spasticity mechanisms and management
DESCRIPTION
Spasticity Mechanisms and Management. Allison Oki, MD October 11, 2014. Objectives. Video – Development/Basic Mechanics of Gait Overview Motor Disorders, Hypertonia, Spasticity Pathophysiology Cerebral Palsy UMN syndrome - Consequences of Spasticity Medical Management - PowerPoint PPT PresentationTRANSCRIPT
SPASTICITYMECHANISMS AND MANAGEMENT
Allison Oki, MDOctober 11, 2014
Objectives
Video – Development/Basic Mechanics of Gait
Overview Motor Disorders, Hypertonia, Spasticity
Pathophysiology Cerebral Palsy UMN syndrome - Consequences of Spasticity Medical Management Neurosurgical Interventions: ITB and SDR
Development
Bipeds center of mass (COM) level of S2
Inherently unstable
Continual postural adjustment to maintain COM within base of support
Sit 6 mo Crawl 9 mo Independent
walking 12 mo Gait maturation
at 6.5 years
Motor System
Motor system hierarchical
chain of command
extends from the cortical centers down to the nerves that innervate the muscles
Components of Motor System Supplementary
motor cortex Cortical motor
control centers Basal Ganglia Cerebellum Brainstem Motor
nuclei Central pattern
Generators
Motor Pyramid
Pyramidal and Extrapyramidal Upper Motor NeuronsPyramidal
direct corticospinal tractFine coordination motion
Extrapyramidalindirect cortco-bulbo-spinal tracts (vestibular/ reticular tracts)Balance, posture, coordination
Central Pattern Generators
Located in the SC generate a consistent specific movement pattern
Analogy – piano key and note, central pattern generator when stimulated produces the same movement pattern
Anterior horn of SC Pyramidal – lateral Extrapyramidal - medial
Motor Disorders
Disorders of multiple neural components basal ganglia cerebellum cerebral cortex brainstem descending spinal tracts
Hypertonia is a component of many motor disorders Spasticity, dystonia and rigidity
Motor Disorders
Pyramidal cortical projections to
the brainstem (corticobulbar)
SC (corticospinal)
clinically: weakness and increased stretch reflexes
“pyramidal”“upper motor neuron”
weakness
Extra-pyramidal Injury to BG,
cerebellum or non-primary motor cortical areas
clinically: abnormal motor control without weakness or changes in spinal reflexes
What is spasticity?
“Spasticity is a motor disorder characterized by a velocity dependent increase in tonic stretch reflexes, with exaggerated tendon jerks resulting from hyperexcitability of the stretch reflex, as one component of the upper motor neuron syndrome” Lance 1980
Resistance to stretch increases with increasing speed and varies with the direction of the joint movement
Rapid rise in resistance to stretch above a threshold speed or joint angle
Sanger et al, Classification and Definition of Disorders Causing Hypertonia in Childhood, Pediatrics 2003
Hypothetical Mechanism
Pathophysiology of SpasticityTheories
Imbalance between excitatory and inhibitory impulses to the alpha motor neuron in the spinal cord
Due to a loss of descending inhibitory input to the alpha motor neuron due to injury to the cortical spinal tracts
DescendingInhibition
SensoryExcitation
Cerebral Palsy: Definition
Primary abnormality of movement and posture secondary to a nonprogressive lesion of a developing brain
Represents a group of disorders rather than a single entity
Abnormal motor control and tone in the absence of underlying progressive disease
Epidemiology CP Most common motor
disorder of childhood 3.6/1000 school age
children Higher survival rate
of premature infants
Etiology – majority of term infants do not have an identifiable cause
Causative factors Prematurity Infection Inflammation Coagulopathy
Greatest RF prematurity <37wks Incidence highest in
the very premature
Pathology CP >80% abnormal
neuroimaging PVL – white matter
near the lateral ventricles
Premature 90% vs term 20%
IVH Corticospinal tract
fibers to LE are medial to UE → spastic diparesis
Common Gait Deviations CP
Location Impairment Potential Effects
Hip ↑ adductor tone Scissoring, difficulty advancing leg in swing
↑ iliopsoas tone Anterior pelvic tilt, lumbar lordosis, crouched gait
↑ femoral anteversion Intoeing, false genuvalgus, compensatory external tibial torsion
Abductor weakness Trendelenberg gait
Knee ↓ hamstring ROM Crouched gait
Hamstring/Quad co-contraction Stiff-kneed gait
Ankle ↑ gastroc tone/contracture Toe walking, genu recurvatum, difficulty clearing foot during swing
Internal tibial torsion Intoeing, ineffective toe-off
External tibial torsion Out-toeing, ineffective toe-off
Varus ↑ supination in stance or swing
Valgus ↑ pronation in stance or swing, midfoot breakdown
Upper Motor Neuron Syndrome UMNS
Positive
Spasticity Spastic Dystonia Clonus/ hyper-reflexia Reflex flexor and
extensor spasms Associated reactions
Negative
Weakness Fatigue Loss of selective
motor control Sensory deficits Incoordination Poor balance
Allison Brashear, Spasticity and Other Forms of Muscle Overactivity in the Upper Motor Neuron Syndrome, Nathaniel H. Mayer, Ch.1 Positive Signs and Consequences of an Upper Motor Neuron Syndrome, 2008
David Scrutton et al, Management of the Motor Disorders of Children with Cerebral Palsy, H. Kerr Graham, Ch.8 Mechanisms of Deformity
UMNS
UMNS disability = positive + negative + rheologic properties
Rheologic properties: viscoelastic properties of the muscle and other soft tissues
Structural changes occur in the muscle cells causing intrinsic muscle stiffness (Olsen et al. 2006)
Combined effects of all signs → chronic unidirectional postures and movements that are generated by a net balance of muscle torques exerted across the involved joints
Allison Brashear, Spasticity and Other Forms of Muscle Overactivity in the Upper Motor Neuron Syndrome, Nathaniel H. Mayer, Ch.1 Positive Signs and Consequences of an Upper Motor Neuron Syndrome, 2008
UMNS
Torque – force generated by muscle acting through a bony lever arm →rotational movement
Normal movement is bi- or multi-directional, agonist and antagonist torques create motion
UMNS → net unidirectional movements (positive signs) often persist as postures because voluntary bi- or multi-directional movement is impaired (negative signs) → chronic effects on soft tissue, joint structures and bone
Allison Brashear, Spasticity and Other Forms of Muscle Overactivity in the Upper Motor Neuron Syndrome, Nathaniel H. Mayer, Ch.1 Positive Signs and Consequences of an Upper Motor Neuron Syndrome, 2008
Why is spasticity important?
Clinically diagnosed and treated
Musculoskeletal and neurologic exam Tone, reflexes, strength,
coordination
Spasticity →
significant disability
ADLs Seating Comfort Contracture Loss of ROM Negative impact on
function Bone deformity Pain Skin Hygiene Ability to provide cares
Allison Brashear, Elie Elovic, Spasticity Diagnosis and Management, 2010, Ch 1.1 Why is spasticity important?
Secondary effects of SpasticityMay effect function and long-term outcome Persistent muscle imbalance → muscle/tendon
contractures → joint or bone deformities weak antagonists muscles → require passive
stretch for a minimum of 6 out of 24 hrs to maintain muscle length (Tardieu 1988) and to avoid development of a fixed contracture (Eames 1999)
Abnormal forces across joints → prolonged abnormal posture, increase energy expenditure, impair function, and negatively affect both the caregiver’s and patient’s QOLL. Andrew Koman, MD et al, Botulinum Toxin Type A in the Management of Cerebral Palsy, 2002, Wake Forest University Press, p.40
Abnormal Forces across Joints Ankle and subtalar → fixed equinus, equinovarus
or equinovalgus hindfoot deformities Adductor and iliospoas spasticity → hip
subluxation and dislocation Once a critical degree (50%) of hip subluxation is
present, dislocation is inevitable unless intervention occurs (Reimers 1987)
The resultant pelvic obliquity compromises sitting balance → chronic pain
L. Andrew Koman, et al, Botulinum Toxin Type A in the Management of Cerebral Palsy, 2002, Wake Forest University Press
Bone Deformity
Abnormal muscle forces act on a growing skeleton
Hips and spine → essential in weight bearing and positioning
Femur → muscle and gravity loading forces during growth
Muscle forces in CP → increased anteversion of femoral neck
hip flexion, adduction and internal rotation of the femur → femoral head in a superoposterolateral direction, out of the acetabulum → coxa valgus: deformation of the femoral head and shallow acetabulum
Randall L. Braddom, Physical Medicine and Rehabilitation, 3rd Edition, Chapter 54: Cerebral Palsy, p.1249
Hip Dysplasia
Hip Subluxation
James R. Gage et al, The Identification and Treatment of Gait Problems in Cerebral Palsy, 2009, Kevin Walker, Chapter 3.4 Radiographic Evaluation of the Patient with Cerebral Palsy
Bone Deformity
Asymmetric muscle pull → deformity of the spine Kyphosis, scoliosis, rotational deformities
Comfort Tone Sitting Standing alignment Balance
Severe → respiratory function compromise
Randall L. Braddom, Physical Medicine and Rehabilitation, 3rd Edition, Chapter 54: Cerebral Palsy, p.1249
Goals of Spasticity Management Decrease spasticity Improve functional ability and independence Decrease pain associated with spasticity Prevent or decrease incidence of contractures Prevent bony deformity Improve ambulation, mobility, function Facilitate hygiene Ease rehabilitation procedures Improve ease of caregiving
Traditional Step-Ladder Approach to Management of Spasticity
Neurosurgical procedures
Orthopedic procedures
Neurolysis
Oral medications
Rehabilitation Therapy
Remove noxious stimuli
Interdisciplinary team
Patient and family Neurologist Neurosurgeon Occupational therapist Physical Therapist Physiatrist Orthopedic Surgeon Primary care physician
Rehabilitation Therapy
Stretching Weight bearing Inhibitory casting Bracing Strengthening
EMG biofeedback Electrical
stimulation Positioning
Oral Pharmacologic Management
Baclofen Diazepam Clonidine Tizanidine Dantrolene
Sodium
Allison Brashear, Elie Elovic, Spasticity Diagnosis and Treatment, 2010, Ch.15 Pharmacologic Management of Spasticity: Oral Medications
Systemic medications: limitations
Sedation Hypotension Confusion Weakness Nausea For generalized rather than focal
spasticity
Baclofen – GABA analog
Binds to presynaptic GABA-B receptors in the brainstem, dorsal horn of SC and other CNS sites
Depresses both monosynaptic and polysynaptic reflexes by blocking the release of NTS
Inhibition of gamma motor neuron activity to the muscle spindle
Because these reflexes facilitate spastic hypertonia, inhibition reduces the overactive reflex response to muscle stretching or cutaneous stimulation
Baclofen
Dystonia Baclofen some
supraspinal activity that may contribute to clinical side effects
Orally – relatively low concentrations in CSF
Side Effects Central SE – drowsiness,
confusion, attentional disturbances
Others – hallucinations, ataxia, lethargy, sedation and memory impairment
Lower seizure threshold Sudden withdrawal →
seizures, hallucinations
Baclofen
Pharmokinetics Relatively well
absorbed, peak effect 2 hrs, t ½ 2.5-4 hours
Excreted unchanged by kidney, 6-15% metabolized in the liver
Schedule 3x a day due to short half life
Considerations: Cerebral lesions more
prone to SE DOC for spinal causes
Diazepam - Benzodiazepine
MOA: does not directly bind to GABA receptors
Promotes the release of GABA from GABA-A neurons
Enhanced pre-synaptic inhibition, likely why useful in epilepsy
All CNS depressants Anti-anxiety, hypnotic,
anti-spasticity and anti-epileptic
Side Effects: Sedation and lethargy Impair coordination and
prolonged use can lead to physical/psych dependence
Effective doses vary considerably, upper doses primarily limited by SE
Rapid withdrawal → irritability, tremors, nausea and seizures
Neuromuscular Blockade
Goal: Restore balance between agonist and antagonist muscles
Why is this important? Shortened over contracted muscles → decreased muscle
growth despite linear bone growth → antagonist muscles become over-lengthened → weakness and imbalance
Contractures → bone and joint deformity → impaired function Early intervention – life long patterns of mobility Blockade of agonist muscles → improved stretch, ROM,
increased resting length, antagonist muscles can continue activity and strengthening
Ann H. Tilton, Injectable Neuromuscular blockade in the treatment of Spasticity and Movement disorders, Journal of Child Neurology, 2003:18:S50-66
Botulinum Toxin A in the management of spasticity related to CPBTX-A is currently used for children of all
ages with CP for spasticity management as determined by the practitioner
This use is off-label in the US Dysport (British formulation), approved in
UK and EU for “treatment of dynamic equinus foot deformity due to spasticity in ambulant pediatric CP patients, two years of age or older…UE spasticity post-stroke, spasmodic torticollis, blepharospasm, and hemifacial spasm”L. Andrew Koman, MD et al, Botulinum Toxin Type A in the Management of Cerebral Palsy, 2002, Wake Forest University Press
Neuromuscular Junction
NMJ – connection between the peripheral nerve and muscle fibers
Signals from the motor neuron are transmitted by the release of Ach from presynaptic vesicles
Ach crosses the synaptic cleft and attaches to post-synaptic receptors → muscle contraction
L. Andrew Koman, MD et al, Botulinum Toxin Type A in the Management of Cerebral Palsy, 2002, Wake Forest University Press
Neuromuscular Junction
Chemodenervation, The Role of Chemodenervation in the Management of Hyperkinetic Movement Disorders, We Move 2007
Selected Literature Review
1990 several studies supported the safety and efficacy of therapeutic BTX in children with CP
Goals: decreasing spastic equinus, improving crouch knee gait, decreasing hip flexion, improving hand use
Studies demonstrated changes in muscle tone (reduction in spasticity scores), improvements in ROM, and kinematic changes in gait analysis
However, functional benefit was not demonstrated in blind, randomized controlled trials
2013 Systematic review of interventions for children with CP: state of the evidence – BTX was recommended for spasticity reduction and improved walking
Iona Novak et Al, A systematic Review of interventions for children with cerebral palsy: state of the evidence, Developmental Medicine & Child Neurology, 2013
Selected Literature Review
Why is it so difficult to show functional benefit? Weakness and poor coordination co-exist in
persons with spasticity, perhaps reducing muscle overactivity is not sufficient to see a functional change in the absence of a robust post-treatment program
Variability in injection protocols patient selection Insensitive outcome measures Individualized treatment
Geoffrey L. Sheean, Botulinum treatment of Spasticity: Why is it so difficult to show a functional benefit?, Current Opinion in Neurology, 2001, 14: 771-776
BoNT
IndicationsDynamic deformity –function, pain, progressive deformityEquinus, crouch gait, pelvic obliquityUE Focal dystoniaMuscle imbalanceSialhorrhea
ContraindicationsAllergic rxn to toxin or vehicleResistance to toxin effectsSignificant muscle weaknessFailure to respond to injectionsFixed contracture
Side Effects
Most common weakness
Hoarseness or trouble talking
Dysarthria Loss of bladder
control Trouble breathing Trouble swallowing
FDA warning label and risk mitigation strategy 2009
Advise patients to seek immediate medical attention if they develop any of these symptoms
Equinus
Gastrocnemius
Soleus
Posterior tibialis
Phenol Injections
Injections of phenol were used for several decades prior to the advent of BoNT-A
Chemical neurolysis – phenol injected onto a motor nerve denervating that particular muscle
EMG stimulus to localize the target nerve
Can be injected into:Motor points: Motor neurons within a muscleMotor nerves: before they innervate a muscle
Phenol Injections
Localization of the motor neuron needs to be precise. Time required depends on which and how many nerves are injected
Typically requires multiple needle placements and burns with injection – anesthesia in sensory aware/ cognitively aware child
Dosing guidelines not well established in peds
<30mg/kg considered safe
Phenol Injections
Adverse EffectsDysesthesias most commonTypically occur if phenol injected into a sensory nerve, can result in burning sensation or hypersensitivity to touch that can last for several weeksIbuprofen, gabapentin or carbamazapine
Phenol Injections
Duration of action3-12 months, can be longer than 1 yrIncreased duration typically occurs in muscles with more accessible nerves Obturator - hip adductors Musculocutaneous nerve - biceps motor points within the medial hamstrings are more difficult to find
Discussion
Both BoNT and phenol cause selective and temporary muscular denervationTreatment for focal spasticityDifferent mechanisms of actionPhenol has proven effectiveness, immediate onset, low cost and potentially longer duration of effects, but generally less popular than BoNTTechnical challenges with administration, concerns for safety and adverse effects
Summary
Intramuscular injection of BTX-A well tolerated and efficacious - balance muscle forces across joints
Pre-defining injection goals, appropriate patient selection, and monitoring are essential
equinus deformity, managing selected upper limb deformities, adjunct in the global management of spasticity
Decrease pain related to spasticity, care-giver burden and enhance health-related quality of life
treatment philosophy includes early use in appropriate patients, to avoid contracture, delay/prevent bone and joint abnormalities, and avoid corrective surgery.
Goals of ITB Therapy
Reduce spasticity
Decrease pain associated with spasticity
Improve function Facilitate care
Intrathecal Baclofen vs Oral
ITBCSF acts at GABAB
receptor sites at spinal cordLower doses than required dailyFewer side effects
Oral baclofenLow blood/brain barrier penetration, high systemic absorption and low CNS absorptionLack of preferential SC distributionUnacceptable SE at effective doses
Plasma CSF Plasma (est) CSF
Plasma vs CSF drug levels
Penn RD, Kroin JS. Intrathecal baclofen in the long-term management of severe spasticity. Neurosurg. 1989; 4(2): 325-332.
Intrathecal Delivery
AdvantagesHigher concentration of drug in CSFDecreased SETitrateable
DisadvantagesInvasiveRisk of infectionSurgical riskDevise riskMaintenanceCost
Intrathecal Baclofen Therapy
Baclofen directly to CSF target neurons in the SC
Externally programmable, surgically implanted pump, drug delivered at precise flow rates via catheter placed in the spinal canal
Decreases hypertonicity CP, SCI, MS, Strole trauma or hypoxia
Neurophysiologic effects
Dose dependent decrease in spinal reflex response
Disappearance of tendon taps and decrease in severity of spasms
Biomechanical and neurophysiologic studies – evidence of decreased resistance to imposed stretch, decrease in EMG response
At neuronal level – baclofen acts as potent GABA-B receptor agonist
GABA-B extensively distributed in SC
Baclofen directly administered to the subarachnoid space – enhanced access to receptors → greater reflex inhibition and tone reduction
Intrathecal Baclofen
Patient Selection Grid illustration to compare
various therapies for spasticity
ITB – reversible (neural structures are not surgically altered, dose rate adjustable) and global
Pts with global or multifocal spasticity, who may benefit from adjustable (vs permanent) clinical effects are generally considered as better candidates
Grahm HK, Aoki KR, et al, Gait and Posture, vol II, 2000:67-69
Components of ITB Therapy
Accessible drug reservoir Catheter that connects
drug reservoir to the CSF Programmable –
adjustable for independent patient needs and response
External programming device
Synergistic Therapeutic effects ITB combined with other
modalities for synergist therapeutic effect
Rehabilitative therapies, oral pharmacotherapy, neurolytic procedures and muscle tendon lengthening
Combining ITB with neurolytic procedure –focal dystonic features and global hypertonicity or residual UE hypertonia
Orthopedic procedures and ITB – correction of fixed deformities in the setting of ongoing spastic hypertonia
Concomitant use – in children with CP may reduce the need for subsequent orthopedic surgery
Gertzen et al, Intrathecal baclofen infusion and subsequent orthopedic surgery in patients with Cerebral Palsy. J Neurosurg 1998;88:1009-13
Pump Placement
Ambulatory Function
1. CNS injury or disease, will ITB administration permit ambulation or improve ambulation?
2. Pts able to walk with assistance, will ITB improve their walking ability or allow them to walk independently
3. For pts who are able to walk, will they experience decline of walking ability after ITB?
Isolated case reports of regained ability to walk
Prognosis for improving ambulatory function favors those with better baseline function
Most larger studies report mixed results, some pts improving, smaller percentage significantly worsening, with the largest subgroup non-significant changes overall
Withdrawal
Abrupt cessation → withdrawal, serious and potentially fatal
“itchy, twitchy, bitchy” Pruritus, seizures,
hallucinations, autonomic dysreflexia
Exaggerated rebound spasticity, fever, hemodynamic instability and AMS
Can progress over 24-72 hrs to rhabdomyolysis (CK and phosphokinase), elevated transaminase levels, hepatic and renal failure and rarely death
Treatment: Supportive care Observation and
replacement of baclofen either enteral, or preferably through restoration of intrathecal delivery
Oral baclofen 10 -20 mg PO Q 4-6 hrs prn,
Tranxene 3.75 1-2 tabs mg Q4
Alternating every 2 hrs
ITB Therapy
ITB therapy has become a mainstay of long term spasticity management
Benefits include more potent effects, fewer systemic side effects, titratable
Disadvantages – cost, maintenance, requires vigilance, risk of malfunction of catheter pump system, withdrawal and overdose, surgical risks
Appropriate patient selection and education are critical
SDR: The Basics
First performed in 1913, but did not become popular until 1970’s
Dorsal rhizotomy became selective and outcomes evaluated since 1987
SDR involves cutting sensory nerve roots that when stimulated, trigger exaggerated motor responses as measured by EMG intraoperatively
The Procedure
Multilevel laminectomy vs. minimally invasive approaches
L1 – S1 sensory roots are identified and divided into 3-5 rootlets
Each rootlet is stimulated and responses are measured via EMG
Rootlets with the most abnormal signal are cut
Surgery takes about 4 hours
Potential Complications
Paralysis of legs Neurogenic bladder Sensory loss or dysethesias Wound infection CSF leak
SDR: Outcomes of Metanalysis Children with diplegic CP (GMFCS II-III)
received SDR + PT, or PT w/o SDR. Concluded that SDR + PT is
efficacious in reducing spasticity and has a small effect on gross motor function
McLaughlin J et al. Dev Med Child Neuro 2002, 44: 17-25.
SDR versus ITB
1-year outcomes of 71 children who underwent SDR before 1997 versus 71 children with ITB, matched by GMFCS and age
Both interventions significantly decreased Ashworth scores, increased PROM, improved function and resulted in high parental satisfaction
Compared with ITB SDR provided greater improvements in muscle tone,
PROM, and gross motor function Fewer patients in the SDR group required subsequent
orthopedic procedures No difference between the degree of parents’
satisfaction
Kan P et al. Childs Nerv Syst. 2007 Sep 5.
Outcomes
Short and long term outcomes demonstrate:Decreased spasticityImproved or unchanged strengthImproved gait patternDecreased oxygen costImproved overall function including decreased use of walking aids
Candidacy Determinations
Pre-term birth Imaging consistent with PVL Primarily spastic tone Evidence of fair selective motor control Demonstrated ability to cooperate and
follow through with rehabilitation program
Patient selection
Candidacy Determinations
Red flags Hyperextension at the knee in gait Multiple orthopedic procedures Generalized lower extremity/trunk
weakness Poor incorporation of trunk in gait Poor isolated control of lower extremity
movement Poor rehab potential (behavior, sensory
issues, cognition, social)
Summary
Spasticity: Abnormal, velocity dependent increase in resistance to passive movement of peripheral joints due to increased muscle activity
Spasticity is a type of hypertonia that is a component of the UMNS
Due to a loss of presynaptic inhibition - modulation of the afferent stimulus by the descending tracts
Positive and negative signs of the UMNS collectively cause net unidirectional movements that often persist as postures → chronic effects on soft tissue, joint structures and bone
Spasticity contributes to significant disability
Summary
CP – spasticity is a common clinical feature associated with PVL
Traditional step ladder approach to management: therapies, oral medications, injection therapies, orthopedic procedures, ITB or SDR, patient/family goals
Thank you
References
Sanger et al, Classification and Definition of Disorders Causing Hypertonia in Childhood, Pediatrics 2003
L. Andrew Koman, MD et al, Botulinum Toxin Type A in the Management of Cerebral Palsy, 2002, Wake Forest University Press
James R. Gage et al, The Identification and Treatment of Gait Problems in Cerebral Palsy, 2009, Warwick J. Peacock, Chapter 2.2 Pathophysiology of Spasticity
David Scrutton et al, Management of the Motor Disorders of Children with Cerebral Palsy, H. Kerr Graham, Ch.8 Mechanisms of Deformity
Allison Brashear, Spasticity and Other Forms of Muscle Overactivity in the Upper Motor Neuron Syndrome, Nathaniel H. Mayer, Ch.1 Positive Signs and Consequences of an Upper Motor Neuron Syndrome, 2008
Randall L. Braddom, Physical Medicine and Rehabilitation, 3rd Edition, Chapter 54: Cerebral Palsy, p.1249
James R. Gage et al, The Identification and Treatment of Gait Problems in Cerebral Palsy, 2009, Kevin Walker, Chapter 3.4 Radiographic Evaluation of the Patient with Cerebral Palsy
References Continued
MC Olsen et al, Fiber type-specific increase in passive muscle tension in spinal cord injured subjects with spasticity, Journal of Physiology, 577:339-52, 2006
Allison Brashear, Elie Elovic, Spasticity Diagnosis and Management, 2010, Ch 1.1 Why is spasticity important?
Allison Brashear, Elie Elovic, Spasticity Diagnosis and Treatment, 2010, Ch.15 Pharmacologic Management of Spasticity: Oral Medications
R. Zafonte et al, Acute care management of post-TBI spasticity, Journal of Head trauma Rehabilitation 19(2):89-100
Stretch Reflex Pathway
1. Muscle spindle stretch receptor detects changes in muscle length
2. Myelinated sensory afferent neuron
3. The synapse4. Homonymous motor
neuron5. Muscle innervated by the
motor neuron
L. Andrew Koman, MD et al, Botulinum Toxin Type A in the Management of Cerebral Palsy, 2002, Wake Forest University Press
Stretch Reflex Pathway
Stretch detected by the muscle spindle → CNS by Ia afferents through the dorsal root, connections in the SC:
Homonymouos motor neuron monsynaptic excitatory connection with alpha motor neuron
Heteronymous motor neuron monosynaptic excitatory connections to synergist
Ia inhibitory interneuron projects to alpha motor neurons of antagonist muscles
L. Andrew Koman, MD et al, Botulinum Toxin Type A in the Management of Cerebral Palsy, 2002, Wake Forest University Press
Stretch Reflexes
Reciprocal inhibition – normal pattern simultaneous excitation of agonist and inhibition of antagonist motor neuron
Co-contraction – inappropriate activation of antagonist muscles during voluntary contraction of agonist muscles, superimposed stretch reflex activity – stretching antagonists during movement
joint stability (ie eccentric contraction of the triceps during biceps activation to control flexion of the elbow)
Activated and deactivated at the cortical level
May represent an impairment of supraspinal control of reciprocal inhibition
L. Andrew Koman, MD et al, Botulinum Toxin Type A in the Management of Cerebral Palsy, 2002, Wake Forest University Press
Traditional Step-Ladder Approach to Management of Spasticity
Neurosurgical procedures
Orthopedic procedures Neurolysis/
Chemodenervation Oral medications Rehabilitation Therapy Remove noxious stimuli
Common Patterns of Motor Dysfunction in CP
Most common pattern of spasticity in CP:Upper Extremity Internal rotation of shoulder Elbow flexion Forearm pronation Wrist and finger flexion Thumb in palm
Lower Extremity Hip flexion and adduction Knee flexion Hindfoot valgus Forefoot pronation
Spasticity Associated with CP in Children, Guidelines for the use of Botulinum Toxin A, L. Andrew Koman et al, Pediatric Drugs, 2003, 5 (1) p.11-23
Windswept Deformity
Possible Advantages of Spasticity Maintains muscle tone Helps support circulatory function May prevent formation of deep vein
thrombosis May assist in function
Diazepam - Benzodiazepine
MOA: does not directly bind to GABA receptors
Promotes the release of GABA from GABA-A neurons
Enhanced pre-synaptic inhibition, likely why useful in epilepsy
All CNS depressants Anti-anxiety, hypnotic,
anti-spasticity and anti-epileptic
Side Effects: Sedation and lethargy Impair coordination and
prolonged use can lead to physical/psych dependence
Effective doses vary considerably, upper doses primarily limited by SE
Rapid withdrawal → irritability, tremors, nausea and seizures
Clonidine Central Alpha Adrenergic Agent
Monoamines are widely distributed in CNS
Important role as modulators of spinal neuron excitability
Modulate sensory inputs via presynaptic inhibition of spinal afferent inputs
Also direct inhibitory effect on interneurons
When descending pathways from the brainstem to SC are disrupted, there is a reduction in the NE → increased hypertonia
Clonidine Central Alpha Adrenergic Agent
Centrally acting apha-2 receptor agonist → antispasticity effects
Also alpha-1 receptor agonist → antihypertensive effects
profound nociceptive pain reliever
central sympatholytic effects on BP
Therefore little effect on the BP of persons with complete SCI, but can lower the BP for those with incomplete injuries
Side Effects BP Bradycardia, dry
mouth, ankle edema, depression
Tizanidine – Central Selective Alpha-2 adrenergic agonist
Structurally related to clonidine
1/10 to 1/15 the potency of clonidine in lowering BP or slowing HR
Preference for alpha-2 receptors
Active at both segmental spinal and supraspinal levels in both motor and sensory pathways
No effect on monosynaptic reflexes – standard DTR
No activity at NMJ, no direct effect on skeletal muscle fibers, does not cause any muscle weakness
Extensive first pass metabolism
Tizanidine – Central Selective Alpha-2 adrenergic agonist
Side Effects: Sedation, asthenia,
dizziness, dry mouth Very little hypotension or
bradycardia at clinically relevant doses, virtually none in the lower half of the dose range
Rebound HTN Hallucinations and
nightmares GI - constipation
Precautions Chronic use –
potential for hepatotoxicity
Liver enzymes should be periodically checked as dose is increased
Dantrolene Sodium Direct Acting Muscle Relaxant
No centrally acting SE Acts peripherally by
decreasing release of calcium from SR→ uncoupling electrical excitation from contraction and decreasing the force of contraction
Affects intrafusal and extrafusal fibers, reducing spindle sensitivity
Action is specific for skeletal muscle and affects reflex contractions or spasticity more than voluntary contraction
Weakness -twice the voluntary effort is required to maintain a desired muscle tension
Dantrolene Sodium Direct Acting Muscle Relaxant
Because of propensity to cause weakness several reports advocate limiting use in CP, spasticity of spinal origin and MS pts
1980 AMA “Dantrolene should be used primarily in non-ambulatory pts and only if the resultant decrease in spasticity will not prevent the patient from functioning”
Recent report has recommended as a first line agent in the treatment of spasticity after TBI, especially in the acute setting, as it exhibits minimal cognitive effects and may not interfere with neural recovery
R. Zafonte et al, Acute care management of post-TBI spasticity, Journal of Head trauma Rehabilitation 19(2):89-100
Dantrolene Sodium Direct Acting Muscle Relaxant
Risks: Significant increased risk of
hepatotoxicity, 1% overall, especially with doses over 400mg
Active hepatic diagnosis contraindication RF: female, >35, polypharmacy LFTs need to be monitored, lowest
optimally effective dose should be prescribed
History of Botulinum Toxin A
1875 – Claude Bernard – “poisons can be employed as means for the destruction of life or as agents for the treatment of the sick”
This concept was first used regarding CP in the 20th century
Tardieu – Alcohol as a muscular neurolytic agent, 1970s
Carpenter (Richmond CP Hospital) – 45% alcohol and bupivicaine
1897 van Ermengem (Belgium) identifies Clostridium botulinum, obligate anaerobe bacillus
WWII - Schantz – extensive research identifies the toxins produced by C. botulinum
7 serotypes purified and identified (A-G)
Emphasis on type A, the most potent biologic toxin known
Techniques developed by Schantz and Lammana → commercial preparations available today
Lamanna – produced crystalline BTX-A, forerunner of Oculinum
British military → British formulation BTX-A, DysportL. Andrew Koman, MD et al, Botulinum Toxin Type A in the Management of
Cerebral Palsy, 2002, Wake Forest University Press
History of Botulinum Toxin A
1960s – Alan B. Scott, Opthalmologist in SF, toxin as therapeutic agent for strabismus
1981 – BTX-A in humans dystonia and other movement
disorders Schantz type A toxin, Oculinum used in
these protocols under the oversight of the FDA
1988 – Koman et al, first clinical trial for treatment of spasticity in CP
Oculinum, preliminary results 1993 Subsequent trials, including large
multi-center placebo controlled trials → efficacy of BTX-A for managing equinus foot deformity (Koman 2000)
Since then – BoNT → safe and effective for a large number of neurologic and non-neurologic diseases
regarding CP, additional studies confirmed indication for:
UE CP (Corry 1997, Fehlings 2000)
Analgesia after hip surgery (Barwood 2000)
Crouched gait (Molanaers 1999) Alternative to serial casting
(Corry 1998) Hamstring spasticity (Corry
1999)
L. Andrew Koman, MD et al, Botulinum Toxin Type A in the Management of Cerebral Palsy, 2002, Wake Forest University Press
History of Botulinum Toxin A
1989 – Allergan purchases the Oculinum in stock and the process to produce new bulk source of toxin from Dr. Scott
FDA approves BTX-A for strabismus, blepharospasm, and hemi-facial spasm (>12)
1992 – registers tradename BOTOX
2000 – BTX-A and B (Myobloc/Neurobloc, Solstice) FDA approval for dystonia
2002 – FDA approval for cosmetic use
2004 – FDA approval for hyperhidrosis
2010 – approval for UE spasticity in Adults
Acceptance for treatment of spasticity is growing, with approvals in many European countries
Continued clinical trials for expanding indications
L. Andrew Koman, MD et al, Botulinum Toxin Type A in the Management of Cerebral Palsy, 2002, Wake Forest University Press
Summary
Intramuscular injection of BTX-A is well tolerated and efficacious if used to balance muscle forces across joints in the absence of fixed contractures
Pre-defining injection goals, appropriate patient selection, and monitoring are essential
It is well documented as a treatment option for equinus deformity, managing selected upper limb deformities, and is valuable as an adjunct in the global management of spasticity
It can diminish pain related to spasticity, decrease care-giver burden and enhance health-related quality of life
treatment philosophy includes early use in appropriate patients, to avoid contracture, delay/prevent bone and joint abnormalities, and avoid corrective surgery.