Spasticity and Muscle Overactivity as Components of the Upper Motor Neuron Syndrome
Elie P. Elovic
Michal E. Eisenberg
Neil N. Jasey Jr
Spasticity is derived from the Greek word spasticus, which means “to pull.” It is a component of the upper motor neuron syndrome (UMNS), which is caused by a lesion proximal to the anterior horn cell; in the spinal cord, brainstem, or brain. It has both positive and negative components. Weakness, paralysis, and fatigue are the negative signs of the syndrome, whereas spasticity, athetosis, hyperreflexia, release of primitive reflexes, and dystonia are the positive. Hyperreflexia, spread of reflexes beyond muscles stimulated, hypertonicity, co-contraction, clonus, and rigidity are often seen in association with spasticity (1). Another word that can be used to describe the positive signs of the syndrome is muscle overactivity. The treatment team involved in the management of spasticity may find it one of the most challenging issues confronting them in the care of patients with neurologic disability. The goal of the treatment is to address this muscle overactivity with the fewest side effects and least exacerbation of the negative components of the UMNS.
EPIDEMIOLOGY OF SPASTICITY
Clinicians treating neurological disorders are often confronted with the issue of spasticity and muscle overactivity. There is limited information regarding the prevalence and incidence of spasticity in various conditions. As expected, it depends on the etiology of the UMNS. In spinal cord injury (SCI), Maynard et al. (2) reported a prevalence of 65% to 78% and in 2004, Rizzo et al. (3) reported that 85% of patients with multiple sclerosis (MS) had some spasticity. This information may well be dated, as the introduction of newer agents to slow the progression of the illness may affect the incidence of spasticity that is seen in MS. Studies performed at varying time frames after stroke differ in the incidence of spasticity reported post stroke. A study assessing people 3 months after stroke revealed a prevalence of 19% and 35% in those with hemiplegia (4). On the other hand, a rate of 38% was reported at 1 year post stroke (5).
NORMAL MOTOR FUNCTION AND CONTROL
Requirements for an Effective Motor System
To facilitate the discussion of spasticity pathophysiology, it is useful to discuss normal motor control. To function effectively, the motor system must be able to integrate sensory feedback, control reflex activity, and coordinate volitional movement. It is critical for the controller to have information concerning the position of muscles and joints in addition to muscle velocity. It is also critical for the system to rapidly respond to external forces to control and respond to reflex activity and to initiate and stop motor activity. Feedback must exist among the many pathways that pass through the cortical, subcortical, brainstem, spinal cord, peripheral nerve, and muscle. The most distal unit involved in motor control is the motor unit, a part of the peripheral nervous system that is critical for control based on excitation and inhibition of muscle fibers.
The Motor Unit
The motor unit was first described by Sherrington (6). It is comprised of an a motor neuron and all of the muscle fibers that are innervated by it. Not all motor units are the same, as they differ in recruitment patterns and firing rates. This is a result of the different demands and purposes of individual motor units. The units also differ by the types of muscle fibers that comprise them. There are two major fiber types: type I and type II. Type I fibers are small, red, and oxidative, and they fatigue slowly. Motor unit function reflects the fibers that they contain. Motor units full of type I fibers are responsible for the baseline tonic muscle activity. Type II fibers, on the other hand, are large, white, and anaerobic. These muscles are more powerful and can deliver greater speed and velocity than type I; however, they can fatigue easily. These units are brought in to increase the force or speed of a contraction. Additional motor units are a hybrid of the two fiber types (7,8). When working properly, motor units fire with coordination of agonist and antagonist systems, normal patterns of recruitment and decruitment (9). Katz and Pierrot-Deseilligny (10) reported
the problems that can be created by co-contraction of muscles and muscles firing out of phase or at angles different from their normal areas of activity. This loss of the normal recruitment and decruitment pattern may play a key role in spasticity.
the problems that can be created by co-contraction of muscles and muscles firing out of phase or at angles different from their normal areas of activity. This loss of the normal recruitment and decruitment pattern may play a key role in spasticity.
Normal Regulation of the Motor Unit
The motor control system uses a feedback loop, integrating information about muscle activity, position, and velocity. This enables the motor system to control and coordinate the stimulation of agonist and antagonist muscles around a joint. Critical information required by the control system includes muscle length, velocity, muscle tension, and joint position. This is mediated by a combination of immediate monosynaptic reflexes and more complicated higher-level control involving spinal and supraspinal polysynaptic activity. This activity can either increase or inhibit activity at the motor unit level. Units fire when the net excitation minus inhibition reaches threshold (8).
Muscle Spindle and Golgi Tendon Organs
The muscle spindle plays a critical role in the provision of necessary information for proper motor control. It is attached in parallel to the main muscle mass, and it contains afferent type Ia and II fibers that communicate information concerning position and rate of change of a muscle to the spinal column. The γ motor neuron is an integral component of the muscle spindle. During normal motor function, the γ motor unit coactivates with the a motor neuron and maintains the spindle tension and efficiency (8). Were it not for the γ motor neuron, the muscle spindle would be unable to provide accurate information throughout the muscle’s range of motion (ROM), as the spindle would be under less tension when the muscle contracts. This is analogous to a volleyball net being supported by two poles. The muscle contracting would be similar to the poles being brought closer together.
The Golgi tendon organs also play an important role in coordinating muscle activity. During normal movement the stretch reflex, which is mediated by the firing of the Ia afferent fibers, must be suppressed to allow full movement about the joint. This reflex is monosynaptic and mediated by the Ia afferents and is triggered when a sudden stretch is applied to a muscle, such as tapping on the knee, Some suppression of muscle activity is mediated through the Golgi tendon organs. Found within the muscle tendons, through the Ib fibers and their related interneurons, the Golgi tendon organs limit muscle contraction by facilitating antagonists and inhibiting agonists. Thus, they serve to impose a ceiling effect on muscle contraction and prevent musculotendinous injury (11).
Spinal Interneurons
The spinal interneurons play a critical role in normal motor control and spasticity. The effects of the Ia and Ib fibers mentioned earlier are often mediated through and with the help of interneurons called Ia and Ib interneurons, respectively. Other interneurons, including the Renshaw cell and the propriospinal interneurons, are also an important part of the control process. As mentioned earlier, the Golgi tendon organs generate a ceiling effect for maximum muscle tension. The Ib afferents from these organs connect to their respective Ib interneurons. These interneurons also receive supra- and propriospinal influences from above that facilitate antagonists and inhibit the firing of agonist muscles (8,10). The type Ia interneurons receive activation from the type Ia neurons from the muscle spindle. When activated, the Ia interneurons facilitate agonist activity and reciprocally inhibit antagonist muscles, preventing the futility of co-contraction. Ia interneurons are also under supraspinal influence, and this plays a critical role in strengthening of reciprocal inhibition by the type Ia interneuron. The loss of supraspinal influence on the Ia interneurons plays a critical role in co-contraction and cerebral origin spasticity (12).
The process of recurrent inhibition involves the Renshaw cell, which receives input directly from the a motor neuron. This process shuts off agonist activity by its direct effect on the a motor neuron, in addition to facilitation of antagonist function mediated via the antagonist muscle’s Ia interneuron (13). Tight motor control requires the function of the Renshaw circuit, and a loss of its function may greatly compromise movements (10). Like many other neurons, spinal and supraspinal input influence Renshaw cell function. Renshaw cell inhibition is increased in SCI (14).
Supraspinal Influences
Supraspinal influences play a major role in both volitional movement and the pathophysiology of spasticity. Rothwell et al. (15) demonstrated corticomotorneuronal pathways. Originating from the primary motor cortex, the corticomotorneuronal pathways are specific for specialized coordinated functions such as truncal balance or initiation of fine coordinated hand movements. Loss of these fibers leads to a functional deficit more than to spasticity. Reducing tone from the hands may improve passive and gross hand function but may not greatly improve fine movement (16).
The corticospinal tract is the major motor tract and originates from many areas within the brain. These include the extrapyramidal cells from the prefrontal region, the supplementary motor region, the cingulate gyrus, and the postcentral gyrus of the parietal lobe. The pontine medial reticulospinal and lateral vestibulospinal tracts are the main extensor pathways within the brain. The pontine system facilitates the a and γ motor neurons of the extensors of the limb muscles with some input into the system from the sensorimotor cortex. The lateral vestibular tract is located in the ventromedial portion of the cord and terminates at the spinal cord motor neurons. Stimulating the lateral vestibular tract affects the motor neurons of the flexor muscles differently from the extensors, with the a and γ motor neurons of the flexors inhibited and those of the extensors facilitated. The nucleus of the cerebellum also has an excitatory influence on extensor pathways (17).
Several pathways facilitate flexion. The medullary lateral reticular formation (MLRF) inhibits extensor pathways. The cortex facilitates its action, and cortical injury can lead to
net overactivity of the lower-extremity extensor system. The MLRF demonstrates its effect through its connections to the motor neurons, type Ia interneurons, and type Ib system. In cats, the corticospinal, corticoreticulospinal, and corticorubrospinal, all show significant flexor facilitation. Through interneurons, the corticorubrospinal tract excites flexor motor neurons and inhibits extensors. In addition, the medullary reticulospinal tract is a predominant part of a largely flexororiented system (18).
net overactivity of the lower-extremity extensor system. The MLRF demonstrates its effect through its connections to the motor neurons, type Ia interneurons, and type Ib system. In cats, the corticospinal, corticoreticulospinal, and corticorubrospinal, all show significant flexor facilitation. Through interneurons, the corticorubrospinal tract excites flexor motor neurons and inhibits extensors. In addition, the medullary reticulospinal tract is a predominant part of a largely flexororiented system (18).
PATHOPHYSIOLOGY OF SPASTICITY
Origin of Spasticity
So from where does spasticity come? Dietz and Berger (19) have suggested that intrinsic properties of the muscle itself could explain the changes seen with spasticity. However, Nielsen et al. (20) feel that the term spasticity should only be used when the disorder is a result of “alteration of central processing of sensory input and to exclude structural changes in the muscles.” Based on work from animal models, the concept of “gamma rigidity” was raised. This concept states that through overfiring of the γ motor neuron, the spindle would be too taut and the Ia interneurons would be hyperexcitable. Efforts at identifying this with microneurography failed to confirm this hypothesis (21). Delwaide (22) felt that spasticity resulted from a loss of descending, facilitatory, inhibitory influences that act on Ia interneuron inhibition. In other words, reciprocal inhibition mediated through the Ia interneuron inhibition requires facilitation from higher centers. With injury to the central nervous system (CNS), the interneuron is unable to shut off antagonist muscles firing, with resultant increased velocity-dependent resistance to movement. The concept of a hyperexcitable motor neuronal pool has also been recently raised. In essence, these neurons would be hypervigilant and initiation of firing would occur with less excitation. This may result from a loss of tonic inhibition secondary to a loss of supraspinal influences. Some have expressed the belief that the ionic properties of the membrane itself are changed as well. Other theories that may explain spasticity include central collateral sprouting (23), presynaptic disinhibition (22), and denervation hypersensitivity (24). Neurotransmitters may also play some role in spasticity; some suspects include serotonin and substance P. In animal literature, serotonin has been noted to prolong responses and facilitate extensor responses (25). In general, no singular theory has been able to fully explain the pathophysiology of spasticity.
Other Muscle Overactivities Seen in the UMNS
There are numerous types of muscle overactivity that result from the UMNS that require treatment. As Sheean (26) stated in his excellent review article, the different components are commonly lumped under the term spasticity. As a result, the word is often used generically for muscle over activity from the UMNS. It is important to differentiate them.
In his article, Sheean stressed the importance of understanding the different components of the UMNS and how it may result in different treatment approaches and results. Sheean divides the different components of the UMNS into three distinct categories based on their underlying etiology: (a) spinal reflexes (stretch, nociceptive and cutaneous), (b) efferent drives that are not totally dependent on afferent feedback from the periphery, and (c) disorders of voluntary muscle movement.
As a result of damage to the CNS, there is abnormal processing of spinal reflexes which results in many of the positive components of the UMNS. These reflexes are dependent on afferent feedback from the periphery including muscle stretch, pain or stimulation of the skin. The increase in stretch reflexes falls into this first category and includes tonic (baseline tone) and phasic (from sudden stretch e.g., deep tendon reflexes [DTRs] and spasticity) responses. Other related components include clonus, flexor reflex afferents that result from noxious stimulation and cutaneous reflexes such as the Babinski.
In the second category, Sheean included spastic dystonia and associated reactions. Spastic dystonia is a term that was created by Denny-Brown (27) to describe his observation that some of the spinal cord injured cats held their limbs in a flexed position. The position of the cats’ limbs was not a result of a stretch and therefore was not a result of a reflex activity. This was even more strongly demonstrated when the posture remained after the dorsal root was transected. The only explanation that he could find to account for the observation is a supraspinal efferent drive to the motor neuron. The commonly seen clinical scenario that corresponds to Denny-Brown’s cat model is the stroke patient whose arm rests in a flexed position. Associated reactions are another example of a positive UMNS that results from efferent supraspinal stimulation to the motor neuron. This is often seen when a person’s arm gets progressively higher when he or she tries to push up from a chair or walk a distance. It appears to be related to the amount of effort that the person is exerting and/or the severity of the tone in the extremity (26). One theory regarding the etiology of this phenomenon is an inability to stop the spread of muscle activity. Treating this problem may prevent a person from being thrown off balance, thus facilitating transfers and/or mobility. An important clinical point is that this disorder could be resistant to a treatment that reduces sensory afferent input such as a dorsal root rhizotomy (DRR).
The third category is disorders of voluntary movement. A disturbance in reciprocal inhibition fits this category, as the prevention of pathological reciprocal inhibition is an important component of normal motor control. In the normal state, the type Ia interneuron receives input from the spindle-based Ia neuron and with facilitation from above is supportive of agonist activity and inhibits antagonist firing (12). Two clinical examples of this normal activity is the relaxation of the elbow flexors during attempted elbow extension and the relaxation of the plantar flexors during attempted dorsal flexion.
The authors have chosen these movements because they are commonly affected by pathological reciprocal inhibition as a result of the UMNS. Sheean (26) spoke about two subtypes of this condition. In the first subtype, the inhibition is reduced while in the second, it is increased. When a person tries to extend his or her elbow but contraction of the elbow flexors prevents, slows or at the least makes the movement more difficult, this may well be as a result of reduced reciprocal inhibition. Possible etiologies of this pathology include reflex (tonic and phasic) activity of the elbow flexors or simultaneous activation of the motor neurons of the flexors and extensors. The second type of reciprocal inhibition is that of increased reciprocal inhibition. This is commonly seen in the person who has the ability to dorsi-flex the ankle but is unable to do during attempted ambulation because the reciprocal inhibition generated by pathologic plantar flexors inhibits the tibialis anterior activation. By reducing these muscle overactivities, there is a reasonable likelihood of increasing volitional firing of the antagonist muscle that may improve volitional function. The importance of recognizing these conditions cannot be overemphasized.
The authors have chosen these movements because they are commonly affected by pathological reciprocal inhibition as a result of the UMNS. Sheean (26) spoke about two subtypes of this condition. In the first subtype, the inhibition is reduced while in the second, it is increased. When a person tries to extend his or her elbow but contraction of the elbow flexors prevents, slows or at the least makes the movement more difficult, this may well be as a result of reduced reciprocal inhibition. Possible etiologies of this pathology include reflex (tonic and phasic) activity of the elbow flexors or simultaneous activation of the motor neurons of the flexors and extensors. The second type of reciprocal inhibition is that of increased reciprocal inhibition. This is commonly seen in the person who has the ability to dorsi-flex the ankle but is unable to do during attempted ambulation because the reciprocal inhibition generated by pathologic plantar flexors inhibits the tibialis anterior activation. By reducing these muscle overactivities, there is a reasonable likelihood of increasing volitional firing of the antagonist muscle that may improve volitional function. The importance of recognizing these conditions cannot be overemphasized.
TABLE 50.1 Sample Passive and Active Goals | ||||||||||||||||||||
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TABLE 50.2 Commonly Used Oral Medications | ||||||||||||||||||||||||
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MANAGEMENT OF SPASTICITY AND THE UMNS
An integrated team is required to successfully manage spasticity. Under the direction of a physician skilled in the management of spasticity, the team should be able to deliver the entire continuum of services. The remainder of this chapter addresses the indications and benefits of the different treatment modalities (Table 50-1). How do clinicians decide what treatment to offer? Often the question is answered by the skills of the treating clinician, in that a man with a hammer sees everything as a nail. A physician skilled in chemoneurolysis is far more likely to perform a nerve block than one less comfortable with the procedure. Physicians may be more inclined to prescribe an oral pharmacologic agent than to prescribe serial casting or splinting. Therefore, it is important for the treatment team to communicate effectively and access needed surgical consultations as appropriate. Of note, not all spasticity is dysfunctional. Some women with spasticity use their elbow flexor tone to hold their pocketbooks, whereas lower-extremity tone may assist in transfers, standing, and ambulation. Optimizing function should be the primary outcome parameter in the treatment of spasticity. To maximize quality of life improvements for patients undergoing spasticity management, the entire treatment team must monitor the efficacy and adverse effects of spasticity interventions and adjust treatment accordingly (Table 50-2).
Functional Goals Should be the Target for Treatments
Spasticity and the UMNS are a result overall of an irreversible process within the CNS. Treatment decisions should be made based on the functional limitations imposed by spasticity and the UMNS, neither of which represents an independent disease state. Specific impairments or functional deficits such as pain, problems with position, hygiene, or mobility are the specific issues that therapy should address. Gans and Glenn (1) divided treatment goals into two categories. The first is the management of passive function, such as reduction of pain, positioning, hygiene, splint wearing, and prevention of contracture. The second is related to active functional activities; as they described it, “Diminished capacity of the patient to accomplish useful work with the motor system.” The goals of these treatment interventions are to improve volitional purposeful movement. Some examples include unmasking functional movement that is inhibited by antagonist spasticity, improving transfers, ambulation, and performance of activities of daily living (ADLs).
Treatment Options
Reduction of Noxious Stimulation
The first step in any program to manage spasticity is the reduction of noxious stimulation. Spasticity and muscle overactivity have been shown to be increased as a result of this input (28). Stimulation of the flexor reflex afferents may lead to an increase in pathologic activity (29). The term noxious stimulation encompasses a wide variety of conditions such as a pressure ulcer, ingrown toenail, contracture, kinked catheter, urolithiasis, urinary tract infection, deep venous thrombosis (DVT), heterotopic ossification, fecal impaction, sepsis, and fracture. This is just a partial list. Addressing these conditions should generally be the first approach in spasticity management.
Positioning
Proper positioning is an important component of spasticity management. Poor positioning can result in an increase in spasticity and in decreased ROM, contractures, increased noxious stimulation, pain, and exacerbation of a vicious cycle that can lead to worsening spasticity (30). This is especially true in the ICU and acute hospital (28). Proper goals for a positioning program include improvement in body alignment and greater symmetry. Benefits include easing of nursing care, facilitation of therapy, and maximization of a patient’s function. Postures that should be avoided include a leg scissoring posture (bilateral hip extension, adduction, internal rotation), windswept position (hip flexion, abduction, external rotation on one side and relative hip extension, adduction, and internal rotation on the other), and frog-leg position, which can exacerbate the spasticity. Positioning is also important in the wheelchair. Tone can be minimized by placing the patient with the hips and knees at 90 degrees and by maintaining good torso position (30). While its full implication for treatment has not yet been clarified, the joint angle position during assessment of spasticity contributes to the measurement of both tone and reflexive action at the ankle and elbow joints (31,32).
Stretch and Casting
The UMNS causes muscle shortening for several reasons. One reason is the immobilization of paralyzed muscles in shortened positions. This resultant decrease in longitudinal tension (muscle unloading) can predispose to contracture. Immobilization can also cause a reduction in protein synthesis in immobilized muscles, thus promoting atrophy (33). Spasticity and muscle overactivity also play a part in muscle shortening (34). This can in turn result in an increase in spindle activity and sensitivity (35). Gracies et al. (28) have discussed the need to promote the commencement of stretch early in the treatment of any neurologic condition. Stretch has the advantage of being a focal treatment that can combat the development of the previously mentioned muscle shortening and increase in spindle sensitivity (33).
Schmit et al. (36) have demonstrated the benefit of a relatively brief stretch in the management of spasticity. However, the benefit is short-lived, as the tone returns after a single contraction (37). Therefore, stretch needs to be applied for a longer period of time to have potential functional benefit. A study involving the use of a Lycra garment that provided a stretch of 3 hours demonstrated both an improvement in spasticity and good patient tolerance (38). Stretch has been shown to be useful in volitional movement in both agonist (39) and antagonist muscles (40). Finally, in a nonblinded convenience sample, Selles et al. (41) reported that a 4-week program utilizing a device to deliver “intelligent stretch” was effective in treating spasticity and contracture in stroke patients as measured by joint properties, gaits speed, and subjective reporting. In summary, stretching activities have the advantage of being a local treatment, with limited risk that has demonstrated proven effect in the management of spasticity.
Chronic stretch via casting or splints changes reflexive activity and reduces the stretch reflex (42, 43, 44). Serial casting is defined as the use of successive casts to treat increased tone and contractures. Some of the original work regarding the effectiveness of serial casting in the management of spasticity and contracture comes from the group at Rancho Los Amigos (45), which reported their treatment of the lower extremities in 42 patients with a brain injury. It is not definitely known how often to change serial casts. Pohl’s group (46) performed a retrospective chart review investigating the differences between changing casts every 1 to 4 days versus 5 to 7 days. They found that at 1 month the changes in ROM between the two groups were comparable, but the complication rates were very different. The group with casts changed every 5 to 7 days had a complication rate of over 29% while the group with more frequent changes only had a rate approaching 9%. Almost 13% of the casting efforts had to be discontinued secondary to complications. A review of the literature discussing upper-extremity casting was unable to demonstrate a definitive answer supporting or rejecting casting as a treatment. Using casting to facilitate the action of chemical denervation has been addressed in several studies. Some preliminary studies have shown that using casting in combination with botulinum toxin treatment has increased the treatment effect in the stroke
(47) and cerebral palsy (CP) populations (48). The duration of the effect of serial and bivalve casting has been addressed in several studies. One study demonstrated that the effect was maintained 1 month after its use was discontinued (46). Its use in combination with botulinum toxin has been studied. In summary, casting can be considered a beneficial treatment option in the management of spasticity and contractures and is commonly used in programs with experienced clinicians; definitive recommendations regarding its use cannot be made at this time.
(47) and cerebral palsy (CP) populations (48). The duration of the effect of serial and bivalve casting has been addressed in several studies. One study demonstrated that the effect was maintained 1 month after its use was discontinued (46). Its use in combination with botulinum toxin has been studied. In summary, casting can be considered a beneficial treatment option in the management of spasticity and contractures and is commonly used in programs with experienced clinicians; definitive recommendations regarding its use cannot be made at this time.
Physical Modalities
Physical modalities can play a role in the management of spasticity. Like stretching, they have the benefit of being benign interventions with localized treatment benefits. The use of these agents will most likely remain as part of a spasticity treatment program. Used correctly, the physical modalities can have an important role in spasticity management.
Cooling of muscles is beneficial in the management of spasticity (49,50). It both inhibits the monosynaptic stretch reflexes and lowers receptor sensitivity after it is removed (51,52). Cooling can be used in different ways. The quick icing technique, with ice applied with a light striking movement, results in facilitation of a and γ motor neurons and is used to facilitate antagonist function (53), whereas prolonged cooling can result in decreased conduction velocity and a reduction in the maximal motor complex motor action potential (49,54, 55, 56). The issue of cooling and muscle elasticity was addressed in a study that found a 3% to 10% decrease in elastic stiffness after a 30-minute ice cooling over the calf muscles (56). However, the effect lasted less than 1 hour. Another method of cooling delivery includes the use of an evaporating spray, such as ethyl chloride (57). With their short duration of action, the cooling modalities may have their greatest utility by therapist to reduce muscle overactivity to allow other therapeutic interventions.
Heat is another modality that can be applied in various forms. Ultrasound, paraffin, fluidotherapy, superficial heat, and whirlpool are some of the most common ways heat is applied. Heat’s effect has a short duration (58), and, like cold, its application should be followed immediately by stretching and exercise. The effects of heat on spasticity have been studied in only a limited way. Its major effect seems to be related to an increase in elasticity that may assist in stretching activities (59).
Deeper heating modalities have also been used in the management of spasticity. Wessling et al. (60) demonstrated that 1.5 W/cm2 in combination with stretch resulted in a 20% greater distensibility than stretch alone.
Electrical Stimulation
Electrical stimulation is another modality that can help spasticity management. Transcutaneous electrical nerve stimulation (TENS) units have been shown to be useful in the management of pain. Through its nociceptive action and resultant reduction in pain, it was thought to reduce spasticity. Specifically, by reducing the flexor reflex afferents that are facilitated by nociceptive stimulation (29), Bajd et al. (61) demonstrated a reduction in SCI-related spasticity in three of six patients in a dermatomal pattern, while a group applying TENS in an acupuncture method demonstrated a substantial reduction in spasticity that was partially reversed by coadministration of naloxone (62). Other potential mechanisms of action for spasticity reduction include inhibition or fatiguing of spastic muscles and possible activation of antagonist muscles through the Ia interneurons (63).
Numerous electrical stimulation devices are now being used to facilitate motor recovery secondary to CNS pathology. While the literature concerning these devices deals primarily with recovery; some information regarding their effect on spasticity has been reported. A single-blinded study performed in 2005 evaluated the effect of functional electrical stimulation (FES) on acute stroke patients. This study reported that 15 sessions of 30 minutes of FES administered in a reciprocal fashion to imitate normal gait resulted in improved ambulation and spasticity as measured by the Composite Spasticity Scale (64). Chen et al. (65) tested the effect of surface stimulation on the gastrocnemius of chronic stroke patients showing electrophysiological changes and a trend to a reduced ankle Ashworth score. Aydin’s group (66) provided evidence that TENS may be of value as an adjunct for spasticity management in the stroke population. A recent study (67) on stroke patients demonstrated that ankle plantar flexor tone could be reduced with a combination of Bobath techniques and 9 minutes of stimulation to the dorsal flexor muscles. Some limited results have also been demonstrated with the use of electrical stimulation in people with CP (68,69). Finally, Krause et al. (70) demonstrated that an FES bike was beneficial in the management of spasticity secondary to MS.
Pharmacologic Treatments
Four common methods are currently being used in the delivery of pharmacologic agents. The oldest method is delivery though the enteral system, either by mouth or via gastrostomy tube. Agents such as baclofen, benzodiazepines, or tizandine are delivered in this fashion. These agents undergo systemic absorption and demonstrate an effect throughout the entire body. A second method, which is closely related to enteral delivery, is the use of a transdermal system. An example of this is Catapress TTS. Medications administered in this fashion are also absorbed systemically and demonstrate their effects throughout the body. Transdermal systems differ from the enteral methods by having a more steady-state blood drug level throughout the day with less fluctuation. Intrathecal administration of active agents is a third method of drug delivery. By placing the medications closer to their site of action, systemic side effects are reduced and clinical efficacy is obtained
with lower total doses. Baclofen, morphine, and clonidine are some of the more common medications that are delivered in this manner. Local injection of chemodenervation agents is the fourth method of drug delivery. Agents such as phenol and ethanol classically and now in the last decade the botulinum toxin products fall in this category. This last mode of administration is the best choice for treating a focal issue with a minimum of systemic effects, though some systemic absorption is still detectable.
with lower total doses. Baclofen, morphine, and clonidine are some of the more common medications that are delivered in this manner. Local injection of chemodenervation agents is the fourth method of drug delivery. Agents such as phenol and ethanol classically and now in the last decade the botulinum toxin products fall in this category. This last mode of administration is the best choice for treating a focal issue with a minimum of systemic effects, though some systemic absorption is still detectable.
Specific Components of the Pharmacologic Decision Process
Many factors contribute to the decision of which pharmacologic agent to use in a particular patient. A partial list includes etiology, time since onset of medical issue, prognosis, access to medical services, personal support system, concurrent medical problems, cognitive status, and financial resources. All these items are important. A brilliantly planned intervention that the patient cannot afford is of no value. Similarly, an aggressive outpatient therapy program is of no value if transportation cannot be obtained for the patient.
Etiology
Spasticity may present similarly despite originating from different etiologies. Nonetheless, responsiveness to various treatment interventions may vary depending on the etiology. As an example, enteral pharmacologic agents have been shown to be of great efficacy in the management of spasticity resulting from SCI or MS (73, 74, 75, 76, 77), whereas the benefit in spasticity caused by traumatic brain injury (TBI) or stroke is far less apparent. A further complicating factor in cerebral origin spasticity is the potential for impairment of recovery secondary to treatment (78), or a potentially intolerable cognitive side effect profile even when the agent may be effective (79).
Time Since Onset
As a general rule, more aggressive spasticity interventions are tried later in the course of an event. Medications that may impair recovery are less likely to be used early on. For patients who have low-level functioning post TBI, physicians are less likely to prescribe sedating antispasticity agents. Phenol neurolysis is rarely used early in recovery, as the scarring of muscle and nerve and long duration of action may be undesirable in a recovering patient. Orthopedic interventions are almost never offered early on, as there needs to be stabilization of the neuromuscular structures before permanent surgical intervention. Relative to intrathecal baclofen (ITB), there is now some controversy as to what is considered too early. A recent report from France demonstrated that ITB may be beneficial for recalcitrant spasticity when initiated in the first month post injury (80).
Functional Prognosis
When a patient’s prognosis for motor and functional recovery is very guarded, this may lead clinicians to attempt more aggressive, permanent interventions such as a rhizotomy. The need to facilitate care delivery with aggressive means of reducing spasticity may be preeminent over efforts to promote an unlikely recovery.
Support System
The availability of social support may be an important factor in the management of spasticity. A number of questions should be considered. Can medication administration be supervised in the cognitively impaired patient? A family member or other caregiver may be critical for the physician to safely prescribe medications. Are supervision and assistance available for transportation to therapy or assistance in safe utilization of splinting devices? Will the patient be able to follow up for ITB pump refills or will there be the risk of withdrawal if the patient fails to follow up for pump refills?
Cognitive Status
It is important to assess a patient’s cognitive ability when prescribing treatment. The clinician must address the patient’s ability to be compliant and remain safe while using a treatment modality. Will the patient be noncompliant with a medication and risk withdrawal seizures? Will there be a risk of skin breakdown with the use of a splint or serial cast?
Concurrent Medical Problems
The overall medical condition of the patient being treated must be considered. Patients with hypotension, syncope, balance disturbances, or ataxia may be unable to tolerate the side effect profile of certain agents. Would an oral agent cause hypotension and resultant syncope, exacerbate ataxia, coordination, or balance disturbance? Does the patient have chronic infections that would increase the risk of development of an infection with an indwelling catheter or ITB system?
Distribution of Spasticity
How diffuse is the area that needs treatment? Is there a focal or segmental area that needs treatment or is spasticity distributed diffusely throughout the entire body? If there are only discrete regions or only the discrete regions need to be treated even in the midst of diffuse spasticity, chemodenervation may be most appropriate. If the target condition is more systemic, then treatment that is more global will be necessary.
Financial Issues
ITB and botulinum toxin injections cost thousands of dollars. Paying out of pocket for some modalities is not realistic and the physician, patient, and family have to utilize third-party payers. Some insurance companies are requiring trials with less expensive agents such as oral antispasticity agents before approving toxin injections. Clinicians are often required to justify their decisions and recommendations.
Oral and Transdermal Medications
Oral and transdermal medications are commonly used in the treatment of spasticity. Table 50-3 summarizes the usage of these medications.
TABLE 50.3 Comparisons of Different Treatment Modalities for Spasticity | ||||||||||||||||||||||||||||
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Benzodiazepines
The benzodiazepines were the first agents used in the management of spasticity. Of this class, diazepam (Valium) is most commonly used. Other agents include clorazepate (Tranxene) and clonazepam (Klonipin). Ketazolam (Loftran) is another benzodiazepine that has been trialed for spasticity and is available in Canada but not in the United States (81). The benzodiazepines’ mechanism of action is central in origin, acting on the brainstem reticular formation and spinal polysynaptic pathways (82). The benzodizapines demonstrate their effect via GABAA (γ-aminobutyric acid), which opens membrane Cl– channels with resultant hyperpolarization. The net effect is a reduction of monosynaptic and polysynaptic reflexes and an increase in presynaptic inhibition (81).
Initial dosing for diazepam is 2 mg bid or 5 mg at bedtime, with a gradual titration upward to a maximum of 60 mg/day for adults. Benzodiazepines are well absorbed after enteral administration and peak at 1 hour. There is a relatively long half-life for benzodiapines when accounting for its active metabolites, which ranges between 20 and 80 hours. The side effect profile can be quite problematic, including problems with addiction and withdrawal, ataxia, weakness, cognitive impairment, memory dysfunction, poor coordination, fatigue, and CNS depression that can be potentiated by alcohol. Research with diazepam has demonstrated improvements in painful spasms, hyperreflexia, and passive ROM. Evidence concerning functional improvement is limited.
Clorazepate has been shown to have a more favorable side effect profile than diazepam. In clinical trials, it was noted to have fewer problems with sedation and memory (83,84). Its half-life is relatively short but its active metabolite, desmethyldiazepam, has a half-life of up to 70 hours. In obese patients, the half-life of clorazepate can extend beyond 200 hours (85). Doses of 5 mg bid have been used in clinical trials.
Benzodiazepines in SCI
The greatest benefit for diazepam has been demonstrated in the SCI population. A double-blind crossover study with 22 patients with SCI-related spasticity demonstrated efficacy (86), whereas another study with 21 patients with MS or SCI showed that diazepam is superior to placebo in treating spasticity. Whether the benzodiazepines are better for complete or incomplete lesions is debatable. Whyte and Robinson (87) suggest that benzodiazepines are effective only for incomplete lesions, but this is still controversial (88,89). A survey performed at Veterans Administration SCI programs showed that 70% of prescribers routinely give benzodiazepines to their patients (90).
Benzodiazepines in MS
Studies performed in patients with MS have compared the efficacy and side effect profiles of the benzodiazepines versus baclofen. The two agents had very comparable efficacies and tolerance. Sedation was found more often with the benzodiazepines, whereas the baclofen group had a more varied list of side effects (91, 92, 93).
Benzodiazepines in Acquired Brain Injury (ABI)
Benzodiazepines are rarely used in the ABI population because of their potential for cognitive side effects as well as their potential to compromise motor recovery (78).
Benzodiazepines in CP
Few studies are available concerning benzodiazepine use in the CP population. Engle (94) conducted a double-blind crossover study that demonstrated the efficacy of diazepam in the management of patients with CP. However, determining whether the improvements were behavioral in origin was questionable. Mathew and Mathew (95) demonstrated in a
placebo-controlled study the efficacy of bedtime diazepam administration in improving ADLs and reducing the burden of child care in children with CP without significant adverse side effects. Nogen (96) studied diazepam and dantrolene in patients with CP and found benefit with both agents. Cruikshank and Eunson reported on the utility of intravenous diazepam in their management of planned discontinuation of ITB in three cases of individuals with CP (97).
placebo-controlled study the efficacy of bedtime diazepam administration in improving ADLs and reducing the burden of child care in children with CP without significant adverse side effects. Nogen (96) studied diazepam and dantrolene in patients with CP and found benefit with both agents. Cruikshank and Eunson reported on the utility of intravenous diazepam in their management of planned discontinuation of ITB in three cases of individuals with CP (97).
Baclofen
Baclofen (Lioresal) is another agent that mediates its activity through the GABA system. It differs from the benzodiazepines by mediating its effect via GABAB rather than by GABAA and is active both presynaptically and postsynaptically. Its action presynaptically is to bind to the GABA interneuron, where it causes hyperpolarization of the membrane that prevents the influx of calcium and resultant release of neurotransmitter. When it binds postsynaptically, it hyperpolarizes the cell membrane by acting on the Ia afferents. As a result, baclofen is inhibitory on both the monosynaptic and polysynaptic reflex pathways. Baclofen is eliminated via the kidney, and its half-life is roughly 3.5 hours (81).
When initiating treatment, 5 mg bid to tid is recommended, and this can be increased 5 to 10 mg/day/week. The Physician’s Desk Reference suggests a maximum dose of 80 mg/day, but while not routinely recommended, doses as high as 300 mg/day have been used safely (81). Baclofenrelated side effects reported include sedation, fatigue, weakness, nausea, dizziness, paresthesias, hallucinations, and lowering of seizure threshold. The patient is at greatest risk when the agent is abruptly discontinued, as hallucinations and withdrawal seizures have been reported (87). Since baclofen primarily undergoes renal clearance, dosing may need to be adjusted with kidney-related issues (98). When switching from oral to either IV or ITB administration, one must be wary of potential withdrawal-related issues. This is based on the efficiency of localization that results from IV or intrathecal dosing, as there is a relatively low dose of baclofen in the brain as compared with the lumbar cord region.
Baclofen in SCI and MS
Much of the baclofen literature combines research on patients with SCI and MS; therefore it is appropriate to merge a discussion of baclofen in these populations, although some differences will be highlighted (73,98, 99, 100, 101). Feldman et al. (100) reported that the use of baclofen in patients with MS demonstrated a significant reduction in spasticity as well as reducing painful flexor spasms. Flexor spasms in the SCI population also responded to baclofen administration (73,74,102, 103, 104, 105). It is far more difficult to find studies that demonstrate functional improvement, given that investigations were unable to demonstrate improvements in ADLs and ambulation with administration of baclofen (102,104). Orsnes et al. (106) studied patients with MS treated with baclofen but again found no functional improvement. Nielsen et al. (107,108) studied the effect of oral baclofen on the soleus muscle. Treatment with baclofen reduced ankle stiffness and increased soleus response latency. However, it also was found to increase the weakness in soleus function, which may explain the lack of functional improvement.
Baclofen in ABI
Baclofen in CP
Milla and Jackson (112) conducted the one blinded crossover trial in the CP literature that demonstrated efficacy. Actual functional benefits were not seen, but decreased scissoring and improvements in ROM were noted. The authors reported few side effects and recommended dosing of a total of 5 to 10 mg total per day in divided doses for children 2 to 7 years of age. A recent publication looked at the effect of 4 weeks of oral baclofen on ten children with CP. The authors looked at the effect of medication on neuromuscular activation and ankle plantar flexor torque. Neuromuscular activation was measured using surface electromyography (EMG) generated during maximal voluntary contraction to the M-wave during supramaximal electrical stimulation of the tibial nerve. They noted a statistically significant improvement in neuromuscular activation but this was not accompanied with isometric plantar flexion torque. The authors hypothesize that the agent may be beneficial in the facilitation of strength training (113); however, further work is needed to address this question.
Dantrolene Sodium
Unlike many other agents, dantrolene (Dantrium) is an enteral medication that acts peripherally, at the level of the muscle itself. Its mechanism of action is to inhibit calcium release from the sarcoplasmic reticulum during muscle contraction. Rather than dampening neuronal activation, it reduces the strength of contraction. In addition to its action on the muscle extrafusal fibers, dantrolene reduces muscle spindle’s sensitivity by acting on the γ motor neuron (71). Dantrolene’s primary action is on fast-twitch fibers. Parameters affected by it include easier ROM and tone. Starting dose is 25 mg bid and can be increased weekly by 25 to 50 mg to a maximum of 400 mg/day (114). Dantrolene’s enteral half-life is approximately 15 hours and is given bid to qid (81). Dantrolene’s most wellknown side effect is potential liver toxicity. However, overall this is a rare occurrence, with a rate of only 1.8% (115) when administered for more than 60 days. Even when discovered it is usually reversible. It is found most commonly in women over the age of 40, especially if they had been on high doses, greater than 300 mg for a long period of time (116). Fatal liver failure has been reported in 0.3% of those who received the medication. Therefore, it is critical for clinicians to follow liver function tests (LFT) when prescribing dantrolene. Blood tests should be performed weekly for the first month, monthly
for the remainder of the first year, and four times a year after that. In addition to liver toxicity, other problems associated with dantrolene include weakness, paresthesias, nausea, and diarrhea (81). Rare side effects also include anorexia, enuresis, visual disturbance, acnelike rash, inhibition of platelets, eosinophilic pleural effusion syndrome, and pericardial effusions (116,117). There has also been a single case report of a minimally conscious 43-year-old female with acontractility of the bladder (118).
for the remainder of the first year, and four times a year after that. In addition to liver toxicity, other problems associated with dantrolene include weakness, paresthesias, nausea, and diarrhea (81). Rare side effects also include anorexia, enuresis, visual disturbance, acnelike rash, inhibition of platelets, eosinophilic pleural effusion syndrome, and pericardial effusions (116,117). There has also been a single case report of a minimally conscious 43-year-old female with acontractility of the bladder (118).
Dantrolene in SCI
Since dantrolene is associated with weakness, there have been few trials reported with its use in SCI. An early study by Glass and Hannah (119) reported that it was more effective than diazepam in controlling spasticity but was associated with greater weakness. Studies have demonstrated improvements in ROM and tone but no functional improvement (120,121). Additionally, two cases are reported in the literature where SCI patients responded to dantrolene when treated for baclofen withdrawal (122,123). A recent 2006 Cochrane review failed to reveal any studies of dantrolene in SCI patients rigorous enough to meet the criteria (124).
Dantrolene in MS
There is limited literature describing the use of dantrolene in patients with MS. Again, this may well be due to a poor tolerance, given the undesirable side effect of additional muscle weakness. Two studies performed demonstrated improvement in tone and ROM. However, the benefits were outweighed by the clinical weakness found while on the medication (125,126). Its use in patients with MS cannot be recommended from the literature.
Dantrolene in ABI
Whyte and Robinson (87) have recommended dantrolene for use in the treatment of ABI-related spasticity. Chyatte et al. (127) reported on nine patients with stroke-related spasticity. Although they demonstrated no functional improvements in ADLs and mobility, they noted improved ROM, DTRs, and some upper-extremity function. Ketel and Kolb (128) reported that in their selected population of dantrolene responders, there was an exacerbation of spasticity accompanied by clinical deterioration when they were placed on placebo.
Dantrolene in CP
While reviewing the data concerning the use of dantrolene in patients with CP, Krach (129) reported on four studies that demonstrated good efficacy. Haslam et al. (130) reported decreases in DTRs and scissoring. Dosing in the pediatric population has been up to 12 mg/kg. Verrotti et al. (131) suggested that it could be efficacious when used in combination with diazepam and that it may be more effective than baclofen, with younger children demonstrating better tone reduction and older children showing improved motor movement.
Clonidine
Clonidine (Catapress) is an imidazoline derivative that is primarily an antihypertensive agent. It is a central acting α2-adrenergic agonist that has been shown to demonstrate some efficacy in spasticity management, primarily in SCI. It peaks in 3 to 5 hours when taken orally and has a usual half-life of 5 to 19 hours, with an extended half-life of up to 40 hours in persons with renal impairment. Clonidine’s clearance is primarily renal, with half of it first metabolized by the liver. Clonidine has two distinct mechanisms of action. First, it acts directly on the locus coeruleus and decreases tonic facilitation (81). Second, it also has a spinal mechanism, acting to enhance α2-mediated presynaptic inhibition (132, 133, 134). Clonidine doses as low as 0.1 mg orally are often effective in treating spasticity (133). A transdermal system that allows for more uniform blood levels and easier administration is also available. Side effects reported with clonidine include bradycardia, depression, lethargy, syncope, and hypotension (133,135). There is no literature to date describing clonidine use in patients with MS.
Clonidine in SCI
Two separate reports demonstrate clonidine’s potential efficacy in the SCI population (136,137). Nance et al. (134) showed that resistance to stretch was reduced in her small series of four patients treated with 0.2 mg/day. Donovan et al. (132) reported on the use of clonidine as an adjunct to baclofen in spasticity management. They reported an overall 56% response rate, with improvements noted in persons with paraplegia and tetraplegia with complete and incomplete lesions. The authors reported that three patients who had been responsive had to be discontinued secondary to postural hypertension.
Clonidine in CP
Lubsch et al. (138) published a retrospective chart review of 87 children with the diagnosis of spasticity secondary to TBI or CP who were on either baclofen or clonidine. Eighty-six persons were taking baclofen and only 31 were taken clonidine. Eighty percent of the population studied included in this review had the diagnosis of CP, with the remaining having the diagnosis of TBI. The two populations were not analyzed separately in the paper which further limits its utility. The paper did report on the safety and tolerability of clonidine administration to children with CP in doses ranging from 0.025 to 3.6 mg/day.
Clonidine in ABI
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