CHAPTER 25

Poststroke Spasticity Management With Botulinum Toxins and Intrathecal Baclofen

Anthony B. Ward and Poornashree Holavanahalli Ramamurthy

Spasticity is described as increased muscle tone that is involuntary and clinically recognized as a resistance to passive muscle stretch, increasing with the velocity of stretch (1,2). It is a physiological consequence of an insult to the brain or spinal cord that can have a devastating effect on function, comfort, care delivery, and may also lead to musculoskeletal and other complications, which can lead to further ill-health and even death.

Spasticity was defined by Lance in 1980 as “a motor disorder characterized by velocity-dependent increases in tonic stretch reflexes with exaggerated tendon jerks, resulting from hyperexcitability of the stretch reflex” (1). A more recent description of spasticity was written in 2005 to move away from trying to define it and this is “a disordered sensori-motor control resulting from an upper motor neuron (UMN) lesion, presenting as intermittent or sustained involuntary activation of muscles” (2). It is a common feature of the UMN syndrome (UMNS) following stroke. Poststroke hemiparesis, together with abnormal muscle tone, is a major cause of morbidity and disability and results in substantial burden for patients and caregivers.

Strokes affecting the motor cortex or internal capsule may produce initial hypotonia and absent tendon jerks, followed several days or weeks later by the onset of spastic hypertonia in antigravity muscles (most often muscles crossing two joints that are designed to support the trunk). These patients often demonstrate recognizable antigravity postural patterns characterized by shoulder adduction, and elbow and wrist flexion in the upper limb, and hip adduction, knee extension, and ankle plantar flexion in the lower limb. This abnormal limb posture interferes with personal hygiene, dressing, and mobility, as well as affects the individual’s self-image. Spasticity can also result in urinary incontinence and limit sexual intimacy. In the absence of functionally useful voluntary limb movement, spasticity can maintain an abnormal resting limb posture leading to contracture formation. It can increase the risk of skin and tissue breakdown secondary to positioning difficulties and shearing pressure. These abnormal resting positions can cause articular and peri-articular pain. Spasticity, therefore, indirectly affects many aspects of self-care through the maintenance of abnormal limb posture.

Exaggerated reflex responses to cutaneous stimuli may cause painful flexor or extensor spasms, which can interfere with seating and transferring and cause sleep disturbance. It can also lead to weight loss and/or an inability to gain weight secondary to high caloric expenditure. In patients with functionally useful voluntary limb movement, inappropriate co-activation of agonist and antagonist muscles can impede normal limb movement. Effortful activities may generate inappropriate muscle activity causing involuntary movements in the paretic limbs, which are associated reactions and these can interfere with standing and balance (3). The physical limitations associated with spasticity increases the risk of falls and consequent fractures (4). The deformity or disfigurement from spasticity, pain, and lack of functional independence can all negatively influence the mood of the patient and result in depression.

Spasticity despite its complications has various advantages. It can substitute for muscle strength and may help with weight bearing and hence transfers, standing, and walking. It can maintain muscle bulk, improve circulation, prevent deep vein thrombosis, edema, and also reduce the risk of osteoporosis.

PRINCIPLES OF MANAGEMENT OF SPASTICITY

It is very important to consider the indications for treating spasticity and the expectations from such treatments. Spasticity may be helpful in ambulant patients, allowing them to stand and walk, when the underlying weakness would not otherwise allow them to do so. Therefore, in this instance, reducing muscle tone may worsen their mobility and disable them further. 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, clear thoughts are required of the consequences of treatment in order to arrive at useful goals for both the patient and caregiver.

The most valuable aims of therapy are to increase functional capacity (where it is possible to do so), relieve symptoms and decrease the burden of care. These should be negotiated between the patient, the family, or caregiver and the treating team. The goals of spasticity management should be to:

Effective management of spasticity requires a multidisciplinary team working together with the patient, family, and caregivers (5). There are various factors that influence the treatment of spasticity—duration, size, and location of the lesion; the duration and severity of spasticity and the other concomitant features of the UMNS; current functional status and future goals; underlying diagnosis and comorbidities; success of prior interventions; the likely duration of therapy; the ability to comply with treatment; and the availability of support/caregivers and follow-up therapy.

The primary aim of the treatment of spastic muscles is to maintain length and allow normal positioning of the limbs to prevent secondary soft tissue shortening. Successful treatment strategies have now been developed and there is good evidence of treatment effectiveness. These can vary from the conservative physical therapy and splinting to the more aggressive surgical interventions. The different treatment approaches should be integrated with one another as well as into the overall rehabilitation program of an individual patient.

Spasticity at any given instance is dependent on various factors such as patient’s physical and mental status, the position of the body, and the presence of any noxious stimuli. Due to its multifactorial nature, it is difficult to measure spasticity directly in routine clinical settings. However, measurement of spasticity is essential to assess the response to treatment. Scales are the most common clinical approach to the routine measurement of levels of spasticity. The Ashworth Scale (Table 25.1) is based on the assessment of resistance to stretch when a limb is passively moved. Bohannon and Smith proposed a modification by adding a 1+ point in the scale, which relied on the correct identification of the catch. This is the “Modified” Ashworth Scale (Table 25.1), which is in routine use for the measurement of spasticity, especially after stroke.

TABLE 25.1

ROM, range of motion.

Source: From Refs. (6) and (7).

The options of spasticity management can be broadly grouped into preventive measures, physical management, and medical and surgical interventions.

Prevention consists of identification and treatment of the exacerbating factors. These may include infections (eg, bladder, toenail, ear, or skin); constipation; bladder distension; pressure ulcers; deep venous thromboses; and poststroke pain syndrome (eg, cortical dysaesthesias, central poststroke pain, and thalamic pain).

Physical measures are the mainstay of spasticity treatment. Muscle stretching, serial or inhibitive casting, and splinting/orthotics provide a means to maintain sustained stretching. Postural management through the use of wheelchair seating, standing frames, bed positioning, taping, dynamic and static splints reduces synergy patterns and discourages the development of abnormal posture. An orthosis may help to hold a limb in a functional position, reduce pain, and prevent deformity. Other physical interventions include strengthening of antagonistic muscle groups, functional electrical stimulation (ES), hydrotherapy, massage, vibration, heat modalities, cryotherapy, ultrasound (8), and hippotherapy (9).

PHARMACOLOGICAL MANAGEMENT OF SPASTICITY

All medical interventions are adjunctive to a program of physical treatment, removal of exacerbating stimuli, and patient and carer education. Pharmacological interventions can be broadly grouped into those for the relief of generalized problems of spasticity (oral medication), those for the relief of regional problems of spasticity (intrathecal medication), and those for the focal and multi-focal problems of spasticity (chemodenervation with botulinum toxin [BoNT] or phenol/alcohol induced nerve blockade).

Oral Medicines

The use of oral medications for managing spasticity has been well established, extensively researched and found to be effective. However, oral medications should be used cautiously in early rehabilitation as they can cause unwanted adverse effects that include sedation as well as changes in cognition and mood. Forty percent of patients are unable to tolerate oral agents because of side effects or are unable to achieve an adequate antispastic effect before side effects occur (10). With the development of targeted antispasticity treatments, the role of systemic antispasticity agents in a disease, which causes “focal spasticity problems,” is likely to diminish, particularly in the context of acute rehabilitation (3).

The commonly used oral medications for managing spasticity are baclofen, benzodiazepines, dantrolene sodium, and tizanidine. Gabapentin, clonidine, and cannabinoids are other agents that have been found to be beneficial in selected patient groups.

Baclofen

Baclofen is a gamma-aminobutyric acid (GABA) agonist, and its primary site of action is the spinal cord. It selectively binds to the GABA-B receptors, which are located pre- and postsynaptically and coupled to calcium and potassium channels (11). Presynaptic binding hyperpolarizes the membrane, restricting calcium influx into presynaptic terminals and thereby decreasing neurotransmitter release in excitatory spinal pathways and decreasing alpha motor neuron activity (12). Postsynaptic binding increases potassium conductance and hyperpolarizes the membrane, thus enhancing presynaptic inhibition. Activation of GABA-B receptors may also inhibit gamma motor neuron activity and decrease muscle spindle sensitivity (13,14).

Baclofen is poorly lipophilic and hence has limited ability to cross the blood–brain barrier. Oral administration, therefore, requires higher doses to achieve clinically significant effects. The adverse effects such as lethargy, drowsiness, and sedation are dose related. Oral administration is frequently ineffective in controlling severe spasticity because of dosing limitations and systemic side effects. As many as 25% to 30% of people experience drowsiness, confusion, headache, and lethargy at doses that reduce spasticity (15). Consequently, patients with stroke and other brain injuries who have impaired cognition and arousal are not able to tolerate high doses of orally administered baclofen.

While each of the oral medications has been shown to reduce a patient’s muscle spasticity, many poststroke patients are unable to tolerate the medication’s side effects. Dantrolene has been shown to cause hepatotoxicity in approximately 1.8% of people using the drug (16). A study of the use of tizanidine in poststroke patients with spasticity saw a 40% withdrawal rate due to sedation and drowsiness (17). A study comparing tizanidine with BoNT in patients with upper limb spasticity due to stroke and brain injury demonstrated that BoNT had a statistically significant reduction of tone and decreased incidence of adverse reactions compared with tizanidine, suggesting that the toxin should be considered a first-line therapy for poststroke focal spasticity (18,19).

Botulinum Toxin

BoNT is one of the most potent biologic toxins known to man (20). It is produced by the bacterium Clostridium botulinum. There are seven serologically distinct toxin types named A, B, C, D, E, F, and G. BoNT type A is a powerful neurotoxin that has been developed into a therapeutic agent. In 1980, Dr. Alan B. Scott, used BoNT-A for the first time in humans to treat strabismus. Since then it has been used in various neurologic and nonneurologic indications such as dystonia, blepharospasm, torticollis, tremor, hyperhidrosis, and cosmetic applications. It has been used successfully for the treatment of focal spasticity.

Mechanism of Action. BoNT prevents the release of acetylcholine from the presynaptic nerve terminal, thus blocking peripheral cholinergic transmission at the neuromuscular junction (NMJ). This results in a reduction in muscle contraction and a dose-dependent reversible reduction in muscle power. The serologically distinct toxin types inhibit acetylcholine release into the synaptic cleft by binding one or more of the transport protein chains with high specificity (21,22). Active NMJs take up BoNT more avidly than NMJs at rest. The duration of muscle relaxation is usually 3 to 4 months, with loss of effect occurring through axonal sprouting proximal to the affected nerve terminal and muscle reinnervation by formation of a new NMJ. BoNT is a focal intervention for specific dystonic or spastic muscles.

Duration of Action. BoNT is taken up by the NMJ within 12 hours (23) and its beneficial effect occurs gradually over 4 to 7 days. It blocks neuromuscular synaptic transmission causing relaxation of muscle overactivity. This results in a biomechanical change in the muscle’s function and makes it amenable to stretching and lengthening. In addition, the weakening allows an opportunity for strengthening of antagonist muscles and thereby making it possible to restore balance between the two. The maximal response from the toxin is reached in approximately 4 to 6 weeks and lasts for about 12 to 16 weeks, which can be prolonged when accompanied by an appropriate physical management regimen.

Dosage. BoNT doses are generally adjusted according to the severity of spasticity, number of muscles involved, muscle bulk, age, treatment goals, previous response to BoNT therapy, and adjunct therapy applications. It is common clinical practice to initiate therapy at low, but effective, doses and titrate upward as effects become evident. The potency of BoNT-A is measured in mouse units (MU); 1 MU of BoNT-A is equivalent to the amount of toxin that kills 50% of a group of 20 g Swiss-Webster mice within 3 days of intraperitoneal injection (LD50). The maximum recommended dose in limb spasticity is given in the product information for BOTOX^®, Dysport^®, and Xeomin^® (5). The latter two products have a license for upper limb poststroke spasticity, whereas, BOTOX now has an additional license for spasticity in the ankle and lower leg. The Royal College of Physicians Guidelines gives a table of dosages for BOTOX and Dysport (5).

In order to overcome antibody formation and therapy failure, injecting the smallest effective dose, preventing short injection intervals, and using different BoNT serotypes are encouraged.

Due to the short duration of action, repeated injections are required for prolonged effect. Normally, in long-term conditions, a 3-month interval is recommended between injections to prevent the appearance of secondary nonresponse through immunizing antibodies. There is less of a worry in early rehabilitation following stroke or brain injury, as the majority of patients requiring BoNT only ever need one, or at the most, two injections in their life. As a result, clinicians can be less rigid about allowing a second injection, if required, within 3 months of the first (24).

Preparations. Two antigenically distinct serotypes of BoNT are available in the market as type A and type B. The different preparations of BoNT-A, onabotulinumtoxin-A (BOTOX; Allergan), abobotulinumtoxin-A (Dysport; Ipsen), incobotulinumtoxin-A (Xeomin; Merz Pharmaceuticals), and CS-BOT (Chiba Serum Institute) differ in potency.

Administration. BoNT is injected intramuscularly into specifically selected muscles. In order to ensure uniform uptake of BoNT within muscles, the muscle is injected in more than one site; particularly in larger muscles, it is important to divide the dose across multiple sites. Although it can diffuse through muscle fascial barriers, its effect is concentrated in the injected muscles so that it is possible to generate highly focal weakness (25). The injections do not have to be placed precisely in the motor end plate as BoNT diffuses to some extent within the muscle. Larger and superficial muscles are identified by palpation, while small or deep muscle groups are identified by electromyography (EMG) or ES. Ultrasound, fluoroscopy, or CT also may be used. Local anesthetic cream, general anesthesia, or sedation may be necessary, particularly in children.

Related posts:

Measurement Tools and Treatment Outcomes in Patients With Spasticity Economic Impact of Spasticity and Its Treatment Botulinum Toxin in the Treatment of Upper Limb Spasticity Assessment of Spasticity in the Upper Extremity Techniques and Scales for Measuring Spastic Paresis Pharmacologic Management of Spasticity: Oral Medications

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