Hypertonia Management

Hypertonicity affects the majority of children with CP (109,110). It may occur focally in distinct muscle groups, as is often the case in diparesis or hemipare­sis, or more globally, affecting the majority of axial and appendicular skeletal muscles.

A wide variety of treatment options for hyperto­nicity are available, including oral medications, nerve blocks, and surgery. Determining whether abnormal tone is present globally or focally and the magnitude of its effect on an individual’s musculoskeletal sys­tem, function, and comfort should guide one’s treat­ment plan. The specific goals of tone reduction should always be determined prior to any intervention. The first-line approach should always include stretching, splinting, and positioning as appropriate. Other med­ical or surgical interventions can be can be used in conjunction with these when further reduction in abnormal tone is desired.

Chemical Denervation

Chemical denervation should be considered for the treatment of significant focal increases in tone.

Alcohol Blocks. Alcohol nerve and motor point blocks have been used for many years to reduce focal increases in tone. Phenol injections, at 3% to 5% solutions, either at motor points of selected muscles or perineurally, denature proteins and disrupt efferent signals from hyperexcitable anterior horn cells by inducing necro­sis of axons (111—113). Alcohol blocks have the poten­tial to cause painful dysesthesias (113).

Botulinum Neurotoxin (BoNT). BoNT is a protein com­posed of a heavy chain, which binds nerve terminals at the neuromuscular junction, and a light chain, which is transported into the nerve terminal block­ing the release of acetylcholine presynaptically and thereby weakening the force of muscle contraction produced by the hyperexcitable motor neurons. BoNT exists in seven serotypes, designated A through G. Serotypes A and B are approved by the Food and Drug Administration (FDA) for the treatment of dystonia in adults. The FDA has not approved BoNT for the treat­ment of spasticity in children. BoNT-A is marketed as Botox in the United States and Dysport in Europe. BoNT-B is marketed as Myobloc.

Muscles commonly treated with BoNT include the gastrocsoleus complex, hamstrings, hip adductors, and flexor synergy muscles of the upper extremity. Intramuscular injections can be localized by surface landmarks, electromyographic guidance, and/or ultra­sound. Following injection, muscle relaxation is evident within 48 to 72 hours and persists for a period of 3 to 6 months (115). Dosing is based on units derived from the mouse lethality assay and is not equivalent among the various brands. It is dependent upon both body weight and size of the target muscle(s). Universally accepted dosing guidelines do not exist, but a consen­sus statement (116) and systematic reviews (117,118) of dosing and injection techniques are available for guidance. Injections are typically spaced a minimum of three months apart due to concerns of antibody for­mation in an estimated 5% of patients, resulting in potential resistance (111,119).

Many studies in the literature describe the effects of BoNT-A in children with CP. A systematic review of the literature summarized 17 controlled trials (120). The literature supports improvement in gait over the one to three months following injections into the gas­trocnemius muscles for spastic equinus (121-125). Two small open-label studies found modest improvements in either gait kinematics or muscle length following injection into the hamstrings (126,127). Several small trials evaluating the effectiveness of casting of the ankle in addition to BoNT-A failed to show any add­itional benefit (128-130). Injections into the hip adduc­tors resulted in improved range of motion (131) and decreased postoperative pain in children undergoing adductor lengthenings (132) in two RCTs. Two small RCTs addressing the use of BoNT-A in the upper extrem­ities described modest improvements in tone and ROM, without a significant change in function. The authors of the review concluded that more research needs to be done to determine the optimal choice of muscles, the most appropriate dose and number of injection sites, the safety of repeated and long-term injections, and the risk of development of secondary resistance to BoNT due to antibody formation (120).

Side effects are rare with BoNT, but may include pain during injection, infection, bleeding, a cool feeling in injected limbs, rash, allergic reaction, flulike symp­toms, excessive weakness, and fatigue (123,133,134). Reports of serious or potentially life-threatening side effects from BoNT are extremely rare. The FDA issued a statement on February 8, 2008, identifying cases of respiratory failure and mortality in children with CP linked to injection with botulinum toxin serotypes A and B (135). The FDA stated that “posting the informa­tion does not mean [the] FDA has concluded that there is a causal relationship between the drug products and the emerging safety issue (135).” In addition, rare cases of serious systemic effects have been reported in the literature in children receiving higher doses of BoNT (136,137).

Oral Medications

Oral medications are often used as an early treatment strategy for global spasticity. Medications that are most frequently used include baclofen (Lioresal), dantrolene sodium (Dantrium), clonidine, diazepam (Valium), and tizanidine (Zanaflex). All of these medications work through the central nervous system, with the exception of dantrolene sodium and, therefore, have the potential for sedation (Table 8.2). None of these

medications have been found to be universally effec­tive in relieving spasticity (138), and evidence related to functional improvement is extremely sparse. The choice of medications is, therefore, often based on the impact of potential side effects on the individual patient.

8.2

Medications Used to Treat Spasticity in Children

Source: Reprinted from Physical Medicine and Rehabilitation Clinics of North America, Volume 18, LB Green and EA Hurvitz, pages 866-867, copyright 2007, with permission from Elsevier.

Benzodiazepines.

Baclofen. Baclofen is a GABA analogue that acts at the spinal cord level to impede the release of excitatory neurotransmitters implicated in causing spasticity

(143). Low lipid solubility impedes passage through the blood-brain barrier with more than 90% of the absorbed drug remaining in the systemic circulation

(144). As a result, large doses may be necessary to achieve an effect, which may result in dose-related side effects such as drowsiness. Very few studies have been published regarding the use of oral baclofen in CP. Two small double-blind, placebo-controlled, cross­over trials produced differing conclusions regarding the effectiveness of baclofen in reducing spasticity, but neither employed validated outcome measures (145,146). Additional studies assessed the effect of oral baclofen for reduction of spasticity and improved func­tion in small numbers of subjects with moderate to severe spasticity. One study showed possible delete­rious effects on motor function (117), while the other demonstrated no difference with placebo except in goal attainment (147).

Dantrolene Sodium. Dantrolene sodium is unique in that it works primarily through actions on the skel­etal muscle and not through central nervous system pathways. It inhibits the release of calcium from the sarcoplasmic reticulum, thereby uncoupling electri­cal excitation from muscle contraction and reducing contraction intensity. It is well absorbed within three to six hours after ingestion and is metabolized in the liver to 5-hydroxydantrolene, with peak effect in four to eight hours (148). Doses in children range up to 12 mg/kg/day (142). It is often suggested that dantrolene be considered for the treatment of spasticity of cere­bral origin because its mode of action is not central nervous system-mediated and it is less likely to be sedating (140,142,149). Side effects from treatment, however, can include mild sedation as well as nausea, vomiting, and diarrhea. Use of dantrolene is also asso­ciated with hepatotoxicity (148,150). Liver function studies should be done prior to instituting treatment and periodically while on maintenance therapy (140). There are a few published trials of Dantrium in CP. One report of long-term use of dantrolene in children with spastic diparesis indicated that young children achieved greater levels of function than predicted prior to dantrolene administration and older children were able to move more easily and maintain their highest level of function (151).

Additional oral medications used to treat spas­ticity in children with CP include alpha₂-adrenergic agonists, such as clonidine and tizanidine, as well as certain anticonvulsants, including gabapentin (Neurontin). The alpha₂-adrenergic agonists result in decreased motoneuron excitability by decreasing the release of excitatory amino acids (150). The side effects associated with these agents are frequently the cause of their more limited use and include nau­sea, vomiting, hypotension, sedation, dry mouth, and hepatotoxicity. In addition, reversible liver enzyme elevations have been noted in 2% to 5% of patients (140). Gabapentin is structurally similar to GABA, readily crosses the blood-brain barrier, and is not protein-bound. It does not activate GABA, but results in increased brain levels of it (140). Reports of its use in children with spasticity are not available as of yet.

Intrathecal Baclofen (ITB)

ITB was first described by Penn and associates in 1984 and was FDA-approved for the treatment of spasticity of cerebral origin in 1996. Baclofen is delivered directly to the cerebrospinal fluid via a catheter connected to an implanted device in the abdomen. The device contains a peristaltic pump, a battery with an operational life of four to seven years, a reservoir for baclofen, and elec­tronic controls that permit regulation of the pump by telemetry (143) (Fig. 8.12). This feature allows baclofen infusion rates to be either continuous throughout the

Figure 8.12 Synchromed II programmable pump.

day or at varied dosages in order to accommodate the patient's specific needs. By infusing baclofen directly into the subarachnoid space around the spinal cord, potentiation of GABA-mediated inhibition of spas­ticity can be achieved while minimizing side effects related to high levels of baclofen in the brain (111). Administration of intrathecal baclofen produces levels of baclofen in the lumbar cerebrospinal fluid that are 30-fold higher than those attained with oral adminis­tration (111). The half-life of intrathecal baclofen in the cerebrospinal fluid is five hours (152).

Candidates for ITB have severe, generalized tone that has not been successfully managed with oral med­ications and other more conservative measures. The increased tone must have a significant effect on func­tion, ease of care, or comfort. Intrathecal pumps can be implanted in children generally greater than 15 kg in body weight (111,153). Prior to surgical implanta­tion, a test dose of 50-100 μg of intrathecal baclofen is typically given, via lumbar puncture, to verify a reduc­tion in tone. Occasionally, a repeat test dose at a higher dose is necessary if results are inconclusive.

Once implanted, the intrathecal pump is typi­cally programmed to deliver baclofen at a continu­ous rate, typically at a daily dose similar to the dose given during the trial. The dose is not related to age or weight (152), and intrathecal baclofen dosages typi­cally increase over the first year of treatment and then stabilize (143). Refills of intrathecal baclofen are gen­erally needed every one to six months, depending on baclofen infusion dosage, the size of the pump, and the concentration of the baclofen being used.

Complications from ITB can result from program­ming error, pump failure, catheter failure, and infection. The majority of these problems involve breakage or dis­connection of the catheter, but can also include blockage and kinking (140,154). The most common postoperative complications are pump pocket collections and infec­tions (111). Infection may remain isolated to the pump pocket or may track along the catheter, resulting in meningitis (152,154). Pumps have also been reported to flip, requiring either manual flipping to allow refill or surgical correction of the problem (140).

Catheter or pump dysfunction can result in decreased baclofen delivery and baclofen withdrawal. Intrathecal baclofen withdrawal can also be seen in cases of battery failure without low battery alarm warning (140). Early symptoms of withdrawal include pruritis, dysphoria, irritability, increased spasticity, tachycardia, fever, and changes in blood pressure (155). If not recognized and managed optimally, baclofen withdrawal may progress to serious and life-threat­ening complications, including severe hyperthermia, seizures, rhabdomyolysis, disseminated intravascu­lar coagulation, altered mental status, psychomotor agitation followed by multisystem failure, and death (156,157). Immediate treatment with high-dose oral baclofen and referral to an emergency room setting is recommended in these scenarios. Investigations into the causes for withdrawal should then ensue, including plain radiographs to assess pump and catheter place­ment in comparison to previous radiographs. Further studies may include dye or isotope studies to assess for catheter placement, leakage, and kinking.

Treatment for withdrawal can include any com­bination of oral baclofen, intravenous diazepam, or infusion of intrathecal baclofen through use of a lum­bar drain (158). Cyproheptadine, a serotonin antago­nist, has also been used as an adjunct to baclofen and diazepam for treatment of severe intrathecal baclofen withdrawal (159,160). Dantrolene sodium use should also be considered in patients with suspected rhab­domyolysis as a result of withdrawal.

Overdoses have been reported, typically as a result of human error in programming or refill procedure (140). Symptoms can include nausea, vomiting, respi­ratory depression, and reversible coma. In such cases, the pump is stopped through programming and respi­ratory support is provided until the effects of baclofen have worn off. Intravenous physostigmine or with­drawal of 30 to 40 mL of cerebrospinal fluid can be tried in severe overdoses (155).

A number of studies have reported on the outcomes of ITB. Randomized controlled trials have shown a sig­nificant decrease in spasticity (154,161). Noncontrolled trials have demonstrated improvements in joint range of motion, reduced pain, ease of care, and function (162-166). Treatment with intrathecal baclofen is also associated with an increase in weight gain velocity (167). Retrospective studies in children with cerebral palsy receiving ITB document varying effects on sco­liosis, including rapid progression (168,169) and/or no significant effect on curve progression, pelvic obliq­uity, or the incidence of scoliosis when compared with matched controls (170).

Selective Dorsal Rhizotomy (SDR)

SDR is a neurosurgical procedure that involves partial sensory deafferentation at the levels of L1 through S2 nerve rootlets (171). Operative technique involves the performance of single or multilevel osteoplastic lamine­ctomies, exposing the L2-S2 roots (111,172). Motor and sensory roots are separated to allow for electrical stimulation of individual sensory roots. The selection of rootlets for cutting is based on the lower extrem­ity muscular response to electrical stimulation of the rootlets. Although there is variability in percentages of rootlets cut, in general, a maximum of 50% of the sen­sory rootlets at any level are cut (173). Following the procedure, the reduction in spasticity often unmasks a significant amount of lower extremity weakness. As a result, an extensive amount of intensive therapy is nec­essary to guide the patient through appropriate motor patterns and strengthening programs. Ideal candidates for SDR include children between the ages of 3 and 8 years of age who are GMFCS level III or IV (174).

A meta-analysis of three randomized controlled studies comparing SDR plus physical therapy with physical therapy alone has been completed (174). Findings included a clinically important decrease in spasticity, as well as a small but statistically signifi­cant advantage in function (GMFM-88) with SDR plus physical therapy. The subjects in these studies were primarily ambulatory children with spastic dipare­sis; those with dystonia, athetosis, and ataxia were excluded. An additional larger nonrandomized con­trolled study compared SDR with physical therapy to physical therapy alone in children with spastic parapa­resis, GMFCS levels I to III (175). Results of this study were similar to studies in the meta-analysis, including gains in strength, gait speed, and overall gross motor function in children who received SDR plus physical therapy (175).

Although immediate perioperative complications are not uncommon with SDR, long-term complications such as sensory dysfunction, bowel or bladder dys­function, or back pain are infrequent (176). The risk of subsequent spinal deformities may increase after laminectomies or laminoplasties done in conjunction with SDR, although this may be less of a problem in the lumbar or lumbosacral area than higher in the spinal column (177). Decreased spasticity and alterations in the balance of muscle tone in the trunk and hips may also influence the development of spinal deformities

(177) . A retrospective review of patients who under­went SDR reported a 32% incidence of new spinal deformity at five years after multilevel laminectomies, including scoliosis, hyperlordosis, and hyperkyphosis

(178). SDR may reduce the need for subsequent ortho­pedic surgical interventions (179,180).