Patient-administered injectable medications, such as interferon (IFN) beta 1a, IFN beta 1b, and glatiramer acetate, are the primary agents currently used as disease-modifying therapy for the treatment of relapsing forms of multiple sclerosis (MS).1 However, recent advances in biotechnology have allowed for the development of new biologic treatment options for MS that must be administered by intravenous infusion because of their size and bioactivity profile.
To better manage this developing trend, some neurologists may want to consider setting up an infusion suite in their offices. Office-based intravenous infusion centers have been in existence in oncology practices for several years and are emerging in other disciplines, such as rheumatology, to meet the increased demand for new intravenous therapies.2,3 For neurologists who treat patients with MS who may be interested in setting up in-office capabilities for the infusion of biologic agents, corticosteroids, and/or chemotherapeutic agents, a number of practical, clinical, and financial issues must be considered. This article describes how the Michigan Institute for Neurological Disorders (MIND) set up a comprehensive MS center that offers in-office infusion capabilities. In our experience, office-based infusion suites can provide enhanced patient convenience, tracking, and care, while strengthening the patient-practice relationship and attracting new patients.
Natalizumab (Tysabri, Biogen Idec, Inc., and Elan Pharmaceuticals, Inc.), the first alpha-4 antagonist in the new selective adhesion molecule inhibitors class, was approved in the United States in November 2004 for the treatment of relapsing forms of MS. Natalizumab, administered monthly at a fixed dose of 300 mg IV infusion, is the first monoclonal antibody available for the treatment of MS. Natalizumab and other biologic agents in development, such as the antileukocyte antibody alemtuzumab (MabCampath, Schering, AG), could have a major influence on treatment decisions for patients with MS. Hence, the advent of monoclonal antibody therapy will shift the landscape of MS drug therapy from primarily self-injectable agents to a mixture of self-injectable and intravenous infusable medications.
Until the approval of natalizumab for the treatment of MS, intravenous medications (eg, methylprednisolone, cyclophosphamide, mitoxantrone) were generally reserved for management of either MS exacerbations or progressive disease. Because of this, an estimated 78% of neurologists do not have in-office infusion capabilities.4 Many neurologists refer patients to hospitals, stand-alone infusion clinics, or hematologist/oncologist offices for intravenous infusion. However, accurate tracking and proper follow-up of patients with MS who are referred to these facilities for intravenous therapies may present significant challenges to some clinicians. The difficulties associated with patient referral to other sites and the new intravenous MS treatments in development have prompted some neurologists to consider assuming a greater role in the administration of intravenous therapies.
The MIND MS Infusion Center: Historical Perspective and Evolution
The MIND is a freestanding, privately owned, all-inclusive neurologic facility located in Farmington Hills, Mich. The MIND staffs 20 neurologists and neuroradiologists who offer comprehensive adult and pediatric neurology services. The facility also includes a freestanding MS center with complete infusion capabilities and a staff of 26 full-time MS clinicians, nurses, technicians, and researchers who care for approximately 2000 patients with MS.
At the opening of the MIND facility in April 1989, an infusion center consisting of 3 chairs and 1 registered nurse (RN) was incorporated. The rationale behind including the infusion facility was to provide intravenous methylprednisolone treatment for MS relapses. At the time, the concept of hospital outpatient intravenous administration was not fully developed; therefore, the neurology office-based infusion facility offered a more efficient outpatient setting than inpatient intravenous administration. Then, with the emergence of intravenous chemotherapies for relapsing MS in patients receiving disease-modifying drugs, we began to refer patients to local hematologists/oncologists for intravenous infusion because of their expertise in using infusional chemotherapeutic agents. Initially, patients reported that treatment alongside oncology patients was a positive experience; a "bonding" had taken place between young MS patients and oncology patients. In addition, the oncologists/hematologists reported that the interaction between the 2 groups of patients enhanced the mood of the infusion facility.
We encountered the following challenges with patient referral for intravenous administration (Table 1): dependency on referral site for patient dosing information, patient reports, patient status, and laboratory results; failure to obtain informed consent; monitoring for infusion complications; and inconsistent follow-up. In particular, the necessary feedback regarding mitoxantrone dosing often was missing. Similarly, late or absent patient reports made patient follow-up visits difficult, resulting in treatment delays. Some patients did not receive information on informed consent from office staff before chemotherapy infusion, which resulted in misconceptions among patients regarding the intensive nature of these therapies. Limited resources at referral sites led to infusion in alternative locations, hindering adequate monitoring. Further, our MS patients eventually began to report that receiving infusional therapy alongside oncology patients was depressing. Although we were appreciative of our colleagues' efforts to assist in the care of our patients, these factors led us to reevaluate our options, subsequently resulting in the expansion of our infusion facility.
An 8-member decision-making team was formed to address the practical, clinical, and financial considerations for expansion of the infusion facility within the MIND. This team identified several advantages, opportunities, and challenges (Table 2). Advantages included the following: higher quality of care; increased patient convenience by decreasing time commitment to therapy; caregiver control over patient tracking, status, and follow-up; and a preexisting infrastructure consisting of an infusion-experienced nursing staff, a patient base, and a physician referral base. Expansion of our infusion facilities also provided opportunities in areas such as practice enhancement, practice building, enhanced reimbursement for patient care (including reimbursement for MRI charges), additional space for future biologics, additional research capacity, and research-related reimbursements. However, concerns were expressed over such challenges as increased overhead (staffing and space) costs, unknown future demand for services (which would render the facility either underutilized or overutilized for its capacity), efficient coding and collection of copayments, and costs of intravenous therapies.
After careful analysis, the MIND was expanded in 1999 and has been expanding continually since then. A dedicated MS research component was added in 1999 that allowed for participation in MS clinical trials.
In 2002, the MS center was established and included research capabilities, 3 full-time RNs, and 8 infusion chairs for the increased aggressive utilization of intravenous chemotherapies (primarily cyclophosphamide and mitoxantrone). Further involvement in MS clinical trials and the expected influx of biologics into the MS treatment landscape led to further expansion of the infusion facility. In particular, we participated in clinical trials of natalizumab, which is administered in monthly intravenous infusions. Current facilities include 8 infusion chairs, 5 nurses (2 full-time MS-certified RNs, 2 full-time and 1 part-time infusion RN), and 2 part-time nursing assistants.
In August 2004, plans were approved to enlarge the MS center by 5000 square feet, primarily to double intravenous infusion capacity to 16 chairs and add a postinfusion area for patient monitoring. This expansion is scheduled to be operational in January 2005.
Factors for Assessing Addition of In-House Infusion Capabilities
Incorporation of a neurology office-based infusion facility requires practical considerations related to patient care, practice impact, space, staff, equipment, and supplies, as well as financial considerations (Table 3). Based on our experience, a positive effect on patient care and the practice would be predicted; however, availability of space, staff, and funds are factors specific to each neurology office.
Required equipment for preparing and administering intravenous infusions includes the following: compounding equipment (laminar flow hood for preparation of chemotherapeutic agents only/clean room, gloves, needles, syringes, intravenous fluids), infusion procedure supplies (infusion chair[s], catheters, tubing, securement devices, dressings, infusion pumps, vital signs monitor), and medications and supplies to manage complications (antihistamines, corticosteroids, epinephrine, intravenous fluids, etc). For many neurology practices, a 1-chair facility may suffice; others may require a more extensive facility. Estimated costs for equipment, supplies, and personnel are listed in Table 4. The number of required personnel is dependent on the size of the infusion center; however, we suggest that 1 full-time RN is sufficient for every 4 infusion chairs.
Important financial questions need to be addressed when the addition of an in-office infusion suite is under consideration. In particular, the practice should think about the following: the number of infusion candidates within the practice, payer mix of the infusion candidates, costs to provide the service, and potential reimbursements. Additional financial considerations include developing and adopting procedures for proper coding for insurance reimbursement, efficient copayment collection, and billing.
Summary and Conclusions
The approval of a novel biologic agent that requires intravenous infusion will change the landscape of MS treatment. This biologic agent can be administered in a number of settings, including the hospital, the physician's office, a stand-alone infusion clinic, or an MS clinic with an infusion center. Although some neurologists may have success in referring their patients to infusion clinics or hematologist/oncologist offices for infusions, we originally expanded our infusion center because of challenges encountered with patient referral for intravenous infusion. Based on our experiences, our decision-making team concluded that we could more effectively and efficiently provide infusion for our patients in-house.
We found that expanding our infusion capabilities improved patient quality of care, provided opportunities to build and enhance our practice, and gave us the ability to participate in clinical trial research initiatives. An additional benefit is that the infusion room serves as a "de facto therapy group," in which patients share the burdens of their conditions with one another, lending needed emotional support and hope. Finally, we have found that as patients utilized the infusion center, they achieved a stronger connection with our facility and personnel, rendering them more compliant with treatment.
Howard S. Rossman, DO, is medical director, MS Center, Michigan Institute for Neurological Disorders, Farmington Hills, Mich, and clinical professor of neurology, Michigan State University.
Sonda Lawson, MA, LLPC, is director of MS Services and Clinical Research at the Michigan Institute for Neurological Disorders.
1. Galetta SL, Markowitz C, Lee AG. Immunomodulatory agents for the treatment of relapsing multiple sclerosis: a systematic review. Arch Intern Med. 2002;162:2161-2169.
2. Baker JJ, Leovic TM, O'Connor CA, Pierce CA. Relocating rheumatology patients to a new infusion center at Duke: a case study. Health Care Manag (Frederick). 2003;22:159-169.
3. Baker JJ, Bray M, Seashore B. Reclassifying infusion therapy space at the University of Arizona: a case study. Health Care Manag (Frederick). 2003;22:203-210.
4. St Sure S, Kutter A, Vadas A. Infusion technology knowledge and experience among practicing neurologists. Poster presented at: the 18th Annual Meeting of the Consortium of Multiple Sclerosis Centers; June 2-6, 2004; Toronto.
Table 1 - Challenges with patient referral for intravenous infusion for treatment of MS
- Dependency on referral sites for patient dosing information, patient reports, patient status, and laboratory results
- Failure of the referral site to obtain informed consent
- Morale of MS patients at times affected by interaction with oncology patients
- Limited resources/capacity at many referral sites resulting in:
-Infusion in alternative (often inadequate) locations
-Lack of proper infusion monitoring (cases of mitoxantrone extravasation)
-Difficulty with proper follow-up
MS, multiple sclerosis.
Table 3 - Considerations in creating in-office infusion capabilities
- Enhanced patient tracking (increased patient compliance)
- Improved quality of care
- Autonomy (less reliance on outside providers)
- Practice enhancer/builder (maintains current patients and attracts new patients)
- Amount of space required is dependent on the anticipated number of infusions (to be optimized for each practice; 1 or 2 infusion chairs may suffice)
- Number of required part-time or full-time nurses is dependent on number of anticipated infusions (1 RN for every 4 simultaneous infusions)
- Personnel wages and benefits (nurses, assistants, full-time and part-time options)
- Infusion equipment and supplies
- Direct drug costs
Promising Future Uses for Currently Available Agents
By: Dee Rapposelli
Glatiramer acetate, a disease-modifying agent that inhibits immune-mediated myelin damage in multiple sclerosis, has been shown to reduce neurodegeneration in an experimental model of Parkinson disease (PD). Currently available agents treat symptoms of disease but do not prevent loss of brain cells.
"This is quite a new approach for treating Parkinson disease in that it targets secondary inflammatory responses thought to speed the process of neurodegeneration," explained Howard E. Gendelman, MD, director of the Center for Neurovirology and Neurodegenerative Disorders at the University of Nebraska Medical Center in Omaha. "By using a vaccine approach, the adaptive arm of the immune system can be mobilized to attenuate the microglial responses thought to speed the damage to dopaminergic neurons and their termini during disease."
Gendelman, graduate student Eric Benner, and colleagues established an experimental model of PD by exposing mice to the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). While maintaining a control population, the researchers exposed MPTP-intoxicated mice, via adoptive transfer, to donor splenocytes taken from non-MPTP-intoxicated mice previously immunized with either glatiramer or chicken egg ovalbumin (placebo vaccine). Seven days after MPTP intoxication, the mice were sacrificed and their brains examined.
The researchers ascertained that MPTP exposure significantly compromised dopaminergic synthesis and caused severe nerve damage likened to that seen in the course of PD. However, significantly less degeneration of dopaminergic neurons occurred in the brains of mice injected with glatiramer-treated splenocytes. Treated mice also lost fewer dopamine-transmitting nerve fibers and had only a 4% decrease in striatal dopamine, compared with a 51% decrease in MPTP-intoxicated controls and a 41% decrease in MPTP-intoxicated mice injected with ovalbumin.
For more information, see Benner EJ, Mosley RL, Destache CJ. Therapeutic immunization protects dopminergic neurons in a mouse model of Parkinson's disease. Proc Natl Acad Sci U S A. 2004;101:9435-9440.
MRSI: A Definitive Diagnostic Tool for BPD?
By: Dee Rapposelli
Bipolar disorder (BPD) is one of the more debilitating psychiatric illnesses, primarily because it is too often undiagnosed or, more typically, misdiagnosed. A study reported at the recent annual meeting of the Radiological Society of North America offers hope for definitive diagnosis of BPD. Using magnetic resonance spectroscopic imaging (MRSI), a team from the Mayo Clinic led by John D. Port, MD, PhD, assistant professor of radiology, demonstrated specific differences in brain chemistry between healthy persons and those with BPD.
The study included 21 treatment-naive persons with BPD and 21 age- and gender-matched controls. Using a point-resolved spectroscopy MRSI technique with a 3T longbore scanner, 2 imaging slices were obtained from each participant: one through the basal ganglia, the other through the anterior cingulate gyrus. Metabolite values were adjusted for the amount of cerebrospinal fluid in each voxel. What Port and his team found were significant differences in certain metabolic ratios in the right front white matter and the right leptiform nucleus in bipolar subjects, compared with controls. These areas of the brain are associated with behavior, movement, vision, reading comprehension, and sensory interpretation. "There were clearly different patterns suggesting a chemical fingerprint of bipolar disorder," Port commented. If additional studies can be put in place to confirm these results, Port conjectures that MRSI may be regarded as a valuable diagnostic tool for BPD diagnosis within a few years. According to him, additional research using MRSI should focus on examining brain chemistry during different phases of BPD and the brain chemistry of patients receiving pharmacotherapy for BPD.
Cannabinoids Showing Potential Value in Parkinson, Lou Gehrig Diseases
By: Dee Rapposelli
"No longer a pipe dream," is the suggestive lead-in of a widely distributed press release issued last October touting the potential benefits of cannabinoid compounds in the treatment of Parkinson disease (PD), Lou Gehrig disease-or amyotrophic lateral sclerosis (ALS)-and a number of other debilitating conditions, as reported during last fall's 2004 annual meeting of the Society for Neuroscience. According to Daniele Piomelli, PhD, an expert in cannabinoid research and professor in the Department of Pharmacology at the University of California, Irvine, certain cannabinoid compounds can be harnessed to "provide select benefits to patients while avoiding some of the unwanted effects" associated with marijuana use. Compounds of greatest interest have been WIN 55212-2, delta(9)-tetrahydrocannabinol (THC), and anandamide.
A study of levodopa-induced dyskinesias in animal models, which was published back in September 2003 in the European Journal of Neuroscience, found that a deficiency in endocannabinoid transmission may contribute to levodopa-induced dyskinesias. Study authors conjectured that the complication could be alleviated by activation of the CB1 cannabinoid receptor. Researchers took the study further, treating mice with WIN 55212-2 30 minutes before injecting them with the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), which simulates PD. The results: "We found that the brains of mice treated with the marijuana-like compound were almost indistinguishable from brains of healthy mice," reported principal investigator Andrea Giuffrida, PhD, of the University of Texas Health Science Center in San Antonio.
As for the mechanism of action, Giuffrida explained: "So far, we know that WIN reduces the ability of dopaminergic cells to uptake the neurotoxin MPTP, and therefore protects dopaminergic cells from MPTP-induced damage." She pointed out that the effect is not mediated by the cannabinoid receptor CB1, evidenced by the lack of reversal with administration of CB1 cannabinoid antagonists. "While activation of the CB1 receptor may be relevant in the treatment of dyskinesias, this may not be the case for the neuroprotective action of cannabinoid-like compounds in PD," she said. Findings of this study have not yet been published. Giuffrida and colleagues are currently testing the effects of WIN 55212-2 administered 24 hours after induction of MPTP intoxication to assess its value in the presence of established PD-like neurodegeneration.
Other research being conducting by investigators at the Forbes Norris MDA/ALS Research Center at the California Pacific Medical Center in San Francisco suggests that delta(9)-THC significantly slows the disease process and extends the life span in mouse models of ALS. To evaluate whether specific compounds of marijuana had therapeutic benefit in ALS, study mice were treated with either THC, cannabidiol, both compounds, or placebo daily following onset of signs of disease. Progression of nerve cell degeneration was measured. "Treatment with THC delayed disease progression by 7 days and extended survival by 6 days," reported neuroscientist and study coauthor Mary Abood, PhD. The extended survival corresponds to about 3 years of life for humans, significantly longer than the extra 2 months that can be expected from treatment with riluzole, currently the only FDA-approved drug for the treatment of ALS. Prolonged survival also was seen in mice given both THC and cannabidiol but not in mice given cannabidiol alone.
For further information see:
- Ferrer B, Asbrock N, Kathuria S, et al. Effects of levodopa on endocannabinoid levels in rat basal ganglia: implications for the treatment of levodopa-induced dyskinesias. Eur J Neurosci. 2003;18:1607-1614.
- Raman C, McAllister SD, Rizvi G, et al. Amyotrophic lateral sclerosis: delayed disease progression in mice by treatment with a cannabinoid. Amyotroph Lateral Scler Other Motor Neuron Disord. 2004;5:33-39.
Laser Optic Technology Augurs Quantum Leap for Clinical Neurology
By: Dee Rapposelli
A cross-specialty team of medical researchers and engineers at Vanderbilt University in Nashville, Tenn, has demonstrated that nerve cell stimulation using lasers is more precise and presumably more effective than electromyography and functional electrical stimulation. A drawback of electrical stimulation devices is that they create electrical activity not only in the target neurons but also in the surrounding neurons. The low-intensity infrared laser technology, developed by a team led by Anita Mahadevan-Jansen, PhD, assistant professor of biomedical engineering, has the potential to precisely pinpoint a single target neuron. Experimental studies in rats involving optical (or laser) stimulation of the sciatic nerve demonstrated greater accuracy and muscle control than that achieved with electrical stimulation.
The team foresees rapid development of a device for use in rhizotomy that will be more efficient than current electric probes in identifying target nerves. Envisioned future applications in the realm of rehabilitation medicine include implantable fiberoptic threads running from the brain or spinal cord through the anatomy to naturalistically animate prosthetic limbs.
The same team has been involved in the development of an optical surgical guidance system-a fiberoptic probe-that uses broadband white light and a nitrogen laser to precisely detect cancerous tissue in vivo. The technology has been able to identify the precise margins of brain tumors with 100% accuracy, according to Mahadevan-Jansen. Her husband and coresearcher, Duco Jansen, PhD, assistant professor of biomedical engineering, is, in turn, responsible for developing a novel neurosurgical laser that safely and precisely guides laser pulses through mirror-coated tubes, dubbed "waveguides," to ablate brain tissue with minimal collateral damage.
The technology behind both the guidance system and neurosurgical laser has the potential to significantly decrease risks of complications in neurosurgery, where precision is crucial. The Vanderbilt research team intends to pursue the application of optics in a variety of neurologic and neurosurgical applications that will bring precision to clinical treatments in ways that cannot be achieved by conventional imaging, surgical lasers, or traditional brain surgery.
Genetic Research in PD Foretells Genetic Testing, Clinical Advances
By: Dee Rapposelli
A single genetic mutation in the LRRK2 gene may be at the root of about 5% of inherited cases of Parkinson disease (PD), according to a series of reports published in the January 29 issue of Lancet.
On amplifying and sequencing the coding region of LRRK2, Vincenzo Bonifati, MD, PhD, of the Erasmus Medical Centre, Rotterdam, the Netherlands, and a research team identified a heterozygous mutation (Gly2019Ser) in members of 4 (6.6%) of 61 unrelated families affected by autosomally dominant inherited PD. "This is a significant step forward in our understanding of the causes and mechanisms of Parkinson disease," commented Bonifati, whose team also made headlines earlier in the year on discovering a DJ-1 gene mutation associated with a rare, inherited early-onset form of PD.
The presence of the same mutation in patients from several different populations "raises the question of whether the mutation originated independently in the different cases and families, or if it was transmitted from a single common ancestor," commented Bonifati. Ensuing research will be directed toward further understanding the causes of the disease in an effort to design novel therapies and preventive strategies, he added.
A study conducted by William C. Nichols, MD, of the Cincinnati Children's Hospital Medical Center and a group affiliated with the Parkinson's Study Group-Parkinson's Research: The Organized Genetic Initiative (PROGENI)-found that 35 patients from 20 unrelated families of a total cohort of 358 families (767 persons total) had 1 or 2 copies of the Gly2019Ser mutation, as well as common clinical features of disease.
"Screening for the new mutation will probably become a key component of genetic testing for Parkinson disease in the near future," said Nichols.