Transcript SCI: THE SEARCH FOR A CURE

SCI Overview: Demographics,
Terminology, Clinical issues, &
Research Approaches
 William
McKinley MD
 Dept. of PM&R
 Director SCI Rehabilitation Medicine
Epidemiology of SCI
 Incidence:
40 cases per million
 Prevalence:
 200
200,000 currently in USA
new SCI / year in Virginia
• 80/yr at VCU
– 61% Traumatic (MVA, Violence, Fall)
– 39% Nontraumatic (SS, Neoplasm, ischemia)
Epidemiology (Cont.)
Demographics: Age: 31 yrs, 82% male,
56% Caucasian, 63% employed, 54% single
(NT/SCI older, male = Female)
 Etiology: MVA 37%, Violence 28%, Falls
21%
 90% discharged to home

• Costs: $40-100K (Acute) - $500K (lifetime)

Life Expectancy: lower than average
• Cause of Death: Pulmonary, Cardiac
Model Spinal Cord Injury Care System Locations
*Currently funded systems
SCI Model Systems
5
yr ( $1.8 million)
 Objectives
•
•
•
•
clinical continuum of care
national data collection
focused research (VCU: Employment)
collaborative research
VCU SCI Research
 Etiology
& Rehab Outcome Studies
• violent/nonviolent
• nontraumatic/traumatic
 Secondary
Issues
• medical complidations
• depression/grief
• substance abuse
 Community
Reintegration
• employment / recreation
Key Terminology
 Tetraplegia/Paraplegia
 Neurologic
Level of Injury (NLOI)
• most caudal normal M/S level (ie: C-5)
 Zone
of Injury
• 3 levels distal to NLOI
 Complete
vs Incomplete
• ASIA Classification
ASIA Impairment Scale
Complete – No Sacral Motor / Sensory
 B = Incomplete – Sacral sensory sparing
 C = Incomplete – Motor Sparing (<3)
 D = Incomplete – Motor Sparing (>3)
A =

E = Normal Motor & Sensory
Neurological Recovery
Following SCI
 Zone
of Injury (ZOI)
• Peripheral Nerve root (PNS)
regeneration (1 year)
 “Below ZOI” (Incomplete SCI)
• Neuropraxic recovery (1-3 months)
• Peripheral Sprouting (3-6 months)
• Muscle Hypertrophy (3-6 months)
Neurological Recovery w/in the
Zone of Injury
 Prognostic
indicators:
• Incomplete > Complete
(motor > pin > light touch)
• Time post-injury
• Rate of change
Prognosis for “Functional”
(ASIA D) Recovery (below ZOI)
 Complete
(ASIA A)
0-5%
 Sensory
Incomplete (ASIA B)
20%
 Sensory
Incomplete (ASIA B-2)
40%
 Motor
Incomplete (ASIA C)
60%
Other Prognostic Factors
 Mechanism
of Injury:
• Unil fact dislo > Flexion-Rotation
 Etiology:
• Spinal stenosis > GSW
 MRI: local edema > hemorrhage,
transection
 SSEP – no better than clinical exam
Clinical Impairments After SCI
 Motor
 Sensory
 Bladder/Bowel
 Sexuality
 Autonomic
Nervous System
Medical Complications of SCI
 Infections
(lung, GU)
 Spasticity
 Pressure
Sores
 Pain
 DVT
/ PE
 Orthostasis
 Autonomic Dysreflexia
Functional Impairments
 Mobility
• walking, wheelchair, transfers
 Activities
of Daily Living (ADL’S)
• dressing, feeding, grooming
 Functional
Independence Measure
(FIM)
• 1-7 rating scale for function (Dep….Indep)
Functional Abilities
 C1-C5
motorized W/C
 C-5
feeding
 C6
manual W/C
 C7
key level for functional
Independence (transfers,
dressing)
 C8-T1
finger function
 L2/3
ambulation
Post-Traumatic Changes to
the Spinal Cord
 “Primary”
injury – Immediate nerve
damage will lead to nerve degeneration
 “Secondary” injury – Delayed nerve
injury due to inflammatory response,
ischemia, ca++, free radicals
 Complete is NOT “complete”
• Transection is rare
• 10% can support substantial function
Post-Traumatic SCI changes
 Primary
cell loss
 Secondary Cell loss
• central hemorrhage/ischemia
• wallarian degeneration
 Cystic
degeneration
• Syringomyelia
 Muscle
atrophy
• especially w/LMN loss
Prognosis following SCI
regeneration - “currently” this
does not occur within the CNS
 Nerve
 Neurological
recovery - can occur in
incomplete injuries and w/I the ZOI
 Functional
improvements - occur in
relation to LOI, comp/inc, motivation,
staff training, decreased complications
Why No SCI Regeneration?
 1.
No stimulus for regeneration
• Nerve Growth Factors (NGF)
– (Levi-Montalcini, Nobel Prize)
• PNS has NGF, CNS does not
–Produced naturally
–Protects against cell damage
–Stimulates regeneration
Why No SCI regeneration (cont)
 2.
Inhibitory Factors
• Oligodendrocytes inhibit axon growth
(Schwab-1980’s)
• Antibodies can block this inhibition
 3.
Impenetrable Regions
• Astrocyte scars can block regeneration
SCI Research Approaches
 1.
prevent secondary CNS cell death
 2. Promote Regeneration &
Remyelination
 3. Prevent inhibition
 4. Maximize Function (despite
impairment)
1. Clinical / Pharmacological
Studies to prevent secondary
Injury
randomized, multi-center trials
 outcome measurements:

• neurological improvement
– ASIA, MIS
• functional improvement (FIM)
– walking, bladder, bowel, sexuality
• decreased medical complications
– spasticity, pain
Methylprednisilone (MP):
steroids
 Dual
mechanism of action:
• antioxidant: inhibits lipid peroxidation
• anti-inflammatory: reduces vascular
permeability
• NASCIS - National Acute Spinal Cord
Injury Studies
NASCIS 1 (early 1980's)
 330
patients (double blind randomized,
multi-center)
 compared high (1,000mg/day) and low
(100mg/day) dose MP within 48-72
hours x 10 days
 results: *No significant difference
between high and low MP
and more wound infections in the high
dose group
NASCIS 2 (“Bracken
protocol”- late 1980's)
 470
patients compared both within 8
hours and between 8-12 hours
 compared high dose MP (30mg/kg
bolus and 5.4mg/kg/h x 23 hrs) vs
Naloxone and placebo
 Results: * MP within 8 hours had
significantly greater motor and sensory
recovery than placebo, Naloxone and
8-12 hour group
NASCIS 3 (mid-1990's)
 comparison
of MP with Tirilazed
 Tirilazed inhibits lipid peroxidation
without glucocorticoid fx
 Results: *MP for 48 hours has beneficial
effects.Tirilazed at 48 hours similar to
MP at 24 hours.
Apparent role of lipid peroxidation
Gangliosides (Geisler 1991)
 GM
1- neuroprotective properties, acts
on intracellular calcium
 34
pts with 100mg iv daily x 26 days
 Results:
*GM 1 patients showed
improved LE ASIA motor scores at 1 yr
Sygen (Ganglioside) study
(mid-1990's)
 720
patients, acute and 12 mo f/u
 100 or 200mg daily for 58 days
 Results:
neurological improvement @ 1
year no different than placebo
4-Aminopyridine (4AP)
 selectively
blocks K+ channels in cell
membranes
 improves
 allows
conduction by prolonging AP
propagation through damaged
zones
• normal half-life 3-4 hours
4AP Clinical studies
 Multiple
Sclerosis Studies
 Fampridine (Phase II) SCI study
• randomized, blinded study
 potential
benefits: improve spasticity,
bladder, pain, motor
 ? Adverse
seizures
events: agitation, insomnia,
Other Non-pharmacologic
trials (to prevent 2nd injury)

Surgical decompression
• acute decompression of sp cord
• lack of randomized prospective trials
• ? Incomplete > Complete SCI
• ? timing (4-6 hours), risk factors

Hypothermia
• decreases metabolic requirements
• delayed development of hypoxia
• decreased glutamate & free radical release
• animal studies seem encouraging
SUMMARY: Prevention of
Secondary Injury
 MP
?
(Bracken Protocol)
Gangliosides, 4-AP
 ? surgical decompression, new drugs,
hypothermia
2. Nerve Regeneration
Research
 stimulate
outgrowth in appropriate
directions
 overcome anti-regenerative
characteristics of adult CNS
• inhibition (Anti-Nogo)
• scar/ impenetrability (Chondroitinase)
 convert nerve growth into functional
reinnervation
Aguayo et. al. (1980's)
CNS into PNS –
Regeneration occurs!
 Transplanted
• * Axons need “permissive” environment
• * Schwann cells are critical (NGF’s)
• * results: electrically active small-diameter
unmyelinated axon regeneration
Current Spinal nerve graft
strategies
 Transplantation
• peripheral nerve tissue
• fetal cells
• Genetic precursor cells
–NGF’s, myelin, Antibodies
Remyelination Research
 Schwann
Cell & PNS transplants
 Transplanted embryonic stem cells
• produce oligodendrocytes
 M-1
antibodies stimulate remyelination
3. Removal of inhibition
(Schwab)
 Oligodendrocyte
inhibitory proteins
• inhibit axon growth and myelin formation
 when
treated with antibodies increased axon regeneration in rats
SUMMARY: Nerve
Regeneration
 CNS
axons need
• permissive environment (NGF’s)
• Removal of inhibitions
 Nerve grafts allow for limited regrowth
 ? functional connections
4. Maximize Function (Clinical
Research studies)
 Prevention
& management of acute &
chronic medical complications
 Rehabilitation
 Community
Outcome studies
reintegration & employment
Clinical Research
 Bladder,
spasticity, neuropathic pain
 FES
 Reversing
learned non-use
• biofeedback
• body-weight supported ambulation (BSA)
Technological advances &
enhancing function
 Functional
•
•
•
•
Electrical Stimulation (FES) Diaphragm - phrenic n stim (resp)
Lower ext.- “Parastep” (walking)
Upper ext. - “Freehand” (grasp)
Bladder - FES (voiding)
 Implantable
pumps (spasms, pain)
Current Clinical Trials
 Fetal
SC transplants to treat
progressive syringomyelia
 4-AP for chronic SCI
 Neurotropin-secreting transplants
 Neural stem cell Tx in chronic SCI
 Alternating electrical current sti
 Supported treadmill ambulation
 Nerve bridging
SUMMARY: Future Scenario
(Combination Therapies)
 Prevent
secondary injury
• steroids
 Enhance
Regeneration & Remyelination
• nerve grafting, NGF’s, overcoming
inhibition, guiding axons to target
 Enhance
Restoration
• (Rehabilitation, 4 AP, FES, BSA)
?
Future opportunities
• Vaccines (neuroprotection), stem cells
Preparing for research
 Avoid
irreversible surgical procedures
 Prevent complications
• atrophy (muscle, bone, neuronal)
• contractures
 Revearse
learned non-use & atrophy
• PT, FES, BSA, biofeedback