Klinisch onderzoek VS
We do see patients that want bee venom therapy, and send them home with this info:
Bee Venom Home Protocol
¨ A clinical staff member will train you and a designated person how to administer the Bee Venom Therapy (BVT) injection
¨ The doctor has given a prescription for an allergic reaction. You MUST fill this prescription BEFORE starting your bee venom injections. Remember that every time you are injecting the bee venom there is a POTENTIAL of having allergic reaction.
¨ The designated person must administer injections.
¨ The first bee venom injection:
- Draw 0.05ccs (equivalent to one bee sting) into the syringe.
- To determine where to inject, refer to the map of injection sites
- Clean the area to be injected with hydrogen peroxide. DO NOT USE ALCOHOL OR IODINE which will neutralize the effect of bee venom
- Inject the bee venom intradermally (under the skin)
- Monitor the patient for 30 minutes looking for any of the following reactions:
a. shortness of breath
b. tightness of the chest
c. light headedness
If any of these occur, inject the Epinephrine kit in a large muscle (thigh, arm, or buttock) IMMEDIATELY AND CALL 911 OR TO THE EMERGENCY ROOM.
¨ If other allergic reactions occur such as:
a. redness on the injection site bigger than a silver dollar
b. rash over the entire body
c. itching over the entire body
Take Benadryl 25mg (you can buy this medication at any pharmacy. It is an over the counter drug). Then call a clinical staff member at CMRS.
¨ Localized itching and redness at the injection site are normal reactions to the bee venom injection
¨ Subsequent injection:
a. each weak increase your dose by 0.05cc
b. as your dose increase the number of injections increases proportionally
c. Each injection is 0.05cc at each site. For example week 1, the dose is injection every other day. Therefore, inject 0.05 every other day. Week 2 your dose is 2 injections every other day. Therefore, inject 0.05cc in each of the two sites every other day.
¨ All injections must be done on the spine area for the first seven weeks. As the tendency for swelling of the injection site is less.
¨ Call CMRS every two weeks to monitor your progress. Report how you are tolerating bee venom injections, any improvements, or worsening of your condition since starting the bee venom injections.
¨ Please keep a journal and not any changes you observe
¨ Recommended Supplements:
a. Vitamin C 1000 to 3000mg a day
b. Magnesium 200 to 500mg a day
c. B-complex (look for at least 7-8 different kinds of B vitamins) B1 or Thiamin, B2 or Riboflavin, B3 or Niacin or Niacinamide, B5 or pantothenic acid, B6 or Pyridoxine, B12 or Hydroxocobalamin or cyanocobalamin, folic acid and many more.
d. Multi-vitamin and Multi-minerals. Follow the recommended dosages on the label.
e. Vitamin E 800IU a day (mixed tocopherol)
f. Essential Fatty acids (combination of Omega-3 and omega-6) that is fish oil and/or primrose oil. Take 1-2 capsules twice a day
¨ Drink at least 8 glasses of 8oz. Of filtered water a day
¨ Recommended diet: Avoid sugar or refined carbohydrates and saturated fat. High protein and low carbohydrate is preferred diet. Unlimited fresh vegetables and fresh fruit are highly recommended. Best source of protein is fish, eat fish 3-4 times a week.
¨ For more information regarding sources of protein and carbohydrate, go to your local library and read about protein and carbohydrate.
¨ STORAGE: Keep away from directs sunlight and refrigerates at 0-5 degrees Centigrade. The polypeptide of the venom may separate if stored for a period of time, but it will not lose its potency.
A Copy of our Study:
BEE VENOM THERAPY IN THE TREATMENT OF MULTIPLE SCLEROSIS: A CLINICAL TRIAL
BY
David E. Wester, PA
Submitted in partial fulfillment of the requirements for the degree of Master of Medical Science in Physician Assistant Studies
Midwestern University
Downers Grove, Illinois
August 27, 1999
Bee Venom Therapy in the Treatment of Multiple Sclerosis: A Clinical Trial
Table of Contents
A. Abstract
B. Introduction
C. Methodology
D. Results
E. Discussion
F. Conclusion
G. Appendices
1. Appendix A - ROSS Survey
2. Appendix B - MS Follow-up Form (Pre)
3. Appendix C - MS Follow-up Form (During Bee Venom Treatment)
4. Appendix D - Karnofsky Performance Status Scale
5. Appendix E - Informed Consent
6. Appendix F - Bee Venom Home Protocol
7. Appendix G - Injection Sites
8. Appendix H - Case Studies
ABSTRACT
Recent anecdotal evidence suggests that bee venom therapy (BVT) is effective in the treatment of multiple sclerosis. This study was a scientific attempt to evaluate the efficacy of bee venom injections on stopping or reversing the course of multiple sclerosis. Fifty-one patients with clinically documented MS received anaphylactic testing to ensure safety of participation before being titrated to tolerable, yet effective doses of venom. Therapy was administered 1 – 7 times per week, consisting of an average of 11 intradermal injections (0.1 ml) per session. Patients’ clinical response was evaluated every three months for one year. A positive correlation between BVT and improvement in symptoms related to MS was found. Fifty-eight percent of the participants experienced positive results, 29.8% experienced no benefits, and only one patient reported a worsening of her condition. The first symptoms to respond to BVT were fatigue and endurance, improving by 44 and 42%. Significant improvements were also made in balance and bowel control (32.2%) and coordination (31.4%). Average scores for the ROSS survey went from 36.1 upon enrollment to 48.6 after 12 months. These results indicate that BVT may be a legitimate alternative therapy in the treatment of MS. The findings of this study warrant further inquiry into the effectiveness of BVT using a double blind clinical trial.
INTRODUCTION
Multiple sclerosis (MS) is a neuro-degenerative disease that affects as many as 240,000 Americans, with women being twice as likely to suffer from the disease as men (1). Affected patients complain of gait instability, visual disturbances, fatigue, dementia, sexual and bladder dysfunction and symptoms of brain stem dysfunction (dysphagia, nystagmus, intention tremors, etc.). MS is characterized by either chronic deterioration, called chronic-progressive MS, or periods of exacerbations with subsequent improvements in their condition, known as relapsing-remitting MS.
Neither the cause nor the pathogenesis of MS is known definitively. Because of this vacuum of scientific knowledge, scientists and clinicians alike have been baffled in finding an effective cure or even adequate palliation of the symptoms. The newest mainline research frontier in MS is the use of immunotherapy. It is thought that MS is an autoimmune disease where the body attacks its own healthy myelin cells. Destruction of these insulatory nerve cells causes an increase in patient disability due to increased conduction time for nerve impulses. By either increasing the body’s defense system or retraining the defective defenses, scientists hope to provide a long-term cure for MS.
Bee venom therapy (BVT) is an exciting new field of research for MS. Due to widespread anecdotal support for the efficacy of BVT in MS, combined with the paucity of scientific studies on the subject, researchers have been prompted to take a closer look at this field. In 1997, two studies were awarded funding for research in this area, sponsored by major MS organizations in the United States. Most recently, the Multiple Sclerosis Association of America (MSAA) awarded a grant for a controlled BVT trial to be conducted on progressive MS patients. Clinical results for these studies will not be available until 2000.
Until now, most research with bee venom has focused on treating or decreasing adverse anaphylactic reactions (4-6). For over ten years, allergists have been administering therapeutic doses of venom attempting to desensitize allergic patients to the potent effects of bee stings. Others researchers have noted a beneficial effect of BVT on decreasing the effects of arthritis (7-10). Still others have tried to discover the basic composition and interaction of the components of bee venom and thereby understand its mechanism of action (11-12).
Mainline medical therapy for current treatment of MS consists primarily of using interferons. However, beta-interferons are only approved in the treatment of relapsing-remitting MS and have not been tested for efficacy in chronic-progressive MS. In addition, the most widely prescribed interferon, betaseron, has been shown effective in only about 30 percent of patients by either decreasing their relapse rate or decreasing the development of new lesions (13).
This paper represents the first multi-subject clinical trial of bee venom therapy on multiple sclerosis.
METHODOLOGY
A target population of 80 participants was sought through advertisements on the internet using the web page for Caring Medical Rehabilitation Services (CMRS). The web page contains a brief description of the project, the assumed hypothesis, and additional information on how to become enrolled. Patients were also referred by the National MS Society and through word-of-mouth. Interested applicants phoned the CMRS office for an initial verbal screening, then set up a 2-day appointment for enrollment. Enrollment was conducted on a rolling basis and included only patients with MS documented by either MRI or clinical evaluation by another doctor.
Initial Testing
The first day of testing involved a 1-1/2 hour appointment with Dr. Hauser and one of the staff nurses. During this meeting, the study and its purposes were explained to the applicant and their caregiver, and their disability was graded according to the Related Observable Symptoms Scale (ROSS, appendix A). Participants also filled out a questionnaire addressing their perceived deficit in functional capability (appendix B), against which subsequent questionnaires (appendix C) were compared. All patients were rated initially on the Karnofsky Performance Status Scale (appendix D) and activities of daily living (ADL’s) were also assessed by the clinician. Consent forms (appendix E) were signed by each participant by the end of the first appointment.
Testing was conducted to assess a patient’s allergic response to bee venom. Because of the risk of anaphylactic shock, the patient initially received only 0.025 cc of solution. After 30 minutes, if no signs of allergic reaction occurred, another 0.025 cc of solution was injected. Patients and their caregivers were then educated on self-administration of venom injections, including proper injection sites, dosage amount, and warning signs of allergic reaction development. Patients were told to keep a journal and call CMRS every 2 weeks with an update in their progress. Each patient was also given an Epinephrine kit to use in case of any severe adverse reactions such as shortness of breath, tightness of the chest or light headedness, with the imperative to call 911 or go immediately to the ER.
The next day, enrollees were given a second 0.1 cc test dose of bee venom by their caregiver and were observed again for any adverse reactions. After the 30 minute appointment, participants were sent home with a 60 day supply of venom and syringes. All patients were supplied with a copy of the Bee Venom Home Protocol sheet (appendix F) and a diagram of all available injection sites (appendix G).
Materials
All bee venom used during this study came either from Champlain Valley Apiaries in Middleberry, Vermont or Mihaly Simics’ apiaries in Canada to eliminate excessive variation. Each participant was sent home with a 100cc vial of bee venom solution, to be refrigerated when not in use. New vials of venom were sent to participants at cost per the request of each patient. One bee sting is approximately equivalent to 0.1 cc of venom solution, and was injected intradermally using a 25 gauge hypodermic needle.
Dosing
Each site was cleaned with hydrogen peroxide, then injected intradermally with the equivalent of one bee sting, or 0.1 cc of bee venom solution. Initial dosing was 1 injection every other day for one week. Each week, dosages were increased by one shot per session, until positive effects of the venom reached a plateau. If a reaction developed that was bigger than a silver dollar, patients were told to halve their dose of venom. Patients were also told to halve the dose and conduct injection sessions every day if they noticed a significant functional decrease on the non-sting day. Patients were kept on the smallest effectual dose of bee venom.
Tracking
Objective tracking of improvement/disability was scheduled every three months at the clinic. ROSS surveys, the Multiple Sclerosis Follow-up Questionnaire, and Karnofsky levels were collected on a quarterly basis. Copies of these tracking tools are included in Appendices A, C and D respectively. In addition, any phone conversation with the patient was documented on a flow sheet in the chart, including current bee venom dose levels, changes in symptomatology, and any adverse effects. Official data collection was terminated on each patient once they either reached the 12 month mark or dropped out of the study.
Statistical Analyses
Patient charts were reviewed at CMRS, then data was entered into an Excel spreadsheet. Data was analyzed statistically with SPSS 8.0. A combination of parametric and non-parametric tests were used since the data contained both ordinal and nominal measures. Descriptive data was calculated on all participants, including number of participants, mean values and standard deviations. Demographic information was compiled in a similar manner. The non-parametric Friedman's test was performed in order to calculate the significance of the findings. Data was run in two groups; first on all participants, then on a subset of the population. When analysis of the initial data revealed that effects of BVT often do not become evident until six months after initiating therapy, the second analysis was performed on only those who participated for 6 months or more. General comparisons were made between bee venom data and published data on INF- therapy using published interferon data. Charts and tables were generated to best depict the information collected.
RESULTS
Demographics
A total of 73 participants were enrolled from the period 1/27/97 to 7/6/98. Ten enrollees were unavailable for further phone contact due to relocation, phone number changes, or unavailability. An additional twelve patients only showed for their first 2-day session with no further contact. These twenty-two patients had to be dropped from the study prior to performance of any statistical analysis, bringing the total number of participants to 51. Demographic information is depicted in Table 1.
Out of the 51 original participants, 39 were still enrolled at 3 months, 34 at 6 months, and 18 continued submitting data for the entire year. The primary reason given for dropping out of the study was either discomfort of daily injections or lack of noticeable effect on their symptoms, and was assessed by random phone contact with a sample of patients.
Results were categorized into the following groups: dramatic, good, minimal, none, and negative (Table 2). Gross analysis showed that greater than 68% showed some kind of positive effect, with 58% demonstrating a noticable improvement.
Follow-up Questionnaire
At the initial interview, patients rated themselves an average of 80.7% impaired due to the signs and symptoms of multiple sclerosis. The greatest degree of impairment was noticed in balance, coordination, fatigue, and endurance (Figure 1). Muscle strength and bladder control were also notable areas of impairment. Least impaired were the areas of mental function such as concentration, memory, and mood, as well as vision.
Initial improvements were most noticeable in the areas of fatigue and endurance, mood, numbness, and coordination. However, over a longer period of time, the most dramatic improvements were noticed in fatigue, endurance, balance and bladder control, and coordination (Figures 2-5). Again, the areas showing minimal benefit from the venom seemed to be those that were initially the least impaired. These included vision, as well as the mental functions of memory, concentration, and mood.
Activities of daily living (ADLs) were also assessed through this survey as a way to provide a more objective assessment of debilitation. They are rated on a scale from 0-7, with 0 being a totally dependent patient and 7 being totally independent (Appendices B-C). All but one of the Activities of Daily Living (ADLs) increased significantly while on bee venom therapy, as noted in Table 3. Walking ability was the ADL of greatest benefit, while wheelchair mobility improved the least.
The Karnofsky Performance Scale provides a general assessment of disability, with ratings from 0 being a dead patient to 100 being normal (Appendix D). Initial averages were at 50.0 (requiring considerable assistance to care for self), and steadily improved to a 12 month level of 65.0 (can’t work, and requires minor assistance to care for self). Improvement over the one-year period was significant at p<.0005.
Related Observable Symptoms Scale (ROSS) Survey
The ROSS survey is a scale designed by CMRS for the patient to rate themselves on the different components of MS disability. Rankings are on an ordinal scale from 0-none to 5-excellent (Appendix A). A total score is represented by adding the thirteen items. Initial ratings averaged 36.1 and improved to 48.6 steadily over the 12 month period (Figure 6). Results were significant at p<.0005.
The most dramatic improvement in the first 3 months came in the areas of fatigue, endurance, and bowel control. By the end of 12 months, improvements in fatigue were still the greatest, but balance was second, followed by endurance, coordination and bowel control (Figures 7-10). Except for memory, numbness, concentration, mood, and sexual function, all findings were significant at p<.021 or less.
It became apparent during the study that in many cases, the venom therapy didn’t have an effect until a patient had steadily used it for a period of about 6 months. Therefore, a second analysis was performed on the data after excluding those patients who dropped out of the study prior to 6 months. Data was analyzed a second time using the 34 participants who were still submitting data at 6 months. All descriptive data was recalculated and found to be not significantly different from previous results. All non-parametric tests were run on the smaller group of participants.
DISCUSSION
The most dramatic areas of improvement were found within the areas of most severe initial impairment. For example, fatigue and endurance rated as the third and fourth most severe initial complaint, but were also the areas of largest functional improvement. Similar statements can be made about balance, bladder and coordination impairment. Mental function seemed to be both the least affected by MS symptoms and the least affected by the treatment.
Initial effects of BVT seem to boost energy levels and prevent fatigue, however effects on balance, coordination, muscle strength and bladder control take a while longer to become evident. One can postulate that the bee venom produces a local inflammatory response in the body, thereby inducing anti-inflammatory components to be mobilized. However, an exact mechanism for this finding is unknown, and was outside the scope of this study.
This study explores treatment not only of relapsing-remitting MS, but also chronic-progressive MS. Previous studies have almost entirely been conducted on relapsing-remitting MS. Due to the nature of exacerbations and spontaneous remissions, it is difficult to determine whether the therapeutic agent is responsible for any changes in status. Improvements noted may be due to a relapse, a remission, or truly be associated with the pharmacologic agent being tested. The positive findings within this research offer hope for the 20-30% of MS patients who are progressively chronic.
Side effects
Reported side effects during participation commonly included localized itching and burning at the injection site, along with pain of the injection. One patient experienced a near-anaphylactic reaction during her second month of participation, but resumed administration of the venom at a smaller dose since she valued the positive results she was experiencing. Several participants dropped out of the study while experiencing benefits from the BVT because they didn’t think the benefit was worth the pain of multiple daily injections.
Comparison of BVT with INFb
Interferon-b (INFb) has a reported efficacy of around 30% reduction in exacerbation rate in relapsing remitting MS patients. Administration of the interferons is on either an every other day (Betaseron) or weekly (Avonex) schedule. And costs for the drugs run approximately $10,000 per year. However, none of the interferons have been approved for use in chronic progressive MS. This study of BVT efficacy was performed on a majority of chronic-progressive cases, but also included those with the diagnosis of relapsing-remitting MS. Venom must be administered either daily or every other day and can produce a localized reaction. Cost for the venom is approximately $150 per vial, which can last anywhere from 1-3 months, depending on frequency and dose of administration. This works out to a yearly cost below $2000, a significant savings for those who cannot afford interferons.
Problems
Data may have been adversely affected by having two sources of bee venom. There are no industry standards for bee venom collection, and the procedure for collection likely varied between locations. The geographic diversity between both of the apiaries could also lead to differences in their venom products. Since bees collect pollen from nearby flora, the composition of their venom would likely be different as well. Future studies should use only one source of bee venom to ensure less variation.
Inadequate data collection was also a problem. A shortage in clinic staff (probably due to lack of funding for the study) did not permit contact with each patient at regularly scheduled intervals. Very few patients initiated contact with the clinic to report on their progress, thereby hindering data collection.
Design of the study could be improved by maintaining tighter controls. Subjects should be enrolled from within a certain radius of the clinic and make an initial commitment to attend every follow-up session before enrolling. Ideally, all shots should be administered at the clinic by trained staff, with dosages and injection sites noted in the patient’s chart. This would also allow for more frequent observation of each patients symptoms, and provide opportunities for objective measurements on an ongoing basis (strength, reflexes, ADLs, etc.). MRI tests should be scheduled prior to admission, and then repeated every 6 months to note any decrease in brain or spinal cord lesions due to MS.
To further enhance retention of subjects, they should have a more extensive orientation. Patients should be told at the beginning of the study that it often takes 6-12 months before the positive effects of BVT are noticed. They should plan on enrolling for a minimum commitment of at least 1 year before evaluating whether to continue with the injections. All tools for evaluation and follow-up should be explained initially in detail to the patient and their “significant other” to ensure better data reporting. Quarterly reminder letters or phone calls could also be initiated to each patient.
Further questions
· Is there a difference between stinging with live bees and using intradermal bee venom extract?
· What is the ideal duration of therapy?
· Can a person discontinue the stings after a certain period without a return to their previous condition?
· What is the mechanism of action of the bee venom on MS symptoms?
ANY OTHER QUESTIONS??
CONCLUSION
Therapeutic bee venom injections in patients with multiple sclerosis seem to be effective in decreasing a patient's functional debilitation due to the disease. With over 68% of patients enrolled in the study experiencing some kind of positive effects from the venom, it is clear that BVT is a promising therapeutic avenue for MS researchers to pursue.
Further research needs to be done with tighter controls on data collection before wholeheartedly embracing BVT as an answer for multiple sclerosis patients. It is also clear that further study of the venom itself should be performed in order to determine the mechanism of action of the venom on MS, as well as to develop a better method of venom collection. Pharmaceutical companies could endeavor to synthesize a biologically active analogue or a more concentrated version, which might allow fewer injections. Finally, research should be conducted to determine a mechanism of action for bee venom on multiple sclerosis.
REFERENCES
1. Halbreich U. Multiple Sclerosis: A neuropsychiatric disorder. Washington (DC): American Psychiatric Press, 1993.
2. Rivens TM, Sprunt DH, Berry GP. Observations on attempts to produce acute disseminated encephalomyelitis in monkeys. J Exp Med 1933; 58:39-53.
3. Paterson PY. The demyelinating diseases: Clinical and experimental studies in animals and man. Immunological Diseases, 3rd edition. Little, Brown, Boston, 1400-1435, 1978.
4. Lerch E, Muller UR. Long-term protection after stopping venom immunotherapy: Results of re-stings in 200 patients. J Allergy Clin Immunol 1998; 101:606-12.
5. Graft D, Golden D, Reisman R, Valentine M, et. al. Position statement: The discontinuation of Hymenoptera venom immunotherapy. J Allergy Clin Immunol 1998; 101:573-5.
6. Lariviere WR, Melzack R. The bee venom test: a new tonic-pain test. Pain 1996; 66:271-277.
7. Kroner J, Lintz R, Tyndall M, Anderson L, and Nichols E. The treatment of rheumatoid arthritis with an injectable form of bee venom. Annals of Internal Medicine 1938;2(7):1077-1088.
8. Ainlay GW. The use of bee venom in the treatment of arthritis and neuritis. Nebraska Medical Journal 1939;24:298-303.
9. Lorenzetti GJ, Fortenberry B, Busby E. Influence of bee venom in the adjuvant-induced arthritic rat model. Research Communications in Chemical Pathology and Pharmacology 1972; 4(2).
10. Vick JA, Warren GB, Brooks R. The effect of treatment with whole bee venom on daily cage activity and plasma cortisol levels in the arthritic dog. Am Bee J 1975;(2):52-53,58.
11. Cajal Y, Jain MK. Synergism between Mellitin and Phospholipase A2 from Bee Venom: Apparent Activation by Intervesicle Exchange of Phospholipids.
12. Takei J, Remenyi A, Clarke AR, Dempsey CE. Self-association of disulfide-dimerized melittin analogues. Biochemistry 1998; 37(16):5699-5708.
13. INFB Multiple Sclerosis Study Group. Interferon beta-1b is effective in relapsing-remitting multiple sclerosis. I. Clinical results of a multicenter, randomized, double-blind, placebo-controlled trial. Neurology 1993; 43:655-61.
Table 1. Demographics of Study Participants
Characteristic n of subjects percent overall
Total Number of Participants (N) 51
Gender
Male 15 29.4%
Female 36 70.5%
Age in years
Group average 48.4
30-39 12 23.5%
40-49 16 31.4%
50-59 16 31.4%
60+ 7 13.7%
Type of MS
Relapsing-Remitting 18%
Chronic-Progressive 86%
Number of years since diagnosis with MS
0-5 15 29.4%
6-10 14 27.5%
>10 16 31.4%
Average length of diagnosis 10.1 years
Location
Illinios 13 25.4%
Missouri 7 13.7%
Canada 6 11.8%
Michigan 3 5.9%
Wisconsin 2 3.9%
Indiana 2 3.9%
New York 2 3.9%
Iowa 2 3.9%
Other 14 27.5%
|
Table 2. Categorized Results |
||||
|
|
|
|
Follow-up Survey |
ROSS Survey |
|
Dramatic |
n=15 |
29.4% |
>30% total improvement, or |
>12 point improvement |
|
Good |
n=15 |
29.4% |
10-29% total improvement, or |
7-12 point improvement |
|
Minimal |
n=5 |
9.8% |
<10% total improvement, or |
<7 point improvement |
|
None |
n=15 |
29.4% |
<2% total improvement, or |
< 2 points improvement |
|
Negative |
n=1 |
2.0% |
any total negative response |
any total negative response |
|
Table 3. Activities of Daily Living |
|||
|
|
Initial Rating |
After 1 Year |
Significance |
|
Walking |
3.5 |
4.8 |
p<.001 |
|
Wheelchair |
5.4 |
6.3 |
not sig |
|
Stairs |
2.8 |
3.9 |
p<.005 |
|
Car Transfer |
4.4 |
5.7 |
p<.048 |
|
Bed Transfer |
4.4 |
5.7 |
p<.006 |
|
Toilet Transfer |
4.4 |
5.7 |
p<.006 |
|
Bathtub Transfer |
4.4 |
5.7 |
p<.006 |
|
Bed Positioning |
5.6 |
6.5 |
p<.010 |
And a copy of a second study:
CURRENT TREATMENT OPTIONS FOR MULTIPLE SCLEROSIS: INTERFERON-BETA THERAPY and BEE VENOM THERAPY (BVT)
David Wester, PAM-1
Midwestern University, College of Allied Health Professions
PA 505M/506M - Independent Study II & Masters Project Seminar
May 15, 1998
Literature Review - Current Treatment Options for Multiple Sclerosis: Interferon-beta Therapy and Bee Venom Therapy
Table of Contents
I. Introduction
A. History of MS
B. Definition and Types of MS
C. Transmission and Susceptibilities
D. Common Signs and Symptoms
E. Introduction to Symptomatic Treatment
III. History of Bee Venom Utilization and Research
A. Allergy desensitization
B. Arthritis
IV. Bee Venom Therapy in MS
A. Physiologic Effects
B. Venom Collection
C. Composition
V. Other Treatment Frontiers
A. New Immunotherapies
B. Other Alternative Therapies
VI. Conclusion
I. INTRODUCTION
Multiple sclerosis (MS) is a neuro-degenerative disease that affects as many as 240,000 Americans, with women twice as likely to suffer from the disease as men (1). Affected patients complain of gait instability, visual disturbances, fatigue, dementia, sexual and bladder dysfunction and symptoms of brain stem dysfunction (dysphagia, nystagmus, intention tremors, etc.). MS is characterized by either chronic deterioration (chronic-progressive MS) or periods of exacerbations with subsequent improvements in their condition, known as relapsing-remitting MS.
Neither the cause nor the pathogenesis of MS is known definitively. Because of this vacuum of scientific knowledge, scientists and clinicians alike have been baffled in finding an effective cure or even adequate palliation of the symptoms. The newest mainline research frontier in MS is the use of immunotherapy. It is thought that MS is an autoimmune disease where the body attacks its own healthy myelin cells. Destruction of these insulatory nerve cells causes an increase in patient disability due to increased conduction time for nerve impulses. By either decreasing the body’s defense system or retraining the defective defenses, scientists hope to provide a long-term cure for MS.
Mainline medical therapy for MS consists primarily of using interferons. Beta-interferons are only approved in the treatment of relapsing-remitting MS but have not been tested for efficacy in chronic-progressive MS. The most widely prescribed interferon, Betaseron, has been shown effective in only about 30 percent of patients by either decreasing their relapse rate or decreasing the development of new lesions (2). While these findings provide answers for some MS patients, others cannot afford their overwhelming expense or have a form of MS for which interferons are not approved.
Rising medical costs and chronic pain conditions have prompted many Americans to explore different treatment options. In the last decade, there has been a 47% increase in visits to alternative medicine practitioners, involving almost half of the American population. In 1997, out-of-pocket expenses for alternative treatments almost matched those for unreimbursed physician expenses for the same year, while total number of visits to alternative practitioners exceeded those of allopathic visits (3).
Bee venom therapy (BVT) is an exciting new field of research for MS. Due to widespread anecdotal support for the efficacy of BVT in MS, combined with the paucity of scientific studies on the subject, researchers have been prompted to take a closer look at this field. In 1997, two studies were awarded funding for research in this area by major MS organizations in America. One is a clinical trial, while the other is being performed to determine the effect of bee venom on immune system cells and nerve signaling in mice with a similar disease. Most recently, the MSAA awarded a grant for a clinical trial to begin on dose-efficacy of BVT in treating MS in 16 patients. Results will not be available from these studies until the year 2000.
Historically, most research with bee venom has focused on treating or decreasing adverse anaphylactic reactions. Other research was begun in the 1970’s to determine whether BVT was effective in treating arthritis. Due to conservatively positive findings in these studies, scientists have also attempted to discover the basic composition and interaction of the components of bee venom and thereby understand its mechanism of action.
This paper provides an overview of multiple sclerosis, including the types of MS, its symptomatology, epidemiology, pathology, and common rating scales. In addition, it will also provide an examination of bee venom utilization in recent medical therapeutics. Finally, a section on the efficacy and drawbacks of b-interferon is included that presents current MS treatment modalities, against which future BVT studies can be compared in the fight against MS.
A. History of MS
Multiple Sclerosis was first “discovered” in the 1830’s by Jean Cruveilhier, a Pathology professor at the University of Paris. He found brown patches in the CNS during an autopsy, but was unable to link them to any particular disease. Robert Carswell published an atlas of sketches showing similar neurological spots, thereby confirming Cruveilhier’s findings later in 1838. Friedrich Theodor von Frerichs, a German doctor, is credited with the first clinical diagnosis in a living patient. In 1849, he noted that the disease was more common in young people, that it was progressive and affected first one side of the body, then the other. Others gave similar reports about a new disease that involved recurrent symptoms, blurred vision, loss of balance, paralysis, and loss of feeling in the limbs (4).
A French neurologist, Jean-Martin Charcot, was the first to correlate the pathological findings of Cruveilhier with the clinical diagnoses being made at the time. He first noted the symptoms in his housekeeper, who was affected by the disease, and was able to differentiate them from symptoms associated with paralysis. In 1868, Charcot presented his findings to the French Biological Society, showing that the brown patches were associated with a disease that he called sclerose en plaques, or “hardening in patches.”
B. Definition and Types of MS
MS is a disease that involves demyelination of nerve axons. Myelin is an insulatory covering around nerves that functions to speed impulse conduction along nerves in the CNS. As myelin is broken down, nerve conduction becomes impaired. Nerve conduction impariment is responsible for the symptoms typically associated with an “exacerbation.” In most cases, periods of remission/recovery are noted, which is most likely due to the limited repair ability inherent in myelin cells.
Three broad categories can be used to define MS: benign, chronic progressive and relapsing-remitting types. Only 20% of people with MS have the benign type. Benign MS is characterized by sudden onset with only one or two mild attacks during their lifetime. Attacks are followed by complete remissions with no residual damage. Chronic-progressive MS accounts for another 20-30% of cases and is typified by slow but continuous worsening, with no remissions. Some of these patients are severely disabled while others are not. The final 40% of patients are the relapsing-remitting type. It is characterized by episodes of worsening, followed by progressive resolution in a few weeks. These people do not return often to their previous functional level, and have approximately one exacerbation every 1-2 years (4).
C. Transmission and Susceptibilities
The exact mechanism of disease transmission is unknown. Most likely, the disease is initiated by an environmental trigger in a genetically susceptible person. From epidemiological research, scientists know that MS is more prevalent in certain parts of the world. For example, Canada, Northern Europe, Russia, New Zealand and Southeast Australia, countries either above or below the 37th parallel, have double the likelihood of contracting the disease as their more equatorial neighbors. Migration studies suggest that MS is due to exposure to an environmental agent before the age of 18 years (5). After exposure, a period of latency occurs, with the initial exacerbation occurring at the average age of 28 years (1).
Monozygotic twin studies have led scientists to postulate that a genetic predisposition for the disease does exist, but is not the sole causation of MS. While the concordance rate between monozygotic twins is 26%, the rate in dizygotic twins is only 2.6%, suggesting the genetic involvement (6). It is also noted that the incidence rate of MS within relatives of those affected with the disease is more common than in the general population (7), providing more evidence toward a genetic component of the disease.
Scientists postulate that MS is due to viral exposure during childhood. Some studies have demonstrated the association between the risk of demyelination and the age of onset of typical viral infections (8). It is known that viruses can trigger diseases with relapsing remitting symptoms and concurrent myelin damage. The hypothesis of viral exposure is also supported by findings of high levels of viral antibodies and immunoglobulins in MS patients. A few epidemics of MS have been reported, most notably in the Orkney and Faeroe Islands (9-10), however these are hotly contested as to having other causes (11).
The theory receiving the most attention today is that a herpes virus (HHV-6) is linked with multiple sclerosis. Indeed, 35% of all MS patients are found to test positive for the HHV-6 in their serum (12). In addition, over 70% with the relapsing form of MS showed increased immune reactivity to HHV-6 (13). However, significant flaws remain in this theory. If HHV-6 was the trigger for MS, one would think that all MS patients would test positive for the virus. This clearly is not the case. And with over 90% of the American population being affected by the virus, what factor separates those who contract MS with the vast majority who never exhibit any of its signs and symptoms? It is clear that further research must be conducted before this becomes the plausible explanation for MS transmission or susceptibility.
D. Common Signs and Symptoms
Multiple sclerosis typically affects young adults between the ages of 20-40 years, with double the prevalence in women as in men. Patients often present complaining of diffuse neurologic abnormalities, stemming primarily from three locations within the CNS: the optic nerve, brain stem/cerebellum and the spinal cord (4). Patients also notice that symptoms are often increased by heat. MS “attacks” are defined as acute exacerbations of old symptoms, or the onset of new and different symptoms than what has been previously experienced. Attacks are initiated by increased stress, pregnancy, systemic infections or traumatic injury, and typically occur at one of three locations.
The spinal cord is the most common site of attack, accounting for 42% of MS episodes. Patients having a spinal cord attack complain of fatigue, numbness, weakness and paresthesias. Spasticity in the legs may be manifested as involuntary twitching or as muscle cramping, similar to a “charley horse.” Bladder incontinence and sexual dysfunction are also related to spinal cord attacks.
The second most common type of attack (38%) affects the brain stem and cerebellum (4). A constellation of three symptoms known as Charcot’s triad are most commonly associated with these attacks. These include double vision, imbalance/incoordination and speech trouble. Double vision is a result of demyelinating nerves that supply the eye muscles that causes muscular weakness or muscle jerking. Balance problems may be some of the most problematic, causing a severe degree of debilitation. Dysarthria, or speech problems, are less common and are found in only the more advanced stages of deterioration.
Only seventeen percent of MS attacks are directed toward the optic nerve, however it is one of the most noticeable symptoms. Optic neuritis typically is monocular, with vision being foggy, blurry, fuzzy or distorted. Depth perception can be affected, and some degree of pain may be present with eye movements. While the symptoms of an optic nerve attack can be frightening, these attacks usually last only a few days and typically resolve in two to six weeks. The prevalence of optic neuritis varies geographically, with only 18% of US cases presenting with this complaint, compared to 48% of Japanese MS patients.
E. Introduction to Symptomatic Treatment
Multiple sclerosis is an enigmatic disease. Although it was discovered over 150 years earlier, very little is known about its development and causation. This has baffled scientific attempts to develop any successful comprehensive treatments. Current treatment modalities for MS can be broken down into two broad categories: palliation of symptoms and disease inhibition. Until recently, palliation was the only option available. However, with the recent development of interferon therapy, hope is burgeoning for more effective modes of intervention.
Current treatment options are aimed at relief of individual symptoms. Corticosteroids (e.g., ACTH) are most commonly prescribed for alleviation of acute MS attacks. These have potent anti-inflammatory properties, and can curb the worsening of clinical symptoms during an attack. ACTH is also used in alleviation of acute optic neuritis. Corticosteroids are discouraged for long term use, since they may induce hypertension, diabetes and osteoporosis, destroy connective tissue and inhibit the body’s natural immune response (14). Both sensory symptoms and a type of facial pain known as trigeminal neuralgia can be alleviated by the antiseizure medications Dilantin or Tegretol. Emotional lability associated with MS is treatable with either tranquilizers (e.g. Valium) or antidepressants (e.g. Elavil). There is no consensus of opinion for the pharmacologic treatment of other chronic symptoms such as urinary incontinence, tremors, spasticity and sexual dysfunction. However, a myriad of physical therapy aides are available to help the patient cope with their decreased functional levels (4).
III. HISTORY OF BEE VENOM UTILIZATION & RESEARCH
Bees have long been appreciated for medicinal purposes. Hippocrates, the Father of Medicine, used pulverized bees and been stings in his medical practices. Charlemagne was also reported to have stung himself with bees (15). It was thought that bees had beneficial effects on chronic pain, helped digestion, and could restore vital humors in the body. However, scientific inquiry into bee stings did not begin until the late 19th century. An Austria physician, Phillip Terc, noticed that his rheumatism patients experienced positive results from bee stings (16).
A. Allergy desensitization
In some instances, bee venom can trigger strong allergic reactions in humans. Extreme allergic reactions that compromise the respiratory system through hyperactivation of IgE are termed anaphylactic responses. Other physiologic responses include a decrease in blood pressure, skin rashes, tachycardia, chills and generalized pallor. In more serious cases there is shortness of breath, heart palpitations and constriction, syncope and possible death (17).
Bee venom hypersensitivity occurs in approximately 0.5% to 2% of the population, although it is possible for a person to be unaware of their hypersensitivity. Several treatments exist for the hypersensitive individual who does get stung. Products like Anakit or Epipen are available in pharmacies, and should be carried at all times by susceptible people. While these self-administered treatments can save that person's life, they should still get medical attention by their primary provider as soon as possible.
Some hypersensitive individuals can gradually build up tolerance to bee venom under the supervision of their physician. Controlled administration of bee venom can help to desensitize a person who is either hypersensitive or has an anaphylactic response. Initially, whole body extracts (WBE’s) from honey bees were used to desensitize a person with allergies to bee stings. However, in the 1970’s, venom extracts were proven superior to WBE’s (18). This kind of desensitization, known as venom immunotherapy (VIT), was reserved primarily for those who had severe reactions to getting stung; namely: widespread swelling, shortness of breath, tightness in the chest, sweating, and a racing heart beat. By this process, the immune system is gradually desensitized to the harmful effects of the bee venom, protecting that individual from the risk of anaphylaxis.
Elderly people can also develop hypersensititivity to bee or insect stings. This is possibly due to the age-related deterioration of the immune system. People taking long-term nonsteriod anti-inflammatory drugs (NSAIDs) are also at risk for increased sensitization to bee stings. NSAIDs include such drugs as ibuprofen, aspirin, naproxen, fenoprofen, piroxicam and ketoprofen, and patients taking any product containing these drugs should advise their physician. However, with discontinued use of NSAIDs, the immune system returns to normal functional capacity and only the typical localized reactions should develop if stung again (15).
The question of how long immunotherapy needs to be maintained remains unanswered, and is the subject of current research. At this point, results seem to indicate that a course of 3-5 years of VIT protects approximately 90% of patients over a lengthy period of observation (19). Periodic tracking of hypersensitive patients who have previously undergone VIT is being considered. When challenged with in-hospital stings, patients who are more at risk tend to have higher IgE levels (20-21) and may need additional VIT.
B. Arthritis
For many decades, bee venom has been connected annecdotally with relief of arthritic pains. However, Bodog Beck’s book published in 1935 spurred a flurry of studies on the subject. In his book entitled, “Bee Venom Therapy: Bee Venom, it’s Nature, and its Effect on Arthritic and Rheumatoid Conditions”, Beck stated that rheumatism, myalgia, rheumatic fever, and many forms of arthritis could be alleviated by BVT (22). Kroner et al. were the first to investigate this claim further. Their article on the treatment of rheumatoid arthritis with injectable BV was published in the January 1938 edition of the Annals of Internal Medicine. One hundred patients were enrolled in the study over a fourteen-month period, receiving anywhere from six to 52 injections during that time. Kroner reported that 35 patients showed marked improvement and that 38 were moderately improved (73% of patients showing some degree of improvement). Patients reported relief from pain, decreased swelling, and laboratory tests indicated a decrease in erythrocyte sedimentation rate (ESR) toward normal levels (23).
A similar study was completed just one year later involving thirty-seven patients (24). GW Ainlay reported that sixteen patients were completely cured, while another sixteen had relief from pain, decreased swelling and near normal function (86% of enrollees). Only one patient failed to show any positive response to the BVT. Due to the difficulty in standardizing bee venom and generalized resistance within American medicine, this field of research was only moderately pursued.
Yet in the 1960’s & 1970’s, the question regarding bee venom and arthritis rose once again. This time, research was conducted on animal models first. Bee venom was administered in either rats or dogs, looking to see whether the venom could prophylactically prevent or treat arthritis. Researchers looked at the cage activity of the animals to determine whether any progress was made. The rat study findings demonstrated that prophylactic administration of venom helped prevent arthritic syndromes when assaulted with an adjuvant-induced type of arthritis (25). In dogs, venom was found to increase plasma cortisol levels, increase cage activity of the animals, and prevent their return to earlier dysfunctional levels once the venom was withdrawn (26). They also found that venom achieved its maximal effect over a long period of time.
IV. BEE VENOM THERAPY IN MS
Bee venom therapy (BVT) is an exciting new field of research for MS. Due to widespread anecdotal support for the efficacy of BVT, researchers have been caused to take a closer look at this field. In 1997, two historic studies were awarded funding for research in this area. The Multiple Sclerosis Association of America approved a $250,000 grant to Georgetown University Medical Center for a one year study on chronic progressive MS patients, while The National Multiple Sclerosis Society awarded a one year pilot research grant to Dr. Fred Lublin to determine the effect of bee venom on immune system cells and nerve signaling. This second study will be conducted on mice that have experimental allergic encephalomyelitis (EAE), the non-human equivalent of multiple sclerosis (27). In October 1998, the MSAA awarded a grant for a controlled BVT trial to be conducted on progressive MS patients. Researchers at Georgetown University will be adminstering BV biweekly to sixteen patients over a 2-year period. They will be looking for dose-response relationships between the venom and disease progression. Finally, a similar private study is scheduled for completion by early 1999 and should provide the first available clinical results.
Since there is no published research available on the effects of BVT on MS, this section will describe the physiologic effects of bee venom, contraindications and hypersensitivity reactions, and the general composition of bee venom.
A. Physiologic effects
In different doses, bee venom can have widely varied effects on the human body. Much of the response is determined by a person's allergic reaction to the venom. A person who has no hypersensitivity to bee venom can tolerate from one to five stings without any adverse reactions. They may notice localized symptoms of swelling, redness and itchiness of the skin that may initially be painful, but will transition over time to a warm flushing sensation. An increasing number of stings will cause further detrimental effects in the non-sensitized individual. Cramps, temporary shortness of breath, cyanosis, tachycardia and symptoms of temporary paralysis may occur with a dose of fifty to one hundred stings. Greater than two hundred bee stings may trigger respiratory paralysis, a deadly condition if left untreated. It should be noted that the physiologic response is highly individualized, indicating that some people can tolerate over 1,000 stings. In fact, one case documents an account of an individual who received 2,243 stings and did not die (15).
The cellular effects of bee venom remain more obscure due to its complex and somewhat variable composition. From studies done in the early 70’s, it has become apparent that BVT is a potential adjuvant in treating chronic arthritis. Honeybee venom seems to have steroid-like properties, and one of its components, mellitin, is 100 times more potent than cortisol as an anti-inflammatory agent in laboratory rats (25). Further research on bee venom has suggested that its primary action is a modification of the immune response (28), curiously similar to the effect of INFb and other immunologic substances discussed earlier. One study suggests that this effect is due to a direct stimulation of the T and B lymphocytes in producing IgM immunoglobulins (29). Others suggest that bee venom inhibits the function of macrophages, which directly inhibits the activation of B and T cells (30) as well as decreases the production of interleukin II (31). Further research is needed to determine whether this or another mechanism is responsible for the alleged efficacy of bee venom therapy.
B. Venom Collection
The first methods of collecting large quantities of bee venom were developed in 1954 by two Czechoslovakian researchers, Markovic & Molnar (15). A wire frame was placed upon a rubber sheet, then the bees were stimulated the sting into the rubber by an electrical charge from the wires. Because bee stingers have barbs, the stinger would remain in the rubber sheet and the bees woud die. Venom was collected from the rubber sheet after further processing.
A newer, more economical method was developed in Europe and North America. In this setting, a wire grid is placed over a glass sheet at the bottom of the hive. Bees are again irritated by the electrical charge within the wires, and sting against the glass pane, thereby discharging the venom and keeping their stinger. Venom dries on the pane, and can be scraped off during collection. Venom from many hives can be harvested at the same time, with no noticable intrusion into the life of the hive (15).
C. Composition
Bee venom is a combination of many useful components. Modern biochemical analytical procedures have been used to identify 18 different components of bee venom. The major components of bee venom include the following: enzymes (phospholipase A2, hyaluronidase, acid phosphate), peptides (apamin, melittin, mast-cell degranulation, peptide MCD, secapin, tertiapin, adolapin), biogenic products (histamine) and amines (dopamine, norepinephrine, leukotrienes). The effects of the basic components of bee venom therapy are numerous. Phospholipase A is an enzyme that has radioprotective activity, mastocytolitic, histamine release, blood pressure depressive and antigenic properties. Hyaluronidase is an enzyme that selectively attacks tissue hyaluronic acid polymers. Physiologic and pharmacologic activities of this material are numerous. It has anaphylactogenic, antigenic, immune response and tissue-spread properties. Apamin is a polypeptide consisting of 18 amino acids and has antigenic and anti-inflammatory properties. Melittin is a polypeptide also consisting of 26 amino acids and represents 40-60% of the bee venom. It is mainly responsible for the elevation of plasma cortisol levels when using bee stings in treatment. Pharmacological and physiologic activities of melittin have been specified as antibacterial, antifungal, central nervous system inhibitory, histamine releasing, mastocytololysic, radioprotecting, vascular permeability increasing, and anti-inflammatory. Presently, it is one of the most potent anti-inflammatory agents known and it can be useful in treating arthritis and rheumatism. Another powerful peptide in bee venom is mast cell degranulating peptide (28).
V. OTHER TREATMENT FRONTIERS
Numerous therapies have been suggested in the recent past. Due to the discovery of the autoimmune component of MS, current research centers on immunological therapies for MS. These therapies include interferons (INFb-1a and INFb-1b), anti-CD4 antibodies (cM-T412), Copolymer-1, azathioprine and intravenous immunoglobulin (IVIg). Due to the poor success rate of standard medical therapies, alternative therapies also abound. In addition to bee venom therapy, hypnosis and dietary modifications have been areas of recent study not only in the US, but also abroad.
A. New Immunotherapies
Until recently, the only solution for MS patients lay in palliative treatment. This treatment was far from satisfactory, offering only minimal relief from daily symptoms, and no hope for long-term disease progression. The discovery and initial utilization of INFb in MS treatment opens a new frontier for MS patients.
Interferons were first described in 1957 by Isaac and Lindenmann (32) where their role in viral infection was noted. Chemically, they are a family of proteins that contribute to the body’s natural defenses against microbial, neoplastic and viral insults. Interferons act by binding specific immune cell surface receptors and carry intracellular signals between cells involved in the immune response (33). Relatively few studies have been completed on the utilization of INFb therapy in the treatment of relapsing-remitting multiple sclerosis. Including the initial studies by Jacobs et al. in the early 80’s (34), only five complete studies have been published. The first study used natural interferon from fibroblastic cells. The other four used products synthesized via newer recombinant technology. Three of these studies analyzed the effects of Betaseron on MS (2,35-36), while the fourth examined Avonex effects (37). All five studies demonstrate a positive relationship between INFb intervention and the slowing of disease progression.
As a result of the initial INFb trial, dose recommendations are 8.0 million IU administered every other day (38). Smaller doses of 1.6 million IU were less effective in clinical trials (35). Cost for a 1-year course of Betaseron is approximately $10,000 every year at recommended dosages (38). Side effects were consistent throughout most of the studies. The first side effect noted by Betaseron recipients was that of flu-like symptoms, while INFb-1a subjects did not suffer from a similar reaction. In addition, complaints about injection site reactions were common to all patients from both studies, yet more common in recipients of either of the drugs. Neither of these are cause for great concern, since they are either self-limiting (flu symptoms) or can be managed with proper education (injection site reactions).
An open label trial was conducted to determine the side effects specific to Betaseron and ascertain from patients their principal reason for discontinuance of INFb. A regression analysis of the data showed that the only factors strongly associated with the discontinuance of INFb therapy were depression, fatigue and a chronic progressive disease course (39). Another side effect is inflammation and infection at the injection site. Common symptoms include local redness, bruising and pain, cutaneous and subcutaneous infections, subcutaneous atrophy and necrotic lesions (40). Although this is not a significant factor in discontinuing INFb therapy, it does warrant a search for another form of drug administration. Two cases of autoimmune hyperthyroidism have been documented (41), but this is not a common side effect.
Several other immunotherapies have been recently developed. Johnson, et al., published a randomized, double-blind trial on the effects of Copolymer 1 in 1996. Similar to INFb-1b, a relapse rate of 29% was noted (p=0.007) with Copolymer 1. Neurologic disability was also significantly decreased throughout the 2-year Copolymer 1 study. Copolymer 1 has a more favorable side effect profile when compared to Betaseron (40), as no complications were noted with the liver dysfunction or mental depression. Another advantage is that Copolymer 1 requires monthly administration, compared to every other day for INFb-1b.
Intravenous immunoglobulin (IVIg) has also been recently tested in relapsing-remitting MS. The advantage to this drug is that shots need to be given only monthly, compared to every other day for Betaseron. Clinical trials demonstrate that EDSS was significantly decreased in the treatment group, while disability levels on the EDSS scale were increased in the placebo group (p=0.008) (42).
Anti-CD4 antibodies (cM-T412) have also been administered to MS patients with relapsing-remitting MS. A single-blinded trial was conducted by van Oosten et al. on seventy-one patients. There was a statistically significant reduction of 41% in the number of clinical relapses after 9 months (p=0.02) which was still present after eighteen months, however EDSS progression was not affected (43).
When compared to treatment modalities that have been available in recent years, each of these new immunotherapies offer significant hope to MS patients. Each one has been shown to have significant effect upon disease progression, whether through halting new lesion formation, decreasing exacerbation rates or slowing the rate of disability. Before widespread utilization can occur, three additional steps must occur. First, further testing needs to be done to replicate efficacy levels. Second, FDA approval should be granted for drug prescription to patient populations. Third, comparative studies should be done between all the immunomodulatory drugs to determine which is best for any given population.
B. Other Alternative Therapies
With the historic dearth of effective medical therapies for MS, patients and scientists alike have begun to search for other answers. Diet was one of the first areas of inquiry. In the 1950’s, high fat consumption was proposed as an increased risk factor for the development of MS based on the varied diets of different populations (44-45). Recommended dietary fat modifications include lowering intake to below 30% of total caloric intake and increasing the proportion of polyunsaturated fatty acids (14). Other recommendations include increasing intake of vitamins C, E, B6, beta-carotene and zinc (46), use of evening primrose oil (47) and gluten-free diets (48). While many people have zealously followed this advice, it is crucial to remember that most of these recommendations are not supported by data from clinical studies.
Hypnosis has also been pursued as an adjunctive therapy for MS (49). Only four papers have been published on the subject, and all are case reports. The published papers do suggest that hypnosis has a positive effect in decreasing the symptoms of MS, but small sample sizes and type of reporting confine the studies to mere anecdotal evidence.
VI. CONCLUSION
Although merely a nuisance after the initial symptomatic episode, MS is a severely debilitating disease in its later stages. Little is understood about its causation, etiology, and biochemical progression within the body. New hypotheses continue to proliferate, implicating CD4 T-cells, interleukins and viral susceptibility, yet none have been proven. Before substantial progress can be achieved in MS research, scientists must identify its specific etiology. This would allow the medical field to target pharmacotherapy to the specific disease etiology. Until this is accomplished, treatment remains merely guesswork.
Recent guesswork, however, has prompted researchers to concentrate on the exciting area of immunotherapy. Initial reports indicate positive results from INFb-1a, INFb-1b, anti-CD4 antibodies, copolymer 1 and intravenous immunoglobulin. Alternative therapies also offer considerable promise based on widespread anecdotal evidence. National MS organizations have given credence to the field of alternative medicine by initiating research in the area bee venom therapy. Comparatively more research has been conducted on INFb-1b than any other immunotherapies for MS. Yet before wholehearted recommendation of Betaseron as the best treatment in decreasing exacerbation rates and slowing disease progression, researchers need to resolve the problem of neutralizing antibodies.
Further work is required to determine appropriate treatment options for chronic-progressive MS. If 20-30% of the MS population is afflicted with this type of MS, then there are approximately 72,000 Americans who have no valid treatment for their condition, and therefore no hope for long-term improvement. Since immunotherapies such as INFb seem to slow disease progression, clinical trials should be conducted to determine whether the chronic-progressive MS patient population could benefit.
REFERENCES
1. Halbreich U. MS: A neuropsychiatric disorder. Washington (DC): American Psychiatric Press, 1993.
2. INFB MS Study Group. Interferon beta-1b is effective in relapsing-remitting MS. I. Clinical results of a multicenter, randomized, double-blind, placebo-controlled trial. Neurology 1993; 43:655-61.
3. Eisenberg DM, David RB, Ettner SL, et al. Trends in alternative medicine use in the United States, 1990-1997: results of a follow-up national survey. JAMA. 1998;280:1569-1575.
4. Rosner LJ, Ross S. Multiple Sclerosis. New York (NY): Prentice Hall Press; 1987.
5. Dean G, Kurtzke JF. On the risk of MS according to age at immigration to South Africa. BMJ 1971; 3:725-729.
6. Sadovnick AD, Armstrong H, Rice GPA, Bulman D, Hashimoto L, Paty DS, et al. A population-based study of multiple sclerosis in twins: update. Ann of Neur 1993; 33:281-285.
7. Sadovnick AD, Baird PA, Ward RH. MS: updated risks for relatives. Am J Med Genet 1988; 29:533-541.
8. Compston DA, Vakarelis BN, Paul E, McDonald WI, Batchelor JR, et. al. Viral infections in patients with MS and HLA-DR matched controls. Brain 1986; 109:325-44.
9. Kurtzke JF, Gudmundsson KR, Bergmann S. MS in Iceland. 1. Evidence of a postwar epidemic. Neurology 1982; 32:143-150.
10. Kurtzke JF, Hyllested K. MS: an epidemic disease in the Faeroes. Trans Am Neurol Assoc 1975; 100:213-215.
11. Benedikz J, Magnusson H, Gudmundsson G. MS in Iceland, with observations on the alleged epidemic in the Faroe Islands. Ann of Neur 1994; 36 (Suppl 2):S175-S179.
12. Knox K, Harrington D, Karrington D. Neurology 1996;47:145-148.
13. Emr M. News Release: Herpes virus strain identified as a trigger in MS. National Institutes of Health, 11/24/97.
14. Matthews WB, Acheson ED, Batchelor JR, Weller RO. McAlpine’s Multiple Sclerosis. New York (NY): Churchill Livingstone, 1985.
15. Simics, M. Bee Venom: Exploring the Healing Power. Apitronic, Calgary, 1994.
16. Bee Venom: The natural curative for arthritis and rheumatism. G.P. Putnam's Sons, New York, 1962, Appendix H, pp. 183-197.
17. Dorland's Pocket Medical Dictionary. WB Saunders, Co. Philadelphia, Pennsylvania, 1995.
18. Light WC, Reisman RE, Rosario NA, Arbesman CE. Comparison of the allergenic properties of bee venom and whole bee body extract. Clin Allergy 1976; 6:293-300.
19. van Halteren HK, van der Linden PWG, Burgers JA, Bartelink AKM. Discontinuation of yellow jacket venom immunotherapy: Follow-up of 75 patients by means of deliberate sting challenge. J Allergy Clin Immunol 1997; 100:767-70.
20. Blaauw PK, Smithuis LOMJ. The evaluation of the common diagnostic methods of hypersensitivity for bee and yellow jacket venoms by means of an in-hospital sting. J Allergy Clin Immunol 1985; 75:566-72.
21. Egner W, Ward C, Brown DL, Ewan PW. The frequency and clinical significance of specific IgE to both wasp (Vespula) and honey-bee (Apis) venoms in the same patient. Clinical and Experimental Allergy; 28:26-34.
22. Beck, Bodog. Bee Venom Therapy. New York: Appleton, 1935.
23. Kroner J, Lintz R, Tyndall M, Anderson L, and Nichols E. The treatment of rheumatoid arthritis with an injectable form of bee venom. Annals of Internal Medicine 1938;2(7):1077-1088.
24. Ainlay GW. The use of bee venom in the treatment of arthritis and neuritis. Nebraska Medical Journal 1939;24:298-303.
25. Lorenzetti GJ, Fortenberry B, Busby E. Influence of bee venom in the adjuvant-induced arthritic rat model. Research Communications in Chemical Pathology and Pharmacology 1972; 4(2).
26. Vick JA, Warren GB, Brooks R. The effect of treatment with whole bee venom on daily cage activity and plasma cortisol levels in the arthritic dog. Am Bee J 1975;(2):52-53,58.
27. Paterson PY. The demyelinating diseases: Clinical and experimental studies in animals and man. Immunological Diseases, 3rd edition. Little, Brown, Boston, 1400-1435, 1978.
28. Chang YH, Bliven ML. Anti-arthritic effect of bee venom. Agents and Actions 1979; 9:205-211.
29. Hyre HM, Smith RA. Immunological effects of honeybee venom using barb/c mice. Toxicon 1986; 24 (5):435-440.
30. Hadjipetrou-Kourounakis L, Yiangou M. Bee venom, adjuvant induced disease and interleukin production. J Rheum 1988; 15:1126-1128.
31. Somerfield SD. Bee venom and arthritis: magic, myth or medicine? New Zel Med J 1986; 281-283.
32. Isaac A, Lindenmann J. Virus interference. I. The interferon. Procedural Research Society of London [Biol] 1957; 147:258-67.
33. Weinstock-Gutmann B, Ransohoff RM, Kinkel RP, Rudick RA. The interferons: biological effects, mechanisms of action and use in MS. Ann Neur 1995; 37:7-15.
34. Jacobs L, O’Malley J, Freeman A, et al. Intrathecal interferon reduces exacerbations of MS. Science 1981; 214:1026-1028.
35. The INFB MS Study Group and the University of British Columbia MS/MRI Analysis Group. Interferon beta-1b in the treatment of MS. Neurology 1995; 45:1277-1285.
36. The INFB MS Study Group and the University of British Columbia MS/MRI Analysis Group. NABs during treatment of MS with interferon beta-1b. Neurology 1996; 47:889-894.
37. Rudick RA, Goodkin DE, Jacobs LD, Cookfair DL, Herndon RM, et al. Impact of interferon beta-1a on neurologic disability in relapsing MS. Neurology 1997; 49:358-363.
38. Goodkin DE. Interferon beta-1b. The Lancet 1994; 344:1057-1060.
39. Neilley LK, Goodin DS, Goodkin DE, Hauser SL. Side effect profile of interferon beta-1b in MS. Neurology 1996; 46:552-554.
40. Lublin FD, Whitaker JN, Eidelman BH, Miller AE, Arnanson BGW, Burks JS. Management of patients receiving interferon beta-1b for MS. Am Acad Neuro 1996; 46:12-18.
41. Schwid SR, Goodman AD, Mattson DH. Autoimmune hyperthyroidism in patients with MS treated with interferon beta-1b. Arch Neuro;1997; 54:1169-1170.
42. Fazekas F, Deisenhammer F, Strasser-Fuchs S, Nahler G, Mamoli B, et. al. Randomized placebo-controlled trial of monthly intravenous immunoglobulin therapy in relapsing-remitting multiple sclerosis. Lancet 1997; 349:589-593.
43. van Oosten BW, Lai M, Hodgkinson S, Barkhof F, Miller DH, Moseley IF. Treatment of MS with the monolconal anti-CD4 antibody cM-T412. Neurology 1997; 49:351-357.
44. Swank RI. Treatment of MS with low-fat diet. AMA Arch Neuro Psych 1953; 69:91-103.
45. Swank RI, Dugan BB. Effect of low saturated fat diet in early and late cases of MS. Lancet 1990; 336:37-9.
46. Manley, P. Diet in multiple sclerosis. The Practicioner 1994; 238:358-363.
47. Graham J. MS: A self-help guide to its management. London: Thorsons, 3rd edition. 1993.
48. Hewson DC. Is there a role for gluten-free diets in MS? Hum Nutr 1984; 38:417-20.
49. Sutcher H. Hypnosis as adjunctive therapy for MS. Am J Clin Hypn 1997; 39:283-289.
This is all "in house" information and not to be used or shared with anyone. However the resources listed may be helpful to you.
Sincerely,
Caring Medical
