Multi-Modal Therapy for
Disorders of Consciousness
Philip DeFina, Ph.D.
International Brain Research Foundation
Jonathan Fellus, M.D.
Kessler Institute for Rehabilitation
Eighth World Congress on Brain Injury
Washington, D.C.
March 10-14, 2010
Presentation Outline
1. Need for Improved Therapies for DOC
2. Theory of Brain Reorganization and
Plasticity
3. Multi-modal Care Protocol (MCP)
4. Future Directions: DoD Research Grant
1. Need for Improved Therapies


Traumatic brain injury:
 33% of adults in PVS for one month
recovered within three months, and 52%
recovered within one year. (Multi-Society
Task Force, NEJM)
Non-traumatic brain injury:
 11% of adults in PVS for one month
recovered within three, and 13% recovered
within one year.
Need for Improved Therapies

The literature suggests that Severe Disorders
of Consciousness (SDOC) patients in the
United States, with severe TBI and VS for
greater than 12 months, or with severe
nonTBI and VS for greater than 3 months,
will likely never recover.
Need for Improved Therapies


These patients are typically medically categorized as
untreatable.
 often placed in long-term care facilities or home care
that provides only palliative support and deteriorate or
die due to lack of proactive medical treatment and/or
opportunistic infectious processes.
Places an immense burden on family, community, and
the health care system, as it is estimated that 70% of
those who are in a minimally conscious state due to
trauma remain at a moderate to extremely severe level
of disability one year post injury (Mohonk Report, 2006).
Need for Improved Therapies

In the US, the insurance industry does not
recognize treatment for DOC, as evident in
the lack of Diagnosis-Related Groups
(DRGs) and Current Procedural
Terminology (CPT) codes (AMA, 2009).

Life expectance of 8-10 years (MSTF)
Need for Improved Therapies

Specific pharmacological interventions,
particularly single medication
interventions, have been studied, in an
attempt to improve recovery from MCS
and VS.
2. Theory of Post-Injury
Reorganization and Plasticity
 Injured brain reacts in specific
and significant ways.
 Metabolic cascades
 Excitotoxicity
 Cell death and Apoptosis.
Diffuse Axonal Injury

Result of mechanically induced stretching, shearing or
tearing of nerve fibers

primary pathologic feature of brain injury in all severity
levels of concussion (Kushner, 2001).

increase in neuronal permeability, especially to Ca2+
(reduced mitochondrial metabolism, reduced ATP production)

not detectable by MRI, CT. EEG can detect DAI
(Thatcher, 1998; Collins, 2007; Pardini ,2007)
DAI causes damage to cortical structures

excitatory inputs to the brainstem reticular cells suppressed
due to lack of input (Gaetz, 2004)

Decreased arousal or LOC
Plasticity Following Injury

Long-Term Potentiation (LTP) is
reduced (Hebb, 1949)

Long-Term Depression (LTD)
increased; i.e. a reduction in efficacy of
neuronal synapses (Stent, 1973)

Membrane excitability reduced

Anatomical changes – axon terminals
damaged & synapses reduced
Neuromodulation
By identifying the unique injury
characteristics within the brain’s
electrochemical environment, we can
identify and measure neuromarkers.
Specific interventions and treatments are
then applied in an effort to facilitate and
guide neural plasticity.
Defina, P. et al, (2009). The new neuroscience frontier: Promoting
neuroplasticity and brain repair in traumatic brain injury,
The Clinical Neuropsychologist, 23 (8), 1391-1399 .
Complex Intervention vs. Single
Variable Research Paradigm







Traditional Research: single, controlled variables
Reality of Medical Treatments is Complex.
Multiple Medications and Interventions.
Single design: Unrealistic, ungeneralizable.
Paradigm Shift: Shepperd and others (2009).
Must move to conduct and review Complex
Interventions.
Use Key Components: Trial data, Qualitative
data, Theory.
Standard Model for Assessment/Treatment of
Acute Stage TBI









Coma Rating Scales
CT Scan
Neurologic exam (e.g. cranial nerves, pupil reactivity)
Seizure prophylaxis
Blood pressure control
Blood gases - Monitor
Electrolyte balance – Monitor
Nutritional status
Regulate fluid intake
“Improved survival rates … THEN … sit and wait”
Do not greatly improve or speed recovery
Not predictive of outcome
IBRF Model for Assessment/Treatment of
Acute Stage TBI
Directional Normalization
of brain:
 Electrochemistry
O2 perfusion
 Glucose metabolism
Improve/Optimize:
CNS tissue survival
arousal
 cognition
 motor skills
Standard Model for Assessment/Treatment of
Chronic Stage TBI









Assorted NP test measures
Rating scales
Symptom monitoring
Standard MRI, CT, EEG (limited correlation with
functional recovery)
“sit and wait”
Poor predictor of outcomes
No subtyping
Does not translate to (guide) treatment protocol
Administered beyond critical time window
IBRF Model for Assessment/Treatment of
Chronic Stage TBI




Identification of Neuromarkers
Subtyping of injury
Predicting recovery timeline
Direct relationship between assessment and
treatment protocols


Neuromarkers/assessments DRIVE interventions
Intensive multi-modal therapeutic
interventions through full potential functional
recovery
IBRF Integrated Multi-modal
Approach
IBRF Program Goals:
1)
Identify functional neuromarkers to establish
TBI subtypes.
2)
Comprehensively evaluate the unique patterns
associated with individual TBI subtypes.
3)
Refine integrated multi-modal assessments
that directly guide multi-modal treatment.
4)
Predict treatment outcomes based on TBI
subtypes.
IBRF Brain Injury Model

Assessing Non-Invasive Multimodal Functional
Neuromarkers creates a dynamic and integrated
“Brain Map”

Neuromarkers are used to recognize multianalyte
profiles of:




altered neurophysiological function (electrical,
chemical, metabolic).
neuronal & structural integrity
chemical homeostasis
The Brain Map directly guides treatment
interventions which are correlated to the
assessment measures.
IBRF
Assessment – Treatment – Feedback Loop
Clinical
Outcome
Treatment
Intervention
Multi-Modal
Neurofunctional
Assessment
Neuro-Biomarkers
(Neurologic, Physiologic,
Psychologic, Biologic)
Integrated Functional Mapping:
The IBRF Approach
Combined neurologic assessment modalities: limitations of one modality are compensated for by others
Measure
Marker
Strengths
Associated Treatment
EEG, qEEG
electrophysiology
High temporal resolution (ms)
Source localization of
electrical generators in cortex
EEG brain-computer interface
(BCI) training
Guides tDCS and TMS
EP, ERP
electrophysiological
High temporal resolution (ms)
Measure processing speed
Measure intactness of
sensory pathways
EEG BCI training
Guides tDCS and TMS
MEG
Brain electromagnetism
High temporal resolution
Subcortical structures
Guides tDCS and TMS
B.I.S. Monitor
Level of consciousness
Real-time measure of patient
level of consciousness
Determine patient
receptiveness to treatment
MRI w/ DTI
Structural anomalies
Brain volume
Brain connectivity
Guides medical and surgical
interventions
Neurosurgery
Pharmacotherapy
MRI Spectroscopy
Brain chemistry / metabolites
Provides chemical
neuromarkers
Pharmacotherapy,
nutraceuticals
PET-CT
Metabolic functions
Multiple metabolic
neuromarkers
Pharmacotherapy,
nutraceuticals
Near Infra-red Spectroscopy
O2 concentrations/uptake
Non-invasive O2 exchange
method
Pharmacotherapy,
nutraceuticals
Median nerve stim
IBRF-DOC Theoretical Paradigm –
A Model Based on Neurochemical Autoregulation
Down Regulation
Agonist NT’s
Brain’s Inherent Protective
Mechanism to Sustain Life
Consciousness
Increase Inhibitory NT’s
Antagonist NT’s
Block Receptors
Agonist NT’s
Endorphins
GABA
Up Regulation
MCS
PVS
COMA
down regulation manifests as reduced
perceptual awareness & unresponsiveness
This model developed by Dr. Philip A. De Fina ©
Multi-modal Care Protocol
(MCP)

Screening:


Diagnostics:




Inclusion/Exclusion Criteria
functional neuroimaging (e.g., qEEG)
neurophysiological signal processing
measures of chemical metabolites
Treatment:



Off-label Pharmacological
Median Nerve Stimulation
Nutraceutical Components
MCP Retrospective Study



Retrospective Case Series of data
collected at KIR from 2005-2009 (IRB
approved retrospective).
N=41; VS-TBI, VS-nonTBI, MCS-TBI,
MCS-nonTBI.
Twelve week intervention
Traditional OT, Speech, PT
 Off-label Pharmaceuticals
 Median Nerve Stimulation
 Nutraceuticals

Participant Characteristics
Pre and Post Measures






Disability Rating Scale
Functional Independence Measure
Glasgow Coma Scale
Coma Recovery Scale-Revised
Clinical DX (VS, MCS, Emerged); based
on Mohonk criteria
EEG/QEEG - (data in analysis stage)
DRS, GCS, CRS-R, and Total FIM Scores Between
Admission and Discharge for Entire Sample.
Prognosis for Recovery in DOC Patients Receiving ACP vs.
Standard Care in Published Literature.*
*Clinical change for VS patients was compared to the MSTF11 study; clinical change for MCS patients was estimated based on
published DRS scores ranging from none to moderate disability (see page 43 and Table 4 of Giacino & Kalmar, 1997).
Retrospective Results




Patients showed statistically significant
improvement across all measures.
100% clinical improvement in MCS.
78-86% clinical improvement in VS.
Significant differences between MCP and
published literature, based on multiple outcome
measures.
Sample EEG Data from Retrospective Analysis
Polypharmacy and Risk
Use of multiple medications is routine
in medical treatment: Psychiatric,
Stroke, etc.
 Retrospective Study: No adverse
effects.
 This patient population has been
offered little hope, given limited life
expectancy.

Limitations
of Retrospective Study




Not a controlled, randomized, doubleblinded clinical trial.
No separate standard of care control
group.
Small sample size.
Treatments used in combination, therefore
efficacy of single or different combinations
not observed. Nevertheless…it is the
combination that seems to have the most
impact.
5. Future Directions
Department of Defense
Research Grant Project
Implementation of Advanced Care
Protocol (ACP) Research Project
for Patients with Disorders of
Consciousness
DoD Research Grant
1.
2.
General Hypotheses
By optimizing the electrochemical status of the brain with the
IBRF ACP/MCP, patients with DOC will exhibit more positive
health outcomes than patients who receive a placebo ACP/MCP.
Recovery from DOC is marked by unique and specific patterns of
electrical and chemical neuromarkers.
There will be two groups of participants:
Group 1: Participants receive 12 weeks of the ACP Protocol
Group 2: Participants in a Placebo control group receiving current
medical standard care and placebo ACP Protocol interventions.
Functional Measurement
Instruments






Functional Independence Measure (FIM)
Glasgow Coma Scale (GCS)
Rancho Level of Cognitive Functioning
Scale (LCFS)
Coma Rating Scale-Revised (CRS-R)
Disability Rating Scale (DRS)
Orientation Log (O-Log).
Neuromarker Measurement
Instruments











Electroencephalography (EEG)
Quantitative EEG (qEEG)
Evoked Potentials (EPs)
Event Related Potentials (ERP)
Magnetic Resonance Imaging (MRI)
Diffusion Tensor Imaging (DTI)
Susceptibility Weighted Imaging (SWI)
Magnetic Resonance Spectroscopy (MRS)
Autonomic Nervous System monitoring (ANS)
Near Infrared Spectroscopy (NIRS)
Bispectral Index (BIS).
ACP Interventions

Neuropsychiatric Pharmacology: Off-label use of pharmaceuticals will be
employed to stabilize neurotransmitter functions.

Nutraceuticals: Nutritive Pharmacology will be used to further brain
functions while maintaining effective brain metabolism. A combination of
pharmaceutical grade nutrients, vitamins, and antioxidants are used with
very specific dosing requirements.

Median Nerve Stimulation (MNS): MNS assists in perfusing oxygen to the
brain and increasing blood-brain-barrier permeability. It enhances the
effects of medications in regulating neurotransmitter stability cortically
and sub-cortically (see Cooper & Cooper)

Occupational, Physical, and Speech Therapies: Administration as is
customary in rehabilitation facilities.

Cognitive Enhancement: Cognitive enhancement is a tailored program of
individualized interventions that will be applied at the post emergent level.
It is the application of a variety of training tasks and methods to help
improve brain functions. Such methods may include training in
perception, attention, concentration, visual-motor-sensory skills,
command following, and use of objects.
Contact Information
Philip A. DeFina, PhD
Chief Executive and Scientific Officer
International Brain Research Foundation, Inc.
100 Menlo Park, Suite 412
Edison, NJ 08837
732-494-7600
732-494-7611 FX
pdefina@ibrfinc.org
www.ibrfinc.org
IBRF ACP Team
(alphabetically)









Philip A. DeFina, PhD, CEO, CSO, IBRF
John DeLuca, PhD, VP Research., KFRC; Advisory Board, IBRF
Monika Eller, OTR, Clinical Manager of Inpatient OT, KIR
Jonathan Fellus, MD, Director BI Services, KIR; Advisory Board, IBRF
Pasquale G. Frisina, PhD, Res. & Outcomes Director., KIR; Assisstant
Professor, Mt. Sinai School of Medicine.
Rosemarie Scolaro Moser, PhD, Dir. Res. Prog., IBRF; Dir. RSM Psych.Ctr.
Charles J. Prestigiacomo, MD, Assoc. Prof, Neurol. Surgery, UMDNJ;
Board Member, IBRF
Philip Schatz, PhD, Prof., Saint Joseph’s University; IBRF Consultant
James W.G. Thompson, PhD, Director of Research-TBI/SDOC, IBRF