traumatic brain injury and pain f.antonio luque, m.d. ph.d. neurology

Traumatic Brain Injury and Pain

F.Antonio Luque, M.D. Ph.D.

Neurology

Traumatic Brain Injury

TBI in the USA estimated 180-200 cases/100,000

Around 600,000 New TBI occur every year

10% of these Injuries are fatal.

NIH survey estimates in USA 1.9 million suffer skull fracture or intracranial injury, ½ have suboptimal outcome.

Cost 40 Billion dollars/year

TRAUMATIC BRAIN INJURY

Military Fatalities: By Time PeriodAs of 2/20/07

Period US UK Other* Total Avg Days

5 998 34 21 1,053 2.43 434

4 715 13 18 746 2.35 318

3 579 25 27 631 2.92 216

2 718 27 58 803 1.89 424

1 140 33 0 173 4.02 43

Total 3,150 132 124 3,406 2.37 1,435

US Non Mortal Casualties: Including non-hostile and medical evacuations

As of 2/3/07

Non-Mortal Casualities

Army

Navy

Marines

Air Force

Total

Wounded – No Medical Air Transport Required

10,120 385 5,698

209 16,412

Wounded – Medical Air Transport Required

5,009 137

1,804

55 7,005

Non-Hostile Injuries – Medical Air Transport Required

5,439

223 895

278 6,835

Disease – Medical Air Transport Required

16,111

544

1,209

840 18,704

TOTAL – WOUNDED 15,129 522 7,502 264 23,417

TOTAL – MEDICAL AIR TRANSPORTED

26,559

904

3,908

1,173 32,544

Traumatic Brain InjuryTraumatic brain injury symptoms

Inability to find words

Inability to perform tasks

Confabulating (putting unrelated bits of conversation into conversation gaps)

Impulsivity

Agitation

Poor judgment and poor insight

Sexual inappropriateness, including a lack of sexual inhibitions

For more information, call (800) 877-VETS, or visit www.va.gov.

http://www.va.gov/

Frequency of PCS Symptoms following a MTBI

• Poor concentration 71%• Irritability 66%• Tired a lot more 64%• Depression 63%• Memory problems 59%• Headaches 59%• Anxiety 58%• Trouble thinking 57%• Dizziness 52%• Blurry or double vision 45%• Sensitivity to bright light 40%

Traumatic Brain Injury, VA Health Initiative

Causes of TBI (CDC Data)

• Transportation (MVA) 48.9%

• Falls 25.8%

• Firearms 9.7%

• Other Assaults 7.5%

• Others 7.4 %

• Unknown 0.6%


Severity Grades of TBI

• Mild (Grade 1 ): altered or LOC <30 min with normal CT or MRI, GCS 13-15, PTA < 24 hours.

• Moderate (Grade 2): LOC < 6 hours with abnormal CT and/or MRI, GCS 9-12, PTA < 7 days.

• Severe (Grade 3 & 4): LOC > 6 hours with abnormal CT and/or MRI, GCS < 9, PTA > 7 days.

Traumatic Brain Injury VA Health Initiative

Functional Correlates of Injury Pathophysiology

• Focal Cortical Contusion: ground level fall, assault, gunshot wound. They can have Hemiparesis, aphasia, Seizures, visuoperceptual.

• Diffuse Axonal Injury: motor vehicle accident, non-ground level fall, geriatric ground level fall. They have confuse language, amnesia, apraxia, hypoarousal.

• Hypoxic/Ischemic: anoxia, cardiac arrest, prolonged elevated ICP. They have quadriparesis, spasticity, confusion, amnesia, hypoaraousal.


Frequency of PCS Symptoms following a MTBI

• Poor concentration 71%• Irritability 66%• Tired a lot more 64%• Depression 63%• Memory problems 59%• Headaches 59%• Anxiety 58%• Trouble thinking 57%• Dizziness 52%• Blurry or double vision 45%• Sensitivity to bright light 40%


Specific or subjective PCS

• Neurological or medical: Headaches, Dizziness/vertigo, Tinnitus, blurred or double vision, light and or noise sensitivity, Nausea and vomiting, Fatigue, sleep disturbances, Physical weakness.

• Cognitive: Memory complaints, concentration complaints.

• Psychological: Irritability, Increase aggression, Depression, Anxiety.


Referrals ( Team work)• Audiologist• Kinesiotherapist• Neuro-ophthalmologist• Occupational therapist• Recreational therapist• Speech and language pathologist• Case manager• Neurologist• Neuropsychologist (psychologist)• Physiatrist• Psychiatrist• Social worker (counselor)• Vocational rehabilitation counselor


Comprehensive Assessment of Acquired Brain Injury

History: Accident related facts

Initial neurological presentation

Pre injury information

past medical history and surgical history substance abuse

developmental history

educational history.

Military and legal records

Vocational History

Psychological history

Life stressors

Family history

Post injury treatment interventions

Current functional status

Physical Examination:

Neurological

Cranial nerves 1-12

Deep tendon reflexes and pathological

Sensory exam

Cerebellar exam

Motor exam

Mental status exam

Behavioral assessment

Emotional/psychological status

Musculoskeletal

Head

Face and temporomandibular joints

Extremities

Axial structures (neck, back, pelvis)


Chronic cognitive problems

• Attention problems

• New learning and memory problems

• Executive control dysfunction

• Others (orientation, communication, behavioral, bradyphrenia, etc)


Interplay of cognitive and emotional problems

Psychogenic/Psychiatry symptoms Denial

Anger and irritability

Depression

Rigid compulsive/hypervigilant

Emotional lability

Social withdrawl

Sense of futurelessness

Thought disorder

Personality and conduct disorder

Neurogenic symptoms Anasognosia (lack of awareness of

impairment)

Frustration, catastrophic reaction, reduce information

Lack of initiative, impaired emotional expressiveness (Aprosodias), lower

crying threshold, fatigue

Distractability, inabilityto deal with more than one task at a time, dependence on external controls.

Lability of emotional expressiveness (not the underlying feeling state)

Lack of initiative

Impaired planning

Aphasia, anomia, or confusion

Impulsivity, social disinhibition


• Acute Pain:”Normal sensation triggered by the nervous system to alert you to possible injury.”

• Chronic Pain:”Pain persists, signals keep firing in the nervous system for weeks, months, even years”

NINDS Chronic Pain information page

Pain

• Tissue injury trigers an inflammatory cascade that will alter nociceptive function.

• Plasticity and learning play a role in pain• Synaptic potentiation is facilitated by repetitive noxious

stimulation and at the level of the brain,environmental influences alter the response to noxious stimulation.

• The brain can generate pain in the absence of input from the peripheral nociceptors or the spinal cord. e.g. phantom limb pain

• Therefore a Brain pattern generating mechanism or Neuromatrix has been proposed

Pain: an overview, JD Loeser, R.Melzack . The Lancet 1999: 1607-1609

International association for the Study of Pain:

“Pain is an unpleasant sensory and emotional experience associated with actual or potential tissue damage or describe in terms of such damage”

JD Loeser, R Melzack, The Lancet 1999: 1607-1609 (Pain: an overview)

Components of Pain• Nociception: detection of tissue damage by specialized

transducers attached to A delta and C fibers. Aspirin can prevent inflammation and Local and regional anesthesia can prevent nociception.

• Perception of Pain: triggerd by noxious stimulus, It can be generated by lesion in the peripheral or central nervous system.e.g. diabetic neuropathy, spinal cord injury or stroke. Pain can occur without nociception. The intensity of chronic pain has no relation to the extent of tissue injury or other pathology.

• Suffering:negative response induce by pain and by fear, anxiety, stress, loss of loved objects and othr psychological states. Cassell:”Suffering occurs when the physcial and psychological integrity of the person is threatened”.

• Pain Behaviors: results from pain and suffering and the things the person do or does not do. Examples:”ouch”, gramacing, limping, lying down , recourse to health care, refusing to work, etc.

JD Loeser, R. Melzack, The Lancet 1999: 1607-1609 (Pain: an overview)

The neurobiology of pain, Besson JM The Lancet,1999:353: 1610-1615

Histamine, serotonin, bradykinin, prostaglandins, ATP, H+ ,NGF, TNF alpha, endothelins, interleukins

Pain treatment options: TCA, anticonvulsants, Na+ channel blockers, NMDA receptor antagonists, opioids

Molecular Events of PainPeripheral

Transduction• TRPV1, TRPV2, TRPV3, TRPM8• ASCI, DRASIC• MDEG, TREK-1• BK1, BK2

• P2K3

Peripheral sensitization• NGF, TrkA• TRPV1• Na, 1,8• PKA, PKC isoforms, CalMK IV• Erk1/2, p38, JNK• IL-1β, cPLA2, COX2, EP1, EP3, EP4• TNFαMembrane excitability of primary afferents• Nav 1.8, Nav 1.9• K+ channelSynaptic transmission Presynaptic• VGCC• Adenosine-R• (mGlu-R)

J.Scholz, CJ Woolf:Can we conquer pain? , Nature Neuroscience 2002: 10621067

Molecular Events of PainCentral

Synaptic transmission Postsynaptic• AMPA/kainate-R, NMDA-R, mGlu-R• NK1• Nav 1.3• K+ channelsCentral inhibition• GABA, GABAA-R, GABAB-R• Glycine-R• NE, 5-HT• Opioid receptors• CB1Signal transduction• PKA, PC isoforms• ERK, p38, JNKGene expression• C-fos, c-jun, CREB• DREAM

J.Scholz, CJ Woolf: Can we conquer pain? Nature Neuroscience 2002: 1062-1067

The National Initiative on Pain Control, 2002

BRAIN IMAGING TECHNIQUESPET• Requires relatively long pain stimulation periods (40 – 60s).• Different functional states (e.g., pain and rest) are always acquired in separate scans.• Maximum number of scans that can be acquired is limited by radioactivity dose restraints.• Usually requires multi-patient study designs.• Potential to map neurotransmitter systems and drug uptake in vivo and molecular imaging.• Provides a solution in cases where fMRI cannot be accomplished because of

contraindications.

fMRI• Offers better temporal and spatial resolution than PET.• Pain stimuli do not need to be applied over along period.• The control state and the active pain condition are done in the same run.• Better suited than PET for studying cognitive effects on pain processing.• Unlimited amount of repetitions within a single patient, allowing single participant, and follow-

up studies.• Offers less comfort to the patient (noise, body constrained in the magnet bone).• Requires expensive fMRI-compatible stimulation and monitoring equipment.

MEG• Allows mapping of the sequential activation of brain structures in pain processing.• Provides a direct measure of neuronal activity.• The most ecological technique with the highest comfort and least distress for participants.• Allows conclusions from single trial and single participant studies (great clinical potential).Brain Imaging of clinical pain states..Kipers R, Kehlet H. The Lancet Neurology 2006: 5:1033-1044

Kupers R, Kehlet H The Lancet Neurology 2006: 1033-1044

Temporal SpatialResolution Resolution Advantages Disadvantages

_______________________________________________________________________

PET >49’s >4 mm Measures activity and Radioactivity. subcortical structures. Poor temporal resolution.Stimulus-independent Invasive technique.technique Limited amount of scansAllows receptor binding possible.studies

fMRI 100 ms – 3’s >2 mm Measures activity in Poor patient comfort.cortical and structures. Requires non-magneticExcellent spatial equipment.resolution. Stimulus-dependent

technique.

MEG Milliseconds >2 mm Excellent temporal Difficulties to measuresresolution. subcortical activity.High patient comfort. Requires non-magneticEcological method. equipment.

Stimulus-dependent technique.____________________________________________________________________________________

Characteristics of different brain imaging techniques used in the study of pain.

Kupers R, Kehlet H The Lancet Neurology 2006:1033-1044

Kupers R, Kehlet H, The Lancet Neurology 2006:1033-1044

METHODOLOGICAL DIFFICULTIES IN DESIGN OF BRAIN-IMAGING STUDIES IN CHRONONIC PAIN

• Difficulty in finding a homogeneous population of chronic-pain patients.

• Difficulty in discerning pain-related from psychological-related effects.

• Possible confound by differences in genetic constitution.• Difficulty in dissociation of deafferentiation-related from pain-related

changes in brain activation patterns.• Homologous contralateral area is not an unbiased site fro non-

painful control stimulation.• Difficulty in switching pain on and off in a very precise and time-

locked manner.• Effects of therapeutic interventions could be difficult to dissociate

from pain-related effects.Kupers R, Kehlet H.The Lancet Neurology 2006:1033-1044

B.R. Buchbinder, Division of Neuroradiology MGH, Boston, MA

B.R.Buchbinder, Division of Neuroradiology MGH, Boston, MA

Emergency Neuroradiology, M.Rothman et al. e-medicine, Oct 29, 2003

Epidural Hematoma

Head Injury, Olson DA et al. e-Medicine Oct 2, 2006

Right subdural hematomaIntraparenchymal bleeding

Head Injury, Olson DA et al. e-Medicine Oct 2, 2006

Left frontal contusion Right linear contusion

Emergency Neuroradiology, M Rothman, e-medicine Oct 29, 2003

Bullet

Emergency Neuroradiology, M.Rothman, e-medicine Oct 29, 2003

Metallic rod

traumatic brain injury and pain f.antonio luque, m.d. ph.d. neurology

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