ALS Part 2

                   My Understanding of ALS

The following is my perspective on the nature of ALS.  ALS is a poorly understood phenomenon and there are other perspectives which may be just as reasonable as mine, or more so.

1.  ALS is a collection of motor neuron disorders which have a number of initial causes, but lead to similar findings on autopsy.  So-called Guamanian ALS is sufficiently different that it ought not to be lumped together with ALS.   Furthermore as the biochemistry of ALS is slowly unraveled, it will become necessary to dissociate familial ALS from sporadic ALS even though they share similar symptoms and autopsy findings.  In the comments which follow here, when I refer to ALS, I mean specifically sporadic ALS, and do not necessarily include other ALS syndromes.

2.  ALS is often compared with other neurodegenerative diseases such as Parkinson’s and Alzheimer’s diseases.  This lumping together obscures a very important fact of ALS:  its infrequent and sporadic nature.  In this respect ALS has much more in common with autoimmune disorders than with the common degenerative diseases.

3.  Those who have been seeking “the cause” of ALS have collectively found it everywhere:  mercury or other heavy metal toxicity, aluminum, fluoride, exposure to retroviruses, undiagnosed bacterial infection, exposure to pesticides or other nerve agents, organochlorines in drinking water.… there’s no end to it.  The “Wapner Critereon” for getting off this path is this:  all those “causes” are common, but ALS is rare.  Therefore:  those causes may be in some way contributing factors, but they’re not the root of the problem.  This seems to be confirmed by epidemiological studies of ALS which have come up very nearly empty-handed.  The obvious place to look, when the roll of the dice has wiped out correlation in epidemiological studies, is genetics.  In my opinion, the tendency to get ALS is inherited, and that inheritance is then convolved with environmental factors which modulate the way that tendency is actually expressed in the individual.

UPDATE:  Reuters published a story 6 Feb 06 that a study of 392 pairs of ID and frat twins over 65 in Sweden at least one of whom had been diagnosed with Alzheimer’s, showed Alzheimer’s has a genetic basis of 79%,  the remaining variation being explained by different exposure to environmental influences.  ……..Twin studies in general tend to show results of this sort.  When you decided what make & model & color of car to buy, 79% of that choice was probably made 9 months before you were born.  NOTE:  What religion people claim to practice, and whether or not they are criminals, is almost entirely a matter of cultural circumstance, not heredity.  How people practice their religion is probably largely a matter of heredity, but I haven’t seen any research on that.

4.  Serum glutamate is consistently higher than normal in individuals diagnosed with sporadic ALS.  Since glutamate is neurotoxic in excess of normal levels, it has been customary to attribute neuron damage in ALS to glutamate.  However, this does not seem to explain the specificity for motor neurons characteristic of ALS.  …….Because serum glutamate is not something included in ordinary screening tests, it is unknown whether the onset of sporadic ALS is accompanied by a rise in serum glutamate, or whether the serum glutamate was high all along in those individuals predisposed to ALS.

5.  The gut breaks down proteins to extract glutamate, which it then uses for energy in lieu of glucose.  The gut also intercepts free glutamate for this same purpose.  In my opinion the regulation of serum glutamate levels is something that happens primarily in the gut, and that those who are looking at the nervous system for clues as to why glutamate regulation goes awry, are looking in the wrong place.

6. There are reports of higher than normal glutamate levels in cerebrospinal fluid and of lower than normal glutamate levels in motor neurons, in people diagnosed with ALS.  It appears to me that the experimental difficulties in making these measurements are sufficiently great as to make the reported results not worthy of confidence.  I’m not saying “it ain’t so”, merely saying don’t place large bets on those results without further evidence.

7. The role of glutamate in the motor neuron is to open the calcium channel to allow the entry of Ca++ irons, depolarizing the cell and triggering the propagation of a depolarization soliton.  So in the end it is not glutamate per se which is excitory, it is Ca++. 

8.  If the cell cannot regulate the input of Ca++, or cannot accomplish its redox and removal, the cell will be unable to restore its charged state and will be unable to initiate a subsequent discharge.  Such a cell, though it may be biologically alive, is functionally dead as a nerve cell.

9.  Calcium channel blockers are potentially useful for inhibiting the excess intake of Ca++ by nerve cells.  The most obvious such calcium channel blocker is magnesium. Clinical studies are underway with a much more expensive synthetic calcium channel blocker as part of an ALS drug cocktail, I presume the synthetic drug being preferred because it is more costly.

10.  This bring us to the problem of “why just motor neurons”?   I’m now going on memory from an article I read recently, and will probably mess up a few factoids, but here’s the general picture.  Motor neurons remove calcium by relying on certain proteins which are not found elsewhere.  In a study of about 30 persons diagnosed with sporadic ALS, all of them exhibited antibodies for those specific proteins.  Familial (SOD-1 mutation) ALS controls did not exhibit those antibodies.   ……As with serum glutamate, it is unknown whether these antibodies are present long before the onset of ALS symptoms, or whether their presence coincides with the onset.

11.  There is a widely accepted belief in the ALS literature that ALS is a self-sustaining degenerative process which once triggered, proceeds on its own even if the trigger is removed.  While there is undoubtedly some truth in this, in my opinion the notion that the self-sustaining process dominates the picture isn’t being greeted with nearly enough skepticism.  My sniffer tells me that underlying causes remain relevant.

12.  There is a widely accepted belief in the ALS literature that free radical damage esp. to the mitochondria is a key process in cell destruction, and that the cure is high levels of antioxidants.  There is mouse model and in vitro evidence in favor of antioxidants being helpful:  however it is misleading to think that ALS is caused by antioxidant deficiency.  Not even familial ALS patients who cannot produce superoxide dismutase (a key antioxidant) exhibit a generalized picture of antioxidant deficiency. (The problem seems to be not the lack of SOD, but the toxicity of the molecule which the defective gene synthesizes in lieu of SOD.)    ……..All that having been said, cells under attack from degenerative processes, especially those involving energy such as Ca++,  have abnormally high loads of free radicals, and require abnormally high levels of antioxidants to soak up those free radicals.

13.  Ammonia is a byproduct of metabolic processes and is toxic to cells.  One of the ways that the cell regulates both ammonia and glutamate is to combine the two to form glutamine, which itself is harmless although it probably serves as a reservoir for glutamate resynthesis.

14.  Glutamate combines with something else (as I recall, cysteine and glycine) to form glutathione, which is the most important antioxidant within nerve cells.  This is also a means by which glutamate is regulated.

15.   An overexcited cell will tend to redox until either the oxygen supply or the energy supply runs out.  At that point you have a nonfunctional cell which has begun dying through either starvation or asphyxiation (to use a rescaled analogy), and unless rescued in time, it will die.  Some drugs, and also cooling, slow down or interfere with the thermodynamic disintegrative chemical processes which go on in a hypoxic or energy-deprived cell, making its subsequent resuscitation more likely.

16.  There is a widespread belief among ALS researchers that inflammation is one of the key processes involved in the ALS disease process.  There is in vitro (and I believe mouse model) evidence that anti-inflammatory drugs may be useful for ALS therapy.  Minocycline is the preferred anti-inflammatory in clinical trials, apparently because of its high cost and in disregard to its serious dangers.

17.  There is a widespread belief among ALS researchers that the ability of the body to repair nerve damage which has already occurred, is important in determining the rate of decline of the ALS patient.  This does not lend itself very readily to in vitro research, and the expense of doing research on human subjects has stifled progress in this area.   Nonetheless I consider this very important and will bring up the subject later on.

18.  The onset of ALS is frequently associated with trauma.  There is also a slight but apparently significant epidemiological correlation with prior participation in varsity sports. There may be more than one phenomenon at work here.  My guess, based on interpretation of my own personal experience, is that in primary lateral sclerosis, the ALS is latent as a tendency in the motor cortex to disintegrate if not reinforced, and that immobilization resulting from an injury then frees that latent tendency to manifest itself.

19.  As ALS progresses, the skin takes on an inelastic character and is resistant to the development of bedsores.  To my knowledge this skin condition is not seen in other than ALS patients.  I don’t know what the underlying biochemistry of “ALS skin” is, or what its connection to the motor neuron aspect of the disease is.  This deserves further research.

20.  I have been diagnosed with PLS.  I can tell the problem is in the motor cortex because there are movements which I literally forget how to do, and have to figure them out.

21.  In my case history I mentioned the “hot spot”, a paraesthesia which was present over the quadriceps for 2-3 years before any motor symptoms developed.  So, are these two things connected; and if so, how?   Here’s my theory:   …….Motor control is part of a feedback loop involving sensation.  This is a fundamental principle of physical therapy. …….. Suppose for a moment that the sensory nerves which provide feedback on muscle action and position were also deteriorating.  That could easily go on unnoticed because those are sensations we’re not usually conscious of.  Lou Gehrig would notice his pitch was slightly off, but a non-athlete could lose a lot of capability and never notice it.  ……Then comes an injury which causes the patient to immobilize the affected region.  The amount of feedback collapses, the motor cortex predisposed to disintegrate is not being constantly reminded how to keep the feedback loop intact, and the sensorimotor control loop falls apart with the motor cortex having become its weakest link.  ……At that point, you have primary lateral sclerosis.  A cascade of paralysis has been set in motion.  It is largely reversible if you catch it quickly enough.  And the things you did to reverse it you have to keep on doing, or it will come right back.

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My perspective on ALS chemotherapy

1.  Antioxidant therapy is widely believed to be good for general health anyhow.  So do it.  The emphasis is on vitamins C and E which are critical for maintaining glutathione.

2.  Target glutathione for boosting.  This means taking NAC, a glutathione precursor, and selenium, an element necessary an enzyme which synthesizes glutathione.

3.  Regulate glutamate intake.  It is impossible to avoid dietary glutamate, but one can avoid foods which have high levels added artificially.  Aspartame, which acts at the same receptors as glutamate, can be completely avoided.  It is unknown to what degree restricting free glutamate intake reduces serum glutamate levels, but taking this precaution is easy enough to do and is risk-free.

If you make a list of your favorite “healthiest foods”, chances are that half of them will be on a list of foods which contain free glutamate.  Tomatoes, cooked potatoes (nobody eats ‘em raw), broccoli, beans, avocados, cabbage, red wine, the more expensive cheeses…..….. forget that stuff, stick with Crisco and Regular Coke and you’ll be safe!  ….. Well, dadgummit, I like healthy foods, and I have no intention to subsist on Crisco and Regular Coke until death do us part. 

So I avoid additives which owe their existence to high glutamate.  I partake generously of healthy foods which may contain free glutamate, but go easy on things like sharp cheeses.

4.  Combat glutamate toxicity.  One way to do this is to take drugs which increase GABA-ergic activity in the cell, which is inhibitory.   Another way is to take drugs which block the calcium ion channel, such as magnesium.  Synthetic calcium ion channel blockers are under investigation in clinical trials, evidently preferred because of their high cost and in disregard for their dangers.   ……Rilutek reduces synthesis of glutamate, and may have some slight benefit: however the stuff is very expensive and has a high incidence of serious side effects.  Many patients who can get it at low cost through insurance plans refuse to take it because of its poor benefit-to-risk ratio.

5.  Take drugs which help restore cellular energy level.  Such drugs include alpha-lipoic acid, and CoQ-10.

6.  Take drugs which improve the ability of the body to maintain and repair nervous tissue. B-vitamins, lecithin, phosphaditylserine, and SAM-E are most frequently mentioned.  More specific neurotrophic growth factors are being researched but results have been inconclusive.  In my opinion, the most important neurotrophic growth factor is not something you eat, but something you do-- physical therapy.

7.  Take adaptogenic drugs which restore balance to the overall organism.  This is a new field to Western medicine, but integral to traditional Chinese and Ayurvedic medicine.  It’s difficult to find rationales for choosing what to take and what not to take.  I have my own preferences which will be discussed later.

8.  Take anti-inflammatories in order to maintain good joint function (permitting effective physical therapy), to inhibit inflammatory processes which are believed to be part of the ALS degenerative cascade, and for general good health.  For everyday use, stick with the natural stuff-- turmeric extract, boswellia, green-lipped mussel, Omega-3’s, etc.  For occasional use as required, ibuprofen: it’s quite safe for most people.  Minocycline and Celebrex are under investigation as anti-inflammatories for treating ALS, but as far as I can figure, the only reason those dangerous drugs are the ones being researched, is because of their high cost.

9.  Take stuff specifically for your joints and bones to keep in them in good shape to facilitate effective physical therapy:  boron, vitamin D, glucosamine, chondroitin, etc.

10.  Take neuroprotective agents if there are any in which you have any confidence. 

11.  Just to be on the safe side, avoid unnecessary exposure to aluminum, which some researchers feel is implicated in both ALS and Alzheimer’s.   The amount of aluminum from beverage cans is probably fairly low, since metallic aluminum forms a strong oxide film. Aluminum cookware with a nonstick coating is presumably safe as far as the aluminum goes:  you can worry about fluoride instead from Teflon if you like-- it’s probably in your drinking water anyhow.  Avoid antiperspirants which contain aluminum or zirconium compounds-- add a few grams of GSE to a bottle of witch hazel, and you’ve got a natural antiperspirant-deodorant which works about as well as any name-brand stuff, and it’s odorless and safe to boot.  …….Many pickled foods esp. “pickles” contain alum as a crunchifying and flavoring agent:  don’t buy ‘em.  The companies that don’t add alum are betting that their cukes were so darn good that no alum was necessary.

12.  Although autoimmunity appears to play a role in sporadic ALS, immunotherapy has so far not proven effective in treating ALS.  The approaches used were probably adapted from experience with other autoimmune diseases.  A new approach designed specifically for sporadic ALS might be quite effective, but to my knowledge nobody has said what sort of approach that would be.

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My perspective on physical therapy.

IMPORTANT NOTE:  My perspective on physical therapy relates to my own situation-- lower-limb onset upper and lower motor neuron disease (mostly upper) in a patient who has been able to remain ambulatory.  Much of what I say here will be irrelevant to other ALS conditions.

1.  The patient must take primary responsibility for physical therapy.  Physical therapy is not something that happens for 1 hour a week, it’s something that you live.  Pay attention to your body, notice its deficits, work on bringing them back-- use it or lose it.

2.  The primary purpose of physical therapy is to keep nerve repair processes going faster than nerve degeneration processes.  Good muscle condition may result from this, and will help it proceed; however control is more important than strength.

3.  I believe, although I have no hard evidence, that nerve degeneration in one area releases chemicals that accelerate nerve degeneration in other areas, and that nerve restoration releases chemicals that accelerate nerve repair in other areas.  In short, it is my opinion that the most powerful neurotrophic factor you can take, is not by mouth, but by appropriate physical therapy.

4.  It is my opinion (shared by many) that the redox mechanisms of the motor neurons of the ALS patient are rate-limited at a lower level than those of the normal person, and therefore it is important to avoid strenuous exercise that could drive the motor neurons into collapse of normal redox processes.  Plenty of low to moderate intensity exercise is fine.  ……With some physical therapy practices, a big chunk of their business is sports medicine, which can lead to a jock mindset of “no pain, no gain”.   And ALS is rare enough that your therapist may hardly know what it is.  So, you and your therapist will have to work with each other to figure out what works for you and what doesn’t.

5.  One of the first things we tried, was electrical stimulation of the atrophied quadriceps muscle to help build up its strength.  But I have primary lateral sclerosis (upper motor neuron disease):  the result was spasticity.  When I told my physical therapist that it didn’t help, it made matters worse, I was stronger without the “help” than with it, he took my word for it and we never bothered with electrical muscle stimulation again.  (For a patient whose paralysis is due to lower motor neuron disease, electrical muscle stimulation might be helpful.)

5.  ALS may be nonsymmetrical, but do your exercises symmetrically.  What your good side does will transfer to the bad side and help it re-learn.  And, doing the same with the left and the right helps you keep track of progress by maintaining a basis of comparison.

6.  Pay special attention to constantly stretch atrophied muscles.  Otherwise they’ll tend to harden into a short mass of scar tissue that will leave you immobilized.

7. Everyday life is full of opportunities to do exercises that target certain muscles.  Seek out those opportunities so you can exercise well and often.  When you wake up in the morning, there’s your first opportunity for physical therapy, even before you even get out of bed.

8.  I started out with a physical therapy clinic once a week, and kept it up for several months.  Meanwhile I was learning how physical therapy works so I could do it at home and create my own exercises.  Later, I realized that my massage therapist could do what they couldn’t do at the physical therapy clinic-- do a check of every relevant muscle every week and constantly revise in a creative way whatever exercises were needed to deal with her findings.  [Fortunately I have a massage therapist who has training and experience with ALS patients and who is comfortable with being creative.]

9.  Massage is good therapy for anyone.  …..One of the popular/professional massage magazines in (I believe) June and July 2005 published a two-part series on massage for ALS patients.  I found the first one on the web but have not found the second one either on the web or on the magazine rack.

10.  My physical therapist told me to get plenty of rest:  it seems to have been good advice.

11.  Quite a few doctors consider physical therapy and therapeutic massage by trained professionals to be “alternative medicine” and are reluctant to prescribe or even to suggest it.  Why?  The doctor himself probably doesn’t know, having subconsciously assimilated the prevailing cultural conditioning.  But any educated European can tell you:  Americans are afraid of the human body.  Remember that Janet Jackson “wardrobe malfunction” uproar at the Superbowl a couple years ago?  Europeans were bewildered.  Why were Americans acting as though they’ve never seen a breast; and seemingly terrified that the glimpse of the nipple might well bring on the Apocalypse?

The reason is that several hundred years ago, the English encouraged the Puritans to get the heck out of town and go to America.  The Puritans as a denomination are long since gone, but they left an indelible imprint on American society, including on how we do medicine.  Not being able to get a prescription for therapeutic massage is just one of the myriad ways whereby we punish ourselves by clinging to the sins of our forefathers.

12.  UPDATE from the “I couldn’t make this up” department: 

www.mdausa.org/publications/Quest/q76massage.html

(Muscular Dystrophy Association)  This web page gives a good overview of how therapeutic massage works.  Then at the end, there are these bizarre disclaimers:  “any massage program that claims to cure or reverse the effects of a neuromuscular disease should be avoided….. anyone claiming to do more than [symptom relief] is a charlatan.”   Gee, even placebos often do better than mere symptom relief!  Somebody doesn’t want you to get the therapy which they already told you is effective.  That’s the “charlatan” by whom you ought not to be deceived.  ……Stuff like this is why so many Europeans think Americans are adolescent hypocrites:  see item 11 above.  

I say that as an ALS patient, you should seek out a massage therapist who admits to having the knowledge and skill to provide more than mere symptomatic relief, one who knows how to produce results that are in principle clinically verifiable (not that the average clinic would bother to verify those results).

If you can’t find a therapist with that set of knowledge and skills, well, even symptomatic relief is good.  After all, symptomatic relief is a big chunk of what a regular MD’s business consists of.

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