Date: Sun, 27 Aug 95 02:42:11 -0400 From: Bob Broedel To: als@huey.met.fsu.edu Subject: ALSD209 ALS-ON-LINE =============================================================== == == == ----------- ALS Interest Group ----------- == == ALS Digest (#209, 26 August 1995) == == == == ------ Amyotrophic Lateral Sclerosis (ALS) == == ------ Motor Neurone Disease (MND) == == ------ Lou Gehrig's disease == == ------ maladie de Charcot == == == == This e-mail list has been set up to serve the world-wide == == ALS community. That is, ALS patients, ALS researchers, == == ALS support/discussion groups, ALS clinics, etc. Others == == are welcome (and invited) to join. The ALS Digest is == == published (approximately) weekly. Currently there are == == 930+ subscribers. == == == == To subscribe, to unsubscribe, to contribute notes, == == etc. to ALS Digest, please send e-mail to: == == bro@huey.met.fsu.edu (Bob Broedel) == == Sorry, but this is *not* a LISTSERV setup. == == == == Bob Broedel; P.O. Box 20049; Tallahassee, FL 32316 USA == =============================================================== CONTENTS OF THIS ISSUE: 1 .. ALS During Pregnancy 2 .. re: ALS During Pregnancy 3 .. re: ALS During Pregnancy 4 .. re: ALS During Pregnancy 5 .. Statement by Dr. Rowland (1) ===== ALS During Pregnancy ========== Date : Fri, 18 Aug 1995 02:28:23 -0300 >From : mjjacka@mi.net (mjjacka) Subject: als during pregnancy I am an anesthesiologist in New Brunswick, Canada A patient of a local obstetrician has developed ALS. This is her first pregnancy, and she is now 19 weeks gestational age. She was diagnosed with ALS 2 weeks ago. Do you know anything about the behavior of ALS during pregnancy? Does it worsen at all, any special considerations, any sources of information? Thanks Mike Jacka MD (2) ===== re: ALS During Pregnancy ========== Date : 18 Aug 95 14:40:05 EDT >From : "Pamela Cazzolli, RN" <74553.2036@compuserve.com> Subject: ALS During Pregnancy Having interacted with nearly 1500 ALS patients in the past 10 years, I recall some incidences of females in their thirties developing ALS during late pregnancy or shortly after childbirth. One woman who had Familial ALS died from breathing failure within a few days after giving birth to her baby who was born prematurely. (Baby survived.) Several other women experienced somewhat rapid deterioration after childbirth. I believe pregnancy may be mentioned in the literature as an antecedent event in some incidences of ALS. I highly recommend that a pregnant woman with ALS carefully follow strategies in conserving energy, as well as maintain an adequate diet in meeting daily protein and calorie requirements. Because the pregnancy may aggravate breathing, use of nasal mask ventilation perhaps may be considered in the event of respiratory compromise. Furthermore, if there is bulbar involvement, it is essential to maintain upper airway clearance through effective respiratory care. Pamela Cazzolli, RN (ALS Nurse Consultant) (3) ===== re: ALS and Pregnancy ========== Date : Fri, 18 Aug 1995 23:23:51 -0700 To : "Pamela Cazzolli, RN" <74553.2036@compuserve.com> >From : eaopp@ucla.edu (Edward Anthony Oppenheimer, M.D.) Subject: Re: ALS and Pregnancy Cc : mjjacka@mi.net, bro@huey.met.fsu.edu Dear Pam, Just signed on and read some of the in-coming email (actually only yours and then Bob Broedel's), regarding ALS and Pregnancy. Your reply is very interesting and unexpected (that is I would have expected respiratory failure to develop as pregnancy advanced and the size of the pregnant uterus limited the diaphragm, I was surprised that the post-partum period was often when respiratory failure occurred). As to management: I would assume that all pregnant women with ALS would want to live to participate in the family experience with a new baby ... (with of course a rare exception), and therefore the use of noninvasive mechanical ventilation should be discussed and offered so that it can be started early (before the VC dips much below 50%) so that the mother with ALS can be safely prepared to ensure respiratory function later in pregnancy as well as in the immediate post partum period. Your vast ALS experience is certainly very, very helpful and impressive !! I would expect that a Medline NLM search regarding ALS/MND and pregnancy would be worth doing too ... but, a quick search using Grateful Med only identified one reference that does not sound very helpful: Moret JE; Di Gioia M; Montaruli V [Subarachnoid anesthesia in a case of cesarean section in a 27-year old patient with amyotrophic lateral sclerosis, in the 39th week of pregnancy]. Ospedale Umberto I. Corato U.S.L. BA/05. Language: Italian Unique Identifier: 92187225 Source: Minerva Anestesiol 1991 Sep;57(9):747-8 In the text "The Diagnosis and Treatment of Amyotrophic Lateral Sclerosis" edited by Donald Mulder (1980), page 28 has a footnote stating that: "...patients with ALS who become pregnant generally will deliver normal infants. The progressive nature of ALS will not be altered by pregnancy." REF: Huston JW, Lingenfelder J, Mulder DW, et al: Pregnancy complicated by amyotrophic lateral sclerosis. Am J Obst Gynecol 72:93-99 (1956). The ALS texts edited by: H. Mitsumoto and F.H. Norris (1994), R.A. Smith (1992), and J. T. Caroscio (1986) - - do not identify pregnancy in the index. I recall that there was an email on June 28th from Stuart Neilson who said that there is a full bibliography of ALS/MND on the WEB at the following URL (it may be possible to search it for "pregnancy" as a keyword): http://http2.brunel.ac.uk:8080/~hssrsdn/ http://http2.brunel.ac.uk:8080/~hssrsdn/alsig/als_rsrc.htm Regards, Tony Edward Anthony Oppenheimer, M.D Pulmonary & Critical Care Medicine Southern California Permanente Medical Group 4950 Sunset Boulevard; Los Angeles, CA 90027-5822 (213) 667-7106 office; FAX: (213) 667-5725 Internet: eaopp@ucla.edu or eoppenheim@kpscal.org (4) ===== re: ALS & pregnancy ========== >From : dendrite@dsp.com Subject: ALS & pregnancy / Urgent Request for Information Date : Sun, 20 Aug 95 15:00:35 EST Need to worry about ventilatory capacity as the uterus enlarges and presses on the diaphragm. Could lead to fetal hypoxia, or sudden death if vital capacity too low. D. Eric Collins, MD Oakland, CA (5) ===== Statement by Dr. Rowland ========== TITLE: PREPARED STATEMENT OF LEWIS P. ROWLAND, M.D. HENRY AND LUCY MOSES PROFESSOR AND CHAIR NEUROLOGY DIRECTOR ELEANOR AND LOU GEHRIG MDA/ALS CENTER NEUROLOGICAL INSTITUTE COLUMBIA-PRESBYTERIAN MEDICAL CENTER NEW YORK, NY 10032 FOR THE US HOUSE OF REPRESENTATIVES COMMERCE COMMITTEE RESEARCH ON AMYOTROPHIC LATERAL SCLEROSIS (LOU GEHRIG'S DISEASE) DATE : FRIDAY, JULY 21, 1995 --------------------------------------------------------------- My name is Lewis P. Rowland. I graduated from the Yale School of Medicine in 1948, interned at New Haven Hospital, and then went to the Neurological Institute at Columbia-Presbyterian Medical Center for training in neurology. I have spent most of the last 45 years in the same institution, but I was a Clinical Associate at the National Institute for Neurological Diseases and Blindness when the Clinical Center at NIH opened in Bethesda in 1953. I also served for a time at Montefiore Hospital in New York City, and for six years, 1967-1973, I was the head of Neurology at the University of Pennsylvania in Philadelphia. I returned to Columbia- Presbyterian in my current position in 1973. I have also served as a medical editor. For 10 years, I was editor-in-chief of Neurology, the official journal of the American Academy of Neurology. I am currently on the editorial board of the New England Journal of Medicine and also the board of The Medical Letter, which follows new drugs as they are approved by the FDA and also evaluates other new treatments. Through all these years, I have been engaged in patient care, teaching, and research. My research has been directed to diseases of nerve and muscle, including amyotrophic lateral sclerosis, which is shortened to the initials ALS. In the past 15 years, that disease has become my consuming interest. In addition to my own research and the investigations of our group at Columbia- Presbyterian, I have been on advisory committees for the major sources of financial support for ALS research: NINDS, the Muscular Dystrophy Association (MDA), and the ALS Association. Amyotrophic lateral sclerosis is hard to say, so the disease goes by other names, too. The most popular in the United States is "Lou Gehrig's disease". But he was not the only celebrity to die from this condition. Senator Jacob Javits was knownpersonally to many who are still in the Senate or the House of Representatives, and his plight was seen widely when he appeared on television in his wheelchair and using a mechanical respirator. Other affected luminaries were Vice-President Henry A. Wallace; Dimitri Shostakovich, the composer; Ezzard Charles, the heavyweight boxing champion; David Niven, the film star; and Charles Mingus, the jazz pioneer. It is not an accident that all of these celebrities were men, because the disease strikes men twice more often than it affects women. It attacks people in the prime of life and it is especially cruel. There is no known way to reverse the disease, even though there may be glimmerings of hope. Without a cure, there is a progressive paralysis of the arms and legs, then speech and swallowing become impossible and, finally, the muscles of breathing are affected. If, like Senator Javits, a tracheostomy is done to connect the patient's windpipe to a mechanical ventilator, the patient may live for years, unable to move a muscle, totally dependent on others for the most elementary acts, and unable to communicate except with the greatest difficulty, by using the eyes for a code or to drive a computer. Some of you may have seen films of the great astrophysicist, Stephen Hawking, who is in this condition. But not everyone can use a computer the way a genius physicist can. To add to the cruelty, the mind usually stays clear. The patient is fully aware of the incapacity and state of total dependency on others. The average life expectancy is 2-4 years from the onset of symptoms, but 20% live more than 5 years, usually much disabled. The disease is truly horrible and it is no accident that most of the several recent TV specials about physician-assisted suicide have included a patient with ALS as the center of interest. ALS is not common. We estimate that about 25,000 people are affected in the That is less than 10% of the number affected by Parkinson's disease (500,000) and much less than to 4 million affected by Alzheimer disease. All three of these conditions are what we call "age-related neurodegenera- tive diseases". They are rarely encountered before age 40, then increase in frequency with each decade up to age 80, and perhaps indefinitely. They are "neurodegenerative" because particular sets of nerve cells seem to get sick and die without easy clues to the cause of cell death. Different sets of brain cells are affected in each of the conditions. That is why the clinical symptoms differ. Only a small number of patients inherit the disease, 5-10% for each, but the pattern of inheritance is the same for each what we call autosomal dominant; that is, they are passed from one generation to the next. There is more to the association of the three conditions. They often occur together in pairs - in the same family or in the same person. That is, dementia, the key problem in Alzheimer disease, is also common in Parkinson disease. Parkinsonism and ALS may be seen together. And, last year, our molecular biologists defined a new disease that is manifest by all three conditions: dementia, parkinsonism, and features of ALS. This may second only to Alzheimer disease as a frequent cause of inherited dementia. So we believe there is something about these age-related diseases that make the elderly susceptible to each of them. That does not mean they all have the same cause, or that an effective treatment for one of them will be effective for all. But it does mean that research on any one of them may influence the other two. Here is an example. For each of the three diseases, there are many theories ofpathogenesis, how the cause of the disease initiates a series of events that culminates in the death of cells in the brain. One of the popular theories in all three diseases is that the metabolism of the brain is impaired. Some natural substances normally stimulate brain cells. However, if these transmitters are abnormally overactive, a state of excitotoxicity results. The normal becomes poisonous and abnormal chemical compounds are found in the brain. Among them are toxic species of oxygen and a condition called "peroxidation" results. This theory was first applied to parkinsonism and one of our young scientists, Serge Przedborski, was studying peroxidation in Parkinson disease. He used a genetically engineered strain of mice that had extra copies of the enzyme that normally sops up the toxic forms of oxygen. He found that the extra copies of the enzyme made the animals more resistant to some excitotoxic street drugs that can cause parkinsonism. This finding bolstered the theory that peroxidation plays a role in Parkinson disease. That enzyme is encoded on chromosome 21 and, in 1993, the familial form of ALS was mapped to the same spot. The fault in familial ALS was thus found to involve mutant forms of this enzyme, which is called superoxide dismutase. Dr. Przedborski and his team were already experienced in dealing with this enzyme, so they soon measured in the blood of patients with ALS. In those patients with the familial form of mutant enzyme protein, the enzyme activity was reduced. But the activity was normal in those who had no family history of other affected relatives. This left a mystery. The clinical conditions are similar, whether the disease is inherited or what we call "sporadic". When the investigators studied the enzyme in the brains of people who had died of sporadic ALS, they found that SOD was normal, but the activity of a different well-known anti-oxidant enzyme was low in affected parts of the brain. So, superoxide dismutase seems to be abnormal in familial ALS and this other enzyme in the sporadic disease. Now, we have clues to both the familial and the sporadic forms of the disease. Although these investigators had started to work on Parkinson disease, they found themselves investigating ALS. So we now have a clue to both the familial and sporadic forms of the disease. I have selected superoxide dismutase as an example of the overlap of the three diseases. But you should know that the discovery of the role of super- oxide dismutase in familial ALS was one of the great discoveries of molecular genetics - because, until this finding we did not have the faintest notion of the cause of familial ALS. Now we know and it becomes an important advance in research on all of the age-related diseases. Credit goes to two neurologist- investigators, Teepu Siddique at Northwestern University and Robert Brown at Harvard. More than that. The discovery of the mutant enzymes and the power of molecular genetics led to a new test of the theory. In so-called transgenic mice it was possible to introduce the human mutation and, remarkably, the mice bearing the abnormal enzyme came down with a form of motor neuron disease. Whether subnormal enzyme activity is responsible for the disease is not clear, because it seems that the mutant protein itself has a noxious effect whether the SOD activity is affected or not. This is what is called a toxic gain of function. There are other theories of pathogenesis that have created an entirely different research atmosphere. A decade or so ago, we did not know how to approach thedisease. Now I would like to tell you briefly about several different approaches, and how two of them have led to possible treatments that have been reported only in the last three months. First, one of the excitotoxin theories involves a natural substance, an amino acid that is normally found in the brain. It is called "glutamate" and is normally released by one nerve cell to stimulate another. In ALS, there is something wrong with the transport mechanism for glutamate, the cellular machinery that takes up the compound from the blood and helps it enter the nerve cell. As a result, glutamate accumulates in fluids around the nerve cells. In excessive amounts, glutamate becomes an excitotoxin and can kill cells. Therefore, a treatment could be designed to block the actions of glutamate and that has been done. Several different anti-glutamate drugs have been tried and found ineffective. In April, this year, however, the trial of a new drug called "riluzole" was completed and a French pharmaceutical company announced that riluzole prolongs the life of patients with ALS for a few months. "A few months" may not sound like much, but if it is true, that would be the first effective treatment for ALS in all history. Another approach to the disease involves a totally different concept. There are substances called nerve growth factors. These are crucial in the develop- ment of the nervous system; they help the cells find their proper places and proper connections as the brain matures. With the advent of genetic engineer- ing, these compounds have been produced in amounts large enough to test in laboratory animals and they prove to be effective in ameliorating the effects of damage - for instance, they help the nerve cell regenerate its process after experimentally cutting the nerve. These growth factors have also been used in humans and there have beentherapeutic trials in ALS of several different kinds of these substances. CNTF or ciliary neurotrophic factor proved to be ineffective. But last month it was announced that insulin-like growth factor or IGF. had a beneficial effect, and there was a similar announcement that another one - BDNF or brain-derived growth factor - is also effective. Unfortunately, the data for these claims have not yet been published in scientific journals so it is difficult to know how enthusiastic we should be. If either of the two has any effect at all, we will feel that we are finally on the track of effective treatment. Let me close with yet another area of progress, one that has gone on in our own laboratories. That is an immunological approach to the disease. A few investigators believe that the disease is always the result of abnormal immune mechanisms, in which the body's defense against infections turns inward and becomes destructive - or what is called autoimmunity. However, not many investigators support that theory. We have taken a different tack to autoimmunity. More than a decade ago, we found that some patients with ALS have an abnormal immune protein in their blood plasma. The condition is called paraproteinemia to indicate the abnormal state. Then, one of our brilliant molecular immunologists, Norman Latov, found that the paraprotein sometimes has antibody activity against normal constituents of nerve cells. From this observation have come two others: First, we found an unusually frequent association of ALS with malignant tumors of the lymph nodes. When this association occurs, chemotherapy of the lymphoma sometimes helps the neurological disorder. A second result of Latov's observation was the discovery of EMG studies to identify a condition that acts like ALS but is actually one of the nerves in the arms and legs - rather than the nerve cells in the spinal cord. Most of these patients haveLatov's anti-neuronal antibody in their blood. Then, Alan Pestronk and a group at Johns Hopkins found that immunosuppressive drug treatment could help the neurological disability. I could go on and tell you more - how transgenic mice are now playing a key role in helping us understand how the cells die and what we could do about them. How structures in the nerve cells called neurofilaments may go awry and how that might lead to treatment. How natural diseases of animals can be models of ALS and how they can be used to study possible new treatments. If only I could convey to you the hope and enthusiasm that is being generated now because we have a new set of research tools and we have made so much progress in the past 5-10 years. We know that the pace of research achievement is accelerating. Every new development leads to still more new advances. That accelerating pace of research gives us hope that we will soon have treatment for this scourge - if only the funding holds up. Let me close on one cautionary note. The achievements I have described depend on advances in basic science, which we believe must be supported. But much of the work I have cited depends on physicians who are investigators and MD-investigators are indeed a threatened species. If young scientists see their world-famous mentors having trouble getting grants because funds are insufficient, the young ones turn away and do something else. It is therefore crucial to take advantage of all the new research leads so that we can evaluate possible new therapies. Some day, we will cure ALS. I thank you for the opportunity to appear here. === end of als 209 ===