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Dx Spasticity Treatment:


"Spasticity is a chronic disorder of muscle stiffness, control, and function resulting from a variety of insults to the CNS, including injury, stroke, multiple sclerosis, and cerebral palsy. With appropriate neurologic, surgical, rehabilitative, and psychosocial interventions, the many debilitating manifestations of spasticity can be treated, thus greatly improving the quality of life of the affected individual. "

Introduction and Pathophysiology:
Spasticity has been defined as an increase in muscle tone due to hyperexcitability of the stretch reflex and is characterized by a velocity-dependent increase in tonic stretch reflexes.

Spasticity usually is accompanied by paresis and other signs, such as increased stretch reflexes, collectively called the upper motor neuron syndrome. Paresis particularly affects distal muscles, with loss of the ability to perform fractionated movements of the digits. The upper motor neuron syndrome results from damage to descending motor pathways at cortical, brainstem, or spinal cord levels, and spasticity evolves in the days and weeks after injury. When the injury that leads to spasticity is acute, muscle tone is flaccid with hyporeflexia before the appearance of spasticity. The interval between injury and the appearance of spasticity varies from days to months according to the level of the lesion. In addition to weakness and increased muscle tone, the signs in spasticity include clonus, the clasp-knife phenomenon, hyperreflexia, the Babinski sign, flexor reflexes, and flexor spasms.

The pathophysiologic basis of spasticity is incompletely understood. The changes in muscle tone probably result from alterations in the balance of inputs from reticulospinal and other descending pathways to the motor and interneuronal circuits of the spinal cord, and the absence of an intact corticospinal system. Loss of descending tonic or phasic excitatory and inhibitory inputs to the spinal motor apparatus, alterations in the segmental balance of excitatory and inhibitory control, denervation supersensitivity, and neuronal sprouting may be observed. Once spasticity is established, the chronically shortened muscle may develop physical changes such as shortening and contracture that further contribute to muscle stiffness.

Selective damage to area 4 in the cerebral cortex of primates produces paresis that improves with time, but increases in muscle tone are not a prominent feature. Lesions involving area 6 cause impairment of postural control in the contralateral limbs. Combined lesions of areas 4 and 6 cause both paresis and spasticity to develop. Physiologic evidence suggests that interruption of reticulospinal projections is important in the genesis of spasticity. In spinal cord lesions, bilateral damage to the pyramidal and reticulospinal pathways can produce severe spasticity and flexor spasms, reflecting increased tone in flexor muscle groups and weakness of extensor muscles.

The pathophysiologic mechanisms causing the increase in stretch reflexes in spasticity also are not well understood. Unlike healthy subjects, in whom rapid muscle stretch does not elicit reflex muscle activity beyond the normal short-latency tendon reflex, patients with spasticity experience prolonged muscle contraction when spastic muscles are stretched. After an acute injury, the ease with which muscle activity is evoked by stretch increases in the first month of spasticity; then, the threshold remains stable until declining after a year.

During the development of spasticity, the spinal cord undergoes neurophysiologic changes in the excitability of motor neurons, interneuronal connections, and local reflex pathways. The excitability of alpha motor neurons is increased, as is suggested by enhanced H-M ratios and F-wave amplitudes . Judged by recordings from Ia spindle afferents, muscle spindle sensitivity is not increased in human spasticity. Local anesthetic injections into spastic muscles in man can diminish spasticity by an effect on gamma motor neurons. Renshaw cells receive inputs from descending motor pathways, and recurrent collateral axons from motor neurons activate Renshaw cells, which inhibit gamma motor neurons. Renshaw cell activity is not reduced significantly in spasticity. Reciprocal inhibition between antagonist muscles is mediated by the Ia inhibitory interneuron, which also receives input from descending pathways. Altered activity in Ia pathways has been shown in spasticity. Inhibitory interneurons acting on primary afferent terminals of the alpha motor neuron also influence the local circuitry. Finally, plasticity and the formation of new aberrant connections in the CNS is another theoretical explanation for some of the events in spasticity.

Nielson et al have reviewed changes in cellular properties and transmission in a number of spinal reflex pathways, which may explain the increased stretch reflex excitability. This review focuses mainly on results derived from the use of noninvasive electrophysiological techniques, which have been developed during the past 30 years to investigate spinal neuronal networks in human subjects; work from animal models is also considered.

Clinical Considerations:
Spasticity is associated with some very common neurological disorders: multiple sclerosis, stroke, cerebral palsy, spinal cord and brain injuries, and neurodegenerative diseases affecting the upper motor neuron, pyramidal and extrapyramidal pathways. While the incidence of spasticity is not known with certainty, the condition likely affects over half a million people in the United States and over 12 million worldwide.

Rizzo et al have analyzed a cross-sectional database of 17,501 patients with multiple sclerosis (NARCOMS registry). Of these patients with multiple sclerosis, 15.7% had no spasticity, 50.3% had minimal to mild spasticity, 17.2% had moderate spasticity, and 16.8% had severe spasticity.

A review of spasticity after stroke has shown that it affects less than one quarter of stroke victims. Ninety-five patients were studied immediately after and 3 months after a first-time stroke. Seventy-seven (81%) were initially hemiparetic, of whom 20 had spasticity. Modified Ashworth score was grade 1 in 10 patients, grade 1+ in 7 patients, and grade 2 in 3 patients. At 3 months, 64 patients (67%) were hemiparetic and 18 were spastic, reflecting 5 whose tone normalized and 3 who became spastic in the interim. Spasticity can have a devastating affect on function, comfort, and care delivery, and it also may lead to musculoskeletal complications. Spasticity does not always require treatment, but when it does, a wide range of effective therapies—used alone or in combination—are now available.
Assessment of spasticity includes identifying which muscles or muscle groups are overactive and determining the effect of spasticity on all aspects of patient function, including mobility, employment, and activities of daily living (ADLs). Physical and occupational therapists are vital members of the team called in to assess and treat the patient with spasticity. Identification of the spastic muscles can be a complex task, since many muscles may cross the joint involved, and not all muscles with the potential to cause deformity will be spastic. Electromyography and diagnostic blocks with local anesthetics can be used to test hypotheses regarding the deformity and provide information for long-term denervation treatments. Studies have been made of assessment tools, such as the Lateral Step Up test for adolescents with cerebral palsy and the Modified Modified Ashworth Scale for the assessment of upper-limb muscles.

In an infant, spasticity is generally manifested by increased muscle tone. Abnormalities of muscle tone are most readily documented by assessing tone of supination and pronation of the upper extremities and dorsiflexion and plantar flexion of the lower extremities. In newborns or small infants, spasticity of the lower extremities becomes evident when the examiner suspends the infant by the feet, upside down, and each lower extremity is released in turn. In spasticity, the released lower extremity remains “hung up.”

Spasticity of the upper extremities:
Muscles that often contribute to spastic adduction/internal rotation dysfunction of the shoulder include latissimus dorsi, teres major, the clavicular and sternal heads of pectoralis major, and subscapularis. In the flexed elbow, the brachioradialis is spastic more often than the biceps and brachialis. In the spastic flexed wrist, carpal tunnel symptoms may develop. Flexion with radial deviation implicates flexor carpi radialis.

In the clenched fist, if the proximal interphalangeal (PIP) joints flex while the distal interphalangeal (DIP) joints remain extended, spasticity of the flexor digitorum superficialis (FDS) rather than the flexor digitorum profundus (FDP) may be suspected. A combined metacarpophalangeal flexion and PIP extension also may occur. A patient may be spastic in only one or two muscle slips of either FDP or FDS. Neurolysis with botulinum toxin is beneficial for spasticity of the intrinsic hand muscles because of their size and accessibility. Spasticity of the lower extremities:
Spastic deformities of the lower limbs affect ambulation, bed positioning, sitting, chair level activities, transfers, and standing up. Equinovarus is the most common pathologic posture seen in the lower extremity. Equinovarus is a key deformity that can prevent even limited functional ambulation or unassisted transfers. Chemodenervation of the extensor hallucis longus (EHL) for striatal toe (ie, hitchhiker's great toe) may reveal co-contraction of the flexor hallucis longus (FHL), which also requires treatment. Overactivity of the hamstrings may indicate that knee stiffness is a defense against knee flexion collapse.

Diagnostic motor point block may reveal whether weakening strategies are indicated for reducing knee stiffness. In the flexed knee, overactivity in the hamstrings is more often medial than lateral. Hamstring contracture is likely to occur from chronic overactivity. Adductor and hip flexor spasticity often coexist and may lead to pelvic obliquity. Complex hip and knee deformities may require a combination of neurolytic and chemodenervation agents. Physical and occupational therapy evaluation:
Physical and occupational therapists play important roles in the management of patients with spasticity. Patients who are candidates for treatment with botulinum toxin injections need baseline evaluations that include areas beyond the muscles being injected, since reduction of local spasticity may lead to more widespread functional changes. Assessments should include evaluation of tone, mobility, strength, balance, endurance, and the need, if any, for assistive devices. A videotape of the baseline examination is of considerable help.

After injection, therapeutic interventions have multiple aims, including strengthening and facilitation, increasing range of motion, retraining of ambulation and gait, improving the fit and tolerance of orthoses, and improved functioning in ADLs. Decreased spasticity and improvements in range of motion and strength have considerable implications for activities such as dressing, bathing, feeding, and grooming.

Standardized assessments for motor control that can be tested for validity and reliability have yet to be devised for use in the patient with neurological deficits. Because the assessment measures themselves may influence tone, running the testing series in the same order each time is important. Muscle tone should be assessed before any functional assessments. The upper extremity is evaluated in the sitting position, and the shoulder rotators, pronators, supinators, wrist flexors/extensors, and finger flexors are assessed with the elbow in 90° of flexion. Other muscle groups are assessed with the elbow extended.

The patient is placed in the supine position for assessment of all muscle groups of the lower extremity except the knee flexors. The patient is then moved to the prone position for assessment of the right, then the left, knee flexors. The Modified Ashworth Scale assessment should be followed by the Bilateral Adductor Tone measure, if required. Goniometric measurements for active and passive ranges of movement follow muscle tone assessment.

Outcome measures:
Measures designed to assess technical and functional outcomes, patient satisfaction, and the cost-effectiveness of treatment can be used to evaluate status and track changes in spasticity management. While double-blind, placebo-controlled studies remain the standard for clinical testing, the single-subject design is a useful alternative in many treatment protocols. Development of validated and reliable outcome measures for spasticity rehabilitation has been hampered by the difficulty of quantifying functionally important parameters such as pain, ease of care, and mobility. Because no single tool can measure the many types of changes possible with treatment, the choice of assessment tools must be based on the functional changes expected from the treatment. A wide range of assessment tools have been reviewed critically for their sensitivity, reliability, validity, and ease of administration.

Most spasticity rating scales are ordinal. Equal intervals between units on an ordinal scale cannot be assumed automatically. Non-interval scaling can be addressed using Rasch analysis, though care must be taken to avoid inappropriate extrapolation. Ratio scales, such as before/after measurements, are useful, reliable, and easy to administer. A technical outcome is an expected change in a measurable variable, based on the technical goals of a procedure. A functional outcome is an expected change in a patient's ability to perform a task. Patient satisfaction measures are concerned with both the result and the process of care delivery. The choice of test must be based on the change expected, and the sensitivity must match the range of expected improvement. Otherwise, the results will be meaningless. Changes in technical measures of spasticity may not correlate well with clinical improvement.

Because agreement among clinical spasticity scales is poor, a comprehensive set of tests is needed to evaluate the effects of treatment. Some of the more commonly used spasticity rating scales are the Spasm Frequency Scale, the Medical Research Council Motor Testing Scale, the Modified Ashworth Scale, the Adductor Tone Rating, and the Global Pain Scale.

Burridge et al have discussed the theoretical and methodological considerations in the measurement of spasticity.[20] They analyzed the measurement of spasticity in the clinical and research environments; made recommendations based on the SPASM reviews of biomechanical, neurophysiological, and clinical methods of measuring spasticity; and indicated future developments of measurement tools. They concluded that methods appropriate for use in research, particularly into the mechanism of spasticity, do not often satisfy the needs of the clinician and the need for an objective but clinically applicable tool is still needed; therefore, standardized protocols for "best practice" in the application of spasticity measurement tools and scales are needed.

Treatment overview:
A variety of strategies are available for the management of spasticity. The treatment of children with spasticity has been the subject of innumerable publications, most of them surprisingly uncritical and devoid of controls. A vital preliminary consideration is the indication for treatment and the expectations from such treatments. For example, in a patient who can walk, a reduction of leg muscle tone may worsen mobility if tone compensates for leg weakness, allowing the patient to stand. Loss of manual dexterity or weakness also does not improve by reducing muscle tone, and therefore treatment of spasticity may not lead to an improvement in function.

Therefore, clearly identifying the goals of the patient and caregiver is vital. Tizard proposes that before treatment is initiated, the following should be considered:
(1) does the patient need treatment?,
(2) what are the aims of treatment?,
(3) do the patient and caregivers have the time required for treatment?, and
(4) will treatment disrupt the life of the patient and caregivers? Specific functional objectives in the management of spasticity include strategies aimed at improving gait, hygiene, ADLs, pain, and ease of care; decreasing the frequency of spasm and related discomfort; and eliminating noxious stimuli.

Various means are available for the treatment of spasticity. Physiotherapy is the most traditional form of treatment and is the principal nonsurgical treatment of spasticity in children. A variety of oral medications have been proposed. Other treatments include neurolysis with the neurotoxins phenol and alcohol, intrathecal baclofen, intramuscular botulinum injection, and surgical treatments, along with appropriate physical and occupational therapies.

Oral Medications:
The use of oral medications for the treatment of spasticity may be very effective. At high dosages, however, oral medications can cause unwanted adverse effects that include sedation as well as changes in mood and cognition. These adverse effects preclude their extensive use in children, since the intellectual function of the majority of children with spasticity is at best precarious, and sedation inevitably results in some degree of impaired learning or school performance.
*Benzodiazepines - Diazepam and clonazepam The benzodiazepines bind in the brain stem and at the spinal cord level and increase the affinity of GABA for the GABA-A receptor complex. This results in an increase in presynaptic inhibition and then reduction of monosynaptic and polysynaptic reflexes. These drugs may improve passive range of motion and reduce hyperreflexia, painful spasms, and anxiety. Diazepam has a half-life of 20-80 hours and forms active metabolites that prolong its effectiveness. The half-life of clonazepam ranges from 18-28 hours. Benzodiazepines should be started at low dosages and increased slowly. In adults, diazepam can be started at 5 mg at bedtime, and if daytime therapy is indicated, the dosage can be increased slowly to 60 mg/d in divided doses. Clonazepam can be started at 0.5 mg at night and slowly increased to a maximum of 20 mg/d in 3 divided doses.

Sedation, weakness, hypotension, adverse gastrointestinal effects, memory impairment, incoordination, confusion, depression, and ataxia may occur. Tolerance and dependency can occur, and withdrawal phenomena, notably seizures, have been associated with abrupt cessation of therapy. Patients who are taking benzodiazepines with agents that potentiate sedation and have central depressant properties (eg, baclofen or tizanidine) should be monitored carefully.
*Baclofen Baclofen is a GABA agonist, and its primary site of action is the spinal cord, where it reduces the release of excitatory neurotransmitters and substance P by binding to the GABA-B receptor. Studies show that baclofen improves clonus, flexor spasm frequency, and joint range of motion, resulting in improved functional status.

Baclofen may be given orally or by intrathecal pump. An analysis by Rizzo et al of a database of 17,501 patients with multiple sclerosis found that the use of oral medication was proportional to the severity of spasticity, with 78% of patients who were severely affected using at least one drug and 46% using at least two. Baclofen was the most commonly used agent, followed by gabapentin, tizanidine, and diazepam. Comparison of 198 patients who used intrathecal baclofen (ITB) and 315 who used oral medications showed that those who used ITB had lower levels of spasticity, less leg stiffness, less pain, and fewer spasms.

The oral dose of baclofen used to treat spasticity ranges from 30-100 mg/d in divided amounts. Tolerance may develop, and the drug must be tapered slowly to prevent withdrawal effects such as seizures, hallucinations, and increased spasticity. Baclofen must be used with care in patients with renal insufficiency, as its clearance is primarily renal. Adverse effects include sedation, ataxia, weakness, and fatigue. When used in combination with tizanidine or benzodiazepines, the patient should be monitored for unwanted depressant effects.

Adverse effects of baclofen can be minimized by intrathecal infusion of the drug (see Other Medical Treatments), because the concentration gradient favors higher levels at the spinal cord versus the brain. Intrathecal baclofen is approved in the United States for the treatment of spasticity of spinal or cerebral origin. In children, intrathecal baclofen is particularly effective for the treatment of spasticity of the lower extremities in a selected group of patients who have responded favorably to a trial dose of intrathecal baclofen. Complications of the procedure are relatively few and usually are limited to mechanical failures of the pump or the catheter. Adverse drug effects are usually temporary and can be managed by reducing the rate of infusion.

Dantrolene sodium:
Dantrolene sodium is useful for spasticity of supraspinal origin, particularly in patients with cerebral palsy or traumatic brain injury. It decreases muscle tone, clonus, and muscle spasm. It acts at the level of the muscle fiber, affecting the release of calcium from the sarcoplasmic reticulum of skeletal muscle and thus reducing muscle contraction. It is, therefore, less likely than the other agents to cause adverse cognitive effects. Its peak effect is at 4-6 hours, with a half-life of 6-9 hours. The dose range is 25-400 mg/d in divided doses (children, dose range 0.5-3.0 mg/kg/d).

Adverse effects include generalized weakness, including weakness of the respiratory muscles, drowsiness, dizziness, weakness, fatigue, and diarrhea. Hepatotoxicity occurs in fewer than 1% of patients; this elevation in liver function test results is seen particularly in adolescents and women who have been treated for greater than 60 days and at dosages greater than 300 mg/d. Dantrolene should not be used with other agents known to cause hepatotoxicity, including tizanidine. If no benefit is seen after 4-6 weeks of treatment at maximal therapeutic doses, the medication should be discontinued.

Data from approximately 50 clinical trials indicate that tizanidine (Zanaflex) is effective for the management of spasticity due to cerebral or spinal damage. Tizanidine is an imidazoline derivative and a central alpha2-noradrenergic agonist. The antispasticity effects of tizanidine are the probable result of inhibition of the H-reflex. It also may facilitate inhibitory actions of glycine and reduce release of excitatory amino acids and substance P, and may have analgesic effects. While spasms and clonus are reduced in patients using tizanidine, the Ashworth Scale does not reveal significant differences from placebo groups. In the long term, however, tizanidine does improve spasms and clonus.

Patients report less muscle weakness from tizanidine than from baclofen or diazepam. In placebo-controlled studies, the efficacy of tizanidine in reducing muscle tone is comparable to that of baclofen and better than that of diazepam. When combined with baclofen, tizanidine presents the opportunity to maximize therapeutic effects and minimize adverse effects by reducing the dosages of both drugs. If tizanidine is prescribed in conjunction with baclofen or benzodiazepines, the patient should be advised of possible potential additive effects, including sedation. In addition, when tizanidine is prescribed with benzodiazepines, liver enzymes should be monitored closely since the combination increases the likelihood of liver toxicity.

Tizanidine is a short-acting drug with extensive first-pass hepatic metabolism to inactive compounds following an oral dose. The half-life is 2.5 hours with peak plasma level at 1-2 hours, and therapeutic and side effects dissipate within 3-6 hours. Therefore, use must be directed to those activities and times when relief of spasticity is most important and titrated to avoid intolerance. It should be started at a low dose, 2-4 mg, preferably at bedtime. It should be titrated carefully to each patient, increasing the dosage slowly and gradually. The average maintenance dosage of tizanidine is 18-24 mg/d. The maximum recommended dosage is 36 mg/d. Patients with impaired kidney function also require gradual titration, since they show a 2-fold increase in plasma concentration.

Dry mouth, somnolence, asthenia, and dizziness are the most common adverse events associated with tizanidine. Liver function problems (5%), orthostasis, and hallucinations (3%) are rare tizanidine-related adverse events.

Other oral agents
Other agents that may be beneficial in selected patients include the following:
*Clonidine has shown efficacy for spasticity in open-label studies. It is a selective alpha2-receptor agonist and may inhibit presynaptic sensory afferents. Hypotension is the main adverse effect.
*Gabapentin is a GABA analogue that modulates enzymes that metabolize glutamate. It may be useful in some patients with spasticity. Sedation can be a bothersome adverse effect.
*Lamotrigine blocks sodium channels and reduces the release of glutamate and other excitatory amino acids.
*Cyproheptadine is a 5-HT antagonist that may neutralize serotonergic inputs. It is beneficial in some patients.
*Cannabinoid-like compounds (dronabinol, nabilone) that act on the cannabinoid receptors (CB1 and CB2) may be useful in muscle spasms and spasticity.
*Standardized oromucosal whole plant cannabis-based medicine (CBM) containing delta-9 tetrahydrocannabinol (THC) and cannabidiol (CBD) may represent a useful agent for the relief of spasticity in multiple sclerosis (MS).

In double-blind study done over 6 weeks, 189 subjects with MS and spasticity received daily active preparation (n=124) or placebo (n=65). The primary endpoint was the change in a daily subject-recorded Numerical Rating Scale of spasticity and showed the active preparation to be significantly superior (P =0.048), and secondary efficacy measures (Ashworth Score and a subjective measure of spasm) were all in favor of active preparation but did not achieve statistical significance.

A meta-analysis suggested that combined THC and CBD extracts may provide therapeutic benefit for spasticity in MS patients, although only subjective relief attained statistical significance.

Other Medical Treatments:
Neurolysis With Neurotoxins, Chemodenervation, and Local Anesthetic Injections of botulinum toxin, phenol, alcohol, or lidocaine can offer significant benefits to the appropriately selected patient as part of a comprehensive spasticity management plan. Many clinicians use various combinations of treatments. The distribution of spasticity is vital in determining whether to use focal or global treatment, and in deciding which measures should be used.

Botulinum toxin:
A guideline from the American Academy of Neurology recommends offering botulinum toxin as a treatment option to reduce muscle tone and improve passive function in adults with spasticity (level A recommendation), and recommends considering botulinum toxin injection to improve active function (level B).

Patients with focal spasms are candidates for focal treatment with botulinum toxin A (BTX-A). Patients with segmental or nongeneralized spasticity may be candidates for systemic or ITB treatment, with BTX-A added for focal symptom relief.

In 2009, the FDA required a boxed warning for all botulinum toxin products—both type A and type B—because of reports that the effects of the botulinum toxin may spread from the area of injection to other areas of the body, causing effects similar to those of botulism. These effects have included life-threatening, and sometimes fatal, swallowing and breathing difficulties. Most of the reports involved children with cerebral palsy being treated for spasticity.

Botulinum toxin type A:
BTX-A injections have been used as a safe and effective treatment for a variety of movement disorders, including muscle overactivity and spasticity. BTX-A therapy is approved by the US Food and Drug Administration (FDA) for the treatment of cervical dystonia, primary axillary hyperhidrosis, strabismus, and blepharospasm in patients older than 12 years. The use of BTX-A to treat spasticity in adults and children is therefore off-label. Controlled clinical trials of BTX-A injections for focal muscle spasticity have demonstrated prolonged yet reversible clinical effects, few adverse effects, and minimal immunogenicity.

BTX-A inhibits acetylcholine release at the neuromuscular junction. Once inside the cholinergic nerve terminal cell, BTX-A inhibits the docking and fusion of acetylcholine vesicles at the presynaptic membrane.[30] The effect of the toxin becomes evident within 12 hours to 7 days, and the duration of effect is usually 3-4 months, but can be longer or shorter. Gradually, muscle function returns by the regeneration or sprouting of blocked nerves forming new neuromuscular junctions.

The results of clinical trials strongly support the efficacy and safety of BTX-A for the treatment of spasticity caused by cerebral palsy, multiple sclerosis, stroke, spinal cord injury, brain injury, or neurodegenerative disease. Major benefits of BTX-A therapy for spasticity include improved function, increased ease of care and comfort, prevention or treatment of musculoskeletal complications such as contractures and pain, and cosmesis.

In a review of 18 open-label or double-blind, placebo-controlled trials by Simpson, botulinum toxin has been shown to be an effective measure for reduction of focal spasticity. Improvements were documented in tone reduction, range of motion, hygiene, autonomic dysreflexia, gait pattern, positioning, and other criteria, though not all criteria tested showed improvement in all studies. Significant adverse effects were not reported in any of the studies. A systematic review of BTX-A therapy in post-stroke spasticity by Rosales et al found an odds ratio of 4.5 (95% confidence index 2.79-7.25) for an improvement of 1 or more points on the Modified Ashworth Scale at 4-6 weeks after BTX-A treatment.

Proficiency in dosing and injecting BTX-A demands the development of considerable skill. Each patient's treatment must be individualized, and appropriate patient selection is important. BTX-A injections are most effective in relieving focal spasticity around a joint or series of joints. Even though BTX-A is a focal treatment, untreated muscles may benefit from the disruption of the synergy patterns that often replace isolated muscle control. Increased range of motion, reduction in spasms, ease of caregiving, and reduced pain are primary goals leading to improved function and quality of life. Treatment begins with mutually agreed upon goals and expectations, a treatment plan that addresses all the clinical issues.

Generally, the relationship between spasticity and voluntary motor control is inverse. Patients with severe spasticity often have less voluntary movement than patients with mild spasticity. Underlying motor control, strength, and coordination should be assessed to project the functional results of reducing spasticity. Since reduction of spasticity in patients with poor selective motor control may not provide mobility, treatment goals of improving positioning, caregiving, or comfort may be more appropriate. Patients with cognitive deficits may not be able to take full advantage of their reduced spasticity; treatment aimed at easing their care or pain may be more beneficial. Patients with painful spasms or contracture often experience significant pain relief after treatment with BTX-A.

In the upper limb, patterns of spasticity that may improve specifically from BTX include an adducted and internally rotated shoulder, flexed elbow, pronated forearm, flexed wrist, thumb-in-palm, and clenched fist.[34] In the lower extremity, BTX injections may particularly improve spasticity causing flexed hip, flexed knee, adducted thighs, stiff (ie, extended) knee, equinovarus foot, and striatal toe. Outcomes should be evaluated by subjective and objective clinical measures including rating scales and videotape recordings that clearly reflect defined goals and objectives.

In summary, common functional goals with neurolysis using the botulinum toxins (or phenol or alcohol) include improving gait, hygiene, and ADLs; easing pain and care; and decreasing spasm frequency. Technical objectives are to promote tone reduction and to improve range of motion and joint position. Once begun, treatment is evaluated constantly; follow-up is crucial to gauge the response and to fine-tune muscle selection and dose as necessary.

When used in the management of spasticity, treatment with BTX-A is almost never used as monotherapy. Complementary therapies, such as physical and occupational therapy, frequently are utilized to maximize anticipated outcomes. These therapies usually are instituted or modified after injection. For example, in a controlled study in 20 children with upper limb spastic cerebral palsy, Kanellopoulos et al found that use of a static night splint after of BTX-A injection resulted in significantly better results after 6 months.

In children, treatment should be initiated at a time when they still are developing their motor control apparatus. This might prevent them from entering a vicious cycle in which CNS lesions affect the musculoskeletal system, thereby preventing the development of motor functions. In addition, experimental data on the formation of a cortical somatotopic map during early life indicate that the periphery plays an instructional role on the formation of central neuronal structures.

BTX-A dosing has to be individualized and is dependent upon muscles involved, prior response, and functional goals. Adverse effects are minimal; however, conditions requiring caution include patients who are hypersensitive to any ingredient in BTX-A, those using aminoglycoside antibiotics, those with neuromuscular disease, and women who are pregnant or potentially lactating.

A consensus on the dosage has been recommended by the Spasticity Study Group. Examples of doses of BTX-A, in clinical trials for spasticity from multiple sclerosis, cerebral palsy, traumatic brain injury, spinal cord injury, and stroke are as follows:
In multiple sclerosis, injection of 400 U of BTX-A into the thigh adductors resulted in significant improvement in spasticity and hygiene compared to placebo.

In spinal cord injury, injection of 20-80 U of BTX-A into the rhabdosphincter resulted in decreased urethral pressure and postvoid residual volume.

In adults suffering from cerebral palsy, injection of 1 U/kg of BTX-A into the medial and lateral gastrocnemius of each leg resulted in an improvement in gait pattern compared to placebo. For children with cerebral palsy, the American Academy of Neurology recommends offering injection of the calf muscles as a treatment option for equinus varus deformity (level A), but does not specify dosage.

In stroke, injections of 75-300 U of BTX-A into the elbow and wrist flexors resulted in significant improvement in results of the Ashworth Scale compared to placebo.

Future trials of BTX-A may be improved by attention to dose-effect response, dose escalation, broader randomization, and more uniform timing of injection in relation to the onset of neurologic deficit.

BTX-A is injected using a 23- to 27-gauge needle. Larger and superficial muscles are identified by palpation, while small or deep muscle groups are identified by electromyography (EMG) or electrical stimulation (ES). Ultrasound, fluoroscopy, or CT also may be used. Local anesthetic cream, general anesthesia, or sedation may be necessary, particularly for some children. Depending on the location and severity of spasticity, BTX-A injections usually are needed at 3- to 6-month intervals to maintain therapeutic benefit. Re-injections should not be given any sooner than 3 months after the last injections to decrease the possibility of antibody formation.

Treatment with BTX-A can be combined with various oral medications, the baclofen pump, and sometimes with phenol or alcohol neurolysis. The primary reason for combining BTX-A with phenol or alcohol neurolysis would be to avoid loss of responsiveness by remaining under the maximum dose per visit. The decision to combine therapies usually depends on the location and number of target muscles involved. If both lower and upper extremities are to be injected, the combination of BTX-A and phenol may be warranted. Although using phenol or alcohol neurolysis is associated with certain difficulties, they provide inexpensive, long-term chemodenervation for some patients, mainly adults.

Antibody formation:
Resistance to BTX-A is characterized by absence of any beneficial effect and by lack of muscle atrophy following the injection. Antibodies against the toxin are presumed to be responsible for most cases of resistance. Resistance has been reported to occur in 3-10% of people.

Repeated, high-dose injections are far more likely to result in antibody formation than are less frequently repeated, low-dose injections. The smallest amount of BTX-A necessary to achieve therapeutic benefit should be used, and the interval between treatments should be extended as long as possible. Booster injections also should be avoided. When the amount injected totals the maximum of 400 units, further injections should not be given before 3 months after the last treatment.

Several types of assays are available to detect the presence of antibody in serum. The most widely used is the in vivo mouse neutralization assay, available through Northview Pacific Laboratories (Berkeley, Calif): telephone number (1(510)548-8440). Injecting 10-20 units into one corrugator/frontalis muscle and testing for the ability to elevate one eyebrow and frown 2-3 weeks later is a simple clinical way to check for resistance. Checking for a marked decrease in compound motor action potential (CMAP) amplitude in an injected muscle may be helpful. This would indicate that resistance has not developed and that the dose or injection site may have been suboptimal.

A number of studies have confirmed that patients with BTX-A resistance may benefit from injections with other serotypes such as botulinum toxin type B (BTX-B). BTX-B, which is now available commercially, and other serotypes, when they become available, may offer hope to patients with resistance to BTX-A.

Botulinum toxin type B:
Schwerin et al have reported the results of a pilot study using BTX-B in children with spastic movement disorders. Twenty-nine children with spasticity underwent 62 treatment sessions with BTX-B. Motor function improvement goals were attained or surpassed in 28 of 46 sessions and partially attained in 12. Care, hygiene, or orthotic management goals were attained in 5 of 12 sessions and partially attained in 6. Correction of limb position goals were attained in 3 of 4 sessions. Of 17 BTX-A nonresponders, 11 attained therapy goals with BTX-B. Side effects included dry mouth (9.7% of sessions), diarrhea (6.5%), and swallowing difficulties (6.5%). Systemic side effects were more likely when the dose surpassed 400 U/kg. The authors recommend a starting dose of BTX-B not to exceed 400 U/kg for children up to 25 kg and a total dose for older children and adults of not more than 10,000 U.

Intrathecal Baclofen:
ITB consists of long-term delivery of baclofen to the intrathecal space. This treatment can be helpful for patients with severe spasticity affecting the lower extremities, particularly for those patients whose conditions are not sufficiently relieved by oral baclofen and other oral medications. Lack of substantial therapeutic benefit from oral baclofen, a mainstay of drug therapy, can result from an inadequate penetration of the blood-brain barrier by the drug. Since unacceptable CNS effects often occur when high doses of baclofen are taken orally, the therapeutic effect usually cannot be improved by increasing the dose. Sedation, somnolence, ataxia, and respiratory and cardiovascular depression are the drug's CNS depressant properties.

Zahavi et al have reported on the long-term effect (>5 y) of ITB on impairment, disability, and quality of life in patients with severe spasticity of spinal origin. Of 21 patients treated, 11 had multiple sclerosis, 6 had spinal cord injury, and the rest had a variety of nonprogressive spinal disorders. The mean length of treatment was 6.5 years. Significant sustained improvement was seen for spasticity (2.82 at baseline, 0.91 at follow-up, p= 0.0) and spasm score (1.79, 0.67, p=0.001). Expanded Disability Status Scale score worsened (7.71, 7.88, p=0.023), as did ambulation index (7.74, 8.05, p=0.027) and overall incapacity status scale score (25.74, 28.76, p=0.011). No significant changes were seen on the Sickness Impact Profile or the Hopkins Symptom Checklist. No significant differences were found for any measure between patients with multiple sclerosis and those with static spinal disorders.

The most common complications were muscle weakness, somnolence, catheter malfunction, and surgery complications. The authors report that all patients but two were satisfied with their treatment and would undergo treatment again. Zahavi and coworkers concluded that the most prominent improvements reported by the patients were increased ease of transfer, better seating posture, ease of care in ADLs (passive), and decrease in pain.

A review of ITB therapy in 174 children with cerebral palsy by Borowski et al found that ITB therapy is safe and effective for severe spasticity in this population, and that patients and caregivers find it highly satisfactory, but that the technique does have a 31% rate of complications requiring surgical management over a 3-year treatment period.

ITB (SynchroMed Infusion System) provides direct, pattern-controlled delivery of baclofen to its target via an implanted, programmable pump. This precise delivery yields better spasticity reduction at lower doses: doses 100 times the intrathecal dose are needed to produce similar benefits if baclofen is taken orally. Thus, adverse effects associated with high dosages of oral baclofen are minimized.

The pump is a small titanium disk that is about 3 inches in diameter and 1 inch thick. It contains a refillable reservoir for the liquid baclofen as well as a computer chip that regulates the battery-operated pump. A telemetric wand programs the dose of baclofen to be received. A flexible silicone catheter serves as the pathway through which the baclofen flows to the intrathecal space. To prevent accidental depletion of baclofen, the pump contains a programmable alarm that sounds when the reservoir needs to be refilled, the battery is low, or the pump is not delivering the baclofen.

ITB can be used to treat severe spasticity from various causes. Benefits of ITB typically include reduced tone, spasms, and pain, and increased mobility. Other benefits may include improved sleep quality, bladder control, self-care, and self-image. It also may allow patients to decrease and often discontinue other spasticity medications. Patient selection, screening, pump implantation, and dosage

ITB should be considered in patients who have disabling spasticity unresponsive to conservative pharmacotherapy or in whom therapeutic doses induce intolerable side effects. Pharmacotherapy should include, but need not be limited to, a trial of oral baclofen. The Ashworth Scale and Spasm Frequency Scale appear to be clinically useful measures of spasticity; a severity of 3 on the Ashworth and 2 on the Spasm Frequency for at least 12 months are considered reasonable criteria for ITB therapy consideration.

The screening process requires the administration of an intrathecal test dose of baclofen (typically 50 mcg, usually not to exceed 100 mcg) via lumbar puncture. Peak effect of the drug usually occurs within 4 hours. Patients who respond positively to the test dose can be considered for long-term ITB therapy. The test dose must be monitored closely in a fully equipped and staffed setting because of the rare risk of respiratory arrest and other life-threatening adverse effects.

The ITB pump generally is implanted near the waistline. The tip of a catheter rests between the first and second lumbar vertebrae in the intrathecal space. The distal end of the catheter loops around the torso and connects to the pump. The dose delivered by the pump is adjusted using the programmer and telemetry wand. This system is non-invasive and affords flexibility in individualizing doses. The initial total daily dose of ITB after implantation may be up to double the screening dose that resulted in a beneficial response. The initial doses should be adjusted and increased carefully and have to be individualized.

About 60 days following surgery or when a stable dose program has been established, the fine-tuning of the dose delivery may begin. Maintenance doses of ITB are as follows:
* For spasticity of spinal cord origin, the dose ranges from 12-2000 mcg/d, with most patients requiring 300-800 mcg/d.
*Patients with spasticity of cerebral origin receive doses ranging from 22-1400 mcg/d. For most patients, doses of 90-703 mcg/d result in therapeutic benefits.
*For children younger than 12 years, the average daily dose is 274 mcg/d, with a range of 24-1199 mcg/d.

The dose may be increased if greater therapeutic benefits are needed, or reduced to alleviate adverse effects. Dose should always be reduced in a stepwise fashion. Sudden withdrawal of ITB can result in cardiovascular instability, fever, and rash, and requires emergency treatment. The pump's reservoir must be refilled every 4-12 weeks, depending on the daily dose. The pump hardware can last 4-6 years, depending upon the battery life, and generally is replaced within 4-5 years.

As with any surgical procedure, the implantation of the pump exposes a patient to risks of infection and spinal fluid leakage, as well as the general risks of general anesthesia. Drowsiness, nausea, headache, muscle weakness, and light-headedness can stem from the pump delivering an inappropriate dosage of baclofen. The pump itself can malfunction, and the catheter can become kinked or fractured. A large and sudden escalation in dose requirement, for example, suggests a catheter complication. In cases such as these, surgical intervention may be necessary. In cases in which overdose is possible, the patient should be brought immediately to the hospital for evaluation.

As some degree of muscle tone may be required to assist in the support of circulatory function, prevent deep vein thrombosis, and optimize ADLs and ease of care, optimizing the change of tone with ITB requires striking a balance between the patient's condition, functional goals, and physiological demands. Since ITB may be appropriate for a broad range of disabilities, from ambulatory to vegetative states, treatment and functional goals must be individualized, clearly understood, and agreed upon by the patient, family, caregivers, and care-provider team before starting treatment. Thus, in summary, appropriately chosen patients with clearly defined and realistic treatment objectives benefit the most from this form of treatment.

Other Treatments:

*Transcranial magnetic stimulation
Centronze et al have reported that repetitive transcranial magnetic stimulation (rTMS) may improve spasticity in patients with MS. They used high-frequency (5 Hz) and low-frequency (1 Hz) rTMS protocols in 19 remitting patients with relapsing-remitting MS and lower limb spasticity. rTMS was applied over the leg primary motor cortex, measuring the H/M amplitude ratio of the soleus H reflex, a reliable neurophysiologic measure of stretch reflex. A significant improvement of lower limb spasticity was observed when rTMS applications were repeated over 2 weeks, lasting at least 7 days after the end of treatment; no effect was obtained after a 2-week sham stimulation. These results are promising and need to be verified by larger well-designed studies.

*Intrathecal bolus injection of phenol Jarret et al have reported that intrathecal bolus injection of phenol can reduce lower-limb spasticity. Twenty-five patients with advanced multiple sclerosis received 1.5-2.5 mL 5% phenol in glycerol at L2/3 or L2/4, and improvements were seen in the Ashworth score, spasm frequency, and pain, although the duration of the beneficial effect was not indicated. No serious adverse effects were reported.

Surgical Treatments:

*Surgical Options
Surgery can play a very important role in the treatment of chronic spasticity. In most cases, complementary neurosurgical and functional orthopedic approaches are used. Children with spasticity represent a different challenge because their spasticity may change as they grow and develop so that, at times, surgery may be undertaken to allow more normal bone and muscle growth. While each surgical approach has certain strengths and weaknesses, none of them completely eliminate spasticity.
*Neurosurgical Treatments The surgical treatment of spasticity has been aimed at 4 different levels: brain, spinal cord, peripheral nerves, and muscle. Each approach has its strengths and weaknesses; none of them completely eliminates spasticity. Stereotactic brain surgery, whether involving the globus pallidum, ventrothalamic nuclei, or the cerebellum, has had little success. Cerebellar pacemakers have been tried; results have been mixed but not ultimately encouraging. Selective dorsal rhizotomy (SDR) is currently the most widely used and effective CNS procedure.
*Selective dorsal rhizotomy
Also known as selective posterior rhizotomy, this procedure involves cutting of selective nerve roots between the levels of L2 and S1 or S2, the fibers lying just outside the vertebral column that transmit nerve impulses to and from the spinal cord. "Dorsal" or "posterior" indicates that the target nerve roots enter the posterior spinal cord. These fibers carry sensory information to the cord from muscle.

Sensory nerves are targeted because of the probable role they play in generating spasticity. Under normal physiologic conditions, excitatory signals from these sensory nerves are counterbalanced by inhibitory signals from the brain, maintaining normal muscle tone. In simplistic terms, when brain or spinal cord damage upsets this balance, excess sensory signaling can lead to spasticity. SDR is thought to improve spasticity by partially restoring the proper physiologic balance between these circuits.

SDR is used to treat severe spasticity of the lower extremities that interferes with mobility or positioning. It has been performed mostly on children with cerebral palsy and less often in adults with spasticity from cerebral palsy or other etiologies. The best candidate for SDR is a person with good strength and balance, little or no fixed contractures in the lower limbs, and strong motivation and support. This procedure is used only when less-invasive procedures are unable to control spasticity adequately. SDR is performed under general anesthesia. The candidate nerve rootlets are stimulated electrically and those that lead to abnormal responses are cut; usually 25-50% of all tested rootlets are cut.

Studies of SDR in children with cerebral palsy have shown that most patients experience a reduction in spasticity and an increase in range of motion immediately after surgery, which persists for at least a year. Cole et al have emphasized the importance of applying strict selection criteria when considering children for SDR, as this is more likely to result in encouraging results. Of 53 children referred for SDR, only 19 (35%) fulfilled their selection criteria. These children showed improvement in cosmesis of gait; clinical examination; and temporal, kinetic, and kinematic parameters of gait analysis.

Relatively few longer-term follow-up studies have been done, and these indicate tone reduction may last for a number of years. Reduction of spasticity can in some instances improve function, with most studies showing some benefit in mobility for subjects with spastic diplegia, but less for those with spastic quadriplegia. The extent of functional improvement after SDR therefore varies, and positive prognostic factors include the extent of mobility before the operation, underlying strength and balance, availability of regular physical therapy after SDR, and the patient's motivation and ability to undertake the rehabilitation process.

The possible complications from the surgery include those involving general anesthesia. Pain, altered sensation, and fatigue may continue for a number of weeks after the operation, as may changes in sleep and bladder or bowel function. Other rare long-term complications include low back pain, scoliosis or kyphosis (ie, spinal curves), and hip displacement.

Other surgical procedures targeting the brain or the peripheral nerves (neurectomy) or involving cerebellar stimulation of the brain have been used in the past with limited success and currently are not recommended for the treatment of spasticity as they are often not successful and produce complications. Musculoskeletal surgery, however, does remain an important procedure for treatment of contractures secondary to spasticity.
*Orthopedic Surgery
These surgeries constitute the most frequently used procedures for spasticity. Two categories of surgical procedures are used: lengthening or release of muscles and tendons, and procedures involving bones. These procedures aim to reduce spasticity, increase range of motion, improve accessibility for hygiene, increase tolerance to braces, or reduce pain. The majority of such operations are performed in children aged 4-8 years.
Contracture release is the most commonly performed orthopedic procedure. The most common site for contracture release is the Achilles tendon. The tendon is lengthened to correct "equinus" deformity. Other common targets are contractures involving muscles of the knees, hips, shoulders, elbows, and wrists. The tendon of a contractured muscle is cut and the joint is then positioned at a more normal angle, and a cast is applied. Regrowth of the tendon to this new length occurs over several weeks, and serial casting may be used to gradually extend the joint. Following cast removal, physical therapy is used to strengthen the muscles and improve range of motion.

In a tendon transfer, the attachment point of a spastic muscle is moved. The muscle can no longer pull the joint into a deformed position and, in some situations, the transfer allows improved function. In others, the joint retains passive but not active function. Ankle-bracing procedures that follow surgery are among the most effective interventions.

Osteotomy also can be used to correct a deformity. A small wedge is removed from a bone to allow it to be repositioned or reshaped. A cast is applied while the bone heals in a more natural position. This procedure is used most commonly to correct hip displacements and foot deformities. Arthrodesis is performed most commonly on the bones in the ankle and foot. It is a fusing together of bones that normally move independently, and this limits the ability of a spastic muscle to pull the joint into an abnormal position. Osteotomy and arthrodesis usually are accompanied by contracture release surgery for fuller correction of the joint deformity.

*Physical and Occupational Therapy
These treatments are designed to reduce muscle tone, maintain or improve range of motion and mobility, increase strength and coordination, and improve comfort. The choice of treatments is individualized to meet the needs of the person with spasticity. Treatments may include any of the following:
*Stretching forms the basis of spasticity treatment. Stretching helps to maintain the full range of motion of a joint and helps prevent contracture.
*Strengthening exercises are aimed at restoring the proper level of strength to affected muscles, so that as tone is reduced through other treatments, the affected limb can be used to its fullest potential. As yet no clear evidence exists that intensive physiotherapy (1 h a day, 5 days a wk) is more beneficial than routine physiotherapy (6-7 h over 3 mo).
*Application of orthoses, casts, and braces allows a spastic limb to be maintained in a more normal position. For instance, an ankle-foot orthosis can help keep the foot flexed and reduce contracture of the calf muscles. A cast is a temporary brace, and serial casting gradually stretches out a contractured limb through the application of successive casts. Proper limb positioning improves comfort and reduces spasticity.
*Brief application of cold packs to spastic muscles may be used to improve tone and function for a short period of time or to ease pain.
*Electrical stimulation may be used to stimulate a weak muscle to oppose the activity of a stronger, spastic one. It also may reduce spasticity for short periods of time. Electrical stimulation is used most often to help flex the ankle for walking, and to help extend spastic fingers.
*Biofeedback is the use of an electrical monitor that creates a signal, usually a sound, as a spastic muscle relaxes. In this way, the person with spasticity may be able to train himself to reduce muscle tone consciously, and this may play a modest role in reducing spasticity.

Medications Used in Treatment:
1. Benzodiazepines: Valium®/diazepam
2. GABA Agonists: Baclofen®
3. Central Alpha Agonists: Zanaflex®/tizanidine
4. Muscle relaxants: Dantrium®/dantrolene
5. Acetylcholine Release Inhibitors: Botox®/onabotulinumtoxina

Suggested Links:
Merck Manual/ Cerebral Palsy
Amyotrophic Lateral Sclerosis and Other Motor Neuron Diseases
Spinal Cord Disorders
Merck Manual/ Hereditary Spastic Paraparesis

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