Spasticity Research Advances Treatment Options

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From Biomechanics Magazine March 2005

Spasticity Research Advances Treatment Options

Spasticity therapy likely inhibits tone both indirectly, by altering

properties of muscle, and directly, through neuromodulation.

By: Pierson, MD, PT

Central nervous system injury results in upper motor neuron syndrome.

Included in this syndrome are both negative (weakness) and positive

(spasticity) motor phenomena. Spasticity is defined as a velocity-

dependent increase in resting muscle tone, manifested by a spastic

catch as the limb is moved through its range, accompanied by

increased or " disinhibited " deep tendon and superficial reflexes. It

may have both tonic (sustained extensor or flexor posturing) and

phasic (clonus, spasms) qualities. As Denny-Brown wrote, " Spasticity

is not a single entity. It has different qualities and distribution,

depending on the loss of one or another of the many factors concerned

in the initiation of movement. " 1 Spasticity does not cause but is the

result of lost volitional movement. Lesions of the descending

inhibitory neural pathways release flexor spasms and increase

proprioceptive stretch reflexes (Table 1).

Delivering functional outcomes

Identifying the components of the motor disability that relate to

spasticity, the selection of treatment targets and effective

treatment delivery, and agreement between patient and physician on

treatment expectations are the primary determinants of positive

functional outcomes in persons with spasticity.2 Ill-considered

treatment goals such as the recovery of normal control of movement

have fueled the argument over whether the treatment of spasticity is

helpful or not.3-6 Appropriate selection of patients and treatment

strategies hinges on a thorough understanding of spasticity and its

contribution to functional disability. Allied treatments in the areas

of pain and continence management, therapeutic exercise, orthoses,

casting, and life skill training are all potential nonpharmacologic

interventions to be considered in concert with medical management.

Effective relief of pain, avoidance of noxious sequelae such as

incontinence and constipation, and appropriate positioning of limbs

to avoid patterns that reinforce abnormal tone all benefit

normalization of spasticity.7

Targeting positive phenomena, such as flexor reflexes that interfere

with gait, transfers, or dressing, can be a rewarding treatment

experience. The multiple sclerosis or spinal cord injury patient with

disinhibited bladder spasms becomes more socially independent when

the spasms are reduced. However, treatment that aims to reduce

overactive deep tendon reflexes or just " relax " a useless hand is

unlikely to produce substantial changes in active movement or

functional independence. Evidence in clinical trials suggests that

more targeted, thoughtful, and stratified studies on the benefits of

spasticity treatment are in order.5

There is no clear evidence that treatment of spasticity via the

different pharmacologic agents and physical modalities inhibits tone

either directly, through neural modulation, or indirectly, through

altering the musculoskeletal or viscoelastic properties of muscle. It

is likely that both mechanisms are at work, depending on the

treatment modality selected and the individual qualities of the

clinical problem.8

Intrathecal baclofen treatment has been linked to functional

improvement in terms of motor and ADL (activities of daily living)

subscores on the FIM (Functional Independence Measure) in low-

functioning quadriplegics, but the improvement was seen in passive

goals, such as ease of perineal access.9 Although tone intensity,

spasm frequency, and ease of caregiving goals all showed improvement

in studies of botulinum toxin type A (Botox) and tizanidine, few

studies to date have demonstrated enhanced voluntary motor control

through objective measures.10-12 One study13 showed improved active

control with Botox, but in that study the change depended on the

degree of spontaneous motor recovery achieved prior to Botox

treatment (Table 2).

Factors influencing treatment selection

A number of factors contribute to the decision of what treatments

will be most beneficial for a particular patient.

Distribution of the spasticity. The determination of tone

distribution as relatively focal and problematic or evenly

distributed throughout large regions of the body should guide the

decision-making process for treatment selection. Tone that is

disproportionately out of control in one region or focus may be more

effectively managed with botulinum toxin or phenol blocks than with

oral medications. These methods have few systemic effects when used

properly and are selective to the nerve distribution or muscles

injected.

Etiology of spasticity. Understanding the etiology of the spasticity

is important for treatment selection and predicting response. Single

epochs of injury, such as infarct or hemorrhage, lead to a

catastrophic insult and recovery profile of gradual motor improvement

followed by leveling off of motor recovery and the development of

spasticity. Deficits then become chronic and associated with varying

degrees of disability. Progressive illnesses like MS, ALS

(amyotrophic lateral sclerosis), and hereditary spastic paraparesis

may require periodic reassessments and ongoing active management of

spasticity and weakness as they change and progress over time.

Lesion location. Anatomic location of disease also affects the

intensity and quality of spasticity. It is well known that traumatic

SCI presents with severe spasm frequency and intensity of tone, while

progressive myelopathy or spasticity of cerebral origin tends to

demonstrate less intensity and spasm frequency.

Duration of spasticity. Long-standing spasticity inadequately treated

may lead to underlying contracture formation, reinforcement of

abnormal patterns of movement, and learned nonuse.14 Heterotopic bone

formation may also complicate the treatment of spasticity.15

Differentiating between soft tissue or bony blocks and more dynamic

impediments (i.e., spasticity) to range of motion may be aided by

manipulation under anesthesia.16 Prior treatment with orthopedic

surgery, phenol block, or botulinum toxin may have persistent

effects, such as altered biomechanics, that can interfere with future

treatments.17. Tendon transfer, in particular, can lead to unexpected

difficulty in further spasticity treatments, particularly selective

muscle treatment with botulinum toxin or motor point block.

Static deformities/presence of contracture. Contractures, regardless

of degree, are defined as fixed limitations of movement within the

arc of a joint's range of motion. There is no definitive cutoff or

percentage of range for which spasmolytic therapy should not be

considered. Rather, the contracture has to be considered in the

context of the patient's situation. It must be kept in mind that

abnormal motor control-including increased resting tone, disinhibited

spinal and brainstem reflexes, and other phenomena such as

heterotopic bone formation and skeletal injury-created those

contractures to begin with. It may therefore be wise to combine

spasmolytic therapies with a surgical or physical intervention (such

as serial casting) in an effort to correct not only the contracture,

but also the processes that created it in the first place. Surgical

release alone may temporarily solve the deformity, but contracture

may recur unless underlying abnormal movement patterns are corrected.

Prognostic indicators

Clinical markers can suggest who might benefit from spasticity

treatment. Markers include tone intensity, comorbid deficits, sensory

loss, postural dyscontrol and cognitive impairment, and level of

motor function prior to treatment.10 Good responders in the pediatric

cerebral palsy population include those with higher Ashworth scores,

less active function, and inability to independently ambulate.

Patient age, dose of medication, and type of cerebral palsy had no

effect in a 2002 study.18

One literature review6 noted that the adult studies contained

unsatisfactory groupings by diagnosis and functional prognosis of

patients. Two patient subsets were found to potentially benefit

functionally. Group one had mild spasticity and the potential for

volitional extension. Group two had severe spasticity that prevented

adequate positioning and passive access to the arm and hand (Table

3).

New developments in treatment strategies

A deeper understanding of the causes and course of spasticity is

directing the search for new treatment options.

Oral medications. Oral medications have been available for some time,

but expert utilization of these medications comes with practitioner

experience. Although the Food and Drug Administration's approved

maximum dose of baclofen is 80 mg/day, case reports in the literature

have used higher doses, up to 240 mg/day.19

Tolerance and effectiveness seem to be the limiting factors in the

upward dosing of the medication. In addition, abrupt withdrawal will

cause significant side effects, including rebound spasticity and

seizure, so the drug should always be tapered away. Baclofen cannot

be dialyzed and should be completely avoided in patients with

dialysis-dependent renal failure. As intimated previously, it has

never shown a functional benefit for ambulation and may increase

weakness in persons with MS.20

Clonazepam can be effective as an analgesic in addition to its

spasmolytic effect. Clinical observation suggests it can be

particularly helpful in persons with complex regional pain syndrome-

associated spastic hemiplegia. epam has been shown to be

effective for athetosis as well as for spasticity in patients with

cerebral palsy, and multiple low doses spaced across the day may be

of benefit for treating spasticity without the sedative effect of

higher but less frequent dosing.21 Clorazepate dipotassium has been

reported to be less sedating than other benzodiazepines and more

effective in reducing tone.22

Dantrolene sodium is worth considering, though hepatotoxicity was

reported in 1.8% of patients on dantrolene for more than two

months.23 Symptomatic hepatitis was seen in 0.6% and fatal hepatitis

in 0.3%. The risks were greatest for female patients over age 30

taking the drug for more than 60 days, on a total dose of more than

300 mg per day, or on polypharmacy. Dantrolene is potentially useful

in all types of CNS conditions and approved for all of them. Its

effect was least robust for patients with MS and most robust for

those with SCI.24,25 It appears to be used more commonly in children

than adults and has been shown to be more effective in cerebral

spasticity than spinal spasticity.26-29

The mechanism of action for lamotrigine is unknown, but it is thought

to act at voltage-sensitive Na+ channels to stabilize neuronal

membranes. In animal models of epilepsy, it reduces the release of

excitatory neurotransmitters.30 It reduced pain and muscle spasm in

one case report and in eight patients with MS.31,32

Tizanidine hydrochloride is a central alpha 2 adrenergic agonist that

inhibits presynaptic release of aspartate and glutamate, enhances

glycine action, decreases tonic stretch and polysynaptic reflexes,

and has an antinociceptive effect in animal models.33 There is a 5%

incidence of elevated liver function. This incidence is two and a

half times greater than that reported for dantrolene.34 Liver

function tests should be monitored at one, three, and six months

after starting tizanidine.

There is ample evidence that gabapentin, which is FDA approved for

seizure but not spasticity, is effective in treating spasticity, but

its mechanism of action is unknown. It is effective for treating MS

phasic spasms,35 and even improved the Ashworth and Extended

Disability Status scores in MS patients.36,37 Choreoathetosis was

reported as an adverse side effect in one case report.38

Botulinum A toxin. As an effective reduction strategy for focal

increases in tone, there is abundant evidence in the spasticity

literature for the use of Botox. It is well known that Botox acts to

inhibit the release of acetylcholine quanta from the presynaptic

terminal, thereby limiting muscle contraction. This is the presumed

mechanism of tone reduction.

Electrophysiologically, Botox decreases the amplitude of the compound

motor action potential (CMAP). Its paralytic effect is enhanced if

toxin is placed close to the motor endplate.39 Effectiveness is

increased in actively contracting muscles, as has been demonstrated

with the use of electrical stimulation.40

Gracies reviewed other possible mechanisms by which Botox might

reduce spasticity.41 These include decreased resistance to passive

motion, enhanced active movement in paretic limbs, blockade of

spastic cocontraction, spastic dystonia and muscle shortening, and

improved strength in the antagonist. Botox is theorized to act

directly upon central synapses to reduce motorneuron excitability,

Renshaw inhibition of the target muscle, and presynaptic inhibition

of the antagonist muscle. It can spread to nearby and remote muscles

and thus may achieve further relaxation in that indirect way.

There have been more than 10 randomized, double-blinded trials of BTX-

A in adult-onset spasticity. The etiologies of the spasticity varied,

and both upper and lower limbs have been treated in these studies.

Although the outcome measures used in each study differ slightly,

reported results in tone reduction were significant. Improved gait

has been reported in open trials, but not in the few double-blinded

trials in which it was an endpoint. Other active functional gains

have been less consistently demonstrated.

The cost of treating focal spasticity was investigated with a

physician survey in a case study format.42 Mean costs were determined

for each treatment scenario, and per-case costs appeared to be lower

when Botox, rather than oral medication, was used in the arm

following stroke. There was a trend towards lower costs when it was

used instead of oral baclofen in the leg after stroke and in the arm

after brain trauma.

Intrathecal baclofen. Experience with intrathecal baclofen continues

to grow since its FDA approval for spinal cord spasticity in 1993.

Its use was expanded to cover spasticity of cerebral origin in

1996.43

The maintenance phase of therapy is critical to the success of the

intervention. Medication refills can be carried out every eight to 12

weeks, and the latest model contains 40 cc of solution, thereby

allowing maximal intervals between refills. The concentration can be

adjusted as needed, though concentrations higher than 2000 mg/cc may

precipitate in the pump. Once the dosage is stabilized, home health

agencies can perform the refills and save travel expenses for the

patient. Effective dose titration precludes rapid change every 24

hours after implant, even though it is allowed by the manufacturer,

because the response is clinically difficult to assess in personal

experience. It is wise to consider slower changes one to two weeks

apart. Abrupt discontinuation of oral baclofen after pump

implantation in our experience has caused withdrawal reactions severe

enough to require hospitalization and should be avoided. Once the

pump has been implanted, patients' oral dose of baclofen (assuming

they are on it) is decreased as the ITB dose is gradually increased.

A physician evaluation should be made at least every six months after

dose stabilization has been accomplished.

Of the options for spasticity treatment, evidence suggests ITB is

most likely to promote functional gains. Patients with MS and SCI

achieved independent bladder care/dressing after six months of

therapy, and skin integrity was improved in three of three patients

in the same cohort.44 Orthopedic surgery planned in 28 of 28 patients

with cerebral palsy subsequent to ITB was no longer needed after

implant.45 Meythaler demonstrated significant reductions in joint

contractures in traumatic brain injury patients treated with ITB.46

The costs of treating contractures in children with CP were lower

with ITB than physical therapy and orthopedic surgery.47 Ambulation

and FIM score improved after stroke-induced spasticity was treated

with ITB. Indirect functional improvement occurred through ease of

caregiving after implantation.48,49

Summary

Medical interventions for spasticity should be considered when

physical measures such as exercise, positioning devices, and

functional electrical stimulation are not effective enough. If

current management is not achieving goals and the patient is not

gaining function-or worse, is losing ground despite treatment-

referral should be considered for one or more of the treatments

discussed above.

When there is no gain and/or pain with ROM, practitioners should

first eliminate the possibility of heterotopic bone formation, but

then spasticity treatment should be initiated. If a patient is unable

to tolerate casts or splints, or requires significant intervention

such as stretching multiple times per day to maintain range, these

pharmaceutical interventions should be part of the initial treatment

considerations for spasticity following upper motor neuron injury.

Pierson, MD, PT, is staff neurologist and vice president of the

Drake Center in Cincinnati.

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TABLE 1. common features of spasticity

-Resistance to passive movement

-Increased, or 'disinhibited,' tendon reflexes

-Multiple lesion combinations recover with a spasticity component

-No solitary lesion causes spasticity

Negative Motor Performance Factors

-Loss of pyramidal function with resulting weakness

-Loss of visually directed movement as feedback

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Table 2. Summary of functional change in spasticity treatment studies

Subsets of functional measures show change

-Less complex vs. more complex

Change seen in subsets of patient populations

-More severely vs. less severely affected patients

-More upper limb and combination studies than lower limb studies

Many studies didn't even measure functional change as an

outcome 'Function' not consistently defined

-Active vs. passive

Consideration of adjunct therapies and their influence on outcomes

inconsistent

-Task-specific training, FES, etc.

Consideration of the effect of ongoing development or

recovery/degeneration inconsistent

-Natural history of the condition not considered

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Table 3. Strategies to achieve a positive outcome

Intervene at the right time

Relieve pain

Avoid further complications

Improve current function

Passive function

- Caregiver ease

- Seating/positioning

Active function

- Isolated motor control

- Position the limb for massed practice