Intrathecal Baclofen for Spasticity

George Jallo MD,Division of Pediatric Neurosurgery

Johns Hopkins University

Spasticity

Spastikos - “to draw or tug” Motor disorder Velocity-dependent increased resistance to passive stretch

Exaggerated tendon jerks Hyperexcitability of the stretch reflex

Pathophysiology of Spasticity

Theory Imbalance between excitatory and inhibitory impulses to the alpha motor neuron

Due to a lack of descending inhibitory input to the alpha motor neuronDescending

InhibitionSensory

Excitation

Pathophysiology of Cerebral Origin Spasticity

Inhibitory signals modulate reflex

signals–tone remains normal

Lack of neural inhibition leads to

spasticity

Normal brain delivers inhibitory neural signals to the spinal cord

Damaged brain fails to generate or sends inadequate inhibitory signals

Pathophysiology of Spinal Origin Spasticity

Inhibitory signals modulate reflex

signals–tone remains normal

Lack of neural inhibition leads to

spasticity

Inhibitory neural signals sent to the

alpha motor neuron

Damaged spinal cord fails to relay

adequate inhibitory signals

Normal Damaged

Possible Advantages of Spasticity

Maintains muscle tone Helps support circulatory function

May prevent formation of deep vein thrombosis

May assist in activities of daily living

Consequences of Spasticity

May interfere with mobility, exercise, joint range of motion

May interfere with activities of daily living

May cause pain and sleep disturbance

Can make patient care more difficult

Measuring Spasticity

Ashworth and Modified Ashworth scales

Spasm and reflex scales Passive quantitative tests Active tests of movement

Factors That May Increase Spasticity

Uncontrollable Urinary tract infection

Kidney stones Menses Bowel impaction or gas Deep vein thrombosis Pneumonia Wounds or infections Progression of disease

Controllable Stress Ingrown nails Restrictive clothing

Fatigue Psychological factors

Change in temperature or humidity

Spasticity Associated with Cerebral Palsy (CP)

Disorders affecting movement posture balance

Injury to the developing brain Permanent and non-progressive Developmental disability

Classifications of Cerebral Palsy

Location of brain lesion pyramidal, extrapyramidal, mixed

Type of movement disorder spastic, dystonic, athetoid, ataxia, mixed

Extent and location of limb involvement monoplegia, diplegia, hemiplegia, paraplegia, tetraplegia

Conditions Associated withCerebral Palsy

Mental retardation, learning disabilities

Seizures Gastrointestinal difficulties Urinary infections Respiratory problems Hearing/vision impairment Orthopedic problems

Goals of Spasticity: Management

Decrease spasticity Improve functional ability and independence

Decrease pain associated with spasticity Prevent or decrease incidence of contractures

Improve ambulation Facilitate hygiene Ease rehabilitation procedures Save caregivers’ time

Spectrum of Care forManagement of Spasticity

InjectionTherapy

Neurosurgery

OrthopedicTreatments

RehabilitationTherapy

PreventNociception

IntrathecalBaclofen(ITB™)

Therapy

OralDrugs

Patient

Traditional Step-Ladder Approach to Management of Spasticity

Neurosurgical Orthopedic Neurolysis

Oral medications Rehabilitation Therapy Remove noxious stimuli

Rehabilitation Therapy Stretching Weight bearing Inhibitory casting

Vibration of the antagonist

Pool therapy EMG biofeedback Electrical stimulation

Positioning and rotary movements

Oral Medications

Baclofen Diazepam Dantrolene Sodium Tizanidine

Site of Action for Oral Drugs

DrugBaclofen:

Diazepam:Dantrolene Sodium:

Tizanidine:

Site of actionGABAb receptors in spinal cordCentral nervous systemSkeletal muscles beyond the myoneural junctionCentral acting (spinal and supraspinal) at alpha2 – adrenergic receptor sites

NeurosurgerySurgical Treatments

Neurodestructive Procedures Neurectomy Myelotomy Rhizotomy Cordectomy Selective Dorsal Rhizotomy

Selective Dorsal Rhizotomy

Two primary goals: facilitate patient care

sitting, dressing, transfers improve function

walking

Surgical procedure where the dorsal (sensory) nerve roots are severed

Orthopedic Surgeries

Soft Tissue Procedures Tenotomy Tendon lengthening Myotomy Tendon transfers

Why Intrathecal vs. Oral?

Baclofen Injection Baclofen injection is delivered to the CSF and thought to act at GABAb receptor sites at the spinal cord

Lower doses than those required orally

Potential for fewer systemic side effects

Oral Baclofen Low blood/brain barrier penetration, with high systemic absorption and low CNS absorption

Lack of preferential spinal cord distribution

Some patients experience unacceptable side effects at effective doses

Advantages of ITB™ Therapy Reversible Potentially fewer systemic side effects

Programmable allows dose titration to give optimal benefit

Effective in reducing spasticity upper and lower extremities1

cerebral and spinal origin

ITB™ Therapy Process

Stage 1: Patient Selection Stage 2: Screening Test Stage 3: Implant Stage 4: Maintenance

Efficacy in Adults and Children 86% cerebral origin (screening test) 97% spinal cord origin (screening test)

Upper and lower extremities Both patients with functional goals and patients with goals of improving comfort and ease of careAlbright, A. Leland. Baclofen in the Treatment of Cerebral Palsy, J Child Neurol 1996; 11:77-83.Becker, R., Alberti, O., and Bauer, B.L. Continuous intrathecal baclofen infusion in severe spasticity after traumatic or hypoxic brain injury, J Neurol 1997; 244: 160-166.Campbell, Susan K., Almeida, Gil L., Penn, Richard D., and Corcos, Daniel M. The Effects of Intrathecally Administered Baclofen on Function in Patients with Spasticity, Phys Ther 1995; 75: 352-362.

Reported Outcomes in Patients with Spasticity of Cerebral Origin

Method 37 patients Spastic quadriplegia ITB Therapy received over a range of 3 - 48 monthsResults 6 and 12 months post implant

muscle tone significantly decreased in lower and upper extremities

25 children capable of self-care at start of study: significant improvement in

ADL upper extremity function hamstring extensibility

Albright AL, Barron WB, Fasick MP, et al. Continuous Intrathecal Baclofen Infusion for Spasticity of Cerebral Origin. JAMA 270(20):2475-77, Nov 24, 1993.

Reported Outcomes in Patients with Spasticity of Spinal Origin

Method 20 patients Diagnosed with spinal cord injury or multiple sclerosis ITB Therapy received over a range of 10-33 monthsResults Statistically significant decreases in muscle tone of

hip, knee, and ankle musculature based on Ashworth score

Statistically significant decrease in frequency of spasms

Functional status tracked in 8 patients (6 months duration):

improved ADL improved bowel and bladder management programs

Parke B, Penn RD, Savoy SM, et al. Functional Outcome after Delivery of Intrathecal Baclofen. Arch Phys Med Rehabil 70:30-32,1989.

Penn RD, Savoy SM, Corcos D, et al. Intrathecal Baclofen for Severe Spinal Spasticity N Engl J Med 329:1517-21,1989.

Drug• Spinal level• Excitatory neurotransmitters

Anatomic figure adapted from Kroin, JS. Intrathecal drug administration: present use and future trends. Clin Pharmacokinet 1992, 22:319-326.

IntrathecalIntrathecalspacespace

Dura-arachnoidDura-arachnoidmembranesmembranes

EpiduralEpiduralspacespace

CSFCSF

To brainTo brain

CapillaryCapillaryabsorptionabsorption

CatheterCatheter

DrugDrug

VertebraVertebra

Spinal cordSpinal cord

How Does Baclofen Injection Work?

GABA Gamma-butyric acid (GABA)

an inhibitory neurotransmitter Baclofen

thought to act as a GABA agonist in the spinal cord, reducing positive input to the alpha motor neuron

Pharmacokinetics of Baclofen

Oral 60 mg dose: 0.024 mcg/mL IT lumbar concentration

Half-life 3-4 hoursIntrathecal 600 mcg/day dose: 1.24 mcg/mL IT lumbar concentration

Lumbar to cervical concentration is 4:1 Half-life 4-5 hours

Pharmacodynamics ofBaclofen Injection Bolus Onset of action is one-half hour to 1 hour after intrathecal bolus

Peak effect at 4 hours after dosing Effects may last from 4 to 8 hoursContinuous Effects are first seen at 6 to 8 hours after initiation of continuous infusion

Maximum effect observed in 24 to 48 hours

Onset, peak response, and duration of action may vary

Interdisciplinary Team Assessment

Considers all facets of patient’s needs and resources

Considers the “whole” person Provides optimal care for the patient

Contraindications of ITB™ Therapy

Patient has a history of allergy (hypersensitivity) to oral baclofen

Infection is present at time of screening or implant

Potential Risks of ITB™ Therapy

Common side effects: hypotonia, somnolence, nausea/vomiting, headache, dizziness

Overdose, although rare, could lead to respiratory depression, loss of consciousness, reversible coma, and in extreme cases, may be life-threatening

Catheter and procedural complications may occur

Causes of Overdose

Dosing error Pump malfunction Programming error Injecting catheter access port during refill

Filling catheter with syringe during surgery

Use of concomitant drugs

Screening Test Flow Chart

Not a CandidateIntrathecal Baclofen Therapy Clinical Reference Guide for Spasticity Management, Medtronic, Inc.

Bolus: 50 mcg

24 hrs afterBolus: 75 mcg

24 hrs afterBolus: 100 mcg

+ -

+ -

+ -

= Positive Response “Implant”

= Negative Response “No Implant”

+

-

SynchroMed® System Components

Pump infuses drug

Catheter delivers drug to the intrathecal (subarachnoid) space of the spinal cord

Programmer allows for precise dosing

easily adjustable dosing

SynchroMed® EL Pump Battery life of approximately 7 years

Flow rates down to48 microliters/day

Four suture loops Matte finish No changes in clinical procedure or pump programming

InDura® IntraspinalTwo-Piece Catheter

Two-piece catheter design

Pre-attached pump connector

Tapered, open tip

Catheter Implant Insert the catheter through the introducer needle to the desired level (T10-T12)

Verify catheter tip position through use of fluoroscopy and CSF backflow

Advancing catheter under fluoroscopy

Pump Implant

Abdominal incision make a pocket for the pump no deeper than 2.5 cm or 1 inch

Titration Period

After First 24-Hour Period Increase dose slowly Increase only once every 24 hours until desired clinical effect achieved Adults with spasticity of spinal origin

10-30% increments Adults with spasticity of cerebral origin

5-15% increments Pediatrics

5-15% increments

Comparison of Techniques

Method Age (Years)

Candidate Outcome Follow -up Care Risks Cost

Oral Medications

Any age Spastic quadriplegia Diffuse spasticity

Mild decrease in spasticity; often need SDR or ITB later

PT, OT as needed Drowsiness Medications: $40 -50/month

Botulinum Toxin Injections

Any age Spastic diplegia or quadriplegia Isolated spasticity

Decrease in spasticity of injected muscles for 2-4 months

PT, OT to increase range of motion

None Injection: $250 -400 Medication: $400 -800 (every 3 -4 months)

Baclofen (ITB) Age> 35 lbs

Spastic quadriplegia; spasticity in legs>arms; Spasticity interferes with comfort, care, ADLS

Decrease in spasticity ; improved speech, ADLs; decrease orthopedic operations; reversible

Frequency of PT, OT depends on goals

Infection: 5 -10% Wound: 5 -10% CSF leak: 5 -10%

Hospitilization and implant: $25,000 -30,000 Initial medication: $400 Refills: $200 -250 (3 -5/year) Pump replacement: 5 -7 years

Rhizotomy (SDR)

4-7 Spastic quadriplegia or diplegia; good leg strength; no severe contractures; severe leg spas ticity

Marked, non -adjustable decrease in spasticity, improved gait, ADLs, permanent

PT, OT Infection: 2% Wound: 2% CSF leak: 3 -5%

Hospitlization and surgery: $20,000 -25,000 PT following surgery: $15,000 -25,000

Conclusions

Intrathecal delivery is an alternative to rhizotomy procedures in children

Advantages: simple, adjustable, reversible

Disadvantages: cost, infection, toxicity