New Treatments for Neuropathy (Part 2)

Edited Chat on www.diabetes.org
Date: June 7, 2000, 9:00 PM EST
Moderator: Deb Butterfield
Subject: Neuropathy
Guest: Dr. Aaron I. Vinik, Research Director, Leonard R. Strelitz Diabetes Institutes
Eastern Virginia Medical School, Norfolk, VA

Moderator:
Welcome to Diabetes Station Dr. Vinik! Would you start by giving us a definition of neuropathy and a brief explanation of what causes it in people with diabetes?

Dr. Vinik:
I am happy to tell you about neuropathy and what causes it. The term refers to damage to the peripheral nervous system. This includes both the voluntary nervous system, i.e. somatic that controls sensation of all types and motor movements as well as the involuntary, or autonomic, nervous system that controls all those functions that are vital for survival but which we are not constantly aware of. Things such as our heart rate, breathing, blood flow in blood vessels, sweating, and bowel and bladder function. The primary cause is hyperglycemia, but this could be mediated by a host of different mechanisms we could talk about.

Moderator:
How prevalent is neuropathy and would you tell us what the host of other mediating factors are - if someone has good Hgb A1c's and neuropathy, what sort of causal factors would you be looking for?

Dr. Vinik:
The prevalence of neuropathy depends on how you define it. If you ask questions such as: Do you have pain, numbness, tingling, burning, constipation, nausea, vomiting and so forth, all symptoms of neuropathy, then about 25% of all patients have neuropathy. If you do one simple bedside physical examination such as an ankle reflex or measure vibration perception, then about 50% of patients have neuropathy. If you embark on more sophisticated methods of detection, then as many as 95% of people seen in the clinic have some form of neuropathy.

It would be wonderful if a good Hgb A1c protected us from neuropathy, but this does not seem to be the case. The DCCT taught us that if you did not have evidence of neuropathy and kept your HgbA1c's at near normal levels, then you could mitigate the likelihood of developing neuropathy. However, once established, other factors begin to play roles that are not reversed by simply reducing the blood glucose. As you all too well know, even pancreatic transplantation with total normalization of glucose may be insufficient to reverse the pathological process set in motion.

Terry:
Thanks for being here Dr. Vinik. Can you tell us if PN (peripheral neuropathy) can cause GERD (gastro esophageal reflux disease)?

Dr. Vinik:
One of the manifestations of PN is GERD due to the dysfunction in the esophagus and delay in gastric emptying.

Terry:
I am taking Prilosec. Is that useful in treating the GERD? Is there anything else that I should do?

Dr. Vinik:
Prilosec decreases gastric acid production and is of value in people with GERD. In diabetes, there may be a need for other mimetic agents to overcome the dysfunctional esophagus and stomach.

Terry:
Is there surgery for esophageal problems related to PN were they to progress?

Dr. Vinik:
Terry there is surgery, but that should be a last resort after all medical options have been exhausted.

Ruth:
Dr. Vinik, would you consider Irritable Bowel Syndrome a form of PN?

Dr. Vinik:
Irritable bowel may be due to an incoordinate action of the nerves of the large bowel but is not a feature of diabetic autonomic neuropathy. If this diagnosis is made however, then one ought to be on the lookout for other conditions that masquerade as irritable bowel.

Terry:
I have GERD and PN and am diabetic. Can you just briefly tell me what the mimetic treatments you mentioned are. My docs do not understand the relationship between PN and GERD and think Prilosec is all that I need to get better.

Dr. Vinik:
Other mimetics for example are erythromycin that binds to a receptor in the gut known as the motilin receptor which is thought to be the sweeper of the gut and responsible for its normal motility. Reglan is another example. The one making the news recently and now being withdrawn from the market is Propulsid.

Moderator:
Why is Propulsid being withdrawn?

Dr. Vinik:
Propulsid was withdrawn because it causes bad arrythmias of the heart.

Jerry:
Can you tell us if the onset of neuropathy is a quick one or a gradual one?

Dr. Vinik:
Neuropathy can start very abruptly. A prime example is what is commonly referred to as "insulin neuritis." People with newly diagnosed diabetes or those who have been on a diet with or without oral agents who are started on insulin, sometimes develop a very painful form of neuropathy the moment they are started on insulin.

Moderator:
How do you establish if neuropathy is getting worse or better if you don't have a baseline to go by?

Dr. Vinik:
The tests for neuropathy require electrophysiology or nerve conduction, quantitative sensory tests for the different modalities of sensation and quantitative autonomic function tests.

If you do not have a baseline, then it is important to establish one the moment your nervous system is examined. Serial examinations thereafter tell you if the condition is getting better, staying the same or progressing. Unfortunately, the rule in diabetes is for progression. We at least now know the rates of progression for the different modalities.

Jerry:
Wow, it all sounds so complicated… so unless we have the test we cannot say for sure whether we have it or not?

Dr. Vinik:
Having the test is a refinement. A good clinical examination and responses to a neuropathy specific questionnaire is where you want to start.

Moderator:
Most often we hear that there is nothing that can be done for neuropathy short of trying ways to mitigate the pain. What types of treatments do you use?

Dr. Vinik:
In 1994, the Lancet stated that all we could do about neuropathy was make the diagnosis and commiserate with the patient. Now we have a whole bunch of new therapies that allow us to make real inroad into the management of the patient with PN. Especially, in light of the fact that we have come to recognize the different clinical syndromes and are beginning to understand their underlying mechanisms. Once you understand what causes the problem, it is a whole lot easier to treat the condition.

Moderator:
Since my pancreas transplant, I have non-diabetic blood sugar levels (Hgb A1C of 4.8), the autoimmune process that caused the diabetes has been halted by the immunosuppression (no steroids) that I take, my neuropathy has improved dramatically, but I still don't have proprioception worth a darn, so I lose my balance. If blood sugar is normal, and I'm on immunosuppression, what other treatments are there?

Dr. Vinik:
Deb, it is good to hear that since the transplant and the suppression of the autoimmunity that you have had a good response with the neuropathy. The loss of balance suggests that the large myelinated fibers have not responded as well. There may be variety of reasons for this that need careful dissection and are not easy for me to delineate here.

Zim:
Would you tell us about nerve growth factor and how soon it will be available?

Dr. Vinik:
Nerve growth factor is a substance that is produced in the human body and is very important for the growth and development of the autonomic nervous system as well as sensory nerve fibers that subserve warm thermal perception and pain. In the adult, it appears to be important for the maintenance of the integrity of these same nerve fibers.

Ruth:
Dr. Vinik, can you explain what you mean by warm thermal perception?

Dr. Vinik:
By warm thermal threshold I mean your ability to detect heating of the skin. One of the big dangers to people with diabetes is the loss of the ability to detect heat. Then they go for a walk on the beach or hot tar and do not sense the heat and burn themselves with all its consequences.

Jerry:
Is it possible then to grow nerve ends?

Dr. Vinik:
Jerry, yes it is possible for nerve fibers to regenerate and to regain some of their function, a heretofor heretical notion.

Zim:
Is there a medication like nerve growth factor soon to be approved for treatment of PN?

Dr. Vinik:
NGF-like drugs are being examined in the laboratory and are in early clinical trials as we speak. These are blinded studies, and we are doing most of them, but I do not have data to share with you at this point.

Moderator:
What are the selection criteria for the blinded studies of NGF?

Dr. Vinik:
The NGF studies have been terminated so the selection criteria no longer matter.

Zim:
The studies of NGF were terminated? What does that mean?

Dr. Vinik:
The NGF studies were terminated after two trials. The initial one was done on 250 people, and it showed that the drug appeared to be effective. This resulted in a large multi-center worldwide trial of the drug in over 1,000 patients, and the results were negative. It is still not clear that the drug was ineffective or that the trial failed to show its effect. Whatever the case, the company decided not to pursue the drug further.

Moderator:
Are any other companies developing NGF? I can't believe that would be the end of it!

Dr. Vinik:
There are other companies that are working with other nerve growth factors, not specifically NGF, so that this avenue remains alive even if NGF has not survived this go around.

Terry:
What is your opinion of the use of ALA (Alpa Lipoic Acid) for PN?

Dr. Vinik:
Alpha lipoic acid is probably one of the most potent antioxidants we know. There have been studies in Europe, visa vie the Aladdin and Dekan studies that show that it is of benefit in painful neuropathy as well as autonomic neuropathy. There are now ongoing research studies in the US addressing some of these issues. Of course, the compound is available over the counter from health food stores and many people are taking it without waiting for the information that will derive from the American studies.

Terry:
I just want to mention that I have taken ALA for almost a year now, and I went from a terrible burning in the feet-with numbness and tingling-to now having no burning (knock on wood) to some numbness and occasional tingling. I buy it over the Net. I also have gotten my sugar in better control so it may be one or both that have helped.

Dr. Vinik:
Terry, that is good news. Also you may know there are two forms of alpha lipoic acid and the dextro rotary isomer also lowers blood glucose and improves lipids. It is also being investigated in the US right now. You may have gotten a double hit from the same compound.
On the Net you can get vitamins and antioxidants from Vitaminshoppe.com

Ruth:
Can you tell us more about the two forms of alpha lipoic acid. What is dextro rotary isomer, is it in the alpha? How can we know that kind to take?

Dr. Vinik:
Alpha lipoic acid is a racemic mixture of both the L (levo) and D (dextro rotary) forms of the compound that is sold over the counter. It is this mixture that has been reported to be of value in PN. It now seems that the D form may have different properties, but this is not in the public domain at this point in time. It is being investigated.

Moderator:
Would you summarize the types of treatments that are available for neuropathies. We've talked about anti-oxidant, NGF-type protocols, blood sugar control, and immunosuppression agents.

Dr. Vinik:
Deb, that is a tall order. For example, the issue of pain management is a long talk in its own right. There are mononeuropathies that require one form of treatment, entrapments require relief, proximal neuropathies require an entirely different form of treatment than distal, and the host of manifestations of autonomic neuropathy require individual approaches. I have recently written two review articles, one in Diabetologia and one in the Canadian Journal of Diabetes Management that are good places to start.

Moderator:
If someone wants to come to the Strelitz Diabetes Institutes for an evaluation, whom should they call?

Dr. Vinik:
They should contact Etta Vinik, who runs our executive medicine program (EMP). You can find out more information about this program at www.evms.edu/diabetes/clinical-executive.

Moderator:
Dr. Vinik, does insurance cover these treatments for neuropathy or are they considered experimental by insurance companies?

Dr. Vinik:
Some insurance companies do cover the treatments, especially those that have been shown in large studies to have effects. Others say that the evidence is not yet in. You need to check with your own insurance company.

Moderator:
Thank you VERY much Dr. Vinik. What a terrific program! I learned a lot! Dr. Vinik is the Director of the Research Institute at the Strelitz Diabetes Institutes at Eastern Virginia Medical School in Norfolk, Virginia. He was speaking with us tonight about diabetic neuropathy. Before I was introduced to Dr. Vinik, I believed that diabetic neuropathy was something you have to live with, but Dr. Vinik knows how to analyze the specific causes of neuropathy and has a novel approach to treating it. Again, thank you for taking the time to talk to us tonight.

Dr. Vinik:
It was a pleasure Deb. Take Care.