ABi research presentation by Dr. Peter Fox. UT Health Science Center, San Antonio, Texas.

1. Peter T. Fox, MD & Mariam Ishaque PhD
May 12, 2016
CHILDREN WHO
SURVIVE DROWNING:
THE YOUNGEST
LOCKED-IN SYNDROME

2. Outline
 Who survives drowning?
 Epidemiology
 What brain funtions are preserved?
 Functional MRI Network Analysis
 Behavioral assessments
 Why so much functional preservation?
 Neuroanatomical Studies.
 Where do we go next?

3. Drowning Epidemiology
 Estimated 372,000 annual drowning deaths worldwide
 3rd leading cause of unintentional injury death worldwide
 2nd leading cause in children
 Bimodal incidence distribution
 Highest drowning rates in children < 4 years
 Second peak in adolescents (males)
 For every pediatric drowning death, ≥ 2 survivors
hospitalized
http://www.who.int/mediacentre/factsheets/fs347/en/; Weiss 2010, Ped 126(1): c253-62

4. CDC MMWR 2012; 61(19):344-7
Nonfatal unintentional drownings in the US, 2005-2009

5. Anoxic Brain Injury (ABI)
 Hypoxic-anoxic brain injury; hypoxic-ischemic brain
injury (HI-BI)
 Brain depends on second-by-second supply of oxygen
and glucose
 Functional failure begins within seconds after disrupted
circulation
 Brain cells begin to die in about 4 minutes
 Irreversible injury in 4 - 10 minutes
 Persistent coma in few additional minutes
Topjian 2012, Neurocrit Care 17(3): 441-67

6. Acute Clinical Management
 ER and ICU
 Stabilize cardiopulmonary function
 Control Seizures
 Hypothermia
 Prognostication is extremely difficult
 Imaging is normal or non-specific
 Outcome ranges from no impairment to chronic vegetative state
 Acute function does not predict chronic function
 Information provided to family bleak and/or non-commital
 Withdrawl of care a common recommendation (7/10 in our cohort)
Topjian 2012, Neurocrit Care 17(3): 441-67

7. Significance

8. • “Watches television and emotionally responds to it by smiling, laughing,
getting scared, etc.”
• “Loves watching television… he gets angry when the news or other
programs that are not one of his favorite shows begin.”
• “Like stories that have more age-appropriate content; does not like
children’s books… He absolutely will not listen to Winnie the Pooh.”
• “Especially understands and responds to complimentary phrases. When
told ‘You’re so pretty,’ or ‘What beautiful hair you have,” she starts
smiling right away.”
• “Mom cannot tell him she’s going out of town until the day of because he
will not sleep.“
• “Likes ‘potty’ humor.”
• “He enjoys listening to more mature conversations, such as when mom
and friends are discussing dating prospects.”
• “Will laugh/smile intentionally during inappropriate conversations, like
when others are discussing neighborhood gossip.”

9. Before Accident: After Accident:
Shared with permission from family

10. What Function is Preserved?
 Resting-state fMRI
 Functional imaging performed at rest (no task).
 Requires minimal patient cooperation
 Network analysis commonly applied
 Regions co-varying across time
 Networks persist during sleep or sedation
 Resting-state networks mirror task-activation
networks.

11. Resting-state Networks (RSNs)
Smith et al., 2009, PNAS

12. Subjects
 22 subjects studied
 11 children with ABI secondary to drowning
 11 age- and gender-matched neurotypical control children
 Age range at injury: 1.4 – 4.8 years
 Age range at scan: 4.3 – 12.8 years
 Criteria
 Medically stable
 ≥ 6 months post injury
 No contraindications to MRI
 Normal sleep-wake cycles

13. Network Templates
L R
Basal Ganglia Cerebellum Sensorimotor Visual 1 Visual 2 Visual 3
Auditory
Le
Frontoparietal
Right
Frontoparietal
Default Mode Execu ve Func on
Absent/Low Moderate High
Basal
Ganglia
Visual 1
Visual 2
Cerebellum
Sensorimotor
Visual 3
Network
CON
ABI
Overla

14. Group Results
CON
ABI
Overlap

15. Visual 1
Visual 2
Auditory
Sensorimotor
Visual 3
Le
Network
CON
ABI
Overlap
Motor Network Preservation
Absent/Low Moderate High
Absent/Low Moderate High
Basal
Ganglia
Visual 1
Amount Network Preserva on
Cerebellum
Sensorimotor
Absent/Low Moderate High
Basal
Ganglia
Visual 1
Amount Network Preserva on
Cerebellum
Sensorimotor

16. Visual & Auditory Network Preservation
Absent/Low Moderate High
Visual 1
Visual 2
Auditory
Sensorimotor
Visual 3
Le
Network
CON
ABI
Overlap
Visual 1
Visual 2
Auditory
Sensorimotor
Visual 3
Network
CON
ABI
Overlap
Visual 1
Visual 2
Auditory
Sensorimotor
Visual 3
Network
CON
ABI
Overlap

17. Cognitive Network Preservation
Absent/Low Moderate High
Visual 1
Visual 2
Auditory
Sensorimotor
Visual 3
Le
Network
CON
ABI
Overlap
Auditory
Le
Frontoparietal
Right
Frontoparietal
Default
Mode
Execu ve
Func on
Auditory
Le
Frontoparietal
Right
Frontoparietal
Default
Mode
Execu ve
Func on

18. 0
1
2
3
4
5
BasalGangliaCerebellumSensorim
otor
Visual1
Visual2
Visual3
Auditory
Le
Frontoparietal
RightFrontoparietal
DefaultM
ode
Execu
ve
Func
on
FrequencyofNetworkAbsence
Network
Frequency of Network Absence

19. Behavioral Assessment
 Developed behavioral assessment and scoring system
 12 dimensions of behavior
 Extensive telephone/videoconference/in-person
interviews with each family
 Confirmed final scoring with each family

20. Behavioral Assessment Form
 10 Likert-type questions
 1 (Low Function) –
5 (Normal Function)
 Behavioral Categories
 Gross Motor Function
 Fine Motor Function
 Eating and Drinking Ability
 Tactile Perception
 Visual and Visuomotor Function
 Auditory Function
 Overall Communication
 Social-Emotional Responsiveness
 Receptive Language Function
 Expressive Language Function

21. Behavioral Evaluation Form
 2 Yes / No questions
 Expression of Pleasure/Displeasure
 Anticipation of the Future
 Score coding for correlation analysis: Yes (5) and No (1)

22. 0
1
2
3
4
5
0 1 2 3 4 5 6 7 8 9 10 11 12
AverageBehavioralScore
1
2
3
4
5
BehavioralScore
Behavioral Category
FineMotor
Ea,ng&Drinking
Tac,le
Visual/Visuomotor
Auditory
Recep,veLanguage
ExpressiveLanguage
Communica,on
Social-Emo,onal
Pleasure/Displeasure
An,cipa,onofFuture
GrossMotorNormal
Func, on
Low
Func, on
Normal
Func on
Low
Func on

23. RSN & Behavioral
Conclusions
 RSN analysis worked…group-wise & per subject
 High concordance with caregiver-driven behavioral
assessment
 Motor networks selectively impaired
 Sensory networks very much intact
 Cognitive networks -- esp. Default mode and language
comprehension -- often preserved
 Much greater cognitive preservation than was
predicted clinically

24. Why So Much Functional
Preservation?
 Structural damage
 Diffuse or focal?
 Standard MRI methods not helpful

25. Structural Neuroimaging
 CT
 Diffuse edema most common
 MRI
 T1- and T2–weighted
 Often normal or subtle pathology
 Diffusion-weighted
 Maps diffusion processes of water
 Most sensitive
 Poor prognostic value Huang & Castillo 2008, RadioGraphics 28: 417-39

26. Structural Neuroimaging:
Our Approach
 Voxel-Based Morphometry (VBM)
 Tract-based Spatial Statistics (TBSS)
 Physiological interpretation

27. Voxel-based Morphometry
(VBM)
 Use to detect consistent structural
damage (tissue loss) across patient
group
 Grey and white matter
 T1-weighted MRI data
 Quantitative, whole-brain analysis
Ashburner & Friston, 2000 Neuroimage 11(6 Pt 1): 805-21

28. Grey
Matter
White
Matter
Controls > Patients

30. Tract-based Spatial Statistics
(TBSS)
 Measure diffusion of water in white matter tracts
 Use to detect consistent white matter micro-structural damage
across patient group
 White matter integrity metrics
 Fractional Anisotropy (FA)
 How directional is water diffusion along a tract?
 Mean Diffusivity (MD)
 How much total diffusion?
  FA,  MD = increased WM integrity
  FA,  MD = decreased WM integrity
Smith et al., 2006 NeuroImage 31:1487-1505

31. FA
Controls > Patients

32. MD
Patients > Controls

34. Pathophysiology?
 Focal – not diffuse – structural
damage
 Grey AND white matter affected
 Does not follow previously
described vascular patterns

35. Pathophysiology?
Mangla et al., 2011, RadioGraphics 31(5): 1201-14

36. Pathophysiology?
 Focal – not diffuse – structural
damage
 Grey AND white matter affected
 Does not follow previously
described vascular patterns
 Explanation?

37. Studyblue.com
Lenticulostriate Arteries

38. C
PIC
MR Angiography

39. Structural Imaging Conclusions
 Anoxic injury from drowning selectively affects deep,
central grey and white matter
 Damaged structures are major motor nuclei (basal
ganglia) and motor tracts (internal capsule, posterior
limb)
 Relative preservation elsewhere
 High concordance with functional imaging findings

40. Overall Conclusions
 Evidence for primary motor-system damage supported
by:
 Functional data
 Behavioral data
 Anatomical (grey and white matter) data
 Diffusion data
 Evidence for residual perceptual, emotive, and
cognitive abilities across functional and behavioral
data
 Together, suggest a locked-in-syndrome variant

41. Locked-in Syndrome
‘Classic’ Locked-
in syndrome

42. Implications
 Ethical
 Acute care decisions
 Long-term prognosis
 Therapeutic optimization and monitoring
 Can we find a way to communicate?
 Quality of life

43. Where do we go From Here?
 Dissemination
 Alert clinical community
 Publish Functional Results
 Imaging techniques applicable to many other conditions
impairing consciousness
 Diagnostics & Prognostics
 Clinical Imaging R & D
 Therapeutics
 Endovascular Therapy R & D

44. Clinical Imaging R & D
 Larger Clinical Imaging Study
 Q: How early will our imaging methods work?
 Acute,
 Sub-acute &
 Chronic patients
 Longitudinal assessments
 Q: Will targeted methods work?
 MRS
 Probabilistic Tractography
 NIH Grant Application
 Conrad Smiles Foundation
 Nonfatal Drowning Survivors’ Registry
 Participant Logistics Support

45. MR Spectroscopy
Radaideh et al., 2012, Neurographics, ASNR

46. Therapeutics R&D
 Assess Endovascular Neuroprotection
 Methylene blue
 Stem cells
 Purinergic receptor stimulators
 Non-human Primate Model
 Rodent models ineffective
 Pilot Study Funding
 NIH Grant Application

47. Thank you.