Transcript Issues in Treatment of the Vegetative and Minimally

Disorders of Consciousness
Neurobehavioral and Neurophysiologic
Methods in Diagnostic and Prognostic
Assessment
Joseph T. Giacino, Ph.D.
JFK Johnson Rehabilitation Institute
NJ Neuroscience Institute
On the Boundaries of Consciousness: A Search for Contact
Reggio Emilia, Italy
March 23-25, 2006
JFK Johnson Rehabilitation Institute
Supporting Agencies
National
Institute on Disability Rehabilitation and
Research (H133A031713):
“Investigating the utility of fMRI in assessing cognition,
predicting outcome and planning treatment in persons
diagnosed with minimally conscious state.”
National
Institute of Health- NINDS (R21HD40987):
“Multidisciplinary assessment of severe brain injury.”
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Continuum of Consciousness
Laureys et al, 2003
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AWARENESS
AWARENESS
AROUSAL
AWARENESS
Vegetative State
Minimally
Conscious State
AROUSAL
Coma
AROUSAL
AWARENESS
AROUSAL
Normal
Consciousness
S. Laureys
Incidence of Diagnostic Inaccuracy
15% (Tresch et al, 1991)
 37% (Childs et al, 1993)
 43% (Andrews et al, 1996)

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Implications of Diagnostic
Non-Specificity and Inaccuracy

Inappropriate treatment decisions

Family adjustment complications

Misleading research findings
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I. Definitions and Diagnostic Criteria
Coma is a state of sustained pathologic
unconsciousness in which the eyes remain closed
and the patient cannot be aroused.
(MSTF, 1994)
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Coma: Course
Almost always resolves within 2-4 weeks
 Resolution signaled by reemergence of eye
opening
 No evidence of awareness of self or environment:

 No
purposeful motor activity
 No behavioral response to command
 No evidence of language comprehension or expression

Usually transitions to vegetative or minimally
conscious state
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Vegetative State
The vegetative state is a condition in which there is
complete absence of behavioral evidence for
awareness of self and environment, with preserved
capacity for spontaneous or stimulus-induced
arousal.
(Aspen Workgroup, 2001)
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Clinical Criteria for Diagnosis of the
Vegetative State
Core Features:



No evidence of sustained or reproducible, purposeful or voluntary
behavioral responses to visual, auditory, tactile or noxious stimuli
No evidence of language comprehension or expression
Intermittent wakefulness manifested by sleep-wake cycles
(Multi-Society Task Force on PVS 1994)
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Clinical Criteria for Diagnosis of the
Vegetative State (cont.)
Ancillary Features:



Sufficient preservation of hypothalamic and brain stem
autonomic functions for survival with medical and nursing
care
Bowel and bladder incontinence
Variable preservation of cranial nerve function (pupillary,
oculocephalic, corneal, vestibulo-ocular, gag, spinal reflexes)
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Persistent Vegetative State
A diagnostic term that denotes a vegetative
state present 1 month after a traumatic or
non-traumatic brain injury
(AAN 1995)
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PVS
Use of the term persistent vegetative state (PVS)
should be avoided. In place of PVS, the term
vegetative state should be used, accompanied by
a description of the cause of injury and the length
of time since onset.
(Aspen Workgroup 1997)
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Permanent Vegetative State
A prognostic term that denotes an irreversible
state which can be applied 12 months after a
traumatic injury and after 3 months following
non-traumatic injury in adults and children
(AAN 1995)
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Probabilities for Recovery of Consciousness and Function at 12
Months After Traumatic and Non-Traumatic Brain Injury for
Patients in the Vegetative State at 3 and 6 Months After Injury
Outcome Probabilities for Adults in PVS 3 Months After Injury
Outcome
Traumatic PVS (n=434)
Dead (%)
PVS (%)
Severe (%)
Moderate/Good (%)
35 (27-43)%
30 (22-38)%
19 (12-26)%
16 (10-22)%
Non-Traumatic PVS (n=169)
46 (31-61)%
47 (32-62)%
6 (0-13)%
1 (0-4)%
Outcome Probabilities for Adults in PVS 6 Months After Injury
Dead (%)
PVS (%)
Severe (%)
Moderate/Good (%)
32
52
12
4
(21-43)%
(40-64)%
(4-20)%
(0-9)%
28 (12-44)%
72 (56-88)%
0
0
____________________________________________________________
Source: Rosenberg & Ashwal, Neurorehabilitation 1996;6(1)
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Prognostic Guideline for Patients in the
Vegetative State (AAN, 1995)
Criteria for Permanence

After 12 months following traumatic brain injury in
adults and children

After 3 months following non-traumatic brain injury
in adults and children

After 1 to 3 months following metabolic and
degenerative diseases

At birth in infants with anencephaly and after 3 to 6
months following congenital malformations of the
brain
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Minimally Conscious State (MCS)
The minimally conscious state is a condition of
severely altered consciousness in which minimal
but definite behavioral evidence of self or
environmental awareness is demonstrated.
(Giacino, et al., Neurology, 2002)
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Minimally Conscious State: Course
Usually exists as transitional state reflecting
improvement (as in coma/VS) or decline (as in
neurodegenerative conditions) in consciousness
 May represent permanent outcome
 Natural history and long term outcome differ
from VS

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Diagnostic Criteria for MCS (Giacino, et al., 2002)
 One or more of the following must be clearly discernible
and occur on a reproducible or sustained basis:
 Simple command-following
 Gestural or verbal “yes/no” responses
 Intelligible verbalization
 Environmentally-contingent (non-reflexive) movements
or emotional responses:
 Smiling/crying
 Vocalizations/gestures
 Object reaching/manipulation
 Visual pursuit
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Comparison of Outcome: VS v. MCS

Increasing evidence that pts in MCS show:
 More
rapid rate of improvement
 Longer course of recovery
 Significantly better functional outcome by 12 months
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Comparison of Outcome at 1 Year in Persons Diagnosed
with VS and MCS
VS NTBI
VS TBI
MCS NTBI
MCS TBI
30
Mean DRS Score
25
20
15
10
5
0
1
3
6
12
Months Post Injury
(Giacino & Kalmar, JHTR, 1997)
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Comparison of MCS TBI Outcome at 1 and 2-5 Years
100
Percentage of Scores
90
80
MCS TBI 2-5 yr
n=20**
MCS TBI 1yr
n=30*
70
60
50
40
30
**Lammi et al, 2005
*Giacino & Kalmar, 1997
20
10
0
0-3
None-Partial
4-11
Mod-Mod/Sev
DRS Score Range
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17-23
Ext Sev-VS
How permanent is permanent?
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Diagnostic Criteria for Emergence from MCS
Reliable and consistent demonstration of one or
both of the following:

Functional interactive communication
 Verbalization
 Yes/no
signals
 Spelling/symbol boards
 Augmentative communication devices

Functional use of objects

Requires discrimination among items
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II. Neurophysiologic Assessment of VS and MCS
“The limits of consciousness are hard to define
satisfactorily and we can only infer the selfawareness of others by their appearance and
their acts.”
Plum and Posner, 1982
The Diagnosis of Stupor and Coma
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Clues From Functional Neuroimaging Studies
Cornell
Columbia
JFK
Nicholas Schiff, MD
Erik Kobylarz, MD, PhD
Fred Plum, MD
Joseph Fins, MD
Rodolfo Llinas, MD, Ph.D.
Urs Ribary, Ph.D.
Joy Hirsch, Ph.D.
Diana Rodriguez, PhD
Steve Dashaw
Ray Cappiello
Joseph T. Giacino, Ph.D. Bradley Beattie
Steven Laureys, MD, PhD
Kathleen Kalmar, Ph.D. Ron Blasberg, MD Melanie Boly, MD
Caroline McCagg, MD
Cyclotron Research Ctr.
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MSK
U. Liege
PET Studies of VS
Behavioral profiles of patients in VS highly
variable
 “Stereotypical fragments of organized behavior”
have been observed in VS patients
 Neurophysiologic substrate underlying these
complex behaviors unknown
 Prognostic relevance of neurophysiologic
profiles unknown

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Neurophysiologic heterogeneity in VS (CMRglu)
65%
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31%
Schiff et al, 2002
Sensory Processing in VS
Visual
Auditory
Somatosensory
Laureys, et al, 2005
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Somatosensory regions active in controls
but not in VS
Laureys, et al., 2005
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Discussion
VS essentially represents a global
disconnection syndrome.
 Isolated modular operations may survive in the
absence of consciousness.

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fMRI Studies of VS and MCS
Passive Listening

Forward narrative



Backward (time-reversed)
narrative



Familiar voice/event
Normal content and prosody
Unintelligible speech
Devoid of content and
prosody
Muffled narrative


Unintelligible speech
Retains prosody but not
content
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Passive Viewing

Passive Viewing
 Faces



Landscapes




Contrast v. faces
Emotionally neutral
Sensitive to PPA
Hands


Emotionally salient
Sensitive to FFA
Sensitive to FG (non-FFA)
or
Flashing Checkerboards

Sensitive to V1
MCS Case Studies (Passive listening only)
Patient 1:




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21 yo male (RH)
18m s/p L temporo-parietal
intracranial hemorrhage w/
brain stem compression
F/U MRI: Large area L T-P
encephalomalacia
Inconsistent one-step
command-following, object
identification, single word
utterances
Unable to communicate
reliably
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Patient 2:





33 yo male (RH)
24m s/p b/l SDHs 2ndary to
blunt head trauma
F/U MRI: R frontal
encephalomalacia +
paramedian thalamic infarct
Inconsistent complex
command-following (go-no
go, countermanding),
occasional verbalization
Unable to communicate
reliably
MCS Case Studies: Patient 3 (w/ passive viewing)
29 yo male (RH)
 MVA v. pedestrian
 18m s/p L temporo-parietal intracranial
hemorrhage w/ brain stem compression
 F/U MRI: Large area L temporo-parietal
encephalomalacia
 Inconsistent one-step command-following
 Unable to communicate

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Healthy Volunteers
 Unrelated/Unknown
to patient
 Demographically matched
 Right-handed
 Able to independently provide consent
 No hx of major neurologic, developmental or
psychiatric disorder
 No implanted hardware above shoulders
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Subject 1
Subject 2
Subject 3
FORWARD
Subject 4
BACKWARD
Subject 5
Subject 6
OVERLAP
Listening to Narratives: Healthy Subjects
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Subject 7
Patient 1
FORWARD
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Patient 2
BACKWARD
OVERLAP
GTm 21
Listening to Narratives
GTs 22
GTt 41
Language Activation Pattern by Condition
Listening to narratives: Patient 3
Forward
Speech
Backward
Speech
Muffled
Speech
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Summary of Passive Listening Results in MCS

Activation pattern similar in MCS patients and
controls
 MCS
patients retain functional connectivity
Language network foci preserved in MCS
despite inability to follow commands or
communicate reliably
 In 2/3 MCS patients (but not controls),
activation markedly reduced during backward
condition

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Viewing Pictures: Patient 3
R R
L
L
Faces
0
Hands
Landscapes
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Summary of Passive Viewing Results in MCS

Selective activation of visual network foci noted
despite complete absence of behavioral evidence for
visual recognition
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Discussion
MCS pts retain connected cortical networks
underlying language and visual processing.
 Loss of activation in MCS pts during backward
narrative may be related to low emotional
salience of these stimuli.
 Recruitable cortical networks associated with
language and visual processing may pre-sage
further recovery.

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Cognitive Processing in the Vegetative State?


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

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20 y/o college student (RH)
Drug overdose (opiates, cocaine, barbiturates)
Cardiac arrest (10 mins to resuscitation in ER)
CT: global ischemic changes on day 2
Admitted to rehab at 3 mths post-injury
No discernible command-following, communication
or visual response (vocalization??)
Spastic contractures all 4 extremities
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Language: VS or MCS?
L
RR
L
Forward Speech
Backward Speech
Forward - Backward
43
Visuoperception: VS or MCS??
RR
L
L
Checkerboard
L
Landscapes
Faces
44
What do these findings mean?
“Functional” locked-in state?
 Activation of cortical association areas not
indicative of conscious processing?

 More
extensive hard-wiring than previously
suspected?
 Isolated surviving modular networks but
insufficient to support consciousness

Other??
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Pressing Questions





Is functional neuroimaging (FNI) an adequate proxy
for neural activity?
Can FNI detect cognitive processing in the absence of
behavioral evidence?
Can FNI improve prognostic accuracy?
Can FNI procedures identify patients likely to benefit
from treatment when behavioral indicators are
unfavorable?
Can FNI help determine which interventions are best
for which patients?
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