Intrathecal baclofen use in adults with cerebral palsy
CONFLICTS OF INTEREST
Dr Krach is a consultant for Medtronic Inc., the manufacturers of the intrathecal baclofen pump.
Linda E Krach, Department of Physical Medicine and Rehabilitation, University of Minnesota, MMC 297, 420 Delaware St SE, Minneapolis, MN 55455, USA. E-mail: email@example.com
Intrathecal baclofen (ITB) is an effective treatment for both spasticity and dystonia in people with cerebral palsy (CP). Its use is becoming increasingly common. ITB is typically associated with fewer side effects than the oral form of the product, but there are risks related to the hardware needed for intrathecal delivery. Much of what has been reported in the literature about ITB is based on experience with children or groups of children and adults; few reports exclusively address its use in adults with CP. These reports indicate that muscle tone is consistently reduced, but there is some variability in functional outcomes. Few well-controlled studies have been done. Controversies remain concerning ITB, including whether a trial is needed before pump implantation, proper catheter tip placement, and programming options, as well as whether it contributes to the development or progression of scoliosis. These and other unanswered questions should be addressed in a systematic way.
LIST OF ABBREVIATIONS
Gamma aminobutyric acid
Spasticity is the most common abnormality of muscle tone associated with cerebral palsy (CP); it affects approximately 70% of those with CP.1 Spasticity is defined as velocity- dependent resistance to movement that is associated with increased deep-tendon reflexes and clonus. Dystonia, another common hypertonia associated with CP, is defined as an involuntary alteration in the pattern of muscle activation during voluntary movement. It is characterized by varying tone, often increased with intent or emotion, and associated with the assumption of abnormal postures.2 It is assumed that hypertonicity interferes with functional abilities, contributes to the development of bony deformities and contractures, and results in discomfort. Intrathecal baclofen (ITB) has been shown to be effective in reducing both of these tonal abnormalities.3–11 ITB is also commonly used to treat hypertonia. A 2008 report noted that 10 000 programmable pumps manufactured by Medtronic, Inc., (Minneapolis, MN, USA) have been implanted for the treatment of tone abnormalities in individuals with CP, of whom 65% were children and adolescents.12
Chemically similar to gamma aminobutyric acid (GABA), baclofen binds with GABAB receptors and results in inhibition of mono- and polysynaptic reflexes.12,13 The effectiveness of oral baclofen has been limited by its sedating side effects. ITB delivers baclofen to its site of action, the spinal cord. It is much more effective at much lower dose levels than oral baclofen and has a reduced likelihood of causing sedation. When baclofen is introduced into the intrathecal sac, the concentration in the cerebrospinal fluid is more than 10 times greater than when the drug is given orally.3 Moreover, there is no detectable blood level of baclofen following intrathecal delivery, which decreases the likelihood of sedating side effects.13
Patient Selection, ITB Pump Implantation, and Management
Intrathecal baclofen is indicated for the treatment of significantly increased muscle tone (Ashworth score ≥3 on a 5-point scale) and when individual goals have been identified for tone reduction. These goals can relate to function, comfort, ease of care provision, or prevention or treatment of deformity. Particular attention should be paid to whether the individuals are using their increased muscle tone in a functional manner, for example, to facilitate transfers or weight shifts.13
There is no consensus about whether all oral antispasticity medications should be exhausted before consideration of ITB treatment. Since ITB requires surgery and long- term follow-up in specialized centers, some advocate that more conservative options be considered first. Other physicians, however, do not believe that a prolonged trial of oral medication is necessary, since it is well established that oral medications have limited efficacy in people with CP. One can consider ITB even in an individual in whom a trial of oral baclofen has failed, since ITB has been shown to reduce tone when such reduction has not been seen with oral administration.7
A second area of controversy is whether a prepump implantation trial of ITB is necessary. This is commonly done with a 50 mcg bolus delivered by lumbar puncture and followed by frequent tone assessments over 6 to 8 hours. Some centers no longer do this trial in individuals in whom spasticity is the main tonal abnormality because ITB is known to be effective in the treatment of spasticity.14 Some advocate a trial to evaluate possible function with a pump. However, the response of a baclofen-naïve individual to a 50 mcg bolus is usually quite different from, and greater than, the response to a constant infusion (the typical starting dose is 100mcg/d). Also, functional outcome after pump implantation is affected by rehabilitation therapy.
Trial infusions are sometimes done. This is the case, for example, if the patient did not respond to a lumbar puncture bolus trial, has significant dystonia or an atypical movement disorder, or if a high catheter-tip placement is being considered to treat upper-extremity hypertonicity. In these cases, a catheter is placed with fluoroscopic guidance and anesthesia. The catheter is tunneled under the skin, brought to the surface, secured, and connected to an external pump.14 Over the course of a few days, different infusion rates can be tried, and if the catheter was placed high in the cervical area, it can be gradually lowered. The individual’s responses should be closely monitored throughout the treatment. Dosage and catheter-tip changes should not be done simultaneously in order to make it possible to evaluate the effects of any one intervention. Individuals with prior spine fusions do not undergo a preimplant trial because to do so would increase the risk of cerebrospinal fluid leak or infection.
There is also lack of agreement about catheter-tip placement. Some advocate higher-level placement for control of upper-extremity tone, at the C7-T2 area, and at T8-T12 for lower-extremity tone.7,15 The effects of different catheter-tip levels have not been systematically evaluated; for example, one published report did not have a matched comparison group.16
After pump implantation, it is helpful to have the patient undergo a physical and/or occupational therapy evaluation before being discharged from the hospital. If the individual was performing weight-bearing activities before the pump implant, physical therapy can give feedback about the possible need for dose adjustments to allow for those weight-bearing activities to continue safely. Equipment such as wheelchair seatbelts and orthoses should be assessed to ensure that it is not causing excessive pressure over the pump area.17
A stable ITB dose is typically not reached until 6 to 9 months after pump implantation. With the programmable pump it is possible to provide ITB at a constant rate or to vary the rate during the course of the day. Some have advocated varying the rate for predictable changes in muscle tone or to optimize baclofen’s effect. The prolonged effect of a single bolus of ITB has been reported.18 Authors of two case series have noted that approximately 50% of the individuals with CP whose pumps they manage have been maintained, at least temporarily, on variable dosing.19,20 There has been no systematic evaluation of dosing methodology.
Potential Complications of ITB Baclofen
Although ITB treatment is effective in the reduction of hypertonicity, it is not without risks. Risks can relate to the hardware, the surgery to place the hardware, or the drug itself.
Infection can range from a superficial stitch abscess to meningitis. Reported rates are quite variable, ranging from 0 to 24%. Such risk is not unexpected following a procedure that involves implantation of a foreign body. Most such infections occur within 60 to 90 days of surgery. There is a very small risk of infection due to pump refill.
A second risk is cerebro spinal fluid (CSF) leaks. One source of such leaks is occult hydrocephalus. These leaks can result from the creation of the tract necessary for catheter placement. The CSF can accumulate subcutaneously by the back incision or in the pump pocket. If the CSF leak is due to occult hydrocephalus, the patient will probably need a ventriculoperitoneal shunt;21,22 if the leak is not due to hydrocephalus, conservative measures, including bed rest, cushioned pressure over the pump site (sheepskin and abdominal binder), and/or acetazolamide,23,24 may be tried. If necessary, a blood patch can be performed. Headaches may occur in patients with significant CSF leaks.10
The catheter is another potential source of hardware-related complication. Reported catheter complications include migration out of the intrathecal space, breakage or a hole, obstruction, detachment from the pump, and, for two-piece catheters, detachment at the site of connections. Catheter-complication rates are quite variable, ranging from 4 to 20%.14,21,24,25
The pump itself has been reported to flip within the pump pocket.24,26 This is particularly likely to happen if a substantial amount of fluid, either CSF or a seroma, collects in the pump pocket and causes the sutures to break. This phenomenon is sometimes discovered when the individual refilling the pump is unable to locate the reservoir port. An x-ray can confirm the pump orientation, and if needed, one can carefully flip the pump back to the correct orientation for the refill. If flipping continues, the catheter can become obstructed or withdraw from the intrathecal space. If flipping is a chronic problem, the pump needs to be surgically resecured.
Drug-related adverse events are typically dose-dependent. A potentially avoidable dose-related drug adverse event is overdose due to programming error. When changing the concentration of drug in the pump, one must program a bolus to account for the lower concentration of drug in the catheter and internal pump tubing. When refilling a catheter after a catheter aspiration, it is necessary to consider only the amount of drug in the catheter. If the drug in the internal pump tubing is included as well, this can result in an overdose.24 If a significant overdose occurs, a catheter aspiration can be done to remove 30 to 40mL of CSF and thereby reduce the total baclofen load in the CSF. The patient should be monitored closely, and resources should be at hand to provide respiratory support if necessary.
Decreases in cognitive function, listlessness, and fatigue have been reported as a dose-dependent adverse event.14,24 Constipation has also been reported with ITB.14,25
There does not appear to be a consistently reported effect of ITB on seizure activity. There are anecdotal reports of increased seizure activity, but a prospective study of children receiving ITB did not report such a change.4,27
Incontinence and urinary retention have both been reported.10 It is thought that decreasing external sphincter activity could result in stress incontinence, while decreasing detrussor activity could result in urinary retention. Dose-dependent impotence has also been reported.28
Intrathecal baclofen withdrawal syndrome is a potentially life-threatening complication of ITB therapy. It may occur when delivery of ITB is interrupted for any reason. The syndrome consists of rapidly increasing muscle tone and spasms, malaise, dysesthesias (typically pruritis), hallucinations, and diaphoresis. If untreated, it can progress to rhabdomyolysis, elevated creatine kinase levels, and multisystem organ failure.29,30 Although benzodiazepines, oral baclofen, and other medications have been used to treat ITB withdrawal, the most effective intervention is to restore the delivery of ITB as soon as possible. This can be done on a temporary basis with placement of a lumbar drain connected to an external pump, as is done in trial infusions of ITB.31
Considerations in Adults with CP
Adults with CP are not a uniform group, but they do present some common concerns. Even though CP is, by definition, a static encephalopathy, people with the disorder often experience a decrease in functional abilities as they age.32 Similarly, they often experience chronic or recurrent pain, fatigue, musculoskeletal problems such as contractures or bony deformities, bowel and bladder problems, dental problems, gastroesophageal reflux, and fatigue. Overuse syndromes and the early onset of osteoarthritis have been reported as well.33,34 Some of these problems are hypothesized to be secondary to reduced reserve and the normal process of aging. Also, those with mobility problems are noted to be at a higher risk of osteoporosis.
The use of physician and hospital services has been evaluated for adolescents and young adults with CP.35 Rates of physician visits and hospitalization were higher for the group with CP than for their age-matched peers to a statistically significant degree. The two most common reasons for hospital admission for adults were respiratory system and digestive system problems; for adolescents, the most common reasons were musculoskeletal and connective tissue system and respiratory system problems.
ITB Treatment and Outcomes in Adults
Most reports of the use of ITB in people with CP have not focused exclusively on adults. Meythaler et al.36 reported their findings with a group of thirteen adolescents and adults who received ITB for over 12 months. The authors reported effective and sustained reduction of muscle tone in the lower and upper extremities. Two individuals in the group required spinal fusion for scoliosis during this first year after pump implantation. They also reported improvement in activities of daily living and transfer status, improved dysarthria, increased comfort, and improved ability to control and manipulate wheelchairs and augmentative communication devices. They also noted that after pump implant, their participants benefited from a period of intensive rehabilitation. Another report on adults with acquired brain injury noted decreased sedation when medications used for tone reduction were discontinued after pump implantation, as well as improvements in functional skills (one patient progressed from wheelchair use to walking with assistive devices) and eased provision of care for those who were dependent on others.37 A review of the use of ITB for adult spasticity owing to spinal or cerebral causes noted that beneficial effects included increased independence, mobility, and self-care abilities. Improved sleep patterns, decreased bladder hyperreflexia, and decreased pain were also reported.38
Relatively little has been written about the effect of ITB on gait. One study, which examined gait in seven people with spastic hemiplegia, including one with CP, showed increased maximum walking speed and stride length after ITB bolus. Kinematically, minimal knee extension and maximal ankle dorsiflexion were increased. The duration of activity of spastic muscles also decreased after ITB.39 A report on gait in 28 individuals with acquired brain injury demonstrated significant improvements in stride length after ITB bolus. Although the effect on velocity was variable, a majority experienced an increase in velocity.40 Francisco and Boake41 reported on 10 stroke patients that had ITB pumps implanted an average of 28.6 months after their strokes. At an average of 8.9 months after pump implantation, the authors noted statistically significant improvements in walking speed, functional mobility ratings (based on the locomotion-walking and stairs items of the Functional Independence Measure, the community-access item of the Functional Assessment Measure, and two unpublished items [sit to stand and stand to sit]), and Ashworth scores. A report on 24 individuals, 21 of whom had spastic CP and three of whom had spasticity after traumatic brain injury, noted improvements of one functional level in nine patients, no change in 12, and worsened gait in three. However, patients and families reported improved walking in 20, unchanged in two, and worsened in two (functional levels were defined as community, household, non-functional, and non-ambulatory).42
It is thought that ITB treatment will decrease the need for orthopaedic surgeries in individuals with CP. Some surgeons prefer to reduce spasticity via continuous infusion of ITB before performing surgical correction of bony deformities. Others refer patients for evaluation for this intervention before a repeat surgery if bony abnormalities have recurred after a previous surgical correction. One study retrospectively reviewed the course of 48 children and adults who had undergone ITB pump implantation and treatment. At the time of pump implantation, orthopaedic surgery was planned in 28; however, only 10 ultimately underwent surgery.43 It has also been suggested that consideration be given to implanting ITB pumps in individuals as they approach adolescence in order to decrease the likelihood of the development of contractures during this time of rapid bone growth. In theory, this could be a temporary measure, followed by weaning and discontinuing the baclofen after growth is completed (Gage JR, personal communication 2006).
A few studies have addressed quality of life in individuals receiving ITB for management of hypertonicity. One survey of 49 participants, including 30 adults, noted that 88% believed that their quality of life had improved with ITB treatment; 8% were not sure. The most frequently noted positive effects were reduced muscle tone without sedation, ease of care for caregivers, easier positioning, less pain/increased comfort, and improved transfers.44 Two studies of adults with spinal cord injury or multiple sclerosis who received ITB for management of their muscle tone reported significant improvement in scores on the Sickness Impact Profile, particularly the physical health, mental health, mobility, and sleep and rest subscales, and on the Hopkins Symptom Checklist.45,46
Cost-effectiveness of ITB therapy has been described. Sampson et al.47 did a literature review of the effect of ITB on function and quality of life. Outcomes were used to estimate potential gains in quality-adjusted life years. They found an acceptable cost-benefit ratio for this UK study. Another group, looking specifically at spasticity related to CP, reported that ITB treatment increased the 5-year cost of treatment in the USA by $49 000, but this was accompanied by a gain of 1.2 quality-adjusted life years, and the result was within the ratio accepted as being cost-effective.48 A third study showed that ITB therapy was more expensive and more effective than standard treatment and that overall it was consistent with the definition of cost-effectiveness in the Netherlands.49
Pregnancy is a special consideration with ITB pump management. There have been case reports of successful use of this modality during pregnancy. Although no specific information is available about the potential teratogenicity of baclofen, children born of these pregnancies have not had abnormalities.50–52 Our center treated one woman with ITB throughout her pregnancy, and she delivered an infant who had no problems.
Deep venous thrombosis is one adverse outcome that has been noted in an adult with CP receiving ITB.53 Others have noted that children who undergo ITB treatment have a higher rate of complications requiring repeat surgical procedures than do adults.54 The great majority of children in this study had a diagnosis of CP, but CP was the diagnosis of less than one-third of the adults.
One case report noted improvement in sleep apnea in an adult with CP after ITB pump implantation; the improvement made it possible to discontinue continuous positive airway pressure during sleep.55
Potential Research Areas
A number of potential areas for investigation related to the use of ITB in adults come to mind. One has to do with function. Does treatment with ITB result in an increase in motor function in subgroups of adults with CP? Does it prevent or slow the apparent loss of function noted in adults with CP? Does it have an effect on endurance or fatigue? If function is impacted, what areas are the most significantly improved in what subgroups of adults with CP? How does ITB affect bowel and bladder function? How do we differentiate the effect of ITB on bowel and bladder function from that of other medications? Baclofen has been reported to reduce the amplitude and frequency of spontaneous contractions of human jejunum in vitro.56 Does it affect the intestine in vivo? A case study has noted that 10 of 14 patients reviewed had deteriorated intestinal function after ITB pump implantation.57 Does ITB affect gastroesophageal reflux? Oral baclofen has been shown to reduce gastroesophageal reflux in children with severe gastroesophageal reflux without neurological impairment. It increased gastric emptying and inhibited transient lower-esophageal sphincter relaxation.58
Does ITB treatment have an effect on the frequency of hospitalizations or the reasons for hospitalization? How does it affect the frequency of physician/licensed health care provider visits? Does it have any effect on the establishment of a medical home?
If part of the stimulus for the maintenance of bone is muscle contraction, does ITB have an effect on bone mineral density? If so, is intervention required to assist with decreasing any deleterious effect?
Does ITB prevent deformity or the recurrence of deformity and, therefore, decrease the frequency of orthopaedic surgery? One short-term follow-up study reported that 91% of hips in 33 individuals with CP treated with ITB did not show deterioration over 1 year.59 Is ITB therapy associated with an increase in the incidence of some deformities? There have been two reports of conflicting findings regarding whether ITB contributes to an increased incidence or rate of progression of scoliosis.60,61 Answering this question definitively will require a multicenter longitudinal study.
Can the temporary use of ITB during the adolescent growth spurt have a beneficial effect on joint mobility and function?
Do complications related to ITB therapy differ between adults and children with CP? To date, studies have not included adult and pediatric populations with similar diagnoses. Is there an age at which one should consider prophylaxis for deep venous thrombosis when inducing relative hypotonia in individuals with CP? What is the incidence of deep venous thrombosis in adults with CP after pump implantation?
What is the optimal dosing technique for the treatment of hypertonicity? Does it vary depending upon the nature of the tonal abnormality – spasticity, dystonia, or mixed tone?
What is the effect of reducing hypertonicity at a young age on the development of pain and/or arthritis in adulthood? How can the pain relief/increased comfort reported by those receiving ITB be more critically assessed? If there is pain relief, is it due to relaxation of muscle tone or to the reported substance p effect of baclofen or other antinociceptive effect?29,38,62
As our experience continues to increase with the use of ITB for the treatment of increased muscle tone in people with CP, we need to systematically address outcomes in order to optimize treatment.