Amyotrophic Lateral Sclerosis - ?update
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.
FIRST ANNUAL HEALTH SCIENCE CENTER RESEARCH WEEK
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.
II. THE HEREDITARY ATAXIAS (N=32)
A. HEREDITARY SPINOCEREBELLAR ATAXIA (HSCA) (N=18)
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.
B. OLIVOPONTOCEREBELLAR ATROPHY (OPCA) (N=4)
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!
C. FRIEDREICH's ATAXIA (FA) (N=7)
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
D. ATAXIA TELANGIECTASIA (AT) (N=3)
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.
III. MULTIPLE SCLEROSIS (MS) (N=10)
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
IV. AMYOTROPHIC LATERAL SCLEROSIS (N=3)
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.
V. HUNTINGTON'S CHOREA (HC) (N=2)
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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* Figures not included in this version
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