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

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Investigation of Pediatric Anoxic Brain Injury from Nonfatal Drowning with MRI

Peter T. Fox, MD & Mariam Ishaque PhDMay 12, 2016Children who Survive Drowning:The Youngest Locked-In Syndrome

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OutlineWho survives drowning?EpidemiologyWhat brain funtions are preserved? Functional MRI Network AnalysisBehavioral assessmentsWhy so much functional preservation?Neuroanatomical Studies. Where do we go next?

About 10 deaths/day~ 400 kids drown in pool/year in US ~ 1500 every year in US 1-3% of all drowning victims admitted to hospital suffer severe neurological injuries$273 million for direct and indirect costs in US two-thirds of deaths occur from May through August; disproportionate on Saturdays and Sundays. Seizure disorder is a known risk factor in drowning. Children with epilepsy are at greater risk of drowning in bathtubs as well as in swimming pools.Long QT syndrome; swimming may be a trigger for LQTSMajority children lapse in supervisionLow % (18) actually witnessed

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Drowning EpidemiologyEstimated 372,000 annual drowning deaths worldwide3rd leading cause of unintentional injury death worldwide 2nd leading cause in children Bimodal incidence distributionHighest drowning rates in children < 4 years Second peak in adolescents (males)For every pediatric drowning death, 2 survivors hospitalizedhttp://www.who.int/mediacentre/factsheets/fs347/en/; Weiss 2010, Ped 126(1): c253-62

About 10 deaths/day~ 400 kids drown in pool/year in US ~ 1500 every year in US 1-3% of all drowning victims admitted to hospital suffer severe neurological injuries$273 million for direct and indirect costs in US two-thirds of deaths occur from May through August; disproportionate on Saturdays and Sundays. Seizure disorder is a known risk factor in drowning. Children with epilepsy are at greater risk of drowning in bathtubs as well as in swimming pools.Long QT syndrome; swimming may be a trigger for LQTSMajority children lapse in supervisionLow % (18) actually witnessed

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CDC MMWR 2012; 61(19):344-7

Nonfatal unintentional drownings in the US, 2005-2009

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 circulationBrain cells begin to die in about 4 minutesIrreversible injury in 4 - 10 minutesPersistent coma in few additional minutes Topjian 2012, Neurocrit Care 17(3): 441-67

Acute Clinical ManagementER and ICU Stabilize cardiopulmonary functionControl SeizuresHypothermiaPrognostication is extremely difficultImaging is normal or non-specificOutcome ranges from no impairment to chronic vegetative stateAcute function does not predict chronic functionInformation provided to family bleak and/or non-commitalWithdrawl of care a common recommendation (7/10 in our cohort) Topjian 2012, Neurocrit Care 17(3): 441-67

Some signs for poor prognosis brain death criteria; anoxic myoclonus, etc 6

Significance

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 childrens books He absolutely will not listen to Winnie the Pooh.

Especially understands and responds to complimentary phrases. When told Youre so pretty, or What beautiful hair you have, she starts smiling right away.

Mom cannot tell him shes 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.

Before Accident: After Accident:

Shared with permission from family

https://www.youtube.com/watch?v=Zu54lHljJ_k

https://www.youtube.com/watch?v=zZMy9vN71V0

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What Function is Preserved?Resting-state fMRIFunctional imaging performed at rest (no task).Requires minimal patient cooperationNetwork analysis commonly appliedRegions co-varying across timeNetworks persist during sleep or sedationResting-state networks mirror task-activation networks.

About 10 deaths/day~ 400 kids drown in pool/year in US ~ 1500 every year in US 1-3% of all drowning victims admitted to hospital suffer severe neurological injuries$273 million for direct and indirect costs in US two-thirds of deaths occur from May through August; disproportionate on Saturdays and Sundays. Seizure disorder is a known risk factor in drowning. Children with epilepsy are at greater risk of drowning in bathtubs as well as in swimming pools.Long QT syndrome; swimming may be a trigger for LQTSMajority children lapse in supervisionLow % (18) actually witnessed

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

DMN autobiographical memory, internal monitoring, ToM, perception of self 11

Subjects22 subjects studied 11 children with ABI secondary to drowning 11 age- and gender-matched neurotypical control childrenAge range at injury: 1.4 4.8 years Age range at scan: 4.3 12.8 years CriteriaMedically stable 6 months post injury No contraindications to MRI Normal sleep-wake cycles

Network Templates

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Group Results

CONABIOverlap

Motor Network Preservation

Absent/LowModerateHigh

Visual & Auditory Network Preservation Absent/LowModerateHigh

Cognitive Network Preservation Absent/LowModerateHigh

Frequency of Network Absence

Behavioral AssessmentDeveloped behavioral assessment and scoring system 12 dimensions of behaviorExtensive telephone/videoconference/in-person interviews with each family Confirmed final scoring with each family

No standard battery of tests in this disorder19

Behavioral Assessment Form 10 Likert-type questions1 (Low Function) 5 (Normal Function)Behavioral CategoriesGross Motor FunctionFine Motor FunctionEating and Drinking AbilityTactile Perception Visual and Visuomotor FunctionAuditory FunctionOverall CommunicationSocial-Emotional Responsiveness Receptive Language Function Expressive Language Function

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Behavioral Evaluation Form 2 Yes / No questionsExpression of Pleasure/DispleasureAnticipation of the Future Score coding for correlation analysis: Yes (5) and No (1)

RSN & Behavioral ConclusionsRSN analysis workedgroup-wise & per subjectHigh concordance with caregiver-driven behavioral assessment Motor networks selectively impaired Sensory networks very much intact Cognitive networks -- esp. Default mode and language comprehension -- often preservedMuch greater cognitive preservation than was predicted clinically

Mediates meaningful per-subject, per-network interpretation 23

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

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Structural NeuroimagingCTDiffuse edema most commonMRIT1- and T2weightedOften normal or subtle pathology Diffusion-weightedMaps diffusion processes of water Most sensitive Poor prognostic value

Huang & Castillo 2008, RadioGraphics 28: 417-39

Reversal sign in a 4-month- old victim of nonaccidental trauma.(a) Unenhanced CT scan shows diffuse cortical swelling and hypoattenuation in the white matter relative to areas of pre- served cortex, a finding that is referred to as the reversal sign and generally portends a poor prognosis. A small amount of ex- traaxial hemorrhage adjacent to the left frontal lobe is also seen (arrow). (b) Unen- hanced CT scan demonstrates the white cerebellum sign. The cerebellar hemi- spheres (*) are hyperattenuating relative to the supratentorial structures, which are hypoattenuating due to edema.

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Structural Neuroimaging: Our ApproachVoxel-Based Morphometry (VBM)Tract-based Spatial Statistics (TBSS)Physiological interpretation

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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

Will injury be focal or diffuse? 27

Grey MatterWhite MatterControls > Patients

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Tract-based Spatial Statistics (TBSS)Measure diffusion of water in white matter tracts Use to detect consistent white matter micro-structural damage across patient groupWhite 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

MD trace (sum) of the three eigenvalues

Hyperacute stroke dec RD inc FA Studies have shown reduced FA with preserved MD in wallerian degenerationreduced FA with increased MD in the infarctreduced FA with preserved MD in the corticospinal tractIn a longstanding cerebral infarct it is thought that cell lysis and loss of normal tissue architecture expand the extracellular space, allowing water molecules to diffuse more freely

The difference in diffusion properties between the primary lesion and the degenerated tract (reduced FA with increased MD in the infarct; reduced FA with preserved MD in the corticospinal tract) may allow DTI to distinguish between the primary lesion and associated wallerian degeneration

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FA

Controls > Patients

Tbss_flll; con > patient 31

MD

Patients > Controls

Con > pat32

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Pathophysiology?

Focal not diffuse structural damage

Grey AND white matter affected

Does not follow previously described vascular patterns

Add blood supply pic

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Pathophysiology?

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

Add blood supply pic

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Pathophysiology?

Focal not diffuse structural damage

Grey AND white matter affected

Does not follow previously described vascular patterns

Explanation?

Add blood supply pic

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Studyblue.comLenticulostriate Arteries

PCA The thalamus derives its blood supply from a number of arteries: the polar artery (posterior communicating artery), paramedian thalamic-subthalamic arteries, inferolateral (thalamogeniculate) arteries, and posterior (medial and lateral) choroidal arteries. These are all branches of the posterior cerebral artery.37

CPICMR Angiography

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

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Overall ConclusionsEvidence for primary motor-system damage supported by:Functional dataBehavioral data Anatomical (grey and white matter) dataDiffusion dataEvidence for residual perceptual, emotive, and cognitive abilities across functional and behavioral dataTogether, suggest a locked-in-syndrome variant

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Locked-in Syndrome

Classic Locked-in syndrome

Indepedently confirm VBM analysis; Pathology almost entirely limited to one tractROI MRS; to prognosticate motor deficits- FA values from bilateral PLICs could help prognosticate as well41

ImplicationsEthicalAcute care decisionsLong-term prognosis Therapeutic optimization and monitoring Can we find a way to communicate? Quality of life

Quality of life ask Liz 42

Where do we go From Here?DisseminationAlert clinical communityPublish Functional ResultsImaging techniques applicable to many other conditions impairing consciousnessDiagnostics & PrognosticsClinical Imaging R & D TherapeuticsEndovascular Therapy R & D

About 10 deaths/day~ 400 kids drown in pool/year in US ~ 1500 every year in US 1-3% of all drowning victims admitted to hospital suffer severe neurological injuries$273 million for direct and indirect costs in US two-thirds of deaths occur from May through August; disproportionate on Saturdays and Sundays. Seizure disorder is a known risk factor in drowning. Children with epilepsy are at greater risk of drowning in bathtubs as well as in swimming pools.Long QT syndrome; swimming may be a trigger for LQTSMajority children lapse in supervisionLow % (18) actually witnessed

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Clinical Imaging R & DLarger Clinical Imaging StudyQ: How early will our imaging methods work? Acute, Sub-acute & Chronic patientsLongitudinal assessmentsQ: Will targeted methods work?MRSProbabilistic TractographyNIH Grant ApplicationConrad Smiles FoundationNonfatal Drowning Survivors RegistryParticipant Logistics Support

About 10 deaths/day~ 400 kids drown in pool/year in US ~ 1500 every year in US 1-3% of all drowning victims admitted to hospital suffer severe neurological injuries$273 million for direct and indirect costs in US two-thirds of deaths occur from May through August; disproportionate on Saturdays and Sundays. Seizure disorder is a known risk factor in drowning. Children with epilepsy are at greater risk of drowning in bathtubs as well as in swimming pools.Long QT syndrome; swimming may be a trigger for LQTSMajority children lapse in supervisionLow % (18) actually witnessed

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

MR spectroscopy (MRS)Magnetic resonance spectroscopy is a non-invasive in vivo method that allows the investigation of metabolic changes of intracellular metabolism in cerebral ischemia.The concentrations of metabolites detected by MRS are relatively low (220 mM) compared to the concentration of water (83.4 M) detected by MRI.This sequence is very sensitive to local magnetic field inhomogeneity.N-acetyl aspartate (NAA)NAA acts as a neuronal marker as it is almost exclusively confined to neurons in the human brain, where it is found predominantly in the axons and nerve processes. It has a sharp peak at 2.01 parts per million (ppm).LactateLactate is not normally detected within the brain. It is the end product of anaerobic glycolysis during ischemic conditions. It has a doublet peak at 1.33 ppm.Lactate is elevated in the infarct core due to ischemic necrosis and in the penumbra due to hypoxia in the at risk tissue.StrokeNAA is reduced in the infarction core due to neuronal damage. With infarction progression, this reduction will spread to the penumbra.The extent of NAA reduction correlates with the infarct age (see right) because of ongoing neuronal necrosis and replacement of neuronal tissue with gliosis.

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Therapeutics R&DAssess Endovascular NeuroprotectionMethylene blue Stem cells Purinergic receptor stimulators Non-human Primate Model Rodent models ineffectivePilot Study FundingNIH Grant Application

Stem cells This model will be critical for developing a neural stem cell-based therapeutic approach for patients with anoxic brain injury. The neural stem cells will be delivered either intravenously or through intra-parenchymal injection into the affected brain area. This model will enable the assessment of the neural stem cells ability to protect against the chronic sequelae of anoxic brain injury by secreting neurotrophic factors. Grafted neural stem cells may also be tested for replacing lost neurons and oligodendrocytes and for restoring myelin formation and motor function.

Purinergic receptor stimulation Our laboratory has identified mitochondrial metabolism of astrocytes to be a key target for pharmacologic intervention, not only because astrocytes play a central role in regulating brain metabolism, but also because they are essential for neuronal health and support.Here we review current literature pertaining to the pathobiology of stroke, along with the role of astrocytes and metabolism in stroke. We also discuss our research, which has revealed that pharmacologic stimulation of metabotropic P2Y1 receptor signaling in astrocytes can increase mitochondrial energy production and also reduce damage after stroke. Previously demonstrated to be neuroprotective in rodents after stroke and in ex vivo human brain tissue after oxygen glucose deprivation.

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Thank you.