multiple sclerosis research update
aj746 at LAFN.ORG
Wed Mar 22 15:52:45 EST 1995
MS MEDICAL RESEARCH HIGHLIGHTS
Myelin Basic Protein-attempts to reduce cd4+ T-cell population with
oral medicine,mbp.Very successful in men in double blind trial.Now
in multicenter trials 8-94.Dr Weiner.
Vitamin B12-long known as necessary for brain, known to be
necessary for myelin growth.Also,there appears to be some
correlation with low b12 and ms,although there is no cause -effect
established.Supplement with b12 shots reported widely to be
helpful;anecdotal.No trials,but much research by Dr. Reynolds.
Mitoxantrone-a medicine already approved for cancer,thus available.
Novantrone is its name.This medicine ,given by infusion,in
hospital,has produced dramatic,quick,and long lasting
improvement.Tested on 200+people at Ulm U. In Germany.There is a
max lifetime dose after which much care for myocardiopathy must be
given.No multicenter trials are underway.there is a new article to
Cladribine_approved for hairy cell leukemia as Leustatin,was tested
by scripps on 51 people,double blind.Three monthly infusions were
given,with generally positively results.Scripps,dr j.Sipe.They
think subcutaneous injections will be used in future.future plans
include a multicenter trial under leadership of scripps.Info
available @ 1-800-998-6098.
4 Aminopyridine_an existing chemical,manufactured by Regis.Acts by
improving nerve conduction even in presence of myelin damage.Some
spectacular results,in motor vision were observed.There is a
problem of seizures as a possibility if blood level of 4ap gets too
high.Must manage its use.Results are spectacular in giving
temporary relief.This is not a cure.Van diemen,polman are main
researchers.Now in multicenter trials.Some 100 people already
tested.a new report is available.
Cop-I add report****************
Monoclonal antibody_functions by making long term reduction of cd4+
population after 10 days of treatment.Bf5 is the name.21 People
were treated.Patients were relapse free six months post treatment.
Monoclonal antibody cmt412,an anti cd4 antibody was tested on 29
people with ms.They got a prompt and long lasting reduction in cd4
cells three hours after treatment.Edss was stable for an extended
time,and the medicine was well tolerated.Dr lindsey.
Azothioprene-has apparently had the effect of slowing disease
progression in a test group of forty patients,reducing relapse rate
as well.Its use in ms is recommended.Dr Milanese.
Methotrexate- developed at cleveland Clinic,Mellen center,Dr.Donald
Goodkin.They conducted a double blind trial with chronic
progressive patients.no publication has yet been released.the
Mellen letter very crudely describes the results,in semi scientific
terms.Whatever benefits there were were minor.No mode of action
was described.patients received weekly treatment over two years.No
toxicity was found.This drug is used for Rheumatoid Arthritis.It
was successful in Preventing EAE in animals.53% showed progression
while on medicine vs 83% of placebo patients.best results were seen
on upper extremity function.methotrexate is widely available,has
been used for years in leukemia.
We see the possibility that just by reducing the cd4+population in
the csf we minimize the tendency for continuing worsening.If we add
b12 simultaneously we improve conditions for healing whether
naturally or by some new agent.
We need a mechanism of action for each medicine,but it is clear
that the immune system,and in particular the cd4+ t-cells are the
main target of much of the new research and human trials.
Technical Articles Summary
Recent articles about multiple sclerosis are presented. The
citation for each article is given so that you may acquire the
article in full.
1. Double blind pilot trial of oral tolerization with myelin
antigens in multiple sclerosis (Harvard/Brigham and Womens
Science, 26 feb, 1993: 1321-1324; Howard l. Weiner M.D. And others.
It is thought that ms is an autoimmune disease wherein certain
cells recognize and attack the central nervous system.It is known
that, in rats,eae, an ms-like disease, could be ameliorated by
injecting myelin basic protein(mbp).Human trials were conducted
earlier which proved the safety of the oral mbp (bovine myelin).The
present trial was carried out on a group of 30
a period of one year. Only exacerbating-remitting patients were
selected.The results were that the use of oral mbp caused a
reduction of cd4 t cells-the cells believed responsible for
attacking the myelin sheath. More important,on a statistical basis
there was improvement in the patients.This was determined by
measuring the frequency of attacks and changes on the disability
scale(edss) rankings. Although it was not known why, all of the
patients were exacerbation free during the one year period, while
females continued to suffer exacerbations.All males who were on mbp
were stable or improved one full point or more on the six point
edss scale.One female improved,the rest were stable or worse. There
werE no toxicities associated with this treatment.All male patients
in this study have remained on mbp for 2 1/2 years with continued
stabilization of the disease. This treatment would appear to hold
good prospects for causing improvement in ms patients.Multicenter
trials started in mid 1994.
2. Interferon Beta in multiple sclerosis.
Three articles in neurology, april, 1993. 641-643, 662-667,655-661.
Authors are :Barry g.W. Arnason,M.D.:D.W.Paty,m.D.:Ifnb multiple
sclerosis study group.
The essence of this project was a multicenter, placebo controlled,
double blind trial over a span of three years with 372 ambulatory
patients.Two different amounts of IB were administered, by
subcutaneous injection, every second day. Thus there were three
groups in the trial. The precise mode of action of interferon
beta(ib) is not presently known.However,it is not presented as a
possible cure. The main results were that:patients on the ib
experienced,statistically, some improvement in mri scores. 66% Of
patients on maximum dose of IB showed more than 10% reduction in
mri placque area over the three years.Most notable was a reduction
in exacerbations from 1.21 Per year (average) for the placebo
group to 0.84 Per year for the group on maximum dose of IB.In
addition the severity of attacks was reduced for those on IB. The
effect of the treatment on Edss disability status at the end of the
three year trial was that,on average,both placebo and IBb patients
worsened.Placebo group edss(disability scale) status was a
worsening from 2.8 To 3.2 Versus 3.0 To 3.1 For the IB
group.Interferon beta(ib) has been approved by the FDA,and is now
in wide use.
3 Multiple sclerosis and vitamin B12 metabolism (england).
A review of newly admitted kings college hospital patients
showed that patients with definite ms had mild but significantly
enlarged red blood cells(macrocytosis) compared with an age
and sex matched neurological control group admitted to the same
ward.This effect is typical of vitamin b12 deficiency. In
a study of patients with ms,dr.Reynolds found significant
lowering of serum vitamin b12.Using a new and very sensitive
technique, they found a significant lowering of cerebrospinal
fluid (csf) b12 levels. In some cases, even though serum b12 was
normal. Reynolds states that it is very unlikely that this
association is coincidental.He asks "at the very least it may be
asked whether the associated vitamin b12 deficiency from any
cause is aggravating the underlying ms or hindering the process
of remyelination ?" He closes by calling for more research in
this area. new work by dr Kari of Japan seems to have found the
reason for r-binder problems and b12 deficiency.
Abstracts Of Articles
Reynolds EH. Multiple sclerosis and vitamin b12 metabolism.
Journal of neuroimmunology, 1992 oct, 40(2-3):225-30.
Abstract: Multiple sclerosis (ms) is occasionally associated with
vitamin b12 deficiency. Recent studies have shown an increased
risk of macrocytosis, low serum and/or csf vitamin b12 levels,
raised plasma homocysteine and raised unsaturated r-binder
capacity in ms. The aetiology of the vitamin b12 deficiency in
ms is often uncertain and a disorder of vitamin b12 binding or
transport is suspected. The nature of the association of vitamin
b12 deficiency and ms is unclear but is likely to be more than
coincidental. There is a remarkable similarity in the
epidemiology of ms and pernicious anaemia. Vitamin b12
deficiency should always be looked for in ms. The deficiency may
aggravate ms or impair recovery. There is evidence that vitamin b12
is important for myelin synthesis and integrity but further
basic studies are required.
Reynolds E.H.,Bottiglieri T; Laundy M; Crellin RF; Kirker SG.
Title: Vitamin B12 metabolism in Multiple Sclerosis.
Archives of Neurology, 1992 Jun, 49(6):649-52.
Abstract: We have previously described 10 patients with multiple
sclerosis (ms) and unusual vitamin b12 deficiency. We have
therefore studied vitamin b12 metabolism in 29 consecutive cases
of ms, 17 neurological controls,and 31 normal subjects. Patients
with ms had significantly lower serum vitamin b12 levels and
significantly higher unsaturated r-binder capacities than
neurological and normal controls, and they were significantly
macrocytic compared with normal controls. Nine patients with ms
had serum vitamin b12 levels less than 147 pmol/l and, in the
absence of anemia, this subgroup was significantly macrocytic
and had significantly lower red blood cell folate levels than
neurological and normal controls. Nine patients with ms had
raised plasma unsaturated r-binder capacities, including three
patients with very high values. There is a significant
association between ms and disturbed vitamin b12 metabolism.
Vitamin b12 deficiency should always be looked for in patients with
ms. The cause of the vitamin b12 disorder and the nature of the
overlap with ms deserve further investigation. Coexisting vitamin
b12 deficiency might aggravate ms or impair recovery from ms.
Sandyk R; Auerbuch GI.
Vitamin B12 and its relationship to age of onset of multiple
International Journal of Neuroscience, 1993 Jul-Aug, 71(1-4):93-9.
Abstract: Attention has been focused recently on the association
between vitamin B12 metabolism and the pathogenesis of multiple
sclerosis (MS). Several recent reports have documented vitamin B12
deficiency in patients with MS. The etiology of this deficiency in
MS is unknown. The majority of these patients do not have
pernicious anemia and serum levels of the vitamin are unrelated to
the course or chronicity of the disease. Moreover,vitamin B12
does not reverse the associated macrocytic anemia nor are the
neurological deficits of MS improved following supplementation with
vitamin B12. It has been suggested that vitamin B12 deficiency
may render the patient more vulnerable to the putative viral
and/or immunologic mechanisms widely suspected in MS. In the
present communication, we report that serum vitamin B12 levels in
MS patients are related to the age of onset of the disease.
Specifically, we found in 45 MS patients that vitamin B12 levels
were significantly lower in those who experienced the onset of
first neurological symptoms prior to age 18 years (N = 10)
compared to patients in whom the disease first manifested after age
18 (N = 35). In contrast,serum folate levels were unrelated to age
of onset of the disease. As vitamin B12 levels were statistically
unrelated to chronicity of illness, these findings suggest a
specific association between the timing of onset of first
neurological symptoms of MS and vitamin B12 metabolism. In
addition, since vitamin B12 is required for the formation of myelin
and for immune mechanisms, we propose that its deficiency in MS is
of critical pathogenetic significance.
Multiple Sclerosis and Vitamin B12 Metabolism [editorial].
Journal of Neurology, Neurosurgery and Psychiatry, 1992 may,
Abstract: Multiple Sclerosis (ms) is a human disease characterized
by chronic demyelination in the brain caused by immunological
mechanisms involving t-lymphocytes and macrophages. Recently
developed models of chronic relapsing forms of experimental
allergic encephalomyelitis, sharing many of the clinical and
pathological features of ms, and new discoveries of efficient
autoregulatory mechanisms intrinsic to the immune system, have
suggested new possibilities for therapeutic intervention in ms.
Moreover, recent data support the concept that the immune system
is exposed to a broad framework of regulation, including
neuroendocrine control. In particular, interfering with secretion
of the lactogenic hormone prolactin and of glucocorticoids has
consistently resulted in a reduction of clinical and pathological
manifestations of the disease. In this review, frank berkenbosch
and colleagues highlight several of the possible therapeutic
opportunities for the treatment of ms.There is now more info on b12
and ms in the literature.
Frequin ST; Wevers RA; Braam M; Barkhof F; Hommes OR.
Decreased vitamin B12 and folate levels in cerebrospinal fluid and
serum of multiple sclerosis patients after high-dose intravenous
Journal of Neurology, 1993 May, 240(5):305-8.
Abstract: Twenty-one patients (15 women, 6 men) with definite
multiple sclerosis (MS) were treated with 1000 mg intravenous
methylprednisolone-succinate (MP) daily for 10 days. Before MP
treatment there was a negative correlation (r = 0.59, P = 0.0084)
between serum vitamin B12 and progression rate, defined as the
ratio of the score on Kurtzke's Expanded Disability Status Scale
and disease duration. A significant decrease was demonstrated in
the cerebrospinal fluid (CSF) and serum levels of folate and in the
CSF level of vitamin B12 after MP treatment. The decrease in serum
B12 was not statistically significant. After MP treatment all
median levels of vitamin B12 and folate were below the reference
medians. We hypothesize that low or reduced vitamin B12/folate
levels found in MS patients may be related to previous
corticosteroid treatments. Otherwise a more causal relationship
between low vitamin B12/folate and MS cannot be excluded.Further
studies may be required to clarify the vitamin B12 and folate
metabolism in patients with MS.
Current therapy of multiple sclerosis:Mitoxantrone.
Nervenarzt,1994 Feb 65 (2) 136-138
Authors: E.Mauch,H.H.Kornhuber, et.Al(Ulm university,germany)
title:the course of multiple sclerosis under cyclophosphamide or
mitoxantrone as compared with the spontaneous course or
Journal: neurology,psychiatry and brain research (1993)1:220-227
Abstract: The course of ms under cyclophosphamide (cp) or
mitoxantrone (mx) treatment has been compared with the spontaneous
course of ms in 241 patients with definite ms.Use of cortisone or
acth showed no difference from spontaneous groups.While the state
of the patients deteriorated(kurtzke scale) in the control group by
about 1/2 point per year,there was a significant improvement in the
cp and mx groups.Thus both the cp and mx were effective in
stabilizing the patients over three years.The main acute side
effect ofcp and mx was nausea,which may be taken care of by
drugs.The main risk of mx in the long term is myocardiopathy.If one
treats patients with mx every three months,one can treat ms
effectively for three to four years. The anti tumor drugs in this
paper should be given only by hospitals competent in the
symptomatic management of ms,especially in management of the
neurogenic bladder by training methods. Mitoxantrone is an existing
approved cancer medicine known as Novantrone.
Noseworthy JH; Hopkins MB; Vandervoort MK; Karlik SJ; Lee DH;
Penman M; Rice GP; Grinwich KD; Cauvier H; Harris BJ; et al.
An open-trial evaluation of mitoxantrone in the treatment of
progressive MS. Neurology, 1993 Jul, 43(7):1401-6.
Abstract: We treated 13 patients with progressive MS with
Mitoxantrone. All patients received a standard IV dose of
mitoxantrone (8 mg/m2) every 3 weeks for a total of seven
infusions, with dosage adjustments depending on the hematologic
profile at the nadir. The treatment was well tolerated, with the
most common side effect being mild nausea. Four of seven women
developed transient secondary amenorrhea. The postenrollment
clinical behavior of these patients was generally more favorable
than during the 18 months prior to enrollment (only three of 13
patients developed an increase in the Expanded Disability Status
Scale of more than 0.5 points), suggesting a possible treatment
effect, but comparison with two historical control groups (both
the active and placebo groups from the Canadian Cooperative Trial
of Cyclophosphamide and Plasma Exchange) does not suggest that
mitoxantrone was efficacious. Eight of 12 patients had evidence of
MRI activity on 13 of 29 follow-up visits. This small,open-labeled
pilot study did not provide strong support for proceeding with a
randomized, controlled trial of this dosage regimen of mitoxantrone
in patients with progressive MS.
Cladribine (2-cda) in treatment of chronic progressive ms
abstract:51 patients received four monthly courses of 0.7 Mg/kg of
cladribine or placebo,double blind.Cerebrospinal fluid (csf) and
brain mri were evaluated at six and 12 months.Average neurological
scores,demyelinated volumes on mri,and concentrations of
oligoclonal bands in csf were stable or improved in patients
receiving cladribine but continued to deteriorate in patients
receiving placebo.We conclude that cladribine influences favorably
the course of chronic ms. Cladribine is now an approved medicine
for hairy cell leukemia,known as leustatin.They conclude that in
future the medicine may be given subcutaneously.Multicenter trials
The current status of studies of aminopyridines in patients with
Annals of Neurology,1994,36 suppl :s118-121**************
The effects of 4-aminopyridine in ms patients.Results of a
randomized,placebo controlled,double blind,concentration
Neurology 1994 june,44 (6) 1054-9**********************
van Diemen HA; Polman CH; vn Dongen MM; Nauta JJ; Strijers RL; van
Loenen AC; Bertelsmann FW; Koetsier JC.
4-Aminopyridine induces functional improvement in multiple
sclerosis patients: a neurophysiological study.
Journal of the Neurological Sciences, 1993 Jun, 116(2):220-6.
Abstract: This study reports on the neurophysiological measurements
that were performed in the context of a randomized,
double-blind, placebo-controlled, cross-over study with
intravenously administered 4-aminopyridine (4-AP) in 70 patients
with definite multiple sclerosis (MS). A beneficial effect of
4-AP was found for both visual evoked response and eye movement
registration parameters.This study extends the experimental data
obtained on animal nerve fibers, showing that 4-AP can improve
impulse conduction in demyelinated nerve, to clinical data which
indicate that 4-AP induces an objective improvement in the central
nervous system function in MS-patients. It thereby also provides a
theoretical basis for clinical efficacy of 4-AP in MS.
Van Diemen HA; Polman CH; Koetsier JC; Van Loenen AC; Nauta JJ;
4-Aminopyridine in patients with multiple sclerosis: dosage and
serum level related to efficacy and safety.
Clinical Neuropharmacology, 1993 Jun, 16(3):195-204.
Abstract: In a recent randomized, double-blind, placebo-controlled
crossover trial, we demonstrated efficacy of 4-aminopyridine
(4-AP) in improving disability of patients with multiple
sclerosis (MS). Here we describe the relationship between
dosage, serum level, efficacy, and safety of intravenously and
orally administered 4-AP in the same group of 70 MS patients.
After both intravenous and oral administration there was a
significant relationship between serum levels and 4-AP doses used
(p < 0.001 and p < 0.01, respectively). The use of 4-AP in oral
doses three times a day showed a large variation and fluctuation
in serum levels. After 12 weeks of oral treatment (maximum daily
dosage 0.5 mg/kg body weight), a statistically significant
improvement was found for the smooth pursuit gain of the eye
movements (estimated effect 0.14, 95% confidence interval
0.06-0.23, p < 0.001). The amount of improvement was significantly
related to 4-AP serum levels (p = 0.0013). Side effects after
intravenous 4-AP occurred frequently and were very troublesome
(pain in infusion arm, dizziness). Side effects during oral
treatment (dizziness, paresthesias)were very mild and occurred
30-45 min after intake of the medication and could be related to
high serum levels.
Author: Polman CH; Bertelsmann FW; van Loenen AC; Koetsier
JC.Title:4-aminopyridine in the treatment of patients with multiple
sclerosis. Long-term efficacy and safety.
Journal:Archives of Neurology, 1994 Mar, 51(3):292-6.
Abstract: OBJECTIVE: To study the long-term efficacy and safety of
4-aminopyridine in patients with multiple sclerosis. DESIGN: Case
series, follow-up varying from 6 to 32 months. SETTING:
University referral center. PATIENTS: Thirty-one patients with
definite MS, 23 of them being exposed to long-term
administration (6 to 32 months) of 4-aminopyridine, since they
showed a favorable initial response to the drug. INTERVENTIONS:
Long-term oral treatment with 4-aminopyridine in daily doses of
up to 0.5 mg/kg of body weight. MAIN OUTCOME MEASURES:
Neurologic functions and symptoms as reported by the patients;
side effects. RESULTS: Twenty of 23 patients who showed a
favorable initial response benefited from long-term
administration. Ambulation and fatigue (each in 13 patients) and
visual function (in five patients) were most frequently reported
to be improved. Three major side effects did occur during a
follow-up of 406 patient months: a generalized epileptic seizure
in two patients and hepatitis in one. CONCLUSIONS: Although a
substantial proportion of patients with multiple sclerosis seem
to benefit from long-term administration of 4-aminopyridine,
additional studies are needed to clarify the exact value of the
drug. ( ELAN IS DOING THESE STUDIES,MULTICENTER,IN 1994 )
MYELIN BASIC PROTEIN*******************************
Weiner HL;Mackin GA;Matsui M;Orav EJ;KhourySJ;DawsonDM;HaflerDA.
Double-blind pilot trial of oral tolerization with myelin antigens
in multiple sclerosis [see comments].
Science, 1993 Feb 26, 259(5099):1321-4.
Abstract: Multiple sclerosis (MS) is thought to be an autoimmune
disease mediated by T lymphocytes that recognize myelin
components of the central nervous system. In a 1-year
double-blind study, 30 individuals with relapsing-remitting MS
received daily capsules of bovine myelin or a control protein to
determine the effect of oral tolerization to myelin antigens on the
disease. Six of 15 individuals in the myelin-treated group had at
least one major exacerbation; 12 or 15 had an attack in the
control group. T cells reactive with myelin basic protein were
reduced in the myelin-treated group. No toxicity or side effects
were noted. Although conclusions about efficacy cannot be drawn
from these data, they open an area of investigation for MS and
other autoimmune diseases.(multicenter trials started in mid 1994)
Author: Duffy JD; Campbell J.
Title:Bupropion for the treatment of fatigue associated with
multiple sclerosis [letter].
Journal:Psychosomatics, 1994 Mar-Apr, 35(2):170-1.
Unique ID: 94225039.**************************
Author: Fisk JD; Pontefract A; Ritvo PG; Archibald CJ; Murray TJ.
Title:The impact of fatigue on patients with multiple sclerosis.
Journal:Canadian Journal of Neurological Sciences, 1994 Feb,
Abstract: Although fatigue is recognized as a symptom of MS, there
have been insufficient methods for evaluating this symptom. We
administered the Fatigue Impact Scale to 85 MS patients and 20
hypertensive patients. Neurologic impairment, mental health, and
general health status were also assessed. MS patients reported
significantly higher fatigue impact than hypertensive patients.
Most MS patients reported fatigue as either their worst (14%), or
one of their worst (55%) symptoms. Disease classification and
neurologic impairment had little bearing on Fatigue Impact Scale
scores in the MS sample. The best predictive models for mental
health and general health status in the MS sample both included the
Fatigue Impact Scale as a significant factor. This study
demonstrates that: 1) fatigue is a very prevalent and severe
problem in MS, 2) fatigue impact cannot be predicted by clinical
measures of neurologic impairment, 3) fatigue has a significant
effect on the mental health and general health status of MS
AUTHOR: RUMBACH,L,BATTAILARD D.M.GALMICHE,J,HENLIN,JL,ET AL
Title:Treatment of multiple sclerosis with anti-CD4
monoclonal antibody. A preliminary report on B-F5 in 21 patients.
Journal:Journal of Autoimmunity, 1993 Dec, 6(6):771-86.
Twenty-one patients with definite active multiple sclerosis (MS)
were treated with a monoclonal anti-T CD4/B-F5
(murine IgG1) antibody for 10 days. Side effects were observed
in 11 patients during the first infusion. These side effects were
accompanied by and probably related to a transient increase
in IL6 and TNF alpha serum levels. This problem led to treatment
interruption in one patient. Neither clinical improvement nor
deterioration was observed in the course of treatment. EDSS
improvement (> 1 point) occurred in six patients one month
post-treatment. One month after the end of treatment total
lymphocytes and CD3+ and CD4+ cells were significantly decreased.
Cytokine analysis performed in serum and in CSF before and after
treatment showed no induced modifications. Ten patients developed
xenogenic antibodies. It is of interest that the patients with
relapsing-remitting forms were relapse-free at the 6th month
Author: Lindsey JW; Hodgkinson S; Mehta R; Siegel RC;
Mitchell DJ; Lim M;Piercy C; Tram T; Dorfman L; Enzmann D; et al.
Title:Phase 1 clinical trial of chimeric monoclonal anti-CD4
antibody.in multiple sclerosis.
Journal: Neurology, 1994 Mar, 44(3 Pt 1):413-9.
Abstract: We conducted an open trial of cM-T412, a chimeric
monoclonal anti-CD4 antibody, in 29 patients with MS. This
antibody caused a prompt and long-lasting depletion of circulating
CD4 (helper/inducer) lymphocytes. The mean (+/- SE)CD4 count for
the group decreased from 870 (+/- 66) cells/mm3 at baseline to 76
(+/- 11) 3 hours after treatment, and then increased to 425 (+/-
38) at 1 month after treatment and 475 (+/- 39) at 6 months after
treatment. Numbers of CD8 (cytotoxic/suppressor) lymphocytes,
B-lymphocytes, granulocytes, and monocytes changed transiently but
showed no significant long-term effects. The most common side
effects were headache,nausea, myalgia, fever and tachycardia
occurring in the first few hours after treatment. No serious
effects occurred. Kurtzke EDSS scores remained stable,and MRI
scans showed less contrast enhancement 1 week after treatment. We
concluded that treatment of MS patients with cM-T412 chimeric
anti-CD4 antibody is well tolerated at the doses tested and
produces a long-lasting, selective depletion of CD lymphocytes.
Experimental therapy of relapsing remitting multiple sclerosis with
ANNNALS OF NEUROLOGY,1994 36 SUPPL:S115-117.********************
CAUSES OF MS***********************************
Author: Mumford CJ; Wood NW; Kellar-Wood H; Thorpe JW; MillerDH;
Title:The British Isles survey of multiple sclerosis in twins.
Journal: Neurology, 1994 Jan, 44(1):11-5.
Abstract: During a 27-month recruitment period, we identified 146
individuals with multiple sclerosis (MS) who have a twin. A single
clinician interviewed and examined 105 pairs of twins, and we
confirmed zygosity using minisatellite probes. Including two
suspected cases, 11 of 44 (25%) monozygotic twin pairs were
concordant compared with two of 61 (3%) dizygotic twin pairs--two
of 33 (6%) like-sexed and zero of 28 (0%) opposite-sexed. MRI was
performed in 64 of 105 co-twins, and showed abnormalities
consistent with demyelination in 13% of monozygotic and 9% of
dizygotic co-twins who were clinically unaffected. These findings
are similar to the results of most previous studies of MS in twins
in which zygosity was not unequivocally established and where the
majority of clinically unaffected co-twins were not studied by MRI;
the difference in concordance rates in monozygotic and dizygotic
twins indicates a significant genetic component in the etiology of
Evidence that mercury from silver dental fillings may be an
etiological factor in multiple sclerosis.
Science of the Total Environment 1994 march 15,142 (3): 191-205***
On the Causes of Multiple Sclerosis.
Medical Hypotheses, 1993 Aug, 41(2):93-6
Abstract: Evidence on aetiology in multiple sclerosis suggests that
the prevalence depends on the interaction of two factors, diet and
exposure to visible sunlight. The dietary features which may be
beneficial include supplementation with fish oils, avoidance
of saturated fats, and the associated intake of antioxidants
with unsaturated fatty acids. Inhibition, by antioxidants, of
the enzyme lipoxygenase inhibits leukotriene synthesis, and the
presence of fish oils leads to the production of leukotrienes with
less inflammatory properties. This is of particular importance in
the retina where leukotrienes might be the underlying cause of
retrobulbar neuritis. The antioxidant properties of vitamin A
may also lead to inhibition of leukotriene synthesis. Visible
solar radiation could be of benefit therefore by releasing vitamin
A from visual pigment rhodopsin. The interaction of these two
factors may explain the epidemiological observations on the
prevalence of multiple sclerosis.
MERCURY AND MS*********************************
Eley BM; Cox SW.
The release, absorption and possible health effects of mercury from
dental amalgam: a review of recent findings.
British Dental Journal, 1993 Sep 11, 175(5):161-8.
Abstract: Recently many articles have appeared on the subject of
mercury from dental amalgam and some of these have questioned its
safety as a dental material. This article reviews critically
the evidence on mercury release from dental amalgam restorations,
its absorption, accumulation and excretion by the body, and its
possible relationship to ill-effects.Finally, brief recommendations
are given for the handling and usage of dental amalgam.
Mercury and multiple sclerosis.
Acta Neurologica Scandinavica, 1993 Jun, 87(6):461-4
Abstract: It has occasionally been claimed that multiple sclerosis
(MS) may be due to a chronic mercury intoxication, e.g. from
mercury liberated from dental fillings. Therefore, the present
communication compares the mercury content assayed by neutron
activation in 8 macroscopically normal areas (frontal lobe) of
MS autopsy brains with those of 8 control samples. No significant
differences could be traced between the two groups concerning total
mercury. However, the lipid-soluble mercury (preferably methyl
mercury) expressed per cell unit (DNA) was found significantly
decreased in MS. These data may be explained either by a wash-out
of lipid soluble mercury due to break-down of the blood-brain
barrier in MS or to abnormalities in methylation processes probably
related to the vitamin B12 metabolism in MS.
Milanese C; La Mantia L; Salmaggi A; Eoli M.
A double blind study on azathioprine efficacy in multiple
Journal of Neurology, 1993 May, 240(5):295-8.
Abstract: Forty patients, affected by multiple sclerosis with
remitting-relapsing or progressive course, were included in a
double blind study of treatment with azathioprine (2 mg/kg/day)
lasting 3 years. The mean changes on the Expanded Disability
Status Scale and in the survival analysis show a trend in favor of
azathioprine both in slowing disease progression and reducing
relapse frequency.These findings, repeatedly observed in similar
trials, indicate that azathioprine should be used in the treatment
of multiple sclerosis.
GEOGRAPHICAL DISTRIBUTION OF MS*****************************
Ebers GC; Sadovnick AD.
The geographic distribution of multiple sclerosis:
Neuroepidemiology, 1993, 12(1):1-5.
Abstract: The decisive conclusions to be drawn from the geography
and prevalence of MS are: (1) a north-south (as well as
west-east in the United States) gradient exists independent from
genetic/racial factors; (2) major differences in prevalence
occur in the absence of difference in latitude; (3) individuals
from the same ethnic derivation have either the similar prevalence
or have very different prevalence rates in widely separated
geographical areas, and (4) specific resistance isolates are shown
to exist regardless of latitude. Existing prevalence information
leads to the almost inescapable conclusion that the geography of MS
cannot be explained by any single known environmental or genetic
factor(s) in isolation. A combination and distribution of both
genetic and environmental factors appears to be required to
explain the available data on MS and geography.
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