glenn et al. 1989; 5. Wilson et al. 2003; 6. Rao et al. 1985; 7. Elovic et al. 2003; 8. Stanislav 1997; 9. Kline et al. 2007; 10. Bleiberg et al. 1993)

RR of Mania after TBI: Treatmentof Mania after TBI: TreatmentRRx x of Mania after TBI: Treatment of Mania after TBI: Treatment

• Valproate, in most cases, is relatively neutral with respect to its effects on cognition and motor function after TBI (1,2)

• Quetiapine may improve mania and also comorbid aggression and cognitive impairmentcomorbid aggression and cognitive impairment (3,4,5)

• ECT has been reported to be helpful in the p ptreatment of posttraumatic mania (6)

(1. Dikmen et al. 2000; 2. Temkin et al. 1999; 3. Kim and Bijlani 2006; 4. Oster et al. 2007; 5. Daniels and Felde 2008; 6. Clark and Davidson 1987)

RRx x of Mania after TBIof Mania after TBI• Valproate or quetiapine are probably best first‐choices for posttraumatic mania

• Carbamazepine is second‐line

• There is no data for lamotrigine or for any of the other atypical antipsychotics in posttraumatic maniamania

– in this population, these still are probably preferable to treatment with lithium haloperidol ortreatment with lithium, haloperidol, or benzodiazepines

• ECT may be considered for severe or refractory• ECT may be considered for severe or refractory posttraumatic mania

RR of Mania after TBIof Mania after TBIRRx x of Mania after TBIof Mania after TBI

Th bli h d t di f• There are no published studies of psychotherapies for the treatment of

tt ti iposttraumatic mania

• Supportive counseling and family therapy• Supportive counseling and family therapy may be reasonable to employ, but their effectiveness is not presently establishedeffectiveness is not presently established

Pathological Laughing and CryingPathological Laughing and Crying

• An uncommon but potentially serious p ydisturbance of affect regulation after TBI

f f 5 11% i th fi t t i j– frequency of 5‐11% in the first year post‐injury

– uncertain frequency in the late period following injury

• Frequently mistaken for depression or• Frequently mistaken for depression or bipolar disorder

(Zeilig et al. 1996; Tateno et al. 2004)

Pathological Laughing and CryingPathological Laughing and CryingA. Frequent brief episodes of involuntary and uncontrollable crying and/or

laughing

B. Episodes of crying and laughing may involve an episode‐congruent feeling, but do not necessarily reflect and do not produce a persistent change in the prevailing mood

C. Episodes are excessively intense with respect to the stimulus that incites them, and may be inappropriate to the context in which they develop (i.e., laughing when crying would be expected or vice versa)(i.e., laughing when crying would be expected or vice versa)

D. Episodes reflect a change from usual affect regulation

E. There is evidence of an underlying neurological conditionE. There is evidence of an underlying neurological condition

F. The episodes are subjectively distressing and/or produce clinically significant impairments in social, occupational, or other important

t f f tiaspects of function

(Wortzel, Anderson, and Arciniegas 2007)

P th l i l L hi d C iPathological Laughing and Crying

• Although PLC may occur with depression scores on• Although PLC may occur with depression, scores on this measure are not correlated with scores on depression measuresp

• Improvement of PLC occurs independently of improvement in depressionimprovement in depression

– suggests that PLC and depression are distinct disturbances f l lof emotional regulation

(Schiffer et al. 1985; Robinson et al. 1993)

Lesion Location in PLC• PLC results from disinhibition or dysmodulation of

pontomedullary periaqueductal gray area‐pontomedullary periaqueductal gray areategmentum/nucleus retroambiguus complex

L i f th i hibit th d i PLC• Lesions of the inhibitory pathways producing PLC include:

fronto pontine projections– fronto‐pontine projections

– cerebello‐thalamo‐fronto‐pontine circuit

– cerebello‐pontine projectionscerebello pontine projections

• Any brain disease impairing these circuits can produce PLC including TBIproduce PLC, including TBI

(Reviewed in Rabins and Arciniegas 2007 and Wortzel, Anderson, and Arciniegas 2007)

RRx x of PLCof PLC• The selective serotonin reuptake inhibitors (SSRIs)

and tricyclic antidepressants (TCAs) are useful treatments of PLC

• In light of their efficacy safety and tolerability SSRIsIn light of their efficacy, safety, and tolerability, SSRIs are recommended as the first‐line agents for this purpose

• Among the SSRIs, agents with short half‐lives, no anticholinergic effects, and limited potential for drug‐g , p gdrug interactions are best suited for use among persons with TBI

– citalopram, escitalopram, and sertraline

(Reviewed in Wortzel, Anderson, and Arciniegas 2007)

RRxx of PLCof PLCx x

• When a TCA is used, nortriptyline, amitriptyline, and imipramine may be useful alternativeand imipramine may be useful alternative treatments for PLC

– among these, nortriptyline is preferred in light of its relatively favorable side‐effect profile

• Catecholaminergic augmentation (e.g., methylphenidate, amantadine, levodopa) may be f b fit b t th d t ti th fof benefit, but the data supporting the use of

these agents for the treatment of PLC are very limitedlimited


RRx x of PLCof PLC• Catecholamine augmentation may be particularly

useful when aimed at the concurrent treatment of posttraumatic hypoarousal, slowed processing, attention impairments, or apathy

• “Mood stabilizers” (e.g., anticonvulsants) are generally ineffective for the treatment of PLC

• Dextromethorphan/quinidine (Neudexta) may be released in the near futurereleased in the near future

– caution when used concurrently with agents metabolized by the CYP450 2D6 pathwaythe CYP450‐2D6 pathway


RRxx of PLCof PLCRRx x of PLCof PLC

(Wortzel et al. 2008)

Posttraumatic Apathyp y• Apathy refers to a neurologically‐determined state of

diminished goal‐directed cognition, emotion, anddiminished goal directed cognition, emotion, and behavior

– diminished ‘motivation’ in this context does not carry the forensic connotation of poor effort or malingering

• The syndrome of apathy reflects injury (usually y p y j y ( ybilateral) to the anterior cingulate‐subcortical circuit

• Frequency of posttraumatic apathy is poorly described

– more common among persons with severe TBI

(Kant et al. 1998; Anderson et al. 1999)

Posttraumatic Apathyp y

• Distinguishing between apathy and depression, h ibl i ti lwhere possible, is essential

– depression: a state of persistent and excessive sadness

– apathy: absence of goal‐directed emotion, behavior, and cognition

• Many agents that improve depression (e.g., SSRIs, TCAs) worsen apathy

• However, agents that improve apathy may also improve depressionimprove depression

Posttraumatic Apathyp y

• Apathy may co‐occur with impulsivity and aggressionaggression

• The combination reflects concurrent injury to the anterior cingulate‐subcortical combined with injury to the lateral orbitofrontal‐subcortical circ itcircuit

• This is a difficult combination to treat pharmacologically

– agents that improve apathy may worsen impulsivity and aggression, and vice versa

RR of Posttraumatic Apathyof Posttraumatic ApathyRRx x of Posttraumatic Apathyof Posttraumatic Apathy

• Non‐pharmacologic interventions are first‐line treatments of apathy

– verbal cueing

– environmental facilitation of activity

id d d/ h d f ilit ti f ti it– guided and/or hands‐on facilitation of activity

(Silver and Arciniegas 2006)

RRxx of Posttraumatic Apathyof Posttraumatic ApathyRRx x of Posttraumatic Apathyof Posttraumatic Apathy

• First‐line: catecholaminergic augmentationg g

– amantadine, bromocriptine, carbidopa/L‐dopa, methylphenidate, dextroamphetamine

• Second‐line: cholinergic augmentation

– donepezil, rivastigmine, galantamine

• Third line: activating tricyclic antidepressants• Third‐line: activating tricyclic antidepressants

– protriptyline, desipramine, amitriptyline

(Silver and Arciniegas 2006; Kraus and Maki 1997; van Reekum et al. 1995; Gualtieri et al. 1989; Chandler et al. 1988; Nickels et al. 1994; Powell et al. 1996; Debette et al. 2002; Lipper and Tuchman 1976; Glen 1998; Evans et al. 1987; Cummings 2000; Levy et al. 1999; Wroblewski et al. 1993; Reinhard et al. 1996)

Anxiety Disorders after TBIAnxiety Disorders after TBI

• 20‐40% in the first year after TBIy– often comorbid with posttraumatic depression

SSRI’ fi li• SSRI’s are first‐line treatments

• Anticonvulsant medications (especiallyAnticonvulsant medications (especially valproate or gabapentin) may be useful if associated with irritability, aggression, and/or y, gg , /pain

B di i b t id d• Benzodiazepines are best avoided

Posttraumatic PsychosisPosttraumatic Psychosis• Very uncommon problem (<5% lifetime risk)

• Atypical antipsychotics are first‐line treatment

– possible pro‐cholinergic effect of olanzapine (via 5HT‐3 andpossible pro cholinergic effect of olanzapine (via 5HT 3 and 5HT‐6 antagonism) has been demonstrated to improve cognition among persons receiving this agent for the treatment of the positive symptoms (hallucinations, delusions) of schizophrenia

– low doses preferable (avoid dose‐dependent D2 receptor blockade and competitive anticholinergic effects)blockade and competitive anticholinergic effects)

• Avoid typical antipsychotics and benzodiazepines

Posttraumatic Agitation/Aggression g gg

• Very common problem– up to 90% of persons with severe TBI in the acute post‐injuryup to 90% of persons with severe TBI in the acute post injury

period; frequency after mild TBI is not well described

• Atypical antipsychotics (especially quetiapine) areAtypical antipsychotics (especially quetiapine) are recommended for severe posttraumatic agitation/aggression during the acute injury period

• Valproate is first‐line therapy for non‐psychotic aggression in the late post‐injury period

• Avoid typical antipsychotics and benzodiazepines whenever possible

Other Neuropsychiatric Sequelae of TBIOther Neuropsychiatric Sequelae of TBI

• Sleep disturbance

– low‐dose trazodone (25‐100 mg) is first‐line

– low‐dose atypical antipsychotics (quetiapine)yp p y (q p )

– avoid benzodiazepines and diphenhydramine

• Fatigue

– treat sleep disturbances first

– stimulants and other dopaminergically‐active agents (ie, amantadine) may be of benefit

– ? modafinil (Provigil)

Other Neuropsychiatric Sequelae of TBI

• Headache

– conform to IHS headache types– conform to IHS headache types

– use standard therapies

id t i li t (i tit i t li El il)– avoid tricyclic agents (ie, amtitriptyline, or Elavil) among cognitively impaired patients

• Epilepsy

– conform to ILAE seizure types

– avoid phentyoin (Dilantin) and carbamazepine (Tegretol) among cognitively impaired patients

– valproate (Depakote) and other newer agents with limited adverse effects on cognition are preferable

Summaryy

• TBI is a common and costly problem

• The neuroanatomy and neurochemistry of TBI predict substantial posttraumatic neuropsychiatric morbidityp p y y

• Post‐TBI (postconcussive) neuropsychiatric symptoms can be grouped into three categoriescan be grouped into three categories

– cognitive

i l/b h i l– emotional/behavioral

– somatic (physical)








Disturbance

Emotional

Factors


DepressionAnxiety


Agitation










PsychosocialFactors

Courses of Recovery after TBICourses of Recovery after TBIop

athy

c E

ncep

halo

sttra

umat

icS

tage

of P

os

Glu, DA, NE, 5HT, GABA

ACh

Adapted from Arciniegas et al. 2010 and Arciniegas and McAllister 2008

S

Summary

• The neuropsychiatric and functional sequelae of TBI bl t t t tare amenable to treatment

– early involvement (once medically stable) in neurorehabilitation improves long‐term outcome

– early patient and family education as well as provision of psychosocial supports improves long‐term outcome

– rational pharmacotherapy (evidence‐based and/or using a priori hypotheses based on the neuroanatomy and neurochemistry of TBI) improves acute and long‐term disability following TBIdisability following TBI

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Traumatic Brain Injury - Denver, · PDF fileTraumatic Brain Injury: ... University of Colorado School of Medicine. ... At the conclusion of this lecture, participants will: 1