Date: Sun, 9 Apr 95 07:10:48 -0400 From: Bob Broedel To: als@huey.met.fsu.edu Subject: ALSD184 ALS-ON-LINE =============================================================== == == == ----------- ALS Interest Group ----------- == == ALS Digest (#184, 09 April 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 == == 620+ 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 .. Abnormal symptoms 2 .. Relationship between injury and ALS? 3 .. Riluzole & Canada 4 .. MDA Riluzole Press Release (1) ===== Abnormal symptoms ========== Date: Fri, 31 Mar 1995 20:38:40 -0600 (CST) >From : "C. Schaefer" Subject: Abnormal symptoms A friend asked that I post the following message as she does not have direct internet access. "My dad was diagnosed with A.L.S. in Feb. 95. He has 3 conditions that do not seem to be typical of A.L.S. They are as follows: 1. Severe dizziness for the past 3 to 4 months, currently controlled by medication. 2. Electromyography (EMG) readings had significantly slowing of neuron velocity. 3. Short term memory loss prograssively increasing for the past 1 to 2 months. I would be interested in comparing notes with anyone else experiencing these conditions in conjuction with A.L.S." My friend would appreciate any responses that might be pertinent. Chuck Schaefer cschaefe@empire.interstate.net (2) ===== Relationship between injury and ALS? ========== Date : Wed, 5 Apr 1995 18:29:04 -0700 >From : g.miller@ix.netcom.com (Gary Miller) Subject: Relationship between injury and ALS? My friend Ken, for whom I suscribed to the Digest, asked me to contribute this for him. While working some time back, doing a lifting motion, I experienced an unbelievable electrical shock starting in the area fo C1-C2 of the cervical spine traveling down my left arm. Initial numbness and tingling followed this event lasting a few minutes. After two months I started noticing faciculations in my left biceps which was initially treated with an oral muscle relaxer with no relief, followed by cervical x-rays and MRIs all of which showed no injury. After consultation with Neurologists and numerous nerve conduction studies, I was diagnosed as having ALS. I was placed in a CNTF study, which I feel was halted prematurely, and am now awaiting news on other possible drug studies. All during the CNTF study, I would again feel this dranatic shock traveling the same path as the first onset. This shock is so pronounced that I feel I can hear the snap as the shock stops at my hand. Repeat MRIs still are negative. Since the initial diagnosis, the wasting and faciculations have extended into my right arm and I am now experiencing some bulbar abnormalities. My question to anyone: Can the ALS be related to the injury and can any correlation be make between the existing sporadic shocks and nerve regeneration or repair. -Any responses to Ken Fovargue c/o g.miller@ix.netcom.com and I'll see that it gets to Ken. Thanks. -- *-- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- --* | Gary Miller g.miller@ix.netcom.com | | 1175 Jasper Avenue (H)520 758-2867 | | Bullhead City, AZ 86442-7070 (W)520 758-3971 | *-- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- --* | Learning isn't a means to an end; | | it is an end in itself. -Robert A. Heinlein | *-- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- --* (3) ===== Riluzole & Canada ========== CANADA NEWSWIRE 04/05/95 NEW TREATMENT BENEFITS FOR ALS PATIENTS CONFIRMED BY CLINICAL TRIALS MONTREAL, April 5 /CNW/ - Clinical trial results released today by the pharmaceutical company Rhone-Poulenc Rorer (RPR) confirm the findings of a previous Phase II clinical trial demonstrating Riluzole as the first medicine to show some impact on survival for patients with Amyotrophic Lateral Sclerosis (ALS) also commonly known as ``Lou Gehrig's Disease''. < parts deleted > Dr. Andrew Eisen, a neurologist based at the Vancouver General Hospital and Health Sciences Centre and a member of the Canadian team of Riluzole investigators suggested that ``these results are important and very encouraging, paving the way for future combination therapies which include Riluzole''. RPR confirmed today that it will soon be seeking approval for Riluzole from the federal Health Protection Branch (HPB). The dossier will be submitted to the HPB by July 1995. The pharmaceutical company also announced that it will be implementing an Early Access Program allowing for a limited release of Riluzole as of July 1995. This program is currently being developed with a number of recognized Canadian ALS centres. For further information on ALS, the ALS Society of Canada can be reached at 1-800-267-4ALS. (4) ===== MDA Riluzole Press Release ========== Date : 08 Apr 95 18:07:12 EDT >From : Barry Goldberg <71154.330@compuserve.com> Subject: MDA Riluzole Press Release Here is a press release from MDA regarding the Riluzole announcement and accompanying attachment. Barry NEWS FROM MDA -- PRESS RELEASE -- 04/04/95 Contact: Jim Brown, MDA Director of Public Affairs, 520-529-5317 Attachment: The New England Journal of Medicine, Vol. 330, No. 9 March 3, 1994, pages 636 and 637, "Riluzole for the Treatment of Amyotrophic Lateral Sclerosis -- Too Soon to Tell?" RHONE-POULENC RORER MAKES PARTIAL ANNOUNCEMENT REGARDING ALS RILUZOLE STUDY ------------------------------------------------- TUCSON, Ariz., April 4, 1995 - The Muscular Dystrophy Association, the nation's largest non-governmental sponsor of research and medical services for people with amyotrophic lateral sclerosis (ALS or Lou Gehrig's disease), said it's not yet possible to evaluate an announcement made today by Rhone-Poulenc Rorer (RPR), regarding the promise of its pharmaceutical riluzole in treating ALS. According to RPR, a clinical trial involving over 950 people with ALS has generally confirmed results of an earlier study published in the March 3, 1994 issue of The New England Journal of Medicine. The drug company reports no statistically significant effect on the rate of muscle function deterioration for the overall ALS population, and a modest increase in survival of both bulbar and limb onset ALS patients receiving riluzole. But, since the statistical evaluation of the trial is ongoing, a final determination of the precise increase in survival is not yet available. "Nothing will sway MDA from its tireless pursuit of every meaningful avenue of investigation to yield a treatment or cure for ALS," said Lewis P. Rowland, M.D., MDA Medical Advisory Committee member and director of the MDA ALS Center at Columbia University. "Clinicians across the country would relish the opportunity to offer families a pharmaceutical or some other treatment to slow the progress of this virulent disease," Rowland added. "However, since RPR has not yet presented the data that form the basis of its conclusions, it's simply not possible to evaluate the potential benefits that riluzole might offer people living with ALS." Rowland urged, that when the company makes its report on the riluzole study during the Academy of Neurology meeting in May, that it present all the data. ALS, which affects some 20,000 Americans, has been called a "desperate disease" that inspires "desperate remedies." It involves relentless, progressive paralysis of all voluntary muscles, leaving patients unable to speak, move or breathe without special equipment, usually within a year of onset. Death usually occurs within two to five years. Riluzole partially blocks the central nervous system chemical glutamate. Trials of this drug and another glutamate blocker, Neurontin, were inspired, in part by MDA-supported research suggesting that a buildup of glutamate may be involved in the nerve cell destruction that occurs in ALS. "Because of the pace and severity of ALS, we must be cautious about premature claims of effective drugs and other remedies," said Stanley H. Appel, MDA Scientific Advisory Committee member and director of the MDA ALS Research and Clinical Center at Baylor College of Medicine. "We must wait until the data are subjected to scientific peer review to know whether riluzole warrants broader clinical trials to determine efficacy. Until then, people living with ALS should continue to follow the advice of their physicians." Since the 1950s, MDA has spent more than $23 million on ALS research and about $75 million on services to people with the disease. The Association, a voluntary health agency working to defeat 40 neuromuscular diseases, supports more than 200 clinics nationwide and six research and clinical centers dedicated solely to ALS. *** Special Attachment THE NEW ENGLAND JOURNAL OF MEDICINE, Vol. 330, No. 9 March 3, 1994, pages 636 and 637 "Riluzole for the Treatment of Amyotrophic Lateral Sclerosis -- Too Soon to Tell?" --------------------------------------------------------------- When it comes to announcing an effective treatment for a currently untreatable disease, investigators have a grave responsibility. Bensimon et al.(1) report in this issue of the Journal that riluzole, a glutamate antagonist, increased survival in one group of patients with amyotrophic lateral sclerosis (ALS) but was not helpful in another group of patients with the same disease. Therein lies a medical mystery. The cause of sporadic ALS in not known. A familial form accounts for about 5 percent of all cases and, in about 40 percent of the families, can be mapped to the gene for superoxide dismutase on chromosome 21. There is no clear linkage to that gene in sporadic cases, which could be due to an environmental agent that increases effective glutamate levels in critical parts of the nervous system, converting this normal amino acid into an excitotoxin, as explained in detail by Lipton and Rosenberg elsewhere in this issue of the Journal(2). Another theory of the pathogenesis of ALS is based on autoimmunity(3), and there are other possibilities. An autoimmune disorder could induce an excitotoxic state(4). Glutamate antagonists have failed in previous therapeutic trials; no benefit was seen with dextromethorphan(5), lamotrigine(6), or branched-chain amino acids(7,8). Riluzole may differ in mechanism of action and may be more effective than the drugs that failed, however. Bensimon et al. studied 155 patients with ALS, including some familial cases. At 12 months, 42 percent of the patients given placebo had died or undergone tracheostomy, as compared with only 26 percent of the riluzole-treated patients. The difference was significant. However, the effect was totally attributable to improved survival among the 32 patients with disease of bulbar onset. Of those 32 patients, 65 percent of those in the placebo group died or underwent tracheostomy, as compared with 27 percent of those given riluzole. In contrast, there was no significant difference in survival or the number of tracheostomies among 123 riluzole-treated and control patients with disease of spinal onset. The survival effect in the bulbar-onset group was so strong that the difference for those patients (21 percent of the study patients) was seen in the entire population. Treatment slightly slowed the rate of decline of limb-muscle strength in the patients with limb-onset disease, but there was no benefit in several other scores of function in the same patients. In essence, benefit was seen only in the patients with bulbar-onset disease, and only in terms of survival without tracheostomy. A discrepancy so profound requires one of two possible explanations. Either the bulbar-onset and spinal-onset forms of ALS are different conditions, or something was amiss in the trial. If it was the trial, a beneficial effect could have been missed in the patients with limb-onset disease, or the apparent benefit in the patients with bulbar-onset disease could have been an artifact. Could limb-onset and bulbar-onset ALS be different diseases? That has never been suggested previously. The fundamental disease process in ALS involves the loss of motor neurons in the cerebral cortex, the motor nuclei of the cranial nerves, and the anterior horn cells in the spinal cord. About 90 percent of all patients have both upper and lower motor neuron signs. Syndromes restricted to upper motor neuron signs (primary lateral sclerosis) or lower motor neuron dysfunction (spinal muscular atrophy) are equally uncommon; some authorities believe they may be different diseases. "Progressive bulbar palsy" seems to be disappearing from modern classifications because almost all patients with dysarthria and dysphagia (implicating the motor nuclei of the 9th, 10th, and 12th cranial nerves) already show signs of disease in the corticospinal tracts (hyperreflexia and Babinski signs) or spinal motor neurons (weakness, wasting, and fasciculation); in fewer than 1 percent of all patients are manifestations restricted to the medulla(9-11). Until now, it has been assumed that symptoms of ALS can begin in the arms, legs, or oropharynx. Even if symptoms in the limbs come first, oropharyngeal symptoms and respiratory insufficiency appear later -- if the patient lives long enough. It has not previously been postulated that the site of onset -- in the medulla or the spinal cord -- distinguishes a special form of the disease. That is why the seeming difference in the results of riluzole therapy in the study by Bensimon et al. runs counter to clinical logic. Why should a drug affect some patients and not others with the same disease? After all, no patient improved, and the disease was not arrested in a single patient, which might have been expected if riluzole were truly effective. We therefore have to look beyond the statistics for an explanation, which may be elusive. The authors themselves examined possibly confounding factors. They found no differences in the placebo and riluzole groups at entry in items of age, duration of symptoms, or vital capacity. But those figures concerned the entire study group, not just the patients with bulbar-onset disease. Were the treatment and control groups of patients with disease of bulbar onset evenly matched? We do not know the specifics, but, according to the data, the patients in the placebo group were slightly older than those in the riluzole group and had a lower "bulbar score" (more severe symptoms). The two groups seemed evenly matched in duration of symptoms and vital capacity, but there might be other aspects of disease severity that were not considered. Also, the rate of progression is not the same for all patients, and there was no pretrial period of observation to ascertain that the symptoms of riluzole-treated and control patients with bulbar-onset disease were changing at comparable rates. In most series, the life expectancy of patients with dysphagia is less than that of patients with limb weakness(12,13). Presumably, they are at greater risk for aspiration, more likely to have impaired cough responses, and therefore more likely to have pneumonia or ventilatory collapse(14). Among the patients with disease of bulbar onset, were the riluzole-treated and control groups matched in terms of the severity of dysphagia itself? Perhaps, by chance, the placebo group included patients with more severe dysphagia, more marginal respiratory function, and a more rapid rate of decline(15). That is, the treatment and control groups may not have been evenly matched, especially since the number of patients with disease of bulbar onset was so small. The authors themselves are at a loss to explain the anomalous results, which they state "can arise by chance." Other trials of riluzole are in progress. What happens now to those studies? Bensimon et al. are not so confident of their results that they would advocate terminating those trials. However, it may now be even more difficult to convince patients to enter studies with a placebo group. Will the drug be available for all patients with bulbar-onset disease? How can we confirm the purported benefit or determine that riluzole therapy is, in fact, without benefit? Patients with ALS and their families are understandably desperate in seeking treatment. In the past decade, they have been misled by announcements of benefit from therapies that later proved to be ineffective, including thyrotropin-releasing hormone, threonine, and branched-chain amino acids. It would be sad if riluzole extended that list. Let us hope that my skepticism is misdirected and that riluzole will actually prove to be effective in all patients with motor neuron disease. [Columbia-Presbyterian Medical Center, New York, NY 120032 -- Lewis P. Rowland, M.D.] REFERENCES 1. Bensimon G. Lacomblez L, Meininger V, ALS/Riluzole Study Group. A controlled trial of riluzole in amyotrophic lateral sclerosis. N Engl J Med 1994; 330:585-91. 2. Lipton SA, Rosenberg PA. Excitatory amino acids as a final common pathway for neurologic disorders. N Engl J Med 1994;330:613-22. 3. Appel SH, Smith RG, Engelhardt JI, Stefani E. Evidence for autoimmunity in amyotrophic lateral sclerosis. J Neurol Sci 1993; 118:169-74. 4. Appel SH. Exciotoxic neuronal cell death in amyotrophic lateral sclerosis. Trends Neurosci 1993; 16:3-5. 5. Askmark H, Aquilonius SM, Gillberg PG, Liedholm LI, Stalberg E, Waopio R. A pilot trial of dextromethorphan in amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry 1993; 56:197- 200. 6. Eisen A, Stewart H. Schulzer M, Cameron D. Anti-glutamate therapy in amyotrophic lateral sclerosis: a trial using lamotrigine. Can J Neurol Sci 1993; 20-297-301. 7. Tests D, Caraceni T, Fetoni V. Branched-chain amino acids in the treatment of amyotrophic lateral sclerosis. J Neurol 1989; 236:445-7. 8. The Italian ALS Study Group. Branched-chain amino acids and amyotrophic lateral sclerosis: a treatment failure? Neurology 1993; 43:2466-70. 9. Norris F, Shepherd R, Denys E, et al. Onset, natural history and outcome in idiopathic adult motor neuron disease. J Neurol Sci 1993; 118:48-55. 10. Lange DJ, Trojaborg W, McDonald TD, Blake DM. Persistent and transient "conduction block" in motor neuron diseases. Muscle Nerve 1993; 16:896-903. 11. Bruyn GW. Progressive bulbar palsy. In: DeJone JMBV, ed. Diseases of the motor system. Vol. 59 of Handbook of clinical neurology. Amsterdam; Elsevier, 1992; 217-29. 12. Mortara P, Bardelli D, Leone M. Schiffer D. Prognosis and clinical varieties of ALS disease. Ital J Neurol Sci 1981; 3:237-42. 13. Gubbay SS, Kahana E, Zilber N, Cooper G, Pintov S., Leibowitz Y. Amyotrophic lateral sclerosis: a study of its presentation and prognosis. J Neurol 1985; 232:295-300. 14. Wiles CM. Neurogenic dysphagia. J Neurol Neurosurg Psychiatry 1991; 54:1037-9. 15. Schiffman PL, Belsh JM. Pulmonary function at diagnosis of amyotrophic lateral sclerosis. Chest 1993; 103:508-13. END ***** RILUZOLE.TXT * MDA Press Release 04/04/95 --- MDA -- Working to find the cure for neuromuscular disease --- === end of als 184 ===