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Office of Public Health & Environmental Hazards Future Tools for Diagnosis and Monitoring of Office of Public Health & Environmental Hazards Future Tools for Diagnosis and Monitoring of mild Traumatic Brain Injury (m. TBI) J. Wesson Ashford, MD, Ph. D Maheen Adamson, Ph. D War-Related Injuries and Illnesses Study Center (WRIISC) Palo Alto VA Health Care System wes. [email protected] gov March 31, 2011

Outline TBI vs. m. TBI Dissecting the injury Differences in structural MRI Why is Outline TBI vs. m. TBI Dissecting the injury Differences in structural MRI Why is standard clinical intervention not enough? • Different types of neuroimaging for the future • • – – – High field-strength MRI (3 T) Arterial spin labelling SWI – susceptibility weighted imaging (blood) f. MRI – function assessment DTI – diffusion weighted imaging - tractography

Definition of mild TBI - review • Loss of consciousness (LOC) duration is relatively Definition of mild TBI - review • Loss of consciousness (LOC) duration is relatively short: less than 1 minute versus less than 10 minutes vs less than 30 minutes • Post-traumatic amnesia (PTA) less than 24 hours • Glasgow Coma Scale (GCS) 13 -15 (acutely) • No penetrating brain injury • No focal neurological findings • (different groups use different definitions)

Complicated Mild TBI • When clinical neuroimaging findings are present following a m. TBI, Complicated Mild TBI • When clinical neuroimaging findings are present following a m. TBI, the classification changes to “complicated m. TBI, ” which has a 6 month outcome more similar to moderate TBI Williams et al. , Neurosurgery 1990; 27(3): 422 -8. Kashluba et al. , Arch Phys Med Rehabil 2008; 89(5): 904 -11. From Belanger, 2009

What are the injuries? • Most Common Primary Injuries • Concussion (shaking of the What are the injuries? • Most Common Primary Injuries • Concussion (shaking of the brain caused by any violent blow the head, usually causing loss of consciousness) • Contusion (bruising) • Subdural hematoma (a bleed immediately under the dura) • Diffuse axonal injury • Most Common Secondary Injuries • Excitotoxicity (release of calcium, binding of magnesium) • Edema • Ischemia

Every Traumatic Brain Injury is Unique (just as no 2 brain tumors, strokes, seizures Every Traumatic Brain Injury is Unique (just as no 2 brain tumors, strokes, seizures are the same) • • Individual head habitus (e. g. , age, skull thickness, protective gear) Brain reserve (cognitive, neuronal), prior injury history Individual repair mechanisms (e. g. , genetics - APOE genotype) Type of injury, non-penetrating, penetrating (may not be noted) Direction of physical force impacting head Orientation / location of force– translational vs rotational Nature of physical energy – • • • Effects on brain – brain stem, cortex, white-matter Complexity, multiplicity of injury, contusion, bleeding, infection Psychological stress, social imperatives Immediate care after injury Chronic care after injury, rehabilitation, support – Amplitude, rise-time, wave-length, duration, reflection CANNOT GROUP PATIENTS FOR PARAMETRIC STATISTICS OR COMPARE ARTIFICIAL GROUPINGS WITH NORMATIVE SCORES

Severity of TBI Cases Treated at DVBIC Sites Severity of TBI Cases Treated at DVBIC Sites

Military Issues regarding TBI • Soldiers in Iraq are being exposed to a large Military Issues regarding TBI • Soldiers in Iraq are being exposed to a large number of blasts (IEDs), many soldiers exposed at the same time • Some soldiers are exposed to many blasts • Soldiers wear body armor that protects vital organs • Helmets protect against missile injuries, but not against blast shock waves. • It is difficult to identify the brain changes with mild TBI • Consequently, many soldiers are getting brain damage and experiencing functional deficits attributable to TBI

What are the forces? Rotational force vector Translational force vector (Figure adapted from Arciniegas What are the forces? Rotational force vector Translational force vector (Figure adapted from Arciniegas and Beresford 2001) Center of mass

TBI Pathology / Mechanisms • Coup-contra-coup – contusion • Collision of medial temporal lobe TBI Pathology / Mechanisms • Coup-contra-coup – contusion • Collision of medial temporal lobe structures, orbito-frontal cortex with bones of base of skull • Breakage of blood vessels – Macro hemorrhages - injury to large blood vessels • Subdural hematoma – local pressure • Epidural hematoma – arterial pressure, rapidly progressing • Subarachnoid bleeding – herniation; normal pressure hydrocephalus – Small hemorrhages – arterioles (30 -150 um) – Microbleeds at the gray-white matter junction • Disruption of blood flow, clotting • Local edema, increased intracranial pressure • Shear injury - breakage of axons (0. 2 – 0. 5 um) – Vulnerability at gray-white matter junctions (Not Diffuse? ? )

The Mechanisms of Damage from TBI ICP= Intracranial pressure CPP= Cerebral perfusion pressure SDH The Mechanisms of Damage from TBI ICP= Intracranial pressure CPP= Cerebral perfusion pressure SDH = Sub Dural Hematoma DAI = Diffuse Axonal Injury Maas et al, Lancet Neurology, 2008 Courtesy Dr. Gary Abrams 11

Complex Interactions of Trauma Sequelae Courtesy Dr. Gary Abrams Complex Interactions of Trauma Sequelae Courtesy Dr. Gary Abrams

Frontal and temporal pole contusions in two cases as reported by Gurdjian (1975). Note Frontal and temporal pole contusions in two cases as reported by Gurdjian (1975). Note the extensiveness of the ventral surface contusions. From Impact head injury: Mechanistic, clinical and preventive correlation (pp. 242, 243), by E. S. Gurdjian, 1975, Springfield, IL: Charles C. Thomas.

Parasagittal plane through the long axis of the hippocampus at post-mortem. Note how the Parasagittal plane through the long axis of the hippocampus at post-mortem. Note how the temporal pole is “cradled” and “hugged” by the middle cranial fossa as well as the sharp edge of the sphenoid ridge, asit juts into the Sylvian fissure. The head of hippocampus is approximately 2 cm from the sphenoid ridge and, when brain compression occurs, can deform over the ridge. From Atlas of the Human Brain (2 nd ed. , p. 83), by J. K. Mai, G. Paxinos, and J. K. Assheuer, 2004, Amsterdam: Elsevier.

Coronal views are presented on top from an older teenage patient who sustained a Coronal views are presented on top from an older teenage patient who sustained a severe traumatic brain injury (TBI). As visualized, the fornix has withered in comparison to the age-matched control. This is thought to represent downstream degeneration of this structure as a result of the hippocampal and medial temporal lobe damage, including temporal horn dilation, that can be seen on the right in comparison with the control subject, where the true inversion recovery sequence MRI scan provides exquisite anatomical detail of the brain. Also, note the marked reduction in the size of the temporal stem and overall reduction in the amount and integrity of the temporal lobe white matter in comparison to the control. Adapted from Bigler, 2007

A patient who sustained a head injury from a fall, where the focal impact A patient who sustained a head injury from a fall, where the focal impact was to the back of the patient’s head, with the resulting contra coup injury to fronto-temporal regions. Axial CT toward the base of the skull depicting acute inferior frontal and anterior temporal lobe contusions, with associated edema. Note the close proximity of the contusions to the sphenoid. Adapted from Bigler, 2007

3 -D spiral CT coregistered with 3 -D thin-slice MRI A middle-aged individual who 3 -D spiral CT coregistered with 3 -D thin-slice MRI A middle-aged individual who sustained a significant temporal lobe contusion as a consequence of a high speed, side-impact MVA. This patient did sustain a significant left temporal lobe contusion, where the followup MRI approximately 2 years post-injury demonstrates significant temporal horn dilation, hippocampal atrophy (compare left and right hippocampal size), and general volume loss of the temporal lobe. Adapted from Bigler, 2007

Note variations in: Location Volume Depth Bigler, Neuropsychology, 2007 Note variations in: Location Volume Depth Bigler, Neuropsychology, 2007

What does the future hold? • High Field Strength MRI (3 T) • Arterial What does the future hold? • High Field Strength MRI (3 T) • Arterial Spin Labeling Perfusion (clinical and research applications) • Susceptibility weighted imaging (enhanced contrast magnitude image which is exquisitely sensitive to venous blood, hemorrhage and iron storage) • Functional MRI (functional correlate of cognition) • Resting states of the brain • DTI (diffusion tensor imaging) with tractography

3 T-MRI R 47 y/o Veterans of OIF, with TBI and CSF leak that 3 T-MRI R 47 y/o Veterans of OIF, with TBI and CSF leak that was surgically corrected. Abnormal behavior noted. MRI scan shows - bifrontal posttraumatic and postsurgical changes

3 T-MRI R 29 y/o Veteran in motorcycle accident. Hit head, LOC, stopped breathing, 3 T-MRI R 29 y/o Veteran in motorcycle accident. Hit head, LOC, stopped breathing, required rescucitation, responded to pain the next day, in coma at deepest level for 24 hours, returned to normal thinking 10 days later. Inappropriate behavior noted. MRI - scattered foci of decreased signal intensity is in the subcortical region on gradient echo pulse sequence in the frontal lobes bilaterally, compatible with history of trauma and likely due to shear injury

Arterial spin labeling perfusion Group activation maps obtained during letter 2 -back working memory Arterial spin labeling perfusion Group activation maps obtained during letter 2 -back working memory task from control subjects (left)and patients with traumatic brain injury studied following either placebo (middle) or methylphenidate (MPH) (right). Frontal activation in patients is reduced on placebo when compared with activation in controls, but normal-appearing activation is restored after MPH administration. Source: Unpublished data courtesy of Junghoon Kim and John Whyte, Moss Rehabilitation Institute.

Susceptibility Weighted Imaging (SWI) Regions of venous vascular content and hemorrhage in a tumor, Susceptibility Weighted Imaging (SWI) Regions of venous vascular content and hemorrhage in a tumor, which are not seen in the conventional postcontrast T 1 -weighted image (left) (Sehgal et al. , 2005).

Functional MRI Functional MRI

Working Memory in m. TBI Mc. Allister et al. , 2001 Working Memory in m. TBI Mc. Allister et al. , 2001

Longitudinal Functional MRI in Severe TBI §Increased activation observed after 6 month evolution in Longitudinal Functional MRI in Severe TBI §Increased activation observed after 6 month evolution in TBI patients during the 3 -back condition. §The most striking changes were seen in the bilateral prefrontal cortex, with left hemisphere predominance. §The second region that showed statistical significant changes was the bilateral parietal posterior region. §Both regions are involved in working memory processes. Statistical Parametric Maps with left as left.

Conventional MRI and resting-state f. MRI correlation analysis in a 21 year-old with verbal Conventional MRI and resting-state f. MRI correlation analysis in a 21 year-old with verbal memory deficits following traumatic brain injury (A) Conventional MRI (FLAIR) revealed bilateral superior frontal lesions but no abnormalities that would explain the patient’s verbal memory deficit (left to right: transverse slices at the level of hippocampus, thalamus, fornix, cingulum). Mac. Donald et al. , 2008

Resting state f. MRI Spatial map of resting BOLD correlations with right hippocampus. Significant Resting state f. MRI Spatial map of resting BOLD correlations with right hippocampus. Significant correlations were observed between the right hippocampus and anterior cingulate as well as anterior thalamus (yellow arrows). Images displayed in anatomic space; patient’s left side on the left side of the images. Mac. Donald et al. , 2008

FA decrease Courtesy of Mike Weiner, VA San Francisco FA decrease Courtesy of Mike Weiner, VA San Francisco

DTI (Diffusion Tensor Imaging) Case Study: Conduction Aphasia after Mild TBI 24 y/o marine DTI (Diffusion Tensor Imaging) Case Study: Conduction Aphasia after Mild TBI 24 y/o marine male – injured by IED explosion in Iraq LOC for about 5 minutes, no clear deficit MRI, PET scans normal Returned to states, family said he was not right Pt presented to Mental Health Emergency Clinic with complaints of not feeling right. Review of notes found Speech Pathology description of conduction aphasia • Pt was scheduled to return to Iraq in 6 weeks • Pt sent to Fort Miley for 4 T MRI scan • • • 3/15/2018 32 War Related Illness & Injury Study Center (WRIISC)

Normal Left: Line number=160 Right: Line number=57 FAD 020 M, 25 yo FAD 354 Normal Left: Line number=160 Right: Line number=57 FAD 020 M, 25 yo FAD 354 M, 24 yo Patient with conduction aphasia Left: Line number=64 Right: Line number=67 Though FAD 354 has fewer fibers in the left side, tractography seems to be in the normal range. Besides, there are other 2 control subjects failed to track the full fiber bundle (may due to technical reason). (Dr. Mike Weiner, Ft. Miley VA, UCSF, ‘ 07)

A Patient above (left side) Control below M Arcuate Fasciculus in orange The normal A Patient above (left side) Control below M Arcuate Fasciculus in orange The normal has extensive branching at both ends of the fasciculus. P Anterior Posterior A M P A – anterior end terminating at Broca’s area -The patient’s termination is stumped, as if it were just a nubbin without dispersion of its terminals -Suggests gray-white sheering M – middle of tract -The patient’s is clearly smaller - The tract seems to be thinned with individual fibers apparent, suggesting loss of fibers in between P – posterior end terminating at Wernicke’s area - Again, the patient’s termination does not have the dispersion of terminals. The patient’s elongation appears to be abnormal growth of some fibers looking for a place to terminate.

A M Patient above Control below AP view Subjects’ Left is on Right A, A M Patient above Control below AP view Subjects’ Left is on Right A, M, P – as on prior slide P Right Left A M P Features on lateral view are apparent on AP view as well, particularly the branching at the Broca’s area anterior end of the tract in the control subject.

Patient above Control below View of Right side M Arcuate fasciculus is smaller on Patient above Control below View of Right side M Arcuate fasciculus is smaller on the Right (no language to communicate) A A – anterior end of tract M – middle of tract P – posterior end of tract P Posterior Anterior M P A Difference between patient and control is less dramatic, but there is clearly less evidence of branching at the terminal ends of the tract in the patient.

Brain Scans Examined after Analysis of DTI Images MRI PET Right 3/15/2018 37 War Brain Scans Examined after Analysis of DTI Images MRI PET Right 3/15/2018 37 War Related Illness & Injury Study Center (WRIISC)

After 4 months of intensive speech therapy, the 4 t MRI/DTI scan was repeated After 4 months of intensive speech therapy, the 4 t MRI/DTI scan was repeated

The significant language areas of the brain. The arcuate fasciculus links the green area The significant language areas of the brain. The arcuate fasciculus links the green area (Wernicke's) to the blue area (Broca's), disruption of this pathway results in conduction aphasia. 3/15/2018 War Related Illness & Injury Study Center (WRIISC) 39

3/15/2018 War Related Illness & Injury Study Center (WRIISC) 40 3/15/2018 War Related Illness & Injury Study Center (WRIISC) 40

Arcuate Fasciculus, Dissection. This partial dissection of the left hemisphere reveals the arcuate fasciculus, Arcuate Fasciculus, Dissection. This partial dissection of the left hemisphere reveals the arcuate fasciculus, an arching bundle of association fibers that courses through the frontal, parietal, and temporal lobes. The arcuate fasciculus, a part of the superior longitudinal fasciculus, interconnects Wernicke's area (the posterior part of the superior temporal gyrus that is involved in the interpretation of spoken language) with Broca's area (the "motor speech" area in the posterior part of the inferior frontal gyrus, the opercular and triangular regions). The arcuate fasciculus is thus essential for normal speech and language function. Note also the optic radiation: the bundle labeled here probably includes fibers of the inferior longitudinal fasciculus, an association fiber bundle that War Related Illness the occipital lobe; the interconnects the superior, middle, and inferior temporal gyri with & Injury Study Center optic radiation fibers are between it and 41 the 3/15/2018 (WRIISC) lateral ventricle. (Wash U)

The Left arcuate fasciculus is substantially larger than the Left Reconstructions of left (a) The Left arcuate fasciculus is substantially larger than the Left Reconstructions of left (a) and right (b) arcuate fasciculus (red) and corticospinal tract (yellow) from a representative participant are superimposed on a parasagittal T 2 -weighted image. Note that fiber tracts are represented with stream tubes to improve visibility; only one sample is rendered of the 600^800 ¢ber tracts generated. (Nucifora et al. , Neuro. Report, 16: 791 -794, 2005) 3/15/2018 War Related Illness & Injury Study Center (WRIISC) 42

Yamada, K. et al. Neurology 2007; 68: 789 – MR tractography depicting damage to Yamada, K. et al. Neurology 2007; 68: 789 – MR tractography depicting damage to the arcuate fasciculus in a patient with conduction aphasia (s/p Left parietal infarct) 3/15/2018 War Related Illness & Injury Study Center (WRIISC) 43

SUSUMU MORI, PH. D. PETER VAN ZIJL, PH. D. Baltimore, Md. Am J Psychiatry SUSUMU MORI, PH. D. PETER VAN ZIJL, PH. D. Baltimore, Md. Am J Psychiatry 164: 7, July 2007, 1005 These figures, taken from a human white matter brain atlas (Mori S, Wakana S, Nagae-Poetscher LM, van Zijl PCM: MRI Atlas of Human White Matter. Amsterdam, Elsevier, 2005), are left lateral views from three-dimensional depictions of fiber pathways, which were developed from normal DTI images. The thalamus, caudate, and putamen and globus pallidus are depicted for anatomic orientation. In box A (Projection and Thalamic Fibers), the anterior, superior, and posterior thalamic radiation derive from the thalamus. The corticobulbar and corticospinal tracts form the projection system. In box B (Association Fibers), the superior and inferior longitudinal faciculus and the superior and inferior frontooccipital faciculus are organized around the basal ganglia. In box C (Limbic System Fibers), the cingulum, fornix, and stria terminalis fibers are depicted; the ventricular system around which limbic fibers are organized is dark gray. In box D (Callosal Fibers), corticocortical connections pass through the corpus callosum. The subset of these tracts that project to the temporal lobe are pink. 3/15/2018 44 War Related Illness & Injury Study Center (WRIISC)

3/15/2018 War Related Illness & Injury Study Center (WRIISC) 45 3/15/2018 War Related Illness & Injury Study Center (WRIISC) 45

Courtesy John Dougherty Courtesy John Dougherty

Demonstration of damage with DTI technique: Figure 4 Lateral view for the tractography of Demonstration of damage with DTI technique: Figure 4 Lateral view for the tractography of the corpus callosum (left column) and fornix (right column) in a control (left upper) and in 11 patients with traumatic brain injury. The tractographs are overlaid on T 2 -weighted MRI. Nakayama et al. , 2006 CONCLUSION: 3/15/2018 War Related Illness & Injury Study Center (WRIISC) DTI techniques may show the critical brain changes associated with TBI that are not seen with other brain imaging approaches. 47

DTI – 2 weeks after TBI Rutgers et al. , 2008 DTI – 2 weeks after TBI Rutgers et al. , 2008

DTI image 16 months after TBI Rutgers et al. , 2008 DTI image 16 months after TBI Rutgers et al. , 2008

Conclusions • • High resolution MRI PET Amyloid imaging Separating PTSD from TBI Understanding Conclusions • • High resolution MRI PET Amyloid imaging Separating PTSD from TBI Understanding the long term effects of m. TBI in OEF/OIF population in the context of neural, behavior and cognitive changes

References Williams DH, Levin HS, Eisenberg HM. Mild head injury classification. Neurosurgery 1990; 27(3): References Williams DH, Levin HS, Eisenberg HM. Mild head injury classification. Neurosurgery 1990; 27(3): 422 -8. Kashluba S, Hanks RA, Casey JE, Millis SR. Neuropsychologic and functional outcome after complicated mild traumatic brain injury. Arch Phys Med Rehabil 2008; 89(5): 904 -11. -

QUESTIONS? ? QUESTIONS? ?