Spasticity Diagnosis and Management

184 iiiâ•… TREATMENT OF SPASTICITY Although many of the technologies that will be very acute stroke, diffusion images rapidly indicate discussed are currently used for research purposes, the area of infarct and theoretically nonsalvageable they hold the possibility of providing clinicians valu- tissue. Perfusion images identify regions of impaired able information regarding disease processes and out- blood flow, which after very acute stroke is often comes. First, it provides in vivo information pertaining larger than the region of diffusion abnormality. This to pathology and physiology that impacts function. difference between diffusion and perfusion abnormal- Enhanced understanding will help researchers develop ities, referred to as the diffusion-perfusion mismatch, new means to treat impairments associated with up- is thought to represent the penumbra, the region of per motor neuron disorders. This new knowledge can the brain susceptible to infarct if restricted blood also be used in conjunction with traditional therapies flow is not restored. Results of several studies have and to aid in developing new technologies to improve indicated that thrombolytic therapy may be helpful rehabilitation outcomes. Last, it will help guide treat- in reducing stroke volume and improving clinical out- ment and predict outcomes that will likely be useful to comes when given up to 6 hours after stroke onset, provide care that is both effective and efficient. rather than just the currently approved 3-hour win- dow when there is a significant diffusion-perfusion Neuroimaging Technologies mismatch (2, 3). Improved clinical outcome appears to be more likely in those with mismatch and isolated Standard CT and T1/T2-weighted MR images of the middle cerebral artery occlusions as opposed to those CNS provide valuable information regarding mac- with concomitant middle cerebral and internal artery rostructural abnormalities arising from trauma and occlusions (4). disease. Unquestionably, these technologies have en- hanced our ability to treat people in more efficient Diffusion tensor imaging (DTI) takes advantage and definitive ways not feasible before their clinical of the fact that water diffuses faster along the orien- implementation. However, in the adult human brain, tation of axons and that fiber bundles as opposed to white matter on both CT scans and T1/T2-weighted across them, properties referred to as an. and isotropy MR images appear homogeneous despite its inherent respectively. Water diffusion is restricted perpendicu- complexity. They also cannot adequately assess mi- lar to fiber tracts because of restrictions imposed by croscopic lesions such as those associated with dif- the axolemma, myelin, and neurofilaments. However, fuse axonal injury or changes in either metabolism or it is relatively unrestricted along the path parallel to the concentration of biological molecules occurring the orientation of the tract. Therefore, the degree in specific disease states. Recent advances in imag- of anisotropy, typically referred to as fractional an- ing technologies are enabling researchers and health isotropy (FA), is high in well-organized white matter care providers to noninvasively peer into the living tracts where water moves rapidly parallel along the brain, enhancing our knowledge of the structure and orientation of the bundle. Images are derived on the function of the CNS that will ultimately improve our basis of the magnitude of FA as well as the orienta- ability to diagnose and treat people with neurologic tion of the fibers within a tract, providing structural disabilities. information pertaining to the integrity of white mat- ter. For example, in cases of traumatic axonal injury Diffusion Imaging where standard neuroimages are often unremarkable, DTI can image disruption of white matter tracts. Dif- Diffusion imaging uses MR technology to detect the fusion tensor imaging also provide a means to image movement of water molecules, providing a means the direction of fiber tracts by color coding them ac- to visualize cerebral tissue based on both the speed cording to their orientation: typically red for left-right, and direction of its movement. The manner in which green for anterior-posterior, and blue for cranial– water diffuses in biological tissue is impacted in spe- caudal directions (5). Although color coding is useful, cific ways, such as by the presence and chronicity of it is 2-dimensional, which limits its ability to assess in- particular disease states. For example, restricted dif- tegrity along an entire fiber tract. Three-dimensional fusion occurs in acutely infarcted cerebral tissue but tractography overcomes this by assessing a tract along later increases as the stroke becomes chronic, offering its entire length. This offers a means to better assess a sensitive means to differentiate acute from chronic both the function and integrity of individual fiber stroke. This can be used clinically when combined tracts that can be used to better understand the func- with findings from cerebral perfusion studies. After tion and connectivity of cerebral structures, to exam- ine the impact specific lesions have on motor function, and image damage to white matter not feasible with standard imaging.

14â•… EMERGING tECHNOLOGIES IN THE MANAGEMENT OF UPPER MOTOR NEURON SYNDROMES 185 Diffusion tensor imaging is becoming more Table 14.1 widely accepted as a means to best assess the degree Compounds Detected by MRS and of axonal injury after traumatic brain injury (TBI). It is effective in imaging axonal disruption in the pres- Their Markers ence of normal-appearing standard MR images (6), the extent and quantity of white matter injury (7), and NAA Neuronal marker the location of white matter tract injury associated Creatine Energy metabolism marker with motor impairment (8). Diffusion tensor imaging Choline Cell membrane disruption, data have also been correlated with both TBI severity and outcomes (9–11) and is becoming a useful tool Myo-inositol inflammation, and changes in to predict motor outcomes poststroke. After stroke, Lactate myelination FA decreases as the time from the infarct increases. Astrocyte marker As Wallerian degeneration progresses after stroke in Metabolism long white matter tracts, DTI detects decreased FA in sites distal but previously connected to the site of in- pression (25). For example, during the first several jury. The magnitude of FA reduction in the pyramidal months after acute stroke, increasing NAA/Cr in the tracts has also been correlated with motor outcomes contralesional hemisphere has been found to be asso- poststroke, providing a potential means to predict ciated with improved neurologic status (23). outcomes (12). Functional Magnetic Resonance Magnetic Resonance Spectroscopy Imaging Magnetic resonance spectroscopy (MRS) determines Functional MRI (fMRI) is a technique that images ce- the relative concentrations of various molecules in rebral regions that are activated during specific motor, specific cerebral regions, which provides informa- sensory, or cognitive activities. It generates images by tion regarding the chemical makeup of the brain in assessing the combination of physiological changes both healthy and disease states. Data are presented associated with metabolic activity, including local- as a graph depicting the concentrations of various ized alterations in blood flow and the levels of vari- compounds, which are then typically presented as a ous forms of hemoglobin. In a technique known as ratio of one compound to another. Information can blood oxygen level difference fMRI, the difference in be obtained from either a single volume of brain, magnetic properties of oxygenated and deoxygenated known as single voxel spectroscopy, or as a 2-dimen- hemoglobin is used to study the combination of meta- sional or 3-dimensional analysis obtained simultane- bolic activity and changes in local blood flow that re- ously over wider regions, referred to as MRS imaging. sult from regional activation. The blood oxygen level Several compounds of interest measured by MRS in- difference response is represented as a bright signal clude N-acetylaspartic acid (NAA), creatine, choline, on fMRI, indicating a region that is more metaboli- myo-inositol, glutamate, and lactate. N-acetylaspar- cally active than surrounding tissue. Its temporal and tic acid is located only in the neuronal tissue, with spatial resolutions are good, both of which are bet- relative decreases in its concentration suggesting neu- ter than those obtained by either single photon emis- ronal injury. Magnetic resonance spectroscopy has sion computed tomography or traditional positron detected reduced levels of NAA after TBI even in the emission tomography scans. An additional advantage presence of normal-appearing standard imaging (13), over positron emission tomography and single photon with evidence indicating it correlates with outcomes emission computed tomography is the lack of radia- (14–16). Determining the relative concentrations of tion exposure associated with fMRI that permits for other compounds provides additional information, as multiple imaging. Like all functional imaging studies, detailed in Table 14.1, which can be used clinically in several factors must be considered when interpreting a number of ways. For example, MRS has been found fMRI data. These include a subject’s ability to coop- to be a sensitive means of differentiating neoplastic erate in a tightly confined MR scanner, medication from nonneoplastic lesions by determining the ration effects on cerebral activation, adequacy of cerebral of NAA to choline, which is typically reduced in neo- blood flow, and inadvertent subject movement during plastic as compared to nonneoplastic lesions (17–22). image acquisition. Data interpretation is complex in Magnetic resonance spectroscopy data have also been that it is important to consider the multitude of possi- found to correlate with several poststroke outcomes, ble reasons accounting for specific activation patterns. including motor recovery (23), apathy (24), and de- For instance, does an activation pattern in a subject

186 iiiâ•… TREATMENT OF SPASTICITY with brain injury differ from a normal control because sess activation patterns occurring during specific re- of the establishment of alternative pathways, practice habilitation interventions. It therefore offers excellent effects, or differences in performance difficulty that temporal resolution that may provide opportunities to exist between injured subjects and normal controls. better develop and assess specific treatment interven- Other important issues to consider during interpreta- tions. It is becoming a more accepted technology now tion include lesion location and size, time postinjury, that it has been correlated with fMRI (32, 36, 37). subject age, the time postinjury the data are obtained, Despite its utility, it is limited by its inability to image the subject’s cerebral dominance, previous injury, beyond the top 2 to 3 mm of cerebral cortex and 1 cm presence of cerebral vascular disease, and type of lateral to the topical sensors. As a result, it may be ef- study design (eg, cross-sectional versus longitudinal). ficacious in evaluating the motor system of the upper Functional MRI has provided valuable insights into extremity but cannot be used to evaluate the lower both normal and pathological cerebral physiology, extremity. In addition, unlike fMRI, cranial reference although there are limitations to its use. The type of points are used to correlate activity with specific ce- activity performed in MR imaging (MRI) scanners is rebral regions, decreasing its spatial specificity. Other restricted, which prevents it from studying many com- problems include difficulties regarding the reduction plex real-world activities and limits its ecological va- of optical signals by the noncerebral tissue, the impact lidity. It is also subject to the same contraindications of pigmentation on signal detection, and the limited as standard MRI. At the present time, it is used as a spatial resolution (38). research tool, although it has potential as a means to guide treatment and assess treatment effects. Emerging Treatments Functional Near Infrared Spectroscopy Constraint-Induced Movement Therapy Functional near infrared spectroscopy (fNIRS) is a Constraint-induced movement therapy has emerged technology that, like fMRI, determines the presence as an exciting therapeutic approach for selected stroke of cerebral activity by assessing the different concen- survivors with plegic upper limbs. It is an intensive trations of oxygenated and deoxygenated hemoglobin therapeutic regimen provided over the course of 12 associated with metabolic activity. However, rather days that restricts the use of the uninvolved upper than assessing the magnetic differences of the 2 com- limb, forcing individuals with stroke to use their ple- pounds, fNIRS assesses the differences in their opti- gic limb to perform activities of daily living (ADL). It cal properties. The system uses light sources placed is based on the theory of learned nonuse, which states on the scalp using a wearable device. The light passes a limb weakened by stroke will not improve if it is not relatively easily through the scalp and skull and into actively rehabilitated. For example, during the course the top few millimeters of the brain. Light sensors of rehabilitation, individuals are taught to walk us- on the scalp detect wavelengths of light that are re- ing their unimpaired and plegic legs, as ambulation flected back to the surface. These sensors can detect requires the use of both lower limbs. However, be- the differences in near infrared wavelength absorption cause many ADL can be performed using only the of oxygenated and deoxygenated hemoglobin reflec- uninvolved upper limb, there may be reduced reha- tive of local metabolic activity. It has demonstrated bilitation efforts directed at improving the use of the ability to assess cerebral activity in the human cor- plegic arm and hand because the primary focus is tex associated with both motor and cognitive tasks often to quickly return an individual to independent (26). It has been used to study various changes in function. In this scenario, individuals with stroke are metabolic patterns in subjects with dementia (27–29), taught not to use their plegic upper limb, a process re- schizophrenia, (30), and stroke (31–35). It has sev- ferred to as learned nonuse. Although compensatory eral advantages over fMRI in that it is less susceptible one-handed strategies are useful to quickly improve to motion artifact as the sensors move with the sub- the performance of specific activities, it does not result ject, and it is considerably less expensive. It is also in cortical reorganization that leads to enhanced use not limited by the same contraindications of fMRI, of the plegic limb. However, CIMT has been shown to such as the presence of metal plates and subject claus- improve the use of stroke-weakened limbs in associa- trophobia. Perhaps most importantly, it is a portable tion with cortical changes (39). system that can assess changes in cerebral activation during tasks performed in settings more ecologically There are several critical factors involved in valid for a particular function. This is not feasible in CIMT, including intense, repetitive practice using an MR scanner. For the same reasons, it can also as- the plegic limb for common functional tasks. This is

14â•… EMERGING tECHNOLOGIES IN THE MANAGEMENT OF UPPER MOTOR NEURON SYNDROMES 187 accomplished in conjunction with physical restriction 20° at the wrist, markedly limiting the number of in- of the unimpaired arm and hand for up to 90% of dividuals who can benefit from its use. waking hours through the use of a mitt, sling, and/or splint. A therapeutic technique, known as shaping, Challenges ahead for CIMT include clarification that trains the plegic limb to move through successive of how much of the motor and functional gains are approximations of a desired task is performed. Tra- derived from the intervention versus the intensity of ditional CIMT is extremely intensive and involves at treatment and whether modifications in dose intensity least 6 hours of daily therapy for 2 weeks. The most impact outcomes. This is an important factor when comprehensive study examining its effectiveness com- considering if it is financially feasible in current and pared to usual rehabilitation care is the EXCITE trial. future economic environments. It included 222 patients with a single stroke sustained 3 to 9 months before the time of enrollment. Com- Virtual Reality pared to the usual treatment group, those receiving CIMT had less self-perceptions of hand function dif- Development of computer technology have led to the ficulty and performed better on several tests of upper creation of enhanced VR programs that permit in- limb function (40). An interpretation of the EXCITE dividuals to interact in computer-generated environ- trial by Dobkin (41) noted that a formalized care strat- ments that simulate real-world settings (45, 46) for egy for the usual treatment group would have helped both clinical and research purposes. It is a modality clinicians critically interpret the value of CIMT, as that uses technology to create virtual environments the CIMT group may have been biased in its self- where feedback, intensity, and duration can be modi- appraisal. In addition, a short phase-in of therapy for fied and used in settings that are more controllable all subjects could have established whether the sub- than natural environments. In this scenario, specific jects were reasonably stable in their affected arm func- therapies can be safely provided that may otherwise tion before randomization, and an interim measure be too dangerous or complex in actual settings. Virtual would have partially addressed whether less-intensive reality environments can therefore reduce concerns CIMT could work as well as traditional CIMT (41). over the consequences of allowing a person with phys- Challenges imposed by the intensity and time com- ical or cognitive impairments to perform potentially mitments of CIMT have led the evaluation of several dangerous activities on their own. The technology modifications in the way it is delivered. For example, is extremely flexibility, capable of remaining com- modified constraint-induced therapy provides treat- pletely consistent over infinite repetitions or altering ment 5 hours daily for 5 days followed by 3 hours a the type and pattern of sensory inputs and task com- day, 3 times weekly over approximately 10 additional plexity that can meet a multitude of clinical, research, weeks. Results using this approach were comparable and assessment needs. Not surprisingly, it has been to traditional CIMT, indicating that alternative meth- gaining wider use in rehabilitation settings for both ods can be successfully used (42). Other modifica- assessments and treatments. tions have used online computer sessions or combined CIMT with robotic therapy (43). In one pilot study, Virtual reality has been shown to be a useful mo- subjects with chronic stroke utilized online therapy ses- dality to improve functional skills after stroke. Jaffe sions with computer-based cameras as they restrained et al. (47) developed a head-mounted device worn like their less impaired upper limb resulting in functional a hat displaying virtual objects. Patients wear it while improvement after 10 weeks of treatment (43). walking on a treadmill, with a harness attached. Move- ment of lower extremities is promoted by negotiating There are other factors that limit the effective- virtual objects obstructing the path. When a virtual ness and application of CIMT. It requires considerable object is not successfully avoided, a virtual collision effort and motivation on the part of those receiving it, occurs that results in feedback to the patient. Perfor- with some evidence indicating that compliance with mance has been shown to improve with additional the mitt restriction to be as low as 32% (44). Ideally, VR training sessions, resulting in fewer “collisions.” subjects should not be at risk for falls because re- This form of VR rehabilitation resulted in improved straint of the more functional upper limb may prevent performance on an actual obstacle course compared the effective use of walking aids, thus predisposing to conventional ambulation training (47). Fung et al. some individuals to injury. Another important factor (48) applied a treadmill mounted on a platform that restricting its use is the relatively small percentage of interfaced with a rear projector. The projector simu- individuals with stroke for whom it has shown to ben- lated a walking environment while the subject received efit. Most trials have included only those individuals auditory, sensory, and visual feedback. Subjects with with active extension of at least 10° at the fingers and stroke who were trained on this system were noted to

188 iiiâ•… TREATMENT OF SPASTICITY have increased walking velocity (48). Improvement in vided results in either an increase or decrease in corti- ambulation has also been demonstrated by combining cal excitability. Therefore, unlike electric stimulation, VR with robotic therapy. Deutsch et al. (49) used a which excites neurons directly, TMS stimulates neu- desktop computer combined with a seated system that ral tissue indirectly by inducing electrical activity via allowed a subject to use their own ankle movements magnetism. The size and extent of the magnetic pulse to operate a foot pedal. The subjects were instructed depend on the spatial configuration of the stimulating to use the foot pedal to “navigate” a virtual boat or coil and the position in which it is held. Current appli- plane while they received visual, auditory, and sensory cations of TMS after brain injury include measuring feedback. Improvements were noted in gait velocity the excitability of central motor pathways, mapping and endurance after 12 hours of training provided cortical representations, and predicting motor recov- over 4 weeks (49). ery (54–56), whereas other potential uses include en- hancing cognitive and motor function resulting from Jang et al. (50) investigated cortical reorganiza- brain injury. tion and associated functional recovery using VR in patients with chronic stroke. Virtual reality was used Transcranial magnetic stimulation can be deliveÂ

14â•… EMERGING tECHNOLOGIES IN THE MANAGEMENT OF UPPER MOTOR NEURON SYNDROMES 189 (64). Interestingly, many studies have examined the clude its inability to stimulate subcortical structures functional impact of inhibiting the uninjured hemi- that restricts its impact to only those brain regions sphere by applying low-frequency rTMS, which is close to the scalp. The precise timing of when brain typically overactive after stroke (65, 66). The over- plasticity might best occur with TMS has not yet been activity of the contralesional hemisphere that is ob- determined, although as previously mentioned, it has served during movement of the paretic limb (67, 68) shown promise at various periods poststroke. is felt to inhibit activation of the lesioned hemisphere, a process referred to as interhemispheric inhibition. Electric Stimulation Low-frequency rTMS applied over the primary mo- tor cortex of the contralesional hemisphere, result- Electrical stimulation can be provided in several ways ing in its inhibition, has been shown to improve the to improve both motor and functional skills after function of the affected hand after acute and chronic injury to the CNS. It can be applied to muscles or stroke in subjects of various ages through the process nerves in the form of neuromuscular electric stimu- of transcallosal inhibition (69–73), that is, decreasing lation (NMES) or to the brain via epidurally placed the activation of the contralesional motor cortex im- electrodes. Neural plasticity occurs when motor learn- pairs its ability to inhibit the lesioned cortex, result- ing is achieved by the performance of goal-oriented, ing in improved motor skills of the hemiparetic limb. highly repetitive active movement training, aimed at Functional MRI data revealed that overall changes in the improved use of a paretic limb. Electrical stimu- cerebral activation patterns associated with rTMS- lation, either applied to muscles involved in a spe- induced inhibition of the contralesional motor cortex cific goal-oriented activity or to the motor cortex appeared similar to normal patterns (74). Transcra- associated with the movement of paretic limbs being nial magnetic stimulation may become a practical trained, provides a means to enhance motor relearn- means to enhance recovery after brain injury because ing and theoretically improve the functional use of the it is portable and can be used during rehabilitation paretic limb. Neuromuscular electric stimulation has interventions. also been studied as a means to reduce shoulder sub- luxation and its associated pain after stroke, as well The changes in cortical excitability induced by as to reduce spasticity. Electrical stimulation enhances TMS has also been studied as a means to manage movement of paretic muscles incapable of sufficiently spasticity in several upper motor neuron conditions, contracting on their own power, which when applied including stroke (75, 76), multiple sclerosis (77, 78), during highly repetitive training activities theoretically and cerebral palsy (79). Corticospinal neurons are enhances motor relearning. known to modulate a and g motoneurons, Ia afferent sensory fibers, and spinal interneurons, all of which Clinical use of NMES can be provided in several are involved in the generation of spasticity. In general, ways. Cyclic NMES provides simulation at a set rate increasing corticospinal tract excitability by using for a predetermined period of time. Electromyogra- rTMS is theorized to inhibit overexcitability of a and phy (EMG)-mediated NMES detects electrical activity g motoneurons, thereby reducing spasticity. Various in a muscle that is generated by the intent to move it rTMS paradigms have been tested with results indi- but is insufficient to contract it for functional activi- cating that it has considerable potential to either re- ties. Once the device detects inherent muscle activity duce spasticity (76–78) and/or increase passive range above a set threshold, it provides an externally gener- of motion (75, 79), thereby an improve functional use ated electrical stimulus that causes the muscle to con- of affected limbs caused by CNS lesions. tract. It has a theoretical advantage over cyclic NMES in that it requires cognitive effort to move a limb, The primary risk of rTMS is inducing seizures, providing a biofeedback component that enhances its which can be minimized by adhering to recommenda- impact on neural plasticity. However, it is useful only tions that limit stimulation parameters, advise moni- in those muscles that an individual can at least par- toring guidelines, and detail contraindications (80). An tially activate on their own. Neuromuscular electric additional risk may be hearing loss, particularly when stimulation can also be provided to specific muscles sessions are provided regularly over several weeks. in an appropriate time sequence to complete mobility Potential uses of TMS after neurologic injury in the or ADL tasks, such as to the ankle dorsiflexors dur- future will include enhancing our understanding of ing the swing phase of gait. This can be achieved by the physiology underlying the behavior by better de- delivering stimulation by using either single-channel lineating the mechanisms, locations, interactions, and or multichannel units. However, as more muscles are adaptability of neuronal networks (81) and exploit- stimulated for complex tasks, such as walking, which ing the effects of stimulation on cerebral plasticity to require the contraction of multiple muscle groups in enhance functional recovery. Limitations of TMS in-

190 iiiâ•… TREATMENT OF SPASTICITY a very specific pattern using multiple channels, the crostimultors that have been successfully implanted system becomes cumbersome and impractical. This is into muscles and used to improve the use of paretic partially being addressed by developing percutaneous upper limbs without adverse effects (101). systems that will be detailed later. Shoulder subluxation occurs in the presence Neuromuscular electric stimulation has been of hemiplegia when there is increased humeral head shown to fairly consistently improve motor function translation relative to the glenoid fossa. It frequently (82–91), strength (85, 88, 90, 91), and use of paretic occurs as a result of hemiplegia and is often accom- limbs for specific tasks (eg, lifting and moving objects) panied with pain. Reduction in both the degree of (88, 90–94) for individuals with stroke at various subluxation and pain has been achieved in selected times postinjury. When used on paretic lower limbs, individuals undergoing NMES to various muscles sup- it has been found to be an effective means to improve porting the shoulder. Neuromuscular electric stimula- gait speed (94–96), an important predictor of success- tion delivery to reduce subluxation has traditionally ful community ambulation. It has also been shown to been provided via skin electrodes overlying the deltoid, be a more effective means to promote motor recov- supraspinatus, and trapezius muscles. However, sur- ery than conventional rehabilitation techniques alone face NMES may cause discomfort given the magnitude (82, 85, 86, 88, 89, 91, 93, 94). However, the stability of stimulation required to pass through skin sufficient of results over time remains uncertain, as some stud- enough to cause muscle contraction. Furthermore, ies documented sustained improvements for up to 9 selective muscle stimulation is challenging using sur- months posttreatment (84, 87), whereas others dem- face electrodes, as unintended muscles are likely to be onstrated that the benefits diminished as the time pos- activated. This has been addressed by placing elec- tinterventions passed (83, 85). It also remains unclear trodes directly into selective muscles using a percuta- which forms of ES are most useful, as different appli- neous system. This system, which permits many hours cations of NMES have not been directly compared to of stimulation daily over a period of many weeks, has each other. It has been suggested that EMG-mediated been shown to be well tolerated and effective in reduc- devices have a theoretical advantage over cyclic sys- ing poststroke shoulder pain associated with sublux- tems, particularly when they are used to assist in com- ation (102), particularly when used early poststroke pleting functional tasks (97), which was supported (103). It avoids the discomfort associated with surface by the results of a metanalysis (98). Despite improve- stimulation (102) and has been shown to maintain ments in motor skill and strength, these devices have pain reduction for at least 1 year after discontinuation not yet been sufficiently studied to determine whether of treatment (104). they are capable of improving quality of life or en- hancing independent function after neurologic injury. Peripheral nerve ES, delivered by cutaneous electrodes, implanted electrodes, or implanted neural Other studies have focused on novel neuropros- prosthetic systems, can reduce spasticity (105). ImÂ

14â•… EMERGING tECHNOLOGIES IN THE MANAGEMENT OF UPPER MOTOR NEURON SYNDROMES 191 approaches. Robots use computer programs that con- improve accuracy. Variable resistance provides force strain inaccurate limb movement during specific tasks along a desired trajectory then unexpectedly removes that can be modified as patients progress in their re- resistance such that patients move along the desired covery, promoting more functionally appropriate mo- path. It has 4 degrees of freedom and requires sub- tor skills. The intensity and automated components jects to apply specific force patterns before providing of robotic therapies specifically address the time and external assistance. However, similar to some other labor constraints associated with traditional thera- devices, it has not been shown to be more beneficial pies, as it can be used with less involvement of trained than conventional training (117). The GENTLE/s RT professionals. It can also enhance patient compliance system moves the arm passively (118). The Haptic- by combining games with treatment, which provide MASTER, part of the GENTLE/s RT system, suspends immediate feedback on performance that serve to the upper limb from a sling to reduce the impact of increase motivation. Changes in motor skills can be gravity. It guides the limb along a smooth predefined easily tracked and documented, which can help guide trajectory and can operate in assistive and resistive therapy, evaluate the efficacy of treatment interven- modes. A study showed improved upper limb func- tions, and provide an additional means to monitor tion as measured by the Fugl-Meyer Scale using the progress. Potential drawbacks of robotic therapy in- GENTLE/s (119). When compared with task practice clude being labor-intensive, the start-up costs, and the with the arm suspended in the sling, the GENTLE/s current lack of validation from clinical trials. How- robot seems to yield a greater rate of improvement for ever, the initial labor-intensiveness arising from staff shoulder range of motion and the ability to perform training plus the cost of the equipment may be offset certain arm movements (118). The Activities of Daily by the long-term cost-effectiveness derived from de- Living Exercise Robot provides active assistance as creasing the amount of direct contact time therapists patients reach toward real objects. This system aims must spend with patients. to deliver poststroke motor rehabilitation paradigms within an ADL-specific context (120). Several robotic devices have been developed, but none have yet been widely used in rehabilitation set- Other robotic systems have used an exoskeletal tings. The first robot used for rehabilitation of hemi- design, such as the Myomo e100. This robot is worn paretic upper limbs was the MIT-MANUS. It has a on a paretic arm as an elbow orthosis and permits 2 degree-of-freedom, back-drivable device allowing patients to interact naturally with objects while giving planar pointing and drawing movements of the shoul- force feedback. It detects surface EMG signals from der and elbow (113). It uses an impedance controller selected muscles, which are used to provide ES to as- with a programmable maintenance between the arm sist with active elbow extension. It has been shown to location and the desired position (62). It has been improve motor skills and reduce spasticity in a group shown to improve motor recovery after acute and of patients with chronic stroke (121). chronic stroke by providing repetitive massed practice of reaching toward a defined end point. The Mirror The previously described robots were designed Image Motion Enabler is an industrial robot coupled primarily to improve proximal arm function. To im- to the arm. It moves the arm in 3 dimensions while prove the functional use of upper limbs, it is also nec- the force feedback assists or resists the patient’s move- essary to focus on hand function. Several such systems ment. It can incorporate use of the uninvolved limb by have been developed and are being investigated. The measuring its position and then provide assistance to Cyberglove and Rutgers Master II-ND glove are de- the weaker limb to mirror its movement. It can also signed to increase range of motion and finger force via be used unilaterally and work in active, passive, and repetitive, stereotyped movements. Evidence suggests resistive modes. It should be noted, however, that it that although they can improve upper limb motor was not shown to be significantly better than neurode- control after acute stroke (122, 123), there were no velopmental training using Bobath therapy 6 months consistent improvements in functional abilities (124). after treatment cessation (114, 115). The Bi-Manu Takahashi et al. (125) studied robot-based hand mo- Track is a bilateral training device focusing on the tor therapy after chronic stroke. Subjects with chronic forearm and wrist, which appears to have an advan- stroke and moderate weakness of the arm and/or tage in improving motor skills compared with practice hand received 3 weeks of therapy emphasizing in- assisted with electric stimulation (116). tense active repetitive movements involving atten- tion, speed, timing, force, and precision. Significant The Assisted Rehabilitation and Measurement gains were noted in the Action Research Arm Test and robot is used to guide the paretic upper limb dur- the arm motor Fugl-Meyer score. This was associ- ing linear reaching activities by applying forces that ated with significantly increased activation within the

192 iiiâ•… TREATMENT OF SPASTICITY lesioned hemispherere on fMRI, suggesting the ability as a more appropriate method to facilitate sensory in- of this system to induce neural plasticity (125). Taub put and maximize much-needed repetition during the et al. (126) examined a more automated version of critical recovery period (131, 132). CIMT using AutoCITE. The system is composed of a computer that interfaces with several workstations The BWSTT is thought to work on various com- where patients are trained to perform specific tasks. ponents of locomotion including posture, balance, The computer provides a series of motor instructions weight shifting, and coordination. One means by which to the patient that mimic the therapeutic interventions it may work is through activation of central pattern of CIMT and provides feedback on their performance generators (CPGs) that are located in the spinal cord. as well as encouragement in a manner similar to a Central pattern generators were initially described in therapist. It reduces the amount of time needed by the invertebrates where it was demonstrated that neuro- therapist to supervise treatment and has been shown nal networks interacted with specific sensory inputs to be as effective as traditional CIMT (126). resulting in locomotion (133). Although the presence of CPGs has not been definitively confirmed in verte- Robotic therapy offers a promising venue for im- brates, there is evidence suggesting they exist in mam- proved motor skills in people with hemiplegia. They mals. Studies examining cats with induced thoracic are capable of providing repetitive, high-intensity, spinal cord lesions revealed that BWSTT resulted in task-specific, and interactive treatments for the im- an improvement in various aspects of gait, including paired limb. The devices can provide force feedback for an increase in both gait speed and number of steps sensorimotor-type training; measure the speed, direc- taken compared to control animals (134, 135). This tion, and strength of residual voluntary activity; and supports the theory that the mammalian spinal cord is evaluate patients’ movements interactively to assist capable of producing reciprocal gait patterns by means them in limb movement through a predetermined of these activated CPGs in the absence of supraspi- trajectory during a given motor task. However, they nal inputs. The improvements in gait in these animals have not gained widespread use for several reasons. also support the notion that neural plasticity is pos- Although most studies examining their use have dem- sible within the spinal cord. Supraspinal mechanism onstrated significantly improved motor skills, even in may also contribute to improved ambulation skills via those with chronic stroke, they have not consistently BWSTT in ways similar to forced-use therapy, as it been shown to improve ADL performance (127). This uses mass practice (the need for multiple repetitions) may be because most studies used insensitive measures and shaping (performing sequentially greater approxi- of function that were not capable of detecting changes mations of a task) through progressive weight-bearing in ability to perform ADLs. A seemingly important ad- and forced use of impaired lower limbs (136). vantage of robots over conventional rehabilitation is its ability to provide highly repetitive treatments over lon- The BWSTT attempts to facilitate automatic ger periods. However, it has been shown that equally walking movements within the context of task-specific intensive therapies provided by either robots or con- training. The patient is placed on a treadmill moving ventional means confer similar results (128). Future at the maximal comfortable walking speed with a por- studies will need to address the functional implications tion of their weight-being supported at the trunk by of these devices as well as their economic feasibility and an overhead harness. The combination of therapists advantage over conventional treatments. and the physical apparatus of the system controls leg movement, patient posture, and balance that aids in Body Weight–Supported mimicking the normal rhythmic nature of gait. The Treadmill Training system offers patients the support to maintain the standing position, which is useful for those who do Body weight–supported treadmill training (BWSTT), not have the muscle strength or postural control to first described by Finch et al. (129), provides a strat- begin overground gait training. Furthermore, it may egy to assist some individuals with neurologic impair- decrease the fear of falling, which combined with its ments to stand and ambulate. It uses a harness system other attributes makes gait training feasible early after that supports a percentage of a patient’s body weight CNS injury (137). Early training postinjury theoreti- that unloads the lower extremities while training to cally enhances more normal-appearing ambulation, walk on a treadmill. Evidence suggests that this may be as the pattern associated with BWSTT resembles nor- an effective method of improving gait quality, walking mal gait better than traditional overground training. speed, and trunk stability after stroke (130). It may Therefore, it may avoid the development of gait de- also be an effective means to encourage a symmetrical viations such as knee hyperextension during stance gait pattern early in the rehabilitation process, as well phase, poor pelvic and trunk motion, gait asymmetry, and decreased step length often associated with tra-

14â•… EMERGING tECHNOLOGIES IN THE MANAGEMENT OF UPPER MOTOR NEURON SYNDROMES 193 Figure 14.1 angiogenesis, facilitation of information processing caused by release of dopamine and/or norepinephrine, Functional near infrared spectroscopy. This figure demon- up-regulation of neurotrophins, and improvement in strates the equipment used and the setup for obtaining mood with decreased depression (146). fNIRS. As noted in the figure, fNIRS is portable, which permits imaging of activated cortical regions during func- Despite promising results, BWSTT has not re- tional tasks in an ecologically valid setting. (Reproduced ceived widespread clinical acceptance. A primary draw- with permission from Kessler Foundation. Photographer, back has been the time and physical demands placed Richard Titus.) on therapists to operate the system properly. Several therapists may be required to move the patient’s limbs and to operate the machinery while trying to ensure appropriate kinematics of the trunk, pelvis, and lower limb. The BWSTT may also be fatiguing for both pa- tients and therapists, thereby limiting the duration of the therapy sessions (147). Furthermore, it has been suggested that each therapist provide sensory informa- tion to the patient on a stride-by-stride basis to achieve maximal benefit. Robotic devices have been developed to address this factor, although these devices are very expensive and recent evidence suggests that their use is no more effective in improving ambulatory skills than ditional ambulation training as the patient attempts Figure 14.2 full weight-bearing. Furthermore, improvements in gait after BWSTT have been associated with changes The DTI image. White matter fiber tracts in the living hu- in cerebral activation patterns in the cerebellum and man brain, visualized noninvasively using DTI, a new midbrain, suggesting its ability to enhance cerebral and evolving MR technique. Images of this sort are used plasticity (138–143). for basic neuroanatomical research, for clinical diagnosis of subtle neurologic disorders, and for guidance of neuro- Studies have largely supported the beneficial ef- surgery. Data for this image were acquired using a 1.5-T fects of BWSTT in term of improvements in the ability Siemens Avanto MR scanner in the New York University to ambulate, posture control, endurance, balance, rate Langone Medical Center Department of Radiology. (Im- of recovery, and gait velocity predominantly in pa- age courtesy of Dr. Yulin Ge and Dr. Daniel K. Sodickson, tients with stroke-related hemiplegia (139, 140), with Center for Biomedical Imaging, Department of Radiology, fewer demonstrating improvements after spinal cord New York University Langone Medical Center.) See color injury (141, 142). Many studies have demonstrated insert. the benefits of BWSTT in improving gait, although a metanalysis of several studies failed to reveal a defini- tive advantage over traditional therapeutic techniques (143). Possible reasons accounting for this include the heterogenicity in the nature and severity of stroke, the demographic distributions of the patients, variations in the intensity and frequency of training, the meth- ods for assistance, and the placebo effect. However, a recent study demonstrated that BWSTT provided no additional benefit to an equal amount of traditional gait training in subjects with hemiplegia (144). De- spite this, there are benefits to ambulation training us- ing BWSTT, including improved cardiovascular fitness (145) and improved upper limb function (146). Hy- potheses explaining the later observation include the positive effect of exercise on cerebral blood flow and

194 iiiâ•… TREATMENT OF SPASTICITY equally intensive conventional therapy (144). Addi- remain unanswered. Accordingly, recovery of func- tional studies are needed to address dosing questions, tion is all too frequently incomplete. Therefore, exist- optimal time to initiate treatment, time to progress to ing technologies must be refined and new modalities overground training, impact of upper extremity sup- developed to further our ability to effectively amelio- port, and most appropriate treadmill speed (41). rate the physical and cognitive sequelae of neurologic injury. Improved outcomes will only be achieved Barbeau and Visintin (140) found that both pre- through greater understanding and dedicated efforts training and posttraining walking speeds were greater to refine existing treatments and develop new modali- on the treadmill than they were in overground walking ties (Figures 14.1 and 14.2). and that the transfer of training from treadmill walking speed to overground walking speed was greater in the References body weight–supported group than in the group with- out this technique. They also observed that partially 1. Rosamond W, Flegal K, Furie K, et al. Heart disease and unloading the lower limbs during training and progres- stroke statistics—2008 update: a report from the American sively increasing the load as the gait pattern improved Heart Association Statistics Committee and Stroke Statistics enhanced the recovery of posture and locomotion (140). Subcommittee. Circulation 2008;117:e25–146. Sullivan et al. 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Pharmacologic Management of Spasticity: Oral 15 Medications Jay M. Meythaler Scott Kowalski Spastic hypertonia encompasses a variety of conditions bladder and bowel emptying (11, 12). The increased that may contribute to increased tone or involuntary muscle tone can also provide a fulcrum at various movement, including dystonia, rigidity, myoclonus, joints to improve posture, aid in sitting, or aid with muscle spasm, posturing, and/or spasticity (1). The transfers. The increased muscle mass over bony prom- neurologic localization of the lesion that is the cause inences can help prevent decubitis ulcers. Hence, spas- of spastic hypertonia may result in the different clini- tic hypertonia is not an entity we wish to completely cal manifestations noted. The other conditions associ- eliminate, just modulate. ated with spastic hypertonia, such as the “clasp knife phenomenon,” Babinsky or Hoffman reflexes, rigid- In general, oral medication has been less success- ity, and particularly acquired dystonia, may be more ful in managing spastic hypertonia after acquired ce- disabling than spasticity in acquired brain injury (2, rebral injury than in spinally related causes of spastic 3), some cases of cerebral palsy (CP) (4), and mul- hypertonia (8, 13). Furthermore, all the potentially tiple sclerosis (MS) (5). For this reason, they are often useful drugs for spasticity have associated central considered to be part of the broader “upper motor side effects that need to be carefully weighed when syndrome,” of which spasticity is a part (6). considering their use. The pharmaceutical manage- ment of spastic hypertonia after CNS injury or illness One of the hallmarks of upper motor neuron has generally been confined to the use of 5 primary injury or illness above the conus medularis is the de- medications: baclofen, diazepam, dantrolene sodium, velopment of spastic hypertonia. It is one of the most clonidine, and tizanidine (1, 6, 8, 14–17). There is disabling aspects of central nervous system (CNS) in- limited evidence that other medications may be useful jury or illness. Spastic hypertonia can interfere with as well. the functional use of remaining motor function, limit the range of motion of a joint, or cause pain. This can Spastic hypertonia clinically presents differently be very disabling with regard to mobility, transfers, when the lesions are in the spine, brainstem, or cere- activities of daily living, sitting, or sleep (7–10). bral cortex (3, 10). The precise neurologic localization of the lesion can result in different clinical manifesta- However, there are positive aspects of spastic tions of spasticity (10). However, one does not treat hypertonia. Spasticity can aid in maintaining muscle spastic hypertonia based upon the anatomic location tone and mass, resulting in increased blood return in of the lesion. Rather, treatment is focused on the clini- the venous system, decreases the incidence of osteopo- cal presentation of the patient. Furthermore, it is clear rosis in paralyzed extremities, and aiding in reflexive that some medications may be preferred for upper 199

200 IIIâ•… Treatment of spasticity limb spasticity, whereas others may be preferred for Table 15.1 lower limb spasticity (5, 17). When one considers the Definition of Ashworth, Spasm Frequency, and cognitive and other side effects of medications, one needs to customize the treatment of medications quite Reflex Scores precisely. Ashworth score No increase in tone Determining the benefit of oral medications for 1 the treatment of spastic hypertonia must focus on 2 Slight increase in tone, giving evaluating the patient with physiologic and functional a “catch” when affected part is outcome measures (18). The scales listed in Tables 3 moved in flexion or extension 15.1 and 15.2 are the most commonly used clinical methods for assessing the clinical treatment of spas- 4 More marked increase in tone, tic hypertonia. These scales have been those that have but affected part easily flexed been most often accepted by the Food and Drug Ad- 5 ministration (FDA) for pharmaceutical and investi- Considerable increase in tone; gational trials to obtain a clinical indication for use 0 passive movement difficult in “spasticity.” They are also easily administered and 1 relatively reliable methods for the clinician to utilize Affected part rigid in flexion in a clinical setting. In addition, the physician should 2 or extension Spasm frequency carefully monitor other medications, including “over- score the-counter medications” due to potential interactions 3 and the effects these medications may have on spas- No spasms tic hypertonia. We will present in detail the most fre- 4 quently utilized oral medications and outline briefly Mild spasms induced by the variations in their recommended uses in cerebral Reflex score stimulation disorders versus spinal disorders and when attempt- 0 ing to treat upper extremity spastic hypertonia versus 1 Infrequent full spasms occurring lower extremity spastic hypertonia. 2 less than once per hour 3 A wide range of potential treatments have been 4 Spasms occurring more than investigated. The clinical pharmaceutical management 5 once per hour of spastic hypertonia after CNS injury or illness has generally been confined to the use of centrally acting Spasms occurring more than 10 drugs mediated through g- (19, 20) and peripherally times per hour acting drugs that inhibit the release of calcium from the sarcoplasmic reticulum (dantrolene) (15) as well Reflexes absent as those that inhibit excitatory neurotransmitter re- lease. We will organize the discussion of these medi- Hyporeflexia cations by the neurotransmitter, through which they mediate their effect. Normal Mild hyperreflexia 3 or 4 beats clonus only Clonus Definitions and rating scales used to evaluate muscle tone (1), spasm frequency (2), and deep tendon reflexes (2, 3). Gamma-Aminobutyric Acid Agonists completely hydrophilic neurotransmitter and there- fore is infinitely lipophobic with a complete inability Gamma-aminobutyric acid (GABA) receptor sites are to cross the blood brain barrier (22–24). widely present in the CNS, and GABA is the third most prevalent neurotransmitter in the CNS. GABA is GABA receptors are distributed in 3 main recep- present in an estimated 60% to 70% of all synapses in tor subtypes A, B, and C, with GABA-A and GABA-B the brain and is inhibitory on a variety of neural path- most clearly involved in the treatment of spastic hy- ways associated with spasticity (10, 19, 21). GABA is pertonia. GABA-A receptors are a heteropentameric always an inhibitory neurotransmitter, affecting both molecule that has at least 3 distinct subunits (25). The presynaptic and postsynaptic inhibitions. GABA is a GABA-A receptor is a ligand-gated chloride ion chan- nel that when activated allows increased chloride ion influx, causing membrane hyperpolarization (26, 27). GABA-B receptors are G-protein coupled and act on voltage-gated calcium channels, including N-methyl-

15â•… Pharmacologic Management of Spasticity: Oral Medications 201 Table 15.2a Spasticity Clinic Initial Evaluation Name: _______________________ MR #: ___________________ Date: __________ Diagnosis: /_/ Spinal Cord Injury /_/ Multiple Sclerosis /_/ Cerebral Palsy /_/ CVA /_/ TBI /_/ Other _____________________________________ Date of Onset: ___________ History: ________________________________________________________ _______________ _________________________________________ _____________________________________________ Surgical Procedures for Spasticity: /_/ None /_/ Rhizotomy /_/ Myelotomy /_/ Neurectomy /_/ Nerve Blocks /_/ Intrathecal Neurolysis /_/ Tendon Lengthening Other __________________________________________________________ History of Seizures: /_/ Yes /_/ No Medication: _________________________ Prior/Current Anti-spastic Drug Use: ____________________ Drug Daily Dose Effectiveness Side Effects Neurologic Assessment: Left Right Left Right Spasticity Shoulder Abduction Elbow Extension Hip Abduction Elbow Flexion Hip Adduction Wrist Extension Hip Flexion Wrist Flexion Knee Extension Knee Flexion Spasms: UE Ankle Dorsiflexion Reflexes: Biceps Plantar Flexion Spasms: LE Reflexes: Knee ankle Functional Assessment: /_/ ambulatory /_/ ambulatory with assistive device /_/ bedridden Mobility:╅╇ /_/ wheelchair Urinary Management: /_/ normal /_/ catheter /_/ type ____________ other: ____________________ Bowel Management: /_/ normal /_/ suppository /_/ digital stim /_/ other: ____________________ Additional Findings: ___________________________________________________________________________ _______________________________________________________________________________________________ _______________________________________________________________________________________________ _______________________________________________________________________________________________ Plan: _________________________________________________________________________________________ _______________________________________________________________________________________________ _______________________________________________________________________________________________ Physician’s signature: __________________________________________ Outpatient evaluation sheets for spasticity clinic. (Forms used with permission from Jay Meythaler, MD, University of Alabama at Birmingham. Copyright Jay Meythaler.)

202 IIIâ•… Treatment of spasticity Table 15.2b Baclofen/Clonidine Pump Clinic Follow-Up Evaluation Name: ___________________________ MR #: ___________________ Date: ____________ Pump Refill: /_/ Yesâ•… /_/ No Actual residual volume: ____cc Refill volume: _____cc Programmer residual volume: _____cc Lot Number: __________________ Concentration: _________ mcg/ml Single bolus given: _________ mcg Program Change: /_/ Yesâ•… /_/ No /_/ complex continuous /_/ periodic bolus╇ /_/ stopped Dose: ____________ mcg/day Infusion mode:â•… /_/ simple Neurologic Assessment: Tone Left Right Left Right Hip Abduction Shoulder Abduction Hip Adduction Elbow Extension Hip Flexion Elbow Flexion Knee Extension Wrist Extension Knee Flexion Wrist Flexion Ankle Dorsiflexion Plantar Flexion Spasms: UE Spasms: LE Reflexes: Biceps Reflexes: Knee ankle Functional Assessment: Mobility: /_/ wheelchair /_/ ambulatory /_/ ambulatory with assistive device /_/ bedridden Urinary Management: /_/ normal /_/ catheter /_/ other: ____________ Bowel Management: /_/ normal /_/ suppository /_/ digital stim /_/ other: ___________ Concomitant Medical Problems: /_/ none /_/ UTI /_/ Pressure sore /_/ other: _____________ Adverse Effect or System Complication: /_/ Yes /_/ No Description: _________________________________________ Refill Alarm Date: _________________________________________ Other Comments: _________________________________________ Physician’s signature: __________________________________________ Outpatient evaluation sheets for spasticity clinic. (Forms used with permission from Jay Meythaler, MD, University of Alabama at Birmingham. Copyright Jay Meythaler.)

15â•… Pharmacologic Management of Spasticity: Oral Medications 203 d-aspartate (NMDA) channels (19, 28, 29). G-proteins Orally delivered baclofen reaches relatively low also increase receptor-operated potassium channel concentrations in the spinal cerebrospinal fluid, even conductance (20). Both mechanisms cause hyperpo- after large oral doses (37). Thus, many patients ex- larization of the motor horn cells, which is often cited perience central side effects, such as drowsiness, as the predominant mechanism for the antispasticity confusion, or attentional disturbances at the dosages effects associated with GABA-B agonists (6, 19). required to reduce spasticity (6, 30, 38, 39). Other central effects of the drug include hallucinations, The GABA-B receptors definitely are involved ataxia, lethargy, sedation, and memory impairment in spasticity treatment (3, 6, 13, 22, 23), whereas the (30, 38–41). Furthermore, those patients with ce- A receptors have some effects on spasticity modula- rebral lesions are felt to be more prone to the cen- tion and have an additional role in seizures manage- trally mediated side effects of medication (1). There ment (3, 6). Because GABA crosses poorly into the is a significant reduction in attention span in some CNS across any membrane (23, 24), drugs have been traumatic brain injury (TBI) patients who have been developed to either indirectly facilitate the release of placed on oral baclofen, even when testing was done GABA or substitute for GABA in CNS as analogs. It after several months on the medication (42). These has been established that GABA inhibits the release effects have been reversible with a withdrawal of ba- of dopamine, norepinephrine (NE), acetylcholine, and clofen. Because cognitive function is critical for sur- serotonin (5). vival and adaptation after CNS injury or illness, any impairment of cognition due to medication may sig- Baclofen nificantly adversely effect the severely brain injured patient. The sudden withdrawal of baclofen, includ- ing baclofen delivered intrathecally, may lead to sei- zures and hallucinations (12, 32). Baclofen, 4-amino-3(p-chlorophenyl) butyric acid, is Pharmacokinetics structurally similar to GABA and binds to presynaptic Oral baclofen is relatively well absorbed with the peak effect within 2 hours of ingestion (42, 43) and GABA-B receptors within the brainstem, dorsal horn of a half-life of between 2.5 to 4 hours (6, 43), but it has a tissue half-life in the CNS estimated to be 3 to the spinal cord, and other CNS sites (30–34). Baclofen 5 hours (43). The drug is excreted unchanged by the kidney, and only 6% to 15% is metabolized by the is a small moleÂ

204 IIIâ•… Treatment of spasticity effective physiologically in improving spastic hyperto- (70, 71). Diazepam is the prototypical benzodiazepine nia as measured by the Ashworth score in the lower of this class of compounds characteristic of the 1, 4- limbs (5). Based upon the observed decrease in tone, nitrogenous ring structures most commonly utilized the authors hypothesize that there was a reduced re- in the United States (70). Diazepam and clonazepam ceptor density for GABA-B receptors in the cervical are both documented to be an effective treatment for and brainstem regions than the thoracic region (5). the initial treatment of spastic hypertonia, but all ben- Further investigation may delineate if there is a differ- zodiazepines (eg, ketazolam, tetraepam,) have been ence of baclofen’s effectiveness on the upper extremi- useful in the treatment of spastic hypertonia (19, 70). ties versus the lower extremities. They differ primarily with regard to the half-life and the cognitive side effects because some are more seda- Seizures are a serious side effect of the use of ba- tive, whereas others have a more profound hypnotic clofen and appear to lower the seizure threshold, re- effect, and this has been the primary differentiation of gardless if the dose of baclofen is increased or decreased these medications. (64–68). Other complications of oral baclofen include euphoria, hallucinations, ataxia, memory impairment, Benzodiazepines do not directly bind to GABA re- lassitude, urinary problems, muscle weakness, dizzi- ceptors but instead promote the release of GABA from ness, hypotension, sedation, memory problems, and GABA-A neurons by facilitating sodium conductance blurred vision (3, 19). Motor weakness is usually the (19, 72–74). This results in enhanced presynaptic in- result of those who are overdosed on the medication hibition and is likely why they are useful in epilepsy or were utilizing their reflexive spastic hypertonia for (70). functional status. The most serious side effects in- volve abrupt withdrawal, which is characterized by These drugs are all CNS depressant medications increased spastic hypertonia, increased deep tendon and are noted for their antianxiety, hypnotic, antispas- reflexes, pruritic symptoms, autonomic instability, halÂ

15â•… Pharmacologic Management of Spasticity: Oral Medications 205 However, there are many who use clonazepam in inhibitor of GABA uptake or degradation (92). Re- adults and vice versa. There are many clinicians who gardless of the mechanism of action, gabapentin does employ other benzodiazepines. increase GABA turnover, and no general statements can be made on the effect of gabapentin on NMDA Diazepam is well established in the treatment of receptors. The mechanism by which gabapentin exerts spastic hypertonia in MS with several clinical trails in its anticonvulsant effect is not known. However, it ap- the literature (46, 59–57, 82–84). Diazepam has been pears now to interact with a unique receptor effecting traditionally utilized for years in SCI even though the voltage-gated N-type calcium ion channels (93). It is data are less well established, with only a few small generally utilized as an adjunctive medication for the studies (46, 85) also in mixed populations of patients treatment of partial seizures (94). with SCI, MS, and stroke. Benzodiazepines have more studies establishing their efficacy in cerebral disorders. Pharmacokinetics In stroke patients, diazepam has been reported to be useful (84-88), but the studies have only small num- Gabapentin is predominately renally cleared, lead- bers of patients and are likely underpowered. There ing to its linear pharmacokinetics (93, 95, 96). The are only a couple of studies documenting the effec- bioavailability of gabapentin is not dose proportional tiveness of clonazepam in spastic hypertonia: one in a (97). As the dose is increased, the bioavailability is de- predominately MS population (89) and another small creased. Gabapentin is eliminated unchanged from the study in pediatric CP patients (90). Considering its systemic circulation by renal excretion, and maximum widespread use, it is rather quite remarkable that there plasma concentration occurs within 2 to 3 hours (98, are so little data. There is relatively more data on the 99) of dosing. Unlike other anticonvulsants, gabapen- use of ketazolam, which is not available in the United tin apparently does not interfere with the elimination States. However, in these head-to-head studies with di- of phenytoin, valproic acid, carbamazepine, and phe- azepam, there was relatively no advantage except less nobarbital (95). frequent dosing (84, 91). Treatment Benzodiazepines are sedative hypnotics and as such tend to exacerbate the complications of mem- Gabapentin was initially designed as a pharmaceutical ory and alertness in patients with cerebral disorders. agent to treat spasticity but was found to be a more Hence, lately, they have not been recommended for potent anticonvulsant for which it is approved for use at least in the early stages of recovery. Benzodi- marketing in the United States (98, 100). Nevertheless, azepines such as diazepam and lorazepam also have there have been small reports of its effectiveness for numerous adverse effects, including generalized CNS spasticity of spinal origin (101–104). However, close sedation with fatigue, drowsiness, and dizziness; para- analysis of these studies indicates that its effectiveness doxical agitation; confusion; and disorientation with has been marginal, particularly in terms of a reduc- periods of blackouts or amnesia (19, 70, 72, 88). tion in the Ashworth score. However, some physicians Rapid withdrawal has been associated with irritabil- continue to note that some patients with spastic hy- ity, tremors, nausea, and seizures (19, 70). pertonia have a clinically meaningful response to the medication. Other GABA derivatives The most frequently noted side effects of gabap- Gabapentin entin are somnolence (25%), dizziness (23%), ataxia (20%), nystagmus (15%), headache (14%), tremor Gabapentin is an analogue of GABA. The mechanism (13%), fatigue (12%), and nausea/vomiting (9%), of action of gabapentin continues to be a subject of although the frequency is claimed to be less frequent debate. In the past, it was believed that gabapentin’s than that noted with most other anticonvulsants effect was not mediated through interaction with the (19, 95, 98). The usage in children has had mixed GABA receptor. However, more recently, it has been results, so it is generally only indicated for those over thought to interact at the GABA receptor. It is known 12 years of age in children (94, 105). When dosing for certain that gabapentin is not converted metaboli- younger children, there are some pediatric epilepsy cally into GABA or GABA agonist, and it is not an dosing guidelines that may be useful that indicate dosing for those 2 years or younger using gabapen- tin syrup 10 mg/kg (106). Dosing for subjects over 2 years received oral capsules based on weight: 200 mg for 16 to 25 kg; 300 mg for 26 to 36 kg; and

206 IIIâ•… Treatment of spasticity 400 mg for 37 to 50 kg (106). There are no stud- emotional labiality (4%) (4). In one large study, seri- ies on the effectiveness of gabapentin on spasticity ous adverse effects were described in more than 15% in children. of those exposed to the medication (115). Dosage is usually limited to 6 to 36 mg/d (105). Dosages in the Tiagabine 48 to 60 mg/d were linked to paradoxical nonconvul- sive status epilepticus, and hence, excessive dosages Tiagabine is an anticonvulsant drug that was de- should be used with caution in those patients with signed to prevent GABA reuptake into neurons (70). spastic hypertonia with a documented seizure disor- First utilized as an add-on therapy for partial epilepsy der (116). (107), more recently, it has been utilized as both an adjunctive medication and a monotherapy for com- Vigabatrin plex-partial seizures and generalized tonic-clonic sei- zures (105, 108). Vigabatrin was another attempt to “tailor make” an irreversible inhibitor of GABA-transaminase predom- Pharmacokinetics inately as an antiepileptic agent (94). By inhibiting the neurotransporters of GABA and increasing the ex- Tiagabine is 96% absorbed orally in most patients tracellular GABA, it has been demonstrated that this reaching peak serum concentration in 45 minutes suppresses seizures (94, 117). Vigabatrin is broadly in most patients although a delay of up to 3 hours licensed in Europe and Latin America. Vigabatirn was has been reported in those with taking other medica- approved by the FDA in January of 2009, but its re- tions that are hepatic metabolized (109). Tiagabine is lease in the United States had been inhibited by its its spectrum of activity and toxicities have been de- association to vision loss. The drug has generally been scribed as similar to those of vigabatrin and gabapen- utilized for and now is the only FDA-approved medi- tin (94, 95, 109). Tiagabine is rapidly metabolized via cation as an adjuvant therapy for refractory partial cytochrome P450 enzyme, and drugs that induce this seizures in both adults and children (94, 118). Use for enzyme will increase its metabolism, including carba- spasticity is off-label, and there are no large studies on mazepine and phenytoin (109–111). However, it has a the use of this drug for spasticity. half-life of only 7 to 9 hours (109, 112). Pharmacokinetics Treatment Vigabatrin reaches peak serum concentration within Tiagabine is usually initiated at a dose of 4 mg once 0.5 to 2 hours (119, 120). It is predominately renally daily. The dose may be increased by 4 mg at the begin- cleared (119) and has a plasma half-life of 5 to 8 hours ning of the second week and then at weekly intervals in adults and 12 to 13 hours in elderly persons (4, 119). by 4 to 8 mg/d, divided in 2 to 4 doses, until a clini- Vigabatrin is not metabolized or significantly protein cal response is achieved (113). The maximum dose is bound (119, 121). The serum levels of liver transami- 32 mg/d. nases are reported to be reduced with vigabatrin, but this has not been associated with hepatic or renal dys- Interestingly, there are no studies on the use of function (95, 119, 122). It has been noted to decrease tiagabine in adults with spasticity. However, there the serum level of phenytoin by 20% to 30% (95, 121). are 2 small open-label trials in the use of tiagabine in The most commonly noted side effects are somnolence/ spastic hypertonia in children (107,114). One small drowsiness (28%), fatigue (28%), dizziness (21%), study in 10 subjects indicated an improvement in the nystagmus (15%), abnormal vision (11%), agitation Ashworth scores of the children (114). Another study (11%), amnesia (10%), depression (10%), and pares- in 14 children who had epilepsy and spastic hyperto- thesia (9%) (4, 120). Doses usually start at 25 mg/kg nia noted an improvement in voluntary motor scores per day and increased up to 125 mg/kg per day as as well (107). needed. One author generally starts most patients on 1000 mg once a day (118), and the drug is generally The most frequent adverse effects of tiagabine are increased to a maximum of 4 g a day in 2 divided dizziness (30%), asthenia (24%), nervousness (12%), doses (4, 120). tremor (9%), diarrhea (7%), depression (5%), and

15â•… Pharmacologic Management of Spasticity: Oral Medications 207 Treatment metabolized, and none of the metabolites are felt to be clinically active (133). It is predominately renally Dosing in adults with spastic hypertonia has been cleared (128, 131). in the range of 2 to 3 g/d in 2 divided doses (121). However, vigabatrin has been of therapeutic value in Treatment the treatment of refractory infantile spasms, although these spasms have been linked to seizure activity (123). Topiramate is usually initiated at doses of 25 to 50 mg/d In 43% of the children there was complete spasm sup- and increased in increments of 25 to 50 mg per week pression and 95% of the children had a greater than (131). It has had limited use in spasticity that has been 50% reduction of spasms with initial treatment (123). primarily confined to open-label case series of children However, a long-term response was noted in only 75% with spasticity from Canavan disease, which causes early of children with symptomatic infantile spasms (123). onset leukoencephalopathy and megalencephaly as well as the infantile spasms of West syndrome, when com- Vigabatrin can cause psychiatric disturbances, bined with vigabatrin (4, 133, 134). It has been reported including aggression and psychosis (95, 121, 124). to be useful in chorea and hemiballismsus after stroke About half of all the patients experience some ad- in 1 case report (135). Topiramate’s most significant verse effects with vigabatrin. The most common are side effects are somnolence and weight loss (4, 131). drowsiness and fatigue, although in children, excita- tion and agitation occur more frequently. Other CNS- Central Alpha-Adrenergic Agents related adverse effects include dizziness, nervousness, irritability, headache, nystagmus, ataxia, paraesthesia, The monoamines are widely distributed within the CNS. tremor, and impaired concentration. Generally, it is In spastic hypertonia, they appear to modulate sensory, felt that patients with significant psychiatric history autonomic, and motor functions through facilitation of should be treated with caution with regard to the use presynaptic inhibition of spinal afferent inputs (20). The of vigabatrin (108). Toxicology studies have associ- monoamines have an important role as modulators of ated vigabatrin with intramyelinic vacuolization or spinal neuron excitability (136). Norepinephrine for the edema in the brains of rodents and dogs (94, 95, 118). spinal pathways is produced in the neurons residing in Vigabatrin may need to be withdrawn if visual symp- the brain in the area called the locus ceruleus (20). The toms develop. Visual field testing should be performed mechanism by which noradrenergic pathways modulate at baseline and during routine follow up, particularly spastic hypertonia is predominately by modulating the in children who have visual field deficits or at risk to sensory inputs via presynaptic inhibition of the spinal develop visual field deficits (125–127). afferent inputs (20, 137). Norepinephrine also modu- lates polysynaptic segmental reflexes where NE agonists Topiramate may restore the vibratory inhibition of spinal reflexes (20, 138). Norepinephrine also has a direct inhibitory Topiramate is another Anti epileptic drug (AED) for effect on interneurons and polysynaptic segmental re- tonic-clonic seizures by blockage of voltage-dependent flexes (20, 139, 140). In essence, the central NE modu- sodium channels (128), an augmentation of gamma- lates spastic hypertonia via central alpha-2 and imidazol aminobutyrate acid activity at some subtypes of the type-I adrenergic receptor agonist activity by both re- GABA-A receptors (4, 129, 130), and antagonism of ducing the stimulating effect of noxious stimulation (20, AMPA/kainite subtype of the glutamate receptor af- 141) and modulating the spindle activity directly related fecting Ca channels (130). to spastic hypertonia (20, 142). When the descending pathways from the brainstem to the spinal cord are disrupted, there is a reduction in the NE in the spinal pathways leading to increased spastic hypertonia. Clonidine Pharmacokinetics Clonidine was one of the first central acting cen- tral alpha-2 and imidazol type-I adrenergic receptor After oral administration, topiramate reaches peak se- rum concentration in 1 to 4 hours, averaging 2 hours in most patients (131, 132), and has an elimination half- life of 21 hours (131). Topiramate is only slightly

208 IIIâ•… Treatment of spasticity agonists to be utilized in spasticity (20). Clonidine is had a similar effect as orally (162, 163). It should be also an alpha-1 central adrenergic agonist. This effect pointed out that oral clonidine may have profound is what is felt to be attributable to its effects as an effects in patients with SCI on autonomic dysreflexia antihypertensive medication, which is antagonized (164) as well as on bladder reflexes, potentially chang- by yohimbine (20, 143–145). Its effects on spasticity ing the voiding patterns of the patients (147). There are predominately attributed to its alpha-2 adrenergic are limited pediatric trials using clonidine for spas- receptor effects by presynaptic inhibition of sensory ticity. The predominant side effects are related to its afferents (137, 138, 145). This is why it is also attrib- effects on blood pressure. Other side effects include uted to be a profound nocioceptive pain reliever (20). bradycardia, dry moth ankle edema, and depression Clonidine’s effects on blood pressure appear to be due (20, 159). Those with a complete high-level SCI may to the central sympatholytic effect of clonidine. As a be less likely to have a significant effect on blood pres- result, clonidine has little effect on the blood pressure sure (147, 148, 159). of people who have complete SCI, but it can lower the blood pressure for normals and those with incomplete Tizanidine injuries (146–148). Pharmacokinetics Tizanidine is a centrally acting, selective alpha-2 ad- renergic and imidazole agonist that is structurally Clonidine is an extremely lipophilic medication with related to the antihypertensive drug clonidine (20). almost uniform distribution whether the medication is However, tizanidine has only one-tenth to one-fiftieth delivered via oral (149, 150), transdermal (151–153), the potency of clonidine in lowering blood pressure intravenous (154, 155), epidural (156), or rectal de- or slowing heart rate (165). This is due to the differ- livery (157, 158). All reach relatively similar systemic ences in preferential receptor selectivity for alpha-2 serum levels. Oral clonidine delivered orally reaches receptors rather than alpha-1 adrenergic receptors. peak serum levels in 1 to 1.5 hours and has a serum Similar to clonidine, tizanidine also has effects on im- half-life of 12 to 16 hours (159). Clonidine is 50% idazol type I receptors. Tizanidine is active at both metabolized by the liver with the rest renally cleared segmental spinal and supraspinal levels in both motor largely unchanged (159). and sensory pathways (20). At the spinal segmen- tal level, tizanidine is a presynaptic inhibitor of ex- Treatment citatory amino acid release and also acts to inhibit Clonidine in the oral form has been utilized quite suc- cessfully for spastic hypertonia in SCI (20, 137, 138, 146, 160). However, all the studies were open-label A-B trials. In patients with stroke, there is 1 case re- port (161). Transdermally, clonidine appears to have Table 15.3 Table of Most Common Adverse Drug Reactions for Antispasticity Medications ADR Incidence Dose Related Clinical Management Sedation 30%–50% Yes Reduce dose Titrate slowly Dry mouth 30%–50% Yes Reduce dose Titrate slowly Asthenia 25%–45% Yes Reduce dose Titrate slowly Dizziness 10%–30% Yes Reduce dose Titrate slowly Elevated hepatic 5% No Monitor at 0,1-3, Discontinue drug transaminases and 6 months Hallucinations 0%–3% No Ask if present Discontinue drug GI effects 4% No Monitor symptom Hypotension 2% Yes Reduce dose Titrate slowly Most common side effects with the use of oral tizanidine.

15â•… Pharmacologic Management of Spasticity: Oral Medications 209 polysynaptic reflexes (166). In the brain, tizanidine 171) (see Table 15.3). Sedation appears to be the most inhibits firing of the locus ceruleus, thereby inhibit- serious side effect in spasticity trials with an incidence ing the normally facilitatory influence of the descend- of 41% to 46% (167–169). Despite its similarity to ing cerebrospinal pathway. Tizanidine has no effect clonidine, there is very little hypotension or bradycar- on monosynaptic reflexes, such as the standard deep dia experienced at clinically relevant doses and virtu- tendon reflex (165). More importantly, tizanidine has ally none in the lower half of the dose range (177). Re- no activity at the neuromuscular junction and has bound hypertension can occur with abrupt cessation no direct effect on skeletal muscle fibers, so it does from higher does (170). Hallucinations and night- not cause any muscle weakness (167–169). In some mares have been reported, and some Gastro intestinal reports, patients actually show apparent increases in (GI) side effects, notably constipation, can occur in muscle strength due to central relaxation of the an- up to 5% of Gastro intestinal patients (170). There tagonist muscles (167). is excellent agreement between researchers and clini- cians with regard to the type and frequency of adverse Pharmacokinetics drug reactions. Perhaps the most significant issue with the chronic use of tizanidine has been its potential for Tizanidine is well absorbed with 50% to 65% absorp- hepatotoxicity, so liver enzymes should periodically tion from oral doses and undergoes extensive first-pass be checked as the dosage is increased (20, 170). metabolism (20). None of the metabolites are phar- macologically active. The half-life of tizanidine is 2.1 Serotonergic agents to 4.2 hours, with peak plasma concentration reached at 1 hour (170, 171). Modified release capsules have a The mechanisms by which serotonin affects spastic peak serum level of 5.7 hours (172) with 60% of the hypertonia are not clearly understood. It is quite clear drug excreted in the urine and 20% recovered in feces that in SCI the presence of serotonin-containing neu- (170). Tizanidine is moderately protein bound (about rons, which originate in the brainstem, is an indica- 30%) and exhibits linear kinetics across the range of tion of an incomplete lesion (20). However, it is also usual doses. It has no effect on the hepatic P450 en- clear that in serotonin syndrome there is an increase zyme system (20, 170). There is a paradoxical “food in tone and spasticity (73, 178, 179). Furthermore, it effect” that alters the pharmacokinetics of tizanidine. has been speculated for some time that drugs that can If taken with a meal, the peak plasma concentration block serotonergic transmission may improve spastic is increased by 33%, and the time to reach this peak hypertonia (20). concentration is reduced by 40 minutes (170). The new modified release capsules somewhat temper this “food Cyproheptadine effect” (170). The overall absorption of the drug re- mains unchanged (170). There are drug interactions; particularly with the concomitant use of ciprofloxa- cin, the tizanidine exposure is increased with risks of excessive sedation and hypotension (173, 174). Treatment The most profound serotonin blocker utilized to block serotonin is cyproheptadine, which has been studied in Tizanidine has been effectively utilized in randomized spasticity (180–182) as well as to treat the symptoms clinical trials for spastic hypertonia in SCI, MS, TBI, of the serotonin syndrome associated with baclofen and stroke utilizing the Ashworth score as one of the withdrawal (69). It was initially approved for vascular outcome measures (167–169, 175). In stroke, there is headaches, anorexia, and hives (4). another prominent open-label study also demonstrat- ing significant effectiveness utilizing the Ashworth Pharmacokinetics score as one of its outcome measures (173). There are no pediatric studies although it is evident that the Besides its profound effects on blocking serotonin, medication is utilized off label (176). Dosing should be cyproheptadine has profound anticholinergic and an- started at 2 mg at night and increased slowly by 2 mg/d tihistaminic effects as well (4, 69, 183). Dosing is usu- every 2 days to a maximum dosage of 36 mg/d. The ef- ally at 12 to 20 mg/d in 3 to 4 divided doses with dose fect of tizanidine is clearly dose-related (167, 177). The most common side effects of tizanidine are sedation, asthenia, dizziness, and dry mouth (167–

210 IIIâ•… Treatment of spasticity increases every 3 to 4 days (4, 69, 182, 183). Cypro- extract have profound antinausea and antianxiety ef- heptadine reaches peak serum concentration in 6 to fects. There has been considerable interest in the use of 9 hours after oral ingestion and has a serum half-life cannabis, particularly in patients with MS (186). The of 16 hours (184). The drug is 57% conjugated in the mechanism of action, other than a reduction in anxiety liver, and the rest is renally cleared (184, 185). or pain, that may cause spastic hypertonia is not clear. Treatment Pharmacokinetics Clinical data supporting the use of cyproheptadine Dronabinal reaches peak serum concentration in 1 to are quite sketchy. It was first reported to decrease 2.5 hours after ingestion and has a biphasic half-life ankle clonus in 6 MS and SCI patients in an open- for the active compounds of 19 to 36 hours (187). label study over 25 years ago (180) and later to im- The drug is rapidly metabolized into the active com- prove walking speeds in an open-label study of 6 SCI pound11-hydroxy-delta-9- tetrahydrocannabinol and patients (181). A larger 3-armed open-label trial on is 10% to 15% renally cleared with the rest cleared 25 SCI patients comparing baclofen, clonidine, and in the feces (187, 188). Dizziness and somnolence are cyproheptadine indicated that on the Ashworth Scale the most common side effects, although ataxia and and the pendulum test, cyproheptadine was superior memory issues have been reported (187). to clonidine and equivalent to baclofen. These data are limited because there was no randomization and Nabilone reaches peak serum concentration in no placebo group. More recently, there is a report that 2 hours and has a half-life of only 2 hours (189). It cyproheptadine may alleviate some of the effects of in- is extensively metabolized by the liver via the P450 trathecal baclofen withdrawal, indicating that GABA- enzyme and predominately excreted in the feces with B receptors do inhibit the release of serotonin and that 20% to 24% renal clearance (189–191). serotonin is involved in movement disorders (69). The most frequent side effects are somnolence and weight Treatment gain with the use of cyproheptadine (20, 185). The recommended initial dose for dronabinol in pa- Cannabinoids tients is 2.5 mg orally twice daily and slowly increased over and may be gradually increased to a maximum Dronabinol of 20 mg/d (187). Nabilone is started at a dosage of 1 mg/d and increased slowly to a maximum dosage of Nabilone 6 mg/d in 3 divided dosages (189). There have been several suggestions on the effectiveness of cannabis- O related compounds on spasticity for years. These stud- ies were either open-label subjective studies (192–194) H OH or small blinded studies utilizing electromyographic H (EMG) analyses (195). Only 2 of the studies were outside of MS, with one having a mixed population O of stroke, MS, and SCI (195), and another subjective study in patients with SCI (194). Cannabis, cannabis extracts, and various synthetic cannabinoids have been touted for years as agents to In a recent large placebo-controlled study, 630 treat spastic hypertonia. It has been the impetus in the participants were treated with oral cannabis extract United States for various states to legalize the medici- (n = 211), delta9-tetrahydrocannabinol (delta9-THC; nal use of marijuana (4, 186). Tetrahydrocanibinoid n = 206), or placebo (n = 213). The trial duration was (THC) is the active ingredient of cannabis. Synthetic 15 weeks (196). The primary outcome measure was versions such as dronabinol and/or nabilone, devel- change in overall spasticity scores using the Ashworth oped for nausea, are versions of delta-9-tetrahydro- Scale. There was no treatment effect of cannabinoids, cannabinol (4). Both of these drugs and the cannabis either cannabis extract or delta9-THC, on the pri- mary outcome measure (196). However, there was a trend toward improvement that was superior with delta9-THC (196). Interestingly, the placebo group improved significantly, and it is not clear as to whether therapies were controlled for in the study population. There was some objective improvement in mobility

15â•… Pharmacologic Management of Spasticity: Oral Medications 211 and patients’ opinion of an improvement in pain, al- (206, 207). Dantrolene’s action is specific for skeletal though there were also some difficulties in the blind- muscle and affects reflex contractions or spasticity ing of the study (196). more than voluntary contraction (208). However, its effect is still significant enough that twice the volun- A 12-month open-label study on these same pa- tary effort is required to maintain a desired muscle tients who continued in the trial for 12 months indi- tension (209). cated that patients felt that both cannabis extract and delta9-THC helped their spasticity (197). This was Pharmacokinetics confirmed objectively only in the deltal9-THC group by an improvement of approximately 2 points on the Dantrolene is well absorbed, approximately 70% Ashworth Scale from the baseline. There was sugges- (210, 211), and has a half-life of 15 hours after oral tive evidence for treatment effects of delta9-THC on administration in adults (212). Peak blood levels are some aspects of disability at 12 months as there was achieved within 3 to 6 hours, and its active metabolite in the shorter 15-week study (196, 197). Interestingly, peaks within 4 to 8 hours (42). It is metabolized by despite the movement for medicinal marijuana, pure the liver via hydroxylation, N-reduction, and acety- cannabis extract was not effective in this extended lation to form 5-hydroxydantrolene and acetylated study (197). There were no major safety concerns. dantrolene (213). Five-hydroxydantrolene is an ac- However, memory issues were not addressed, and this tive metabolite, albeit less potent and acetylated dan- appears to be a significant problem even in those who trolene is inactive (212–214). Approximately 20% are normal and use cannabis (198). Another more re- of an orally administered dose, or 80% of an ab- cent randomized trial on 189 patients did not reach sorbed dose is eliminated by the kidney in the urine as statistical significance on the Ashworth Scale but did 5-hydroxydantrolene (79%), acetylated dantrolene have an improvement in functional status (190). (17%), and unchanged parent drug (1%-4%) (212, 215). Overall, patients felt that these drugs were help- ful in treating their disease in the larger trials (196, Treatment 197, 199). Others have reported improvement in up- per motor neuron-related bladder issues in MS (199). Dantrolene has been found superior to placebo for There are those who feel that the side effects of can- the treatment of spasticity secondary to stroke, TBI, nabis extract can be alleviated by the use of synthetic SCI, CP, and MS (216–220). However, because of its cannabinoids (200), and clearly, the dosing is more propensity to cause weakness, several reports advo- predictable than the organic version. cate limiting its use in CP, spasticity of spinal origin, and MS patient populations, as it may hinder func- OTHER AGENTS tion (15, 85, 217). Correspondingly, in 1980, the American Medical Association released the statement, Dantrolene Sodium “Dantrolene should be used primarily in nonambula- tory patients and only if the resultant decrease in spas- Dantrolene, (1-((5-p-nitrophenyl)furfurylidene)amino) ticity will not prevent the patient from functioning” hydantoin)sodium hydrate or dantrolene sodium, is (221). A recent report has recommended dantrolene the only FDA-approved oral antispasticity medication as a first line agent in the treatment of spasticity af- that is classed as a direct acting skeletal muscle re- ter TBI, especially in the acute setting, as it exhibits laxant. Dantrolene does not exert its effect centrally. minimal cognitive effects and may not interfere with Rather, it acts in the periphery by decreasing the re- neural recovery (217). lease of calcium from the sarcoplasmic reticulum of the skeletal muscle cell, thus uncoupling electrical ex- The recommended initial dosing for adults is 25 citation from contraction and decreasing the force of mg daily for 7 days. This may then be increased to contraction (201–205). This in turn affects intrafusal 3 times daily dosing for 1 week, then to 50 mg 3 times as well as extrafusal fibers, reducing spindle sensitivity daily for 7 days, and then to 100 mg 3 times daily if further dose increase is required (212). The maximum daily adult dose is 400 mg (212). Pediatric dosing is similar to most other medica- tions in that it is weight based. Dosing begins with 0.5 mg/kg daily for 7 days (212). The dose may then be increased as necessary to 0.5 mg/kg 3 times daily for

212 IIIâ•… Treatment of spasticity 1 week, then to 1 mg/kg 3 times a day for 1 week, and Cyclobenzaprine is a centrally acting muscle relaxant then to 2 mg/kg 3 times daily to achieve the desired that has been utilized primarily for muscle spasms. effect (212). Again, a maximum dose of 12 mg/kg per day The mechanism of action is felt to be primarily at the or 400 mg daily should not be exceeded (212, 205). brainstem within the CNS as opposed to the spinal cord. It influences both gamma and alpha motor sys- Dantrolene use is associated with a significantly tems by reducing tonic somatic motor activity (226). increased risk of hepatotoxicity, 1% overall, especially Cyclobenzaprine is structurally related to and may with doses higher than 400 mg a day (212). Not sur- have actions similar to tricyclic antidepressants and prisingly, active hepatic disease is a contraindication as such has profound anticholinergic effects as well to its use. Female gender, age more than 35 years, and (227). Some of its mechanism of action may be an polypharmacy are additional risk factors for hepato- effect on pain. toxicity (222, 223). In one study of 122 cases of dan- trolene-induced adverse hepatic effects, 47 patients Pharmacokinetics (the majority) had asymptomatic elevation of trans- aminases (224, 225). It is suggested that liver function Cylobenzaprine is started at a dosage of 2.5 mg 3 times tests be monitored during dantrolene therapy, and in per day and increased up to 10 mg/d (228). The medi- accordance with good medical practice, the lowest op- cation has a peak serum concentration within 4 hours timally effective dose should be prescribed. with a half-life of 8 hours for immediate release and longer for various extended release versions (229). It Cyclobenzaprine is predominately renally cleared with some hepatic conversion to glucuronides (228, 229). Table 15.4 Cerebral Disorders Spastic Hypertonia Treatment Treatment Paradigm for the First 6 Months After Brain Injury There are no specific studies with this medication, but many physicians use it anecdotally for the treatment of ·╅ Rehabilitation therapies and modalities spastic hypertonia and the pain noted with spasticity. Reduce noxious stimulation One small study on 15 brain injury and SCI patients did not note much of a change in the EMG effect of ° Prevent contractures the patellar deep tendon reflexes (230), but this is not ° Reduce exposure to superficial cold a commonly utilized outcome measure. Dosing starts °Â·â•… Splinting and ROM slowly as above and is titrated up slowly. Somnolence is noted to occur in 39% to 100% of patients taking ·╅ Modalities and/or casting the medication (226). ·╅ Systemic medications Orphenadrine Dantrolene sodium Orphenadrine citrate is another commonly utilized ° Baclofen* (Meythaler et al. JHTR 2004) muscle relaxant (231). It is felt to also work as a °  Predominate lower limb spastic centrally acting muscle relaxant. Receptor studies re- hypertonia ° Tizanidine  Predominate upper limb spastic hypertonia ·╅ Neurolytics Botulinum toxin ° Phenol and alcohol °  Can be irreversable ·╅ Intrathecal baclofen ° Controversy over use in the first 6 months after CNS injury Note: This paradigm was first suggested by the NIH TBI clinical trials centers to control confounding variables poten- tially impacting recovery after injury during the first 6 months after injury. No such paradigms have been established for spinal causes of spastic hypertonia, although most clinicians start with baclofen or benzodiazepines.

Table 15.5 Oral Antispasticity Medications Trial Population, Outcome Measure Result/Comments Spinal Cord Injury n Trial Type Baclofen Duncan 1976 (50) 25 Double-blind, 5-point scale Baclofen superior (p < .01) 15â•… Pharmacologic Management of Spasticity: Oral Medications placebo-controlled, Alpha Hinderer 1990 (235) crossover Unspecified No improvement on baclofen adrenergics Jones 1983 (236) 5-point scale for spasms Baclofen favored Nance 1994 (182) 5 Placebo-controlled 6 Double-blind, Ashworth Scale, Pendulum Tizanidine superior Ashworth Taricco 2000 (237) test (p < .0001), Pendulum (p = .004), placebo-controlled no difference in daily frequency 124 Placebo-controlled Ashworth Scale Tizanidine superior to placebo, (gabapentin, clonidine, diazepam 218 Systematic review amytal, oral baclofen) no evidence for significant clinical effectiveness Rinne 1980 (57) 32 Head-to-head Ashworth Scale No significant difference Nance 1985 (137) (tizanidine vs ba- Clonidine effective Maynard 1986 (160) “may benefit from clonidine” Nance 1989 (138) clofen) “Clonidine has an antispasticity effect in SCI patients” Donovan 1988 (146) 4 Case report Not specified “56% benefitted” Benzodiazepines Corbett 1972 (238) 12 Open-label Clinical spasticity Valium significantly more effective than placebo 6 Placebo-controlled Vibratory inhibition Index, No significant difference H reflex 55 Open-label clinical Observation by patient, trial therapist, and physician 22 Double-blind, ran- Clinical improvement as domized, placebo- determined by examiner controlled, crossover Double-blind, Roussan 1985 (46) 6 crossover, head to Frequency of flexor spasms, head (baclofen vs resistance to passive stretch, diazepam ROM, DTR, clonus (Continued) 213

Table 15.5 214 IIIâ•… Treatment of spasticity (continued) Trial Population, Outcome Measure Result/Comments Gambi 1983 (220) n Trial Type Dantrolene superior (p < .05) Dantrolene Glass 1974 (85) 24 Double-blind, 6-point scale Dantrolene favored sodium crossover, placebo- Dantrolene superior (p = .002) THC is effective controlled Gabapentin improved spasticity (p = .04) 16 Placebo-controlled, 6-point scale Gabapentin may be effective head-to-head (dan- “Diminished” spasticity with trolene vs diazepam) 4-aminopyridine Placebo-controlled Significant improvement over placebo (p = .02) Weiser 1978 (218) 35 4-point scale Hagenbach 2007 (239) Cannabinoids 25 Open-label, placebo- Spasticity Sum Score, Modi- Other drugs Gruenthal 1997 (103) controlled fied Ashworth Scale 25 Randomized, double- Ashworth Scale blind, placebo-con- trolled, crossover Multicenter, placebo- Priebe 1997 (104) 7 controlled, crossover, EMG, Brain Motor Control Segal 1999 (240) clinical trial Assessment Randomized, 21 open-label, active- Modified Ashworth Scale treatment control, dosage-blinded Randomized, Cardenas 2007 (80) 91 placebo-controlled Ashworth Scale Traumatic Brain Injury Baclofen Meythaler 2004 (5) 22 Retrospective Penn Spasm Frequency Scale, Baclofen decreases Ashworth score Ashworth Scale from 3.5 to 3.2 (p=.0044), no signifi- cant change in spasm frequency Alpha Meythaler 2001 (9) 17 Placebo-controlled, Penn spasm frequency scale, No significant difference Penn Scale, adrenergics Harmon 1996 (241) prospective Ashworth Scale Tizanidine favored Ashworth 2 Prospective, double- Modified Ashworth Scale (p = .006) blind, placebo- “Clonidine may be superior to controlled, crossover, placebo” pilot

Benzodiazepines Zafonte 2004 (217) 1 Case report Ashworth Scale Tone improved Dantrolene Hulme 1985 (242) sodium 12 Placebo-controlled Unspecified Study stopped due to somnolence as 15â•… Pharmacologic Management of Spasticity: Oral Medications Cannabinoids Other drugs Stroke Baclofen excessive adverse event Medaer 1991 (243) 20 Double-blind, Ashworth Scale Baclofen superior crossover, placebo- controlled Alpha Medici 1989 30 Head-to-head, Ashworth Scale, 4-point No significant differences adrenergics (175) double-blind, patient self report scale, 5- long-term point muscle strength scale, (tizanidine vs ba- 3-point clonus scale, Kurtzke clofen) Expanded Disability Status Scale Maupas 2004 (244) 14 Randomized, Modified Ashworth Scale, H Tizanidine superior Groves 1998 (245) placebo-controlled reflex 270 Meta-analysis of Ashworth Scale Tizanidiine, baclofen, diazepam double-blind, ran- equally effective domized studies Gelber 2001 (173) 47 Open-label Modified Ashworth Scale Spasticity significantly improved with Benzodiazepines Bes 1988 (246) tizanidine 104 Double-blind, head- 5-point scales for spasticity No significant differences to-head (diazepam and spasm severity vs tizanidine) Kendall 1964 (247) 12 Double-blind, Measurement of PROM and Diazepam reduces spasticity Cocchiarella 1967 (87) crossover angle of catch 19 Randomized, Objective measures of No specific spasmolytic effect double-blind, spasticity observed placebo-controlled Dantrolene Katrak 1992 (248) 38 Randomized, 0–6 motor assessment scale No measurable difference sodium Ketel 1984 (210) double-blind, Chyatte 1971 (249) placebo-controlled 18 Placebo-controlled Unspecified Dantrolene favored 9 Double-blind Methods-Time-Measurement, Dantrolene effective DTR, Clonus, Resistance to passive movement (Continued) 215

Table 15.5 216 IIIâ•… Treatment of spasticity (continued) Trial Population, Outcome Measure Result/Comments Stamenova n Trial Type Tolperisone superior 2005 (250) Cannabinoids 120 Randomized, double- Ashworth Scale No significant difference from placebo Other drugs Ashby 1972 (230) blind, placebo-con- Baclofen superior (p < .001) Cerebral Palsy Milla 1977 (48) Baclofen superior to placebo on Goal Baclofen Scheinberg 2006 (251) trolled, multicenter, Attainment Scale parallel 15 Double-blind, 5-point scale of muscle tone crossover 20 Placebo-controlled Ashworth Scale 15 Double-blind, Goal Attainment Scale, crossover pilot Pediatric Evaluation of Disability Inventory, Modified Tardieu Scale Lopez 1996 (252) 20 Prospective, Ashworth Scale “Significant reduction of spasticity” placebo-controlled, crossover Alpha Vasquez-Briceno 2006 40 Randomized, Ashworth Scale, Posture tone Tizanidine significantly superior adrenergics (253) double-blind, scale placebo-controlled Benzodiazepines Nogen 1976 (254) 22 Head-to-head (diaz- Unspecified No significant differences epam vs dantrolene) Dahlin 1993 (90) 12 Double-blind, Restraint of passive knee Clonazepam significantly reduced placebo-controlled, movements determined by spastic restraint (p < .001) crossover dynamic dynamometer Mathew 2005 (255) 180 Double-blind, Modified Ashworth Scale Diazepam significantly reduced tone parallel, (p < .001) placebo-controlled, randomized Dantrolene Chyatte 1973 (256) 18 Placebo-controlled 4-point scale No measurable difference sodium Denhoff 1975 (219) Haslam 1974 (257) 18 Placebo-controlled Unspecified Dantrolene superior (p < .04) Joynt 1980 (258) 26 Placebo-controlled 5-point scale No statistical difference 21 Placebo-controlled 4-point scale No statistical difference

Cannabinoids Losin 1966 (259) 30 Placebo-controlled 5-point scale Outcomes not clear Other drugs Bjerre 1971 (260) Chlorzoxazone, Hurst 2002 (261) 44 Placebo-controlled 3-point scale, Johnson Scale No significant difference methocarbamol Maritz 1978 (262) 9 Open-label pilot Modified Ashworth Scale Statistically significant improvement study with modafinil 16 Double-blind, Holt’s Criteria, 3-point scale Slight to moderate improvement with crossover with piracetam placebo 15â•… Pharmacologic Management of Spasticity: Oral Medications Chu 2006 (263) 9 Open label Modified Ashworth Scale Tigabine ineffective Multiple Sclerosis Baclofen Brar 1991 (264) 38 Placebo-controlled Ashworth Scale Baclofen favored Duncan 1976 (50) Baclofen superior (p < .01) 25 Double-blind, 5-point scale Baclofen superior placebo-controlled, No significant difference crossover Baclofen superior (p < .01) Baclofen superior (p < .001) Feldman 1978 (51) 33 Double-blind, Unspecified Baclofen favored crossover, placebo- controlled Orsnes 2000 (265) 14 Placebo-controlled Ashworth Scale Sachais 1977 (29) 166 Placebo-controlled, Unspecified Sawa 1979 (58) Basmajian multicenter 1975 (266) Newman 1982 (60) 21 Placebo-controlled 6-point scale 14 Placebo-controlled Unspecified 36 Head-to-head Ashworth Scale, Kurtzke and No significant differences (tizandidine vs ba- Pedersen Scales clofen) Smolenski 1981 (59) 21 Head-to-head, dou- Ashworth Scale, 5-point spas- No significant differences ble-blind (tizanidine ticity scale, 6-point muscle vs baclofen) strength scale Alpha adrenergics Lapierre 1987 (267) 66 Placebo-controlled Unspecified No significant difference Smith 1994 (155) 220 Double-blind, Ashworth Scale, 4-point Scale, No significant difference UK Tizanidine Trial Group 1994 (268) placebo-controlled daily counts Bass 1988 (53) 187 Double-blind, Ashworth Scale Tizanidine superior (p = .004) placebo-controlled 66 Head-to-head 6-point scale, Kurtzke No significant differences (tizanidine vs ba- functional scale, Pedersen clofen) functional disability scale Eyssette 1988 (52) 100 Multicenter, placebo- 5-point scale, stretch reflex No significant differences controlled, head-to- 1-5 scale head (tizanidine vs baclofen) (Continued) 217

Table 15.5 218 IIIâ•… Treatment of spasticity (continued) Trial Population, Outcome Measure Result/Comments Alpha adrenergics Hoogstraten n Trial Type No significant differences Ashworth Scale, 5-point 1988 (62) 16 Head-to-head patient self-report, Kurtzke No significant differences (tizanidine vs ba- Expanded Disability Status Stein 1987 (61) clofen) Scale, Kurtzke Functional No significant differences Benzodiazepines Cartlidge 1974 (55) Systems Incapacity Status, 40 Double-blind, head- Ambulation index No significant differences From 1975 (56) to-head (tizanidine Ashworth Scale, Kurtzke Schmidt 1976 (83) vs baclofen) Expanded No significant differences Cendrowski 1977(89) Disability, Status Scale, 40 Head-to-head Pedersen Scale Clonazepam and baclofen significantly (diazepam vs superior to placebo, No significant baclofen) Ashworth Scale difference between clonazepam and baclofen 16 Head-to-head, dou- Ashworth Scale Diazepam significantly superior to ble-blind (diazepam placebo vs baclofen) 6-point scales for spasticity, “Ketazolam more effective than clonus, reflexes placebo” 46 Head-to-head Dantrolene superior (p < .05) (diazepam vs Modified Ashworth danrolene) Not reported Dantrolene favored 68 Placebo-controlled Wilson 1966 (269) 21 Double-blind, triple 4-Point Scale Basmajian 1986 (91) Gambi 1983 (220) crossover Gelenberg 1973 (270) 14 Double-blind, EMG Tolosa 1975 (271) crossover Dantrolene 24 Double-blind, 6-point scale sodium crossover, placebo- controlled 20 Placebo-controlled Unspecified 23 Placebo-controlled 7-point scale

Cannabinoids Killstein 2002 (272) 16 Randomized, double- Ashworth Scale, Expanded No significant differences blind, placebo-con- Disability Status Scale Vaney 2004 (273) trolled, crossover No statistically significant difference Prospective, random- Ashworth Scale, self-report of compared to placebo Wade 2003 (274) spasm frequency, Rivermead 15â•… Pharmacologic Management of Spasticity: Oral Medications 57 ized, double-blind, Mobility Index Spasticity improved by cannabis Other drugs Collin 2007 (199) placebo-controlled, Patient Reported VAS medicinal extracts crossover Zajicek 2003 (196) Double-blind, ran- Patient reported spasticity May be useful Ungerleider 1987 (275) numerical rating, Shakespeare 2003 18 domized, placebo- Ashworth Scale No beneficial effect (276) controlled, crossover Ashworth Scale, Significant improvement Randomized, subjective ratings No statistically significant differences, Paisley 2002 (277) double-blind, Ashworth Scale No recommendations made, more research needed 189 placebo-controlled Ashworth Scale, “other clini- Randomized, cal measures” Baclofen, diazepam, tizanidine ef- placebo-controlled fective, “no evidence to suggest any difference between the drugs” 667 Double-blind, placebo-controlled, 13 crossover Cochrane review, double-blind, ran- domized, placebo- controlled (baclofen, dantrolene, tiza- nidine, botulinum toxin, vigabatrin, prazepam, threonine, cannabinoids Systematic review 1,200 of randomized, controlled trials (ba- clofen, dantrolene, tizanidine, diaz- epam, gabapentin, threonine) (Continued) 219

Table 15.5 220 IIIâ•… Treatment of spasticity (continued) Other drugs Trial Population, Outcome Measure Result/Comments Mueller 1997 (101) n Trial Type Cutter 2000 (102) VAS, Kutrzke Disability Scale, Statistically significant improvements Dunevsky 1998(278) 15 Double-blind, Ashworth Scale with gabapentin placebo-controlled, Mondrup 1984 (279) crossover Modified Ashworth Scale, Statistically significant reduction in Rudick 1987 (280) Kurtzke Disability Status spasticity with gabapentin Barbeau 1982 (281) 22 Prospective, double- Scale, Subject self-report masked, placebo- controlled, crossover Modified Ashworth Scale, Ex- “Satisfactory release of spasticity, Open-label panded Disability Status Scale significant improvement of functional 2 outcome” with gabapentin Double-blind, cross- Measurement of angle at 16 over which stretch reflex appeared Progabide produced medium by mobilisation of limb improvement Ashworth Scale, Kurtzke Double-blind, Expanded Disability Status 32 placebo-controlled, Scale, Houser Ambulation Progabide effective crossover Index Patient report of clonus, EMG Placebo-controlled activity 6 “Cyproheptadine substantially reduced the signs associated with spasticity”

15â•… Pharmacologic Management of Spasticity: Oral Medications 221 vealed that orphenadrine is an uncompetitive NMDA References type glutamate antagonist (4). It is structurally simi- lar to diphenhydramine but does not directly relax 1.â•… Mann NH. Functional management of spasticity after head muscles (231). It may work by reducing the noxious injury. J Neuro Rehab 1991;5:51–54. stimulation of pain (231). 2.â•… Meythaler JM, DeVivo MJ, Hadley M. Prospective study Pharmacokinetics on the use of bolus intrathecal baclofen for spastic hyper- tonia due to acquired brain injury. Arch Phys Med Rehabil Orphenadrine is usually started at a dosage of 100 mg 1996;77:461–466. orally or 60 mg intravenously once a day as it has a half-life of 13 to 20 hours (231, 232). The medication 3.â•… Meythaler JM. Use of intrathecally delivered medications is predominately renally excreted (231). for spasticity and dystonia in acquired brain injury. Yaksh, editor. Spinal drug delivery. 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Intrathecal Baclofen 16 for Spasticity Michael Saulino Stuart A. Yablon Elizabeth Moberg-Wolff John W. Chow Dobrivoje S. Stokic Intrathecal baclofen (ITB) therapy is a potent method HISTORY OF ITB THERAPY for the management of spastic hypertonia and related features of the upper motor neuron syndrome. Intra- Intrathecal administration facilitates the delivery of thecal baclofen infusion exerts its therapeutic effect neurologically active drugs to target receptors in the by delivering baclofen directly into the cerebrospinal central nervous system (CNS) indirectly via diffusion fluid (CSF) with rapid distribution to target neurons through the CSF. Although this technique has recently in the spinal cord. Intrathecal administration of bacÂ

230 IIIâ•… Treatment of Spasticity investigations expanded the role of this therapy to baclofen action, however, remains elusive. Baclofen spasticity of cerebral origin (stroke, CP, and brain could interfere with signal transmission along various inÂ

16â•… Intrathecal Baclofen for Spasticity 231 reservoir, a method of propelling the drug out of the permanent) clinical effect are generally considered as pump, and a catheter that connects the drug reservoir better candidates. Further, ITB can be combined with to the CSF (Figure 16.1). Although constant flow sys- other modalities for synergistic therapeutic effect, in- tems are available (28), programmable systems are cluding rehabilitative therapies, oral pharmacotherapy, overwhelmingly preferred due to their adjustability neurolytic procedures, and muscle/tendon lengthening for individual patient need and response (29). Addi- procedures (31). Physical techniques such as stretch- tional components are needed for programmable sys- ing, strengthening, bracing, and gait retraining are es- tems, including an external programming device and sential for attaining maximal functional benefit that a communication method between the programmer may follow tone reduction. Patients might continue to and the implanted pump. The propulsion technique utilize oral spasticity agents for a variety of reasons, for variable controlled pumps is typically electronic, including ongoing ITB titration, “breakthrough” necessitating an energy source to drive the system. In spasms, an irregular spasticity pattern, disease pro- contrast, constant-flow pumps can utilize a pneumatic gression, or residual upper extremity tone. Combining propulsion technique. Future components may include ITB therapy and neurolytic procedures is appropriate automated troubleshooting of the system, self-directed for patients manifesting both focal dystonic features patient programming, and integrated sensors to detect and global hypertonicity, or residual upper extremity patient position and functional activity level. hypertonia (32). The indications for combining neuro- orthopedic procedures and ITB therÂ

232 IIIâ•… Treatment of Spasticity to a greater extent than in the upper extremities. More include (1) avoidance of sequential lumbar punctures; cephalad catheter tip placement, however, can po- (2) presumably improved approximation of chronic tentially improve upper limb response (35, 36). The postimplant intrathecal infusion response when com- other advantages of ITB therapy include higher po- pared to single bolus injections; (3) ability to control tency with potentially less adverse effects compared catheter tip placement for the evaluation of upper ex- to oral baclofen, the ability to have a global effect tremity effects; and (4) ability to adjust the infusion on all the affected limbs, and the possibility of later rate while assessing the favorable (and unfavorable) adjustment with changing patient need or progres- effects of ITB administration. The disadvantages of sive disease. The disadvantages include surgical risks catheter trials include increased technical difficulty, (bleeding, infection, damage of neural structures), the increased need for observation, and increased risk of potential for serious adverse effects including over- meningitis and structural damage. Fluoroscopic guid- dose and withdrawal, and the requirement for ongo- ance is generally considered mandatory for catheter ing follow-up with health care professionals for dosing placement. Although antibiotic prophylaxis is usually adjustments and pump refills. Ventricular shunting not needed for bolus trials, it is unclear whether anti- for hydrocephalus is not a contraindication to ITB biotic prophylaxis is needed for short-duration intra- therapy, but practitioners should be aware of poten- thecal catheter trials. Factors to consider include the tial interactions between the devices on CSF flow (37). duration of the trial, patient immunocompetency, and Intrathecal baclofen can also be used in patients with potential chronic bacterial colonization. Evidence sug- seizures with the understanding that this therapy has gests that trial duration is a key risk factor for the de- been occasionally associated with an increased risk of velopment of infectious complications. Thus, the trial seizures (38, 39). should last only as long as required to indicate a po- tential benefit of chronic ITB therapy (43, 47). There For the patient who chooses this form of therapy, is no consensus regarding the optimal method of anes- the preimplant trial is the first of 4 phases of ITB treat- thesia utilized for catheter placement. Local anesthesia ment: (1) trial, (2) surgery, (3) titration, and (4) main- potentially lowers the risk of inadvertent damage to tenance. The preimplant trial involves administration neural structures. However, if excessive patient move- of a test dose of ITB to assess the patient’s response to ment or severe anxiety is anticipated, deep sedation this agent. Typically, a lumbar puncture is performed, or general anesthesia may be warranted (48). There and a bolus of a baclofen solution is injected into the is little evidence to suggest that catheter trials provide CSF. Fifty micrograms of baclofen is the most com- better long-term outcomes compared to bolus trials monly used initial screening dose (40). The onset of when utilized as predictors of postimplant response. clinical effects from a screening bolus occurs within Prospective data in the pain management literature 1 to 3 hours postinjection, and peak effects are typi- suggest no difference in outcomes from either intra- cally observed 4 to 6 hours postinjection. The effects thecal trial method (49), although the generalizability of the screening bolus are always temporary, with the of these findings to ITB spasticity trials is unclear. effects routinely lasting for 6 to 8 hours (25, 41). Pro- longed effects of a single test bolus have been reported Definitions of “success” for screening trials vary. (42). Screening boluses can be repeated if the initial A more liberal description of a successful trial might injection is unsuccessful. “Positive” responses are re- be any improvement in spasticity that suggests future ported in 80% to 90% of bolus trials (40). Generally, benefit from chronic long-term infusion. Subjective antibiotic prophylaxis is not needed for a bolus trial patient reports can be used to assess spontaneous (43). For patients on antiplatelet or anticoagulant ther- spasm frequency and intensity (50). The most com- apy, recommendations from the American Society of monly cited criterion for a successful ITB trial is a Regional Anesthesia are followed (44). Fluoroscopic 2-point reduction on the Modified Ashworth Scale guidance can assist needle localization into the intra- (40). Patients may also demonstrate improvement in thecal space (45) because anatomic landmarks for lum- joint range of motion, both actively and passively. In- bar puncture can be variable. trathecal baclofen trials can potentially differentiate range of motion deficits due to severe spasticity, which An alternative method for conducting trials are potentially reversible without surgery, from fixed involves the placement of a temporary intrathecal contractures. catheter and monitoring the patient response to a short-term continuous infusion of baclofen (46). This Although these evaluation techniques are often technique is more commonly utilized for evaluating useful for patients with hypertonia in resting posi- chronic pain patients for intrathecal opiate therapy. tions, these assessments may be inadequate for the The specifics of catheter placement are described later prediction of ITB effect during active functional tasks. in this chapter. The advantages of catheter ITB trials In these patients, excessive tone reduction may im-

16â•… Intrathecal Baclofen for Spasticity 233 pede the performance of activities such as transfers ity is assured, a number of settings are suitable for and walking. Observation of ambulation, transfers, monitoring the effects of the trial. Examples include posture, and wheelchair propulsion during the trial is outpatient clinics, ambulatory surgical centers, inpa- thus warranted. Adjunctive objective evaluation tech- tient hospitals, and inpatient rehabilitation facilities. niques may be helpful and include neurophysiological Further, it is helpful to use practice protocols or path- assessment (25, 51, 52) and instrumented gait analysis ways to facilitate the consistent assessment of key trial (41, 53). There is an inconsistent correlation between response indicators and reduce the risk of complica- subjective report and objective measures of spasticity tions. As described above, sequential evaluations of (54). During a screening trial, some individuals may tone, range of motion, and strength are required. For experience excessive spasticity reduction during the patients who utilize spasticity to assist with functional peak effect of the ITB bolus. This occurrence is not a mobility, similar sequential evaluations of posture, contraindication for pump implantation because the transfers, and gait should be undertaken. Protocols chronic infusion system has the ability to modulate for the management of adverse events should be in dose and subsequent desired effect. If excessive or place, including spinal headache, bowel and bladder prolonged hypotonia is observed during a screening changes, seizures, and respiratory depression. Because trial, then a repeat trial at a lower dose or continu- the effects of ITB trials are occasionally prolonged, the ous trial may be warranted. Particular care should be practice setting should have the capacity for extended paid to patients who demonstrate improvement on observation. Many experienced practitioners of ITB “passive” measures of spasticity (thus qualifying for therapy believe that inpatient rehabilitation facilities long-term infusion of the basis of trial “success”) yet are an optimal site for trials since these locations of- demonstrate functional worsening during the trial. fer the best ability to assess functional changes and Postimplant rehabilitation in this subset of patients is potentially manage adverse effects. particularly important. Some centers proceed directly to pump implan- Adverse effects can occur during the test phase. tation without a screening trial. For stroke patients, Spinal headache or postlumbar puncture syndrome is 2 justifications have been proposed: (1) the increased a complication of an injection-related dural leak and is risk of spinal hemorrhage while the patients are in an- not a direct medication effect. Spinal headaches occur ticoagulation or antiplatelet therapy and (2) the risk in up to 30% of patients undergoing lumbar puncture of recurrent stroke if these agents are discontinued. and can vary in severity from mild to incapacitating This method reduces the ability to differentiate fixed (55). Postlumbar puncture headache typically wors- contracture from spasticity before implantation. Al- ens when the patient sits or stands up, and decreases though patients may still benefit, it should only be un- in the supine position. These headaches typically be- dertaken after a full discussion with the patient and gin within 2 days but may be delayed for as long as caregivers regarding the risks and benefits of a “no 2 weeks. Spinal headaches can be accompanied by trial” approach. dizziness, neck or arm pain, cranial nerve palsies, tin- nitus, nausea, and distorted vision. Spinal headaches IMPLANTATION are more common in younger women with a low body mass index and in people who have a headache his- Once a positive trial response has been observed, a tory in general. The risk of spinal headaches increases patient may proceed to pump implantation. Patients with the use of larger needles. The headache resolves should be clinically stable before surgery to minimize spontaneously in most patients. Supportive measures perioperative complications. Preoperative antibiotics include bedrest, caffeine, and abdominal binders. Epi- are typically utilized. Patients on chronic anticoagula- dural blood patch is reserved for persistent cases (56). tion will need to discontinue medications in the days Other procedure-related complications include bacte- preceding the procedure (44). The risks of permanent rial and aseptic meningitis. Adverse effects that are pump implantation and infusion are similar to those more likely related to a pharmacologic effect include of the screening trial, with the additional risks of drug nausea/vomiting, urinary retention, hypotension, sei- overdose, drug withdrawal, and device complications. zures, drowsiness/sedation, respiratory depression, and coma. Nausea/vomiting and drowsiness/sedation Various options for pump and catheter placement are the most common adverse effects observed dur- should be considered before the procedure. The size of ing ITB trials, with reported frequency of 2% to 3% the implanted pump should be determined based on (40). the patient’s body habitus and anticipated intrathecal dosing. Smaller and thinner individuals might prefer Although the procedural component of the trial a smaller pump size, either for esthetic reasons or to should take place in a setting where injection steril-