Michelle M. York

A phase I/II trial of recombinant methionyl human brain derived neurotrophic factor administered by intrathecal infusion to patients with amyotrophic lateral sclerosis.

BACKGROUND: Brain derived neurotrophic factor (BDNF) is a potent survival factor for motoneurons. This study investigated the safety and tolerability of recombinant methionyl ( r -metHuBDNF) infused intrathecally by means of an implanted pump in patients with ALS. METHODS: Twenty-five probable or definite ALS were treated with either r -metHuBDNF (25, 60, 150, 400 or 1000 mug/day) or placebo in a 12- week, randomized, double-blinded, sequential, dose-escalation study. Test treatment was interrupted by a washout period from days 11 to 25 to allow the evaluation of laboratory safety measures. In each dose cohort four patients received r -metHuBDNF and one received placebo. On completion of the double-blind period of the study all patients continued to receive r -metHuBDNF in an open-label extension for up to 60 weeks. Lumbar cerebrospinal fluid (CSF) samples were taken periodically from all patients for the measurement of r -metHuBDNF levels and in a minority of patients these were supplemented by cisternal samples. RESULTS: Within days after the initiation of infusion the majority of patients receiving r -metHuBDNF reported mild sensory symptoms, including paraesthesias or a human BDNF sense of warmth, which were usually confined to the lower limbs and were frequently exacerbated by neck flexion. In most instances these symptoms patients with decreased or even disappeared over several weeks. Sleep disturbance, dry mouth, agitation and other behavioural effects were encountered at higher doses (>150 mug/day) and necessitated dose reductions. The spinal CSF levels of r -metHuBDNF were directly related to dose, with a lumbar to cervical ratio of approximately 4:1. CONCLUSIONS: The intrathecal delivery of r -metHuBDNF in doses of up to 150 mug/day was well tolerated and appears feasible. The reversible CNS effects with higher dose indicate that BDNF can be delivered cranially against CSF flow. The small number of patients and the design of the study did not permit conclusions to be drawn about the efficacy of the treatment. (ALS 2000; 1:201-206)

Quality of life: effect of reduced spasticity from intrathecal baclofen.

&NA; Severe, uncontrolled spasticity resulting from spinal cord injury (SCI) and multiple sclerosis (MS) can have a profound effect on the patients ability to function and thus, their quality of life. Spasticity can be dramatically reduced by the continuous infusion of baclofen into the lumbar subarachnoid space using a drug delivery system. The aim of this study was to explore the effect of reduced spasticity on quality of life using intrathecal baclofen therapy. Twenty‐five patients with intractable spasticity treated with intrathecal baclofen participated in this prospective study. Spasticity was measured using the Ashworth and spasm scales.3 Quality of life was measured using the Ferrans and Powers Quality of Life Index (QLI) and the Sickness Impact Profile (SIP). The mean spasm score decreased significantly from 2.6 at baseline to 0.5 after one year (Friedman test; p = 0.000017). The mean Ashworth score decreased significantly from 3.78 at baseline to 1.48 after one year, (Friedman test; p=0.00000014). Though total QLI scores were not significantly different when comparing baseline with one year, the SIP revealed significant changes in the total score as well as the physical and psychosocial subscales. It is likely the QLI did not demonstrate improvement in quality of life due to the emphasis of this tool on nonphysical domains. A qualitative analysis of two openended questions revealed positive statements about the change in quality of life when spasticity is well‐controlled. Measuring changes in quality of life after specific interventions is a difficult task, requiring an accurate operational definition of the concept and valid instruments for measurement.

Implantable Delivery Systems

Initial attempts to bypass the BBB and deliver medications directly to their site of action in the CNS included access by multiple ventricular injections. Unfortunately, repeated injections may damage the brain and increase the patient’s risk for infection. Later attempts at accessing the CNS included the Ommaya reservoir, which was an improvement because it is implanted, but which eventually becomes fibrosed and was difficult for caregivers to access. As a result, implanted delivery systems were developed allowing for easier access and long-term regional therapy.13 Early drug pumps developed in the 1970s were used for delivering heparin, insulin, and chemotherapy. The 1980s marked the decade that expanded drug pump application for treating neurologic disorders such as pain, spasticity, Alzheimer’s disease, and brain tumors. The 1990s is the decade heralding new applications. Currently, there are two delivery systems commercially available for intrathecal drug delivery. The Infusaid pump, manufactured by Shiley, Infusaid, Inc, Norwood, Mass, was the first pump used for intrathecal morphine therapy. The SynchroMed pump, manufactured by Medtronic, Inc, Minneapolis, Minn, was later developed, but with programming capability. These two delivery systems will be discussed further (Table 3.1). Each pump manufacturer has booklets available to patients regarding the delivery system and its application (Fig. 3.1).

Spinal Cord Anatomy

The purpose of this chapter is to provide an overview of essential spine anatomy to assist the reader in understanding various structures of the central nervous system (CNS) and their relevance to intrathecal drug therapy. Structures such as the spine, spinal cord, meninges, cerebrospinal fluid, blood-brain barrier (BBB), blood supply, spinal roots, and spinal tracts will be addressed. Keeping current with this rapidly expanding body of knowledge directly affects the quality of patient care. It allows health care professionals to teach patients about the therapy, refines assessment skills, and provides safe and effective treatments that promote comfort and rehabilitation.

The Operative Course

The operative course, including pre-, intra-, and postoperative periods, is essential to the long-term success of intraspinal drug therapy. Because many patients and their caregivers are quite anxious about the surgical procedure, extensive education is necessary. Teaching related to the operative course will vary since some institutions will implement the screening (see Chapters 6 and 7) and operative procedure during the same hospital admission, whereas other institutions may do these procedures during separate hospital admissions. Also, to keep health care costs at a minimum, the surgical implant may be done on an outpatient basis; although this is not yet common owing to lack of monitoring at home and fears of a potential postoperative overdose. In any case, clinicians must be knowledgeable about the operative course to provide optimal care and to better educate patients.

Pharmacology of Baclofen and Morphine

Understanding the pharmacology of drugs intended for intraspinal use assists the clinician in patient management. Pharmacokinetic factors such as lipid solubility, pH and pKa, molecular weight, and affinity must also be considered when comparing agents to use for specific patient conditions. The potential adverse effects of preservatives and antioxidants on spinal cord tissue must be weighed when considering agents that contain these compounds for intraspinal delivery. Specific agents will be discussed, with emphasis on baclofen and morphine but also addressing new categories of drugs that might be given intraspinally to treat spasticity and pain.

Mechanical System Complications

The mechanical system refers to both the pump and the catheter. System complications related to the drug pump include overinfusion or underinfusion of the drug. However, the vast majority of complications are related to the catheter.19,118,178 Specifically, the catheter may kink, dislodge, tear, or fibrose.179 Treatment of a system complication requires surgical intervention in almost every case.

Intrathecal Baclofen for Spasticity

Spasticity can be a serious complication of trauma to the spinal cord or other disorders that create damage within the spinal cord. Although affecting a small percentage of the population, spasticity can be devastating to the person experiencing it by limiting function, reducing mobility, complicating sleep, causing pain, and interfering with the quality of life. Spasticity management has included exercising and stretching programs, oral medications, and destructive neurosurgical procedures. A new, alternative treatment incorporates the use of an implanted pump which precisely delivers baclofen, through a catheter, directly into the intrathecal space. This treatment has proven to be extremely successful in reducing spasticity and is indicated for individuals with severe spasticity of spinal origin who have failed oral drug therapy. To fully comprehend the treatment of spasticity, one must understand the various definitions of spasticity as well as the physiology of this phenomenon and its interference with quality of life.

Starting Up a Program

Prior to beginning a program using implanted drug pumps for the delivery of intrathecal drugs, significant coordination must take place. The setting where patients will be followed must be chosen, supplies must be purchased, the appropriate personnel must be convened, policies and tools for documentation must be developed, coordination between other departments must be initiated, and reimbursement strategies must be considered. This chapter will alert clinicians to these considerations along with providing useful tools to assist with these efforts.

Intraspinal Morphine for Pain

Pain is an enormous social and economic problem. The treatment of chronic pain is also controversial, in part because of the subjectivity of the complaint. Most health care professionals have been trained to treat acute pain, expecting to see changes in vital signs, facial grimacing, and guarding behavior. However, in the chronic pain patient these signs are not evident. Therefore, the only reliable indicator of the presence of pain is the patient’s self-report. This may prove challenging to the health professional when assessing pain in the patient who reports a pain intensity of 10 on a 0 to 10 scale but does not “look as if he/she is in pain.” Reports of intensity scores that do not correlate with behavior are common and may also reflect coping strategies and other patient-specific variables.