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Amyotrophic Lateral Sclerosis - ?update

Pamela Bower pbower at ra.isisnet.com
Tue Apr 9 11:23:24 EST 1996

In article <DpE97o.BsD at gil.com.au>, mmatus at gil.com.au says:
>Motor Neurone Disease doesn't seem to be heading towards a cure yet.
>A close friend has the disease and only wants to improve the quality of 
>his last few months left.
>?? any amino acid/vitamin supplements available
>?? any radical theory/treatment available 
>Thankyou for your help in advance.

                           October 16-20, 1995
      Treatment of neurodegenerative disease with N-Acetylcysteine
    B.J.Wilder, M.D., Russell W. Hurd, M.S., Scott C. Franzcek, M.D.
            Wendell R. Helveston, M.D., Basim M. Uthman, M.D.
   Department of Neurology and Brain Institute, University of Florida,
                          Gainesville, FL 32610
 Free radical mediated mechanisms have been suggested as contributing
 to the development of several neurodegenerative diseases. Several
 excellent reviews have recently addressed this subject1-3.
 In patients with a hereditary seizure disorder, Progressive Myoclonus
 Epilepsy of the Unverricht Lundborg Type (PME-UL), characterized by
 myoclonus, generalized and absence seizures and deterioration in
 mental function, we found increased activity of the antioxidant enzyme
 extracellular superoxide dismutase (EC-SOD, SOD3)4-5. An increase in
 EC-SOD could potentially disrupt a balance in oxidative metabolism
 since enhanced H2O2 production without compensatory changes in
 catalase or glutathione peroxidase (GSHpx) may lead to increased
 production of more potent free radicals such as the hydroxyl radical
 (Figure 1). This was recently confirmed in animal studies by Oury et
 al.6 in which mice, transgenic for the human EC-SOD gene, had markedly
 increased susceptibility to oxygen-induced seizures.
 Patients were therefore placed on antioxidant vitamins and minerals
 (vitamin E, riboflavin, selenium and zinc). Over a six month period,
 parents and nursing home staff indicated there was some improvement in
 patient condition, particularly in alertness. N-Acetylcysteine (NAC),
 a sulfhydryl amino acid has several characteristics promoting its
 usage as an antioxidant, including scavenging of the hydroxyl radical,
 increased synthesis of reduced glutathione and diminished production
 of H2O2 (Figure 1)7-8. NAC administration was initiated and, at a
 dosage of 4-6 grams daily, produced a reduction in myoclonus,
 increased mobility, and improvements in speech, alertness, and
 Objective improvement in patients with PME-UL with NAC suggested its
 usage in other neurodegenerative disorders. Our initial emphasis was
 the treatment of hereditary movement disorders, particularly the
 hereditary ataxias. More recently, patients with other
 neurodegenerative conditions including amyotrophic lateral sclerosis
 (ALS), multiple sclerosis (MS), diabetic neuropathy and Alzheimer's
 disease have been treated with NAC. We report here results of studies
 with NAC conducted over the last 30 months.
                          PATIENTS AND METHODS
 A total of 61 patients have been treated with NAC for periods from 1
 month to 30 months. Forty eight (48) patients continue in these
 studies. Patients receive NAC either in liquid (Mucomyst or Mucosil),
 as a powder (Spectrum Chemical, Gardena, CA, USP grade), or as a
 flavoured suspension (West Labs Pharmacy, Gainesville, FL) dissolved
 in juice or cola. In this open label study, dosage is 4-6 grams/day
 for adults and 60 mg/kg/day for children divided into 2-3 doses.
 Because of reports of magnesium (Mg) deficiency subsequent to
 treatment with NAC9, all patients receive supplemental Mg. In this
 report, we include patients with PME-UL (N=4), hereditary ataxias
 (N=32), multiple sclerosis (N=10), amyotrophic lateral sclerosis (N=3)
 and Huntington's Chorea (N=2). At baseline, all patients received a
 videotaped neurological exam, and the initial 40 patients received a
 FRESA analysis (FRESA Labs, Redmond, WA) which included red blood cell
 (RBC) activity levels of GSHpx, glutathione reductase, glutathione
 transferase, catalase, superoxide dismutase (SOD1) and plasma
 selenium, zinc, manganese and copper. Disease specific
 neurophysiological, neuropsychological, ophthalmological and genetics
 testing was also performed.
 I. PME-UL (N=4)
 A Florida family with 4 siblings with PME-UL have been treated at the
 University of Florida for over 20 years. Molecular genetic analysis
 confirmed that the gene loci for these patients is located at
 chromosome 21 band q22.310. Treatment with phenytoin was without
 benefit and may have been deleterious11. Patients had a steady course
 of deterioration with various combinations of phenytoin,
 phenobarbital, carbamezepine and other anticonvulsants. Valproic acid
 (VPA) produced marked improvement in these patients when introduced in
 1978. VPA decreased myoclonus and generalized seizure activity such
 that 1 patient was able to attend college briefly. A possible
 mechanism for the beneficial effect of VPA and negative effect of PHT
 is shown in Figure 1.
 Progression of the disease continued however, and at initiation of
 treatment with antioxidants, the 3 eldest were bedridden and could not
 comrnunicate, while the youngest had been in a wheelchair for over 2
 years and received meals and medications in a nursing home.
 Improvement with NAC has included long periods of decreased myoclonus
 in the least affected patient such that she has been able to walk
 unaided for several days at a time. This patient now lives in an
 apartment and provides for her own meals and medications. Her 3 male
 siblings have shown less, but demonstrable, improvement in seizure
 frequency and verbalization. Objective measurements of improvement
 include some normalization of somatosensory evoked potentials (SEPS).
 Giant SEPs (Figure 2), are a characteristic feature of this disorder.
 Eighteen patients with HSCA have been treated with NAC. Five siblings
 (from a family of 14 children of the same parents) demonstrated
 variable signs of ataxia, dysarthria, and oculomotor disturbance.
 Genetic analysis ruled out SCA1 gene localization. All patients claim
 subjective improvement with NAC. The most severely affected sibling
 (male, age 43) has been treated with NAC for 26 months. Improvement in
 eye movement control was marked. Prior to NAC treatment, reading speed
 had decreased from 300 wpm to less than 50 wpm and now the patient has
 regained more speed in reading. He returned to college and is now
 pursuing graduate studies. Prior to NAC, 4 of the siblings had retired
 from full-time work because of balance and fatigue problems. The
 youngest (42), a high school physics teacher, had considered
 disability retirement. Since starting NAC however, he claims fatigue
 and balance are no longer major problems.
 A 67 year old patient with HSCA had steady progression of this
 disorder for 25 years. Two brothers and his father died after years
 with a similar condition. Prior to initiation of NAC, balance was a
 major problem and the patient experienced 8-12 falls a day. According
 to his wife, no falls occurred following NAC treatment for a period of 
 almost 7 months. Dysarthria improved to the point that his
 grandchildren could understand him on the telephone.
 A 43 year old patient with a diagnosis of OPCA had difficulties with
 balance and walking, progressive speech disturbance and diminished
 proprioception and pain sensitivity. Improvement in dysarthria and
 balance were evident 1 month after NAC. At the 3 month visit, the
 patient could discriminate between hot and cold, and had regained some
 touch and position sense. The patient joked that he used to enjoy
 going fishing since previously he could just watch the mosquitos bite
 him - now they hurt!
 A 21 year old female with FA was referred for treatment with NAC.
 FRESA analysis indicated low selenium and GSHpx activity along with
 other enzyme abnormalities (Figure 3). Sirnilar antioxidant changes
 were found in 3 additional patients with FA (Helveston et al. in
 press). After 8 months treatment with NAC and other antioxidants, this
 patient's FRESA profile was normal (Figure 3). During this time, there
 was an improvement in proprioception and a slight decrease in ataxia.
 Greater than 90% of FA patients develop a cardiomyopathy, which is a
 major cause of early death12. Until recent years, cardiomyopathy was a
 major cause of childhood death in low selenium areas of China (Keshan
 Disease) until a program of selenium supplementation of table salt was
 initiated in affected areas and population glutathione peroxidase
 levels increased13.
 Three siblings aged 7, 11, and 13 with AT confirmed by chromosomal
 analysis and lymphocyte radiation fragility testing had questionable
 improvement in their condition after 3 months NAC. However, when 2
 patients were taken off NAC for a period of 2 weeks, rapid
 deterioration in their conditions ensued. These changes included a
 return of copious drooling in the youngest patient, a cornmon symptom
 in younger AT patients.
 AT is a complex multisystem disorder characterized by ataxia, ocular
 telangiectasia, immunodeficiency involving both T and B cell
 functions, 50 to 100-fold increased cancer
 incidence, spontaneous chromosomal breakage and increased sensitivity
 to ionizing radiation14. Recent evidence indicates that NAC treatment
 may be ideally suited to treatment of AT, since, in addition to its
 potentiai as a treatment for ataxia, in-vitro studies indicate NAC is
 chemopreventative, radioprotective and enhances T cell
 functioning15-17. These AT patients have now taken NAC for 15 months.
 There is a marked elevation of the cytokine tumor necrosis factor ÿ
 (TNFÿ) in active MS, and a correlation exists between CSF levels of
 TNFÿ and the severity and progression of disease18. With cytokine
 activation there is increased free radical production and this has
 been demonstrated in MS19. NAC is a free radical scavenger and
 inhibits toxicity of TNFÿ and in the EAE animal model of MS, inhibits
 the development of MS like pathology20. Ten patients with MS have
 taken NAC for a period of up to 16 months. Because of the
 relapsing-remitting course of the disease occurring in many MS
 patients, it is difficult to ascertain efficacy of NAC in these
 preliminary studies. However, two MS patients with longstanding
 inability to speak coherently had a rather dramatic irnprovement in
 speech shortly after starting the drug. Controlled trials are
 necessary to ascertain if NAC can decrease the number of exacerbations
 in MS.
 A role of free radicals in the progression of ALS recently received
 support with the discovery of linkage of familial ALS (FALS) with
 mutations in the gene encoding CuZn SOD (SOD1)21. Levels of SOD1 are
 decreased in patients with FALS but are often norrnal in sporadic ALS.
 In a patient with FALS, FRESA analysis indicated an SOD1 activity of
 approximately 50% of the lower end of the normal range. The remaining
 FRESA profile was normal. NAC treatment has so far been unsuccessful
 in altering the progressive course of this patient's disease. In two
 patients with sporadic ALS, SOD1 activity was normal, but GSHpx and
 glutathione reductase activities were markedly decreased. In these
 patients NAC treatment may have modified the course of the disease as
 one patient (duration of treatment 12 months) has remained stable with
 an increase in grip strength. A second patient has only marginally
 progressed during 17 months of treatment with NAC. Recently, Louwerse
 et al.22 reported on a double-blind trial of NAC in 111 patients with
 ALS. Patients with limb onset but not bulbar onset of ALS had a 50%
 decrease in the one year mortality rate with NAC treatment.
 HC fibroblasts have increased sensitivity to toxic effects of
 glutamate23. This toxicity is partially ameliorated by cystine,
 cysteine and antioxidants24. NAC is a cysteine precursor, suggesting
 its usage in HC. Two male patients aged 43 and 44 with advanced HC
 were treated with NAC for 2 and 3 months respectively. There was no
 obvious improvement in patient condition with NAC treatment and
 patients were discontinued from the study. A longer trial period with
 less advanced patients is necessary to preclude NAC usefulness in this
 Treatrnent with high dose NAC has produced modest improvement in
 several patients with neurodegenerative disorders. Where improvement
 has been noted, it has usually been early in treatment and then tends
 to plateau. Some patients have not seen an initial improvement but
 remain on NAC as a possible means to prevent further progression of
 their disorder. In some 40 patients tested (including patients with
 HSCA, AT, FA, ALS, MS, DN and HC) pretreatment FRESA analysis
 indicated an imbalance in antioxidant enzyme activity. Although a few
 patients claimed some benefit from more traditional antioxidant
 therapies (e.g vitamins A,C,E,B2, and selenium), most patients said
 these were without noticeable benefit. As suggested in Figure 2,
 improvement in physical condition may correlate with improved free
 radical status. This suggests that these enzyme abnormalities are not
 primary in these disorders but occur secondary to whatever gene
 defects trigger excess free radical activity (e.g., GSHpx and SOD are
 readily destroyed by excess superoxide25). This study indicates the
 possibility that if improvement in the antioxidant status occurs, the
 potential exists for arresting progression of the disease and in some
 cases an improvement in patient condition.
 The high level of safety and variety of antioxidant actions of NAC
 suggest it as a very promising new tool for treatment of
 neurodegenerative disorders. In recent months, scientific reports of
 animal and in-vitro studies indicate that NAC inhibits neuronal
 apoptosis26 and toxicity in models of multiple sclerosis20,
 amyotrophic lateral sclerosis27 and diabetic necrosis28. Some of the
 known actions of NAC are listed in Table 1.
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 2.Olanow CW. A radical hypothesis for neurodegeneration. Ann Neurol
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 3.Jesberger JA, Richardson JS. Oxygen free radicals and brain
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 Progressive myoclonus epilepsy of Unverricht-Lundborg type: A clinical
 and molecular genetic study of a family from the United States with
 four affected sibs. Neurol 43:2384-2386, 1993.
 11. Eldridge R, Iivanainen M, Stern R, Koerber T, Wilder BJ.
 Hereditary disorder of childhood made worse by phenytoin. Lancet
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 12.Lechtenberg R. Ataxia and other cerebellar syndromes. In:
 Parkinson's Disease and Movement Disorders. 2nd Edition, J Jankovic
 and E Tolosa (eds), Williams and Wilkins, Baltimore, 1993, pp 419-431.
 13.Yang G, Chen J, Wen Z, et al. The role of selenium in Keshan
 Disease. Adv Nutr Res 6:203-231, 1984.
 14.Woods CG, Taylor AMR. Ataxia telangiectasia in the British Isles:
 The clinical and laboratory features of 76 affected individuals. Quart
 J Med 82:169-179, 1992.
 15.Solen G. Radioprotective effect of N-Acetylcysteine in vitro using
 the induction in DNA breaks as end point. Int J Radiat Biol
 64:359-366, 1993.
 16.Mayer M, Noble M. N-acetyl-l-cysteine is a pluripotent protector
 against cell death and enhancer of trophic factor-mediated cell
 survival in vitro. Proc Natl Acad Sci 91:7496 7500, 1994.
 17.Eylar E, Rivera-Quinones C, Molina C, Baez I, Molina F, Mercado CM.
 N-Acetylcysteine enhances T-cell function and T-cell growth in
 culture. Intern Immunol 5:97-101, 1993.
 18.Sharief K, Hentges R. Association between tumor necrosis
 factor-alpha and disease progression in patients with multiple
 sclerosis. N Engl J Med 325:467-472, 1991.
 19.Glabinski A, Tawsek NS, Bartosz G. Increased generation of
 superoxide radicals in the blood of MS patients. Ann Neurol Scand
 88:171-177, 1993.
 20.Lehmann D, Karussis D, Misrachi-Koll R, Shezen E, Ovadia H,
 Abramsky O. Oral administration of the oxidant-scavenger
 N-acetyl-L-cysteine inhibits acute experiemental autoimmune
 encephalomyelitis. Neuroimmunol 50:35-42, 1994.
 21.Rosen DR, Siddique T, Patterson D et al. Mutations in CuZn
 superoxide dismutase gene are associated with familial amyotrophic
 lateral sclerosis Nature 302:59-62, 1993
 22.Louwerse ES, Weverling GJ, Bossuyt PMM, Meyjes FEP, Vianney deJong
 JMB. Randomized, double-blind, controlled trial of acetylcysteine in
 Amyotrophic Lateral Sclerosis. Arch Neurol 52:559-564, 1995. 23.Gray
 PN, May PD, Mundy L, Elkins J. L-glutamate toxicity in Huntington's
 disease fibroblasts. Biochem Biophys Res Comm 95:707-714, 1980.
 24.May PC, Gray PN. The mechanism of glutamate-induced degeneration of
 cultured Huntington's disease and control fibroblasts. Neurol Sci 70:
 101-112, 1985.
 25.Pigeolet E, Corbisier P, Houbion A, Larnbert D, Michiels C, Raes M,
 Zachary M-D, Remacle J. Glutathione peroxidase, superoxide dismutase,
 and catalase inactivation by peroxides and oxygen derived free
 radicals. Mechs Ageing Devel 51:283-297, 1990.
 26.Ferrari G, YAN CYI, Greene LA. N-Acetylcysteine (D and L
 stereoisomers) prevents apoptic death of neuronal cells. J
 Neuroscience 15:2857-2866, 1995.
 27.Rothstein JD, Bristol LA, Hosler B, Brown, Jr RH, Kuncl, RW.
 Chronic inhibition of superoxide dismutase produces apoptotic death of
 spinal neurons. Proc Nat Acad Sci 91:4155-41S9, 1994.
 28.Sagara M, Satoh J, Zhu XP, Takhashi K, Fuzuzawa M, Muot G, Muto Y,
 Toyota T. Inhibition with N-acetylcysteine of enhanced production of
 tumor necrosis factor in streptozotocin-induced diabetic rats. Clin
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 * Figures not included in this version

>Michael Matus

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