Surakrant Yutthakasemsunt , M.DKhonkaen Regional Hospital

Khonkaen ,Thailand

Posttraumatic syndrome

23 June 2006

Consideration

• Wastebasket term

• No unique clinical diagnostic criteria

• Controversy in etiological details

• Inconsistency clinical presentation

• Limit of study methodological problems

Related Terms• Posttraumatic syndrome:PTS• Posttraumatic stress disorder:PTSD• Posttraumatic stress syndrome• Posttraumatic neck syndrome• Post-Concussive Syndrome:PCS

• Shell shock

• Battle fatigue

• Accident neurosis

• Post rape syndrome

Posttraumatic stress disorder

Neurobiological Changes after TBI– cortical contusions (mostly in severe TBI)

• results in a loss of function served by that area

– white matter lesions• results in interruption of information processing between cortical

areas

– diffuse axonal injury• results in slowed and inefficient information processing• disproportionately affects glutamatergic and cholinergic projections

– results in problems with attention, memory, and various aspects of frontally-mediated cognition (ie, working memory, executive function)

• may affect serotonergic systems• dysfunction in these systems may secondarily affect the efficiency of

function in dopaminergic or noradrenergic systems

Clinical Features

• Somatic-organic or physical problems• Psychosocial or neuropsychiatry

problems• Cognitive problems

Mixed and fluctuating symptom features over time especially neuropsychiatry problems

Patterns of Post-Concussive Symptoms

Filter Effects of CNS Injury• What does depression look like in

someone who is non-verbal?• What does manic hyperactivity look

like in someone with quadriplegia?• How do hallucinations and delusions

present in someone who cannot describe them?

Vulnerability to Side Effects

• Neuropsychiatric patients show increased frequency & severity of side effects to most psychotropics

• Can manifest as worsening of neurological problems (tremor, cognition, slowing, etc.)

Medications and Drugs Associated with Aggression

• Alcohol: intoxication and withdrawal

• Hypnotic and anxiolytics: intoxication and withdrawal

• Analgesics (narcotics): intoxication and withdrawal

• Steroids (prednisone, cortisone, and anabolic steroids)

• Antidepressants: especially during initial phases of Rx

• Amphetamines and cocaine

• Antipsychotics: secondary to akathisia

• Anticholinergic drugs: delirium

• Quinolone antibiotics?

General Principles• Drug Impact on Cognition

• Memory – Benzodiazepines, antidepressants (anticholinergic effects)

• Attention – Benzodiazepines, neuroleptics• Speed of Information Processing –

Benzodiazepines, neuroleptics, others• Thus the very areas most affected by TBI

can be made worse!

Neurotransmitter Dysfunction after TBI• Many neurotransmitters are involved in the

regulation of cognition, emotion, behavior, and physical/motor function

• Principal neurotransmitters in regulation of frontal and frontotemporal functions include:– dopamine– norepinephrine– serotonin– acetylcholine– glutamate – gamma-aminobutyric acid (GABA)

Ways of Altering Synaptic Content of Neurotransmitters

SynthesisStorageReleaseBinding

Re-uptakeMetabolism

Dopamine Agonists

• A variety of agonists have been shown effective in animal models and are used clinically:–Methylphenidate (and other stimulants)–Amantadine–Bromocriptine–Bupropion

Alpha-2-Adrenergic Agonists• Infusion of A2A agonists improves

WM function in primates and rodents• guanfacine can improve WM in

healthy individuals and may improve working memory after TBI

• Methylphenidate also has A2A agonist properties

Cholinergic Augmentation• Multiple studies demonstrate that cholinergic

augmentation, generally using one of several cholinesterase inhibitors (e.g., physostigmine, donepezil) can improve TBI-induced attention and memory deficits even in the late post-injury period (>1 year) in some TBI survivors – Taverni 1998; Whelan 2000; Cardenas 1994;

Arciniegas 2001

Prior to Treatment• Accurate diagnosis is critical first step

• Know what you are treating before treatment

• Are you treating the underlying disorder, or the comorbid psychopathology?

Neuropsychological Battery (Some)• Orientation

– Galvestone Orientation and Amnesia Test (GOAT)• Motor

– Grooved Pegboard test• Attention,Cognition processing Speed

– Wechsler Memory Scale-Revised Digit Span– Symbol Digit Modality Test

• Visual Scanning,Analysis and Construction– Trailmaking Test– Boston Visual Discrimination Test– Wechsler Adult Intelligence Scale-Revised Block Design (WAIS-RBD)

• Language– Control Oral Word Association Test (COWAT)– Multilingual Aphasia Examination Token Test

• Memory– Wechsler Memory Scale-Revised Logical Memory– Rey Auditory Verbal Learning Test (RAVLT)

• Problem Solving– Wisconsin Card Sorting Test

Why learn about medications?

• Improves care

• Improves your clinical skills

• Fosters participation in treatment

• Facilitates holistic approach to care

Psychopharmacological Approach

• Clarify/simplify current regimen

• Clarify critical target symptoms to treat

• Target specific symptoms

Medication approaches

1. amelioration of specific somatic symptoms (e.g., headache, dizziness, sleep disturbances)

2. amelioration of psychobehavior complications

3. augmentation of cognition

Dosage Considerations

Start lower

Go slower

Stop sooner

Psychopharmacological Issues

• At present, there are no FDA approved treatments for cognitive, emotional, or behavioral impairment due to TBI

• Pharmacotherapies are generally modeled after those for patients with phenomenologically similar but etiologically distinct disorders (attention-deficit hyperactivity disorder, Alzheimer’s disease, etc.)

Physical Symptoms After Concussion

• Headache • Fatigue

• Dizziness/ Dysequilibrium • Insomnia

• Aesthenia/ Weakness • Anosmia

• Numbness/ Paresthesias • Photophobia

• Tinnitus/ Hearing ↓↓ • Blurred Vision

• Hypersensitivity to sound

Post-concussive Headache• Musculoskeletal

–Myofascial – Upper Cervical Spine

• Neurogenic – Greater or Lesser Occipital Neuralgia – Scalp Neuroma from laceration or contusion

• Vascular – Not very common (although more-so in

kids/predisposition) --Overlap in receptive fields for upper cervical

dorsal horns and spinal tract of trigeminal nerve• “Dysautonomic”

Treatment of Post-Concussive Headache

• Musculoskeletal: NSAIDs, Amitryptiline, TP injection, PT, Manual Medicine

• Neurogenic: Injection, anticonvulsants, Amitryptiline, counter-stimulants, PT, TENS, Lidoderm patches

• Vascular: Abortive Rx, Preventative Rx

Post-Concussive “Dizziness”

Postural Instability

vs

Vestibular Dysfunction (vertigo, nystagmus)

Post-Concussive Postural Instability

• Musculoskeletal

• Neurological

– Visual

– Proprioceptive

– Vestibular

– Integrative

Post-Concussive Vestibular Dysfunction

• Vertigo

• Gaze Instability

• Postural Control

Post-concussive Vestibular Problems

• Benign Paroxysmal Positional Vertigo (habituates)

• Central Positional (will not habituate)• Cervicogenic (habituates) • Perilymphatic fistula (bed rest, surgery)• Endolymphatic hydrops

– Betahistine, suppressants, surgery • Unilateral Vestibular Loss • Bilateral Vestibular loss

– head and neck are rigid, gaze unstable

Evaluation of Post-Concussive Dizziness

• Neuro-otology consult

• Imaging

• Electronystagmography (ENG)

• Caloric/rotary testing

• Posturography

Treatment of Post-concussive Dizziness

• Physical Therapy – Habituation Exercises – “Liberatory” Exercises (BPPV) – Oculo-vestibular Exercises

• Behavioral • Pharmacological • Surgery

Pharmacological Treatment of Post-Concussive Dizziness

• Meclizine (Antivert) • Scopolamine (anticholinergics) • Benzodiazepines • Antihistamines

– Loratadine ?

All may impede “natural” recovery and/or effectiveness of therapy

Emotional/Affective Symptoms After Concussion

• Irritability

• Lability /inappropriate emotions (Mood change)

• Depression

• Anxiety/agitation

• Decreased libido

• Impulsive

Despite Diagnostic Challenges

• When behaviors change:– New behaviors

– Change in frequency and intensity of previous behaviors

• Have a high index of suspicion for the common psychiatric disorders

Common Behavioral Syndromes in the Injured Brain

• Depressive Syndromes

• Dyscontrol Syndromes

• Attention Deficit Syndromes

• Sleep Disorders

• Psychotic Syndromes

Psychiatric Disorders and TBI

• Disorders of thought content and thought process complicate recovery from TBI

• Psychotic syndromes occur at rates greater than those in general population

• Injury severity positively correlated with risk

• Even in absence of formal criteria,many with TBI have psychotic symptoms

Other Links to Psychosis• PTA

– resembles delirium in many respects– Restlessness, fluctuating level of consciousness,

agitation.– Hallucinations and delusions occur frequently

• Mood Disorders– Depression– Mania

• Seizure Disorders

Aggression and TBI• Acute phase: 35% - 96% of patients exhibit

agitated behaviors– 89 patients assessed during the first six months

after TBI, aggressive behavior found in 33.7% of TBI patients, compared to 11.5% of patients with multiple trauma but without TBI (Tateno et al)

• Recovery phase: 31% - 71% of patients with severe TBI and 5% - 70% of patients with mild TBI are agitated or irritable

• Irritability increases with more TBI’s

Characteristics of Aggression After TBI

• Reactive: Triggered by modest or trivial stimuli• Nonreflective: Usually does not involve

premeditation or planning• Nonpurposeful: Aggression serves no obvious long-

term aims or goals• Explosive: Buildup is NOT gradual• Periodic: Brief outbursts of rage and aggression,

punctuated by long periods of relative calm• Ego-dystonic: After outbursts, patients are upset,

concerned, and/or embarrassed, as opposed to blaming others or justifying behavior

Neuropathology of Aggression• Hypothalamus

Orchestrates neuroendocrine response to sympathetic arousalMonitors internal status

• Limbic systemAmygdala

Activates and/or suppresses hypothalamusInput from neocortex

Temporal cortexAssociated with aggression on both ictal and interictal

status• Frontal neocortex

Modulates limbic and hypothalamic activityAssociated with social and judgment aspects of aggression

Factors Associated with Agitation in Brain Injury

AGITATIONAGITATIONPsychosisPsychosis

AnxietyAnxiety

InsomniaInsomnia

SundowningSundowning

DepressionDepression

Aggression as Aggression as direct effect of direct effect of

Brain InjuryBrain Injury

Medical Medical IllnessIllnessAdverseAdverse

EnvironmentEnvironment

“Past” Treatment of Agitation• Agitation often treated non-specifically

with sedatives

–Should target underlying causes

• No medication is approved by the FDA for agitation or aggression –May reflect inconsistent concepts and

goals

Approach to Dyscontrol Syndromes

• Consider if due to:–Depression–Mania–Psychosis–Environmental factors–Anxiety

• If so, treat accordingly

Evaluation of Cognitive and Emotional Symptoms

• Imaging (not usually very helpful)• Neuropsychological Assessment • Detailed past history • Differential etiologies

– Medications – Concurrent illness – Sleep disorders

Treatment of Post-Concussive Affective/Emotional Problems

• Correct sleep disturbances

• Counseling Pharmacological – SSRI’s – Anticonvulsants (valproate, carbamazepine) – Propranolol – Psychostimulants – Atypical antipsychotics ?

Approach to Depression• Trials of

– SSRI–second SSRI–Low dose Desipramine or Bupropion

• Other–MAOIs–ECT

Approach to Mania• Valproic Acid • Lithium• Combination approaches• Newer anticonvulsants

–Lamotrigine–Topirimate

Approach to Dyscontrol• If not due to other conditions:

–Beta blockers–Lithium–SSRI’s–Antipsychotics–Calcium channel blockers–Anticonvulsants

Nonpharmacological Approach

• Modify environment• Optimize stimulation• Use consistent routines• Assess/adapt to aggravating factors• Behavior management principles• Education• Support of patient and caregivers

Flow Chart for Management of Aggression

Successful?

Employ nonpharmacologicprinciples

Identify ,most prominent neurobehavioral sx cluster match to relevant class

Depressive features Manic features Anxious features Psychotic features Aggression only

AntidepressantsAnticonvulsants

Lithium

AnticonvulsantsAntidepressantsAnticonvulsants

AnxiolyticsAntipsychotics

Empirical trials: blockers

•Anticonvulsants•Lithium

•Antidepressants•Atypicals

Yes

No

Continue treatment as appropriate

Effective? NoContinue as appropriate

Consider eventual empirical withdrawal Yes Adapted from Tariot et al; Ryan

Evidence Based Guidelines• Workgroup for Neurobehavioral Consequences of TBI

– sponsored by IBIA, CDC

• Reviewed current literature

• Class I - randomized, double-blind, placebo controlled

• Class II - data collected prospectively, or retrospective analyses based on clearly reliable data (observational, cohort, prevalence, case control)

• Class III (case reports, retrospective, etc)

IBIA Evidence Based Review of NBC of TBI

• There were no Class I, or II studies found which addressed the treatment of psychotic syndromes

• Some Class III studies addressed these patient populations, many of these had such methodological flaws that they were not useable in establishing treatment guidelines.

Class III – Psychotic Disorders

• Agents Used– Typical Antipsychotics

• Chlorpromazine – Bamrah, 1991; n=1

– Atypical Antipsychotics• Clozapine – Burke, 1999; n=1, Laddomada 1999; n=1

• Olanzapine – Butler, 2000; n=1, Umansky, 2000; n=1

• Risperidone – Schreiber, 1998; n=1

Side Effects and Toxicity• Overall no clear indication from the literature

that those with TBI suffer increased frequency or severity of side effects, nor novel side effects/toxicity

• Usual side effects do occur:– Akathisia on SSRI’s– Mania on TCA’s and SSRI’s– Sedation, weight gain, seizures on Clozapine– Cognitive impairment on Lithium

• Not clear that this is different from those who have not been injured

Conclusions• The use of standard psychotropics for standard

indications (i.e. antipsychotics for the treatment of psychosis) is an option for clinicians– Use same meds, but dose differently– Cannot match clinical profile to neurotransmitter

profile of various meds– There is clearly a need for randomized clinical trials

to assess the efficacy of antidepressants, anxiolytics, and antipsychotics in the treatment of brain-injured individuals

Cognitive Symptoms After Concussion

• Concentration and Attention

• Memory and learning

• Easily distracted

• Slowed thinking ,planning and problem solving

• Language function & communication deficit

Treatment of Post-concussive Cognitive Problems

• R/O contributing factors (Drug treatment) • Correct sleep disturbances • Counseling/Therapy • Pharmacological

– Psychostimulants – Modafinil for excessive daytime fatigue – Antidepressants • SSRI’s • TCA’s (desipramine) • Buproprion

Approach to Cognitive Deficits• Main target domains:

– Memory : particularly working memory– Attention– Executive Functions

• Management– Baseline testing– Trial of DA, A2A, or Cholinergic agent– Methylphenidate – start 5 mg/day– Aricept - start 5 mg/d– Titrate up slowly as tolerated– Discontinue after 2 months if no improvement