Empirical antibacterial
treatment of
infection with Chlamydophila pneumoniae
in Multiple Sclerosis
David Wheldon MB FRCPath
After much controversy there
is now powerful evidence for the respiratory pathogen Chlamydophila
(Chlamydia) pneumoniae being a causal factor in some variants
of the neurological illness multiple sclerosis. A series of remarkable
studies finds:
the presence of C.
pneumoniae gene sequences in the cerebrospinal fluid of patients
who have the disease, and culture of the organism when sensitive
cultural methods are used [Sriram S, Stratton CW, Yao S, Tharp A, Ding
L, Bannan JD, Mitchell WM. Chlamydia pneumoniae infection
of the central nervous system in multiple sclerosis. Ann Neurol.
1999 Jul;46(1):6-14.]
an association of new C. pneumoniae respiratory
infections with episodes of clinical relapse [Buljevac D, Verkooyen
RP, Jacobs BC, Hop W, van der Zwaan LA, van Doorn PA, Hintzen
RQ. Chlamydia pneumoniae and the risk for exacerbation
in multiple sclerosis patients. Ann Neurol. 2003 Dec;54(6):828-31.]
a statistically
significant elevation of C. pneumoniae-specific serum
antibody levels when the disease shifts into the progressive
form [Munger
KL, Peeling RW, Hernán MA, Chasan-Taber L, Olek MJ, Hankinson
SE, Hunter D, Ascherio A. Infection with Chlamydia pneumoniae
and risk of multiple sclerosis. Epidemiology 2003 14:2
141-147]
antibodies to C. pneumoniae in the cerebrospinal
fluid of patients with the disease [(1.) Yao, S., Stratton, C.W.,
Mitchell, W.M., Sriram, S. (2001). CSF oligoclonal bands in multiple
sclerosis represent antibodies against Chlamydophila. Neurology
56, 1168-76. (2.) Fainardi, E., Castellazzi, M., Casetta,
I. et al. (2004). Intrathecal production of Chlamydia pneumoniae-specific
high-affinity antibodies is significantly associated with a subset
of multiple sclerosis patients with progressive forms. Journal
of the Neurological Sciences 217, 181-8.]
evidence of active C. pneumoniae protein synthesis
in the central nervous system, with production of a bacterial
protein evoking an antibody shown to cause death of oligodendrocyte
precursor cells [Cid
C, Alvarez-Cermeno JC, Camafeita E, Salinas M, Alcazar A. Antibodies
reactive to heat shock protein 90 induce oligodendrocyte precursor
cell death in culture. Implications for demyelination in multiple
sclerosis. FASEB J. 2004 Feb;18(2):409-11.]
a
peptide specific to C. pneumoniae causes inflammatory
CNS disease (with some parallels to MS) in rats [Lenz DC, Lu L, Conant
SB, Wolf NA, Gerard HC, Whittum-Hudson JA, Hudson AP, Swanborg
RH. A Chlamydia pneumoniae-specific peptide induces experimental
autoimmune encephalomyelitis in rats.
J Immunol. 2001 Aug 1;167(3):1803-8.]
C. pneumoniae
gene transcription in the CSF of patients with MS [Dong-Si T, Weber J,
Liu YB, Buhmann C, Bauer H, Bendl C, Schnitzler P, Grond-Ginsbach
C, Grau AJ. Increased prevalence of and gene transcription by
Chlamydia pneumoniae in cerebrospinal fluid of patients with
relapsing-remitting multiple sclerosis. J Neurol. 2004
May;251(5):542-547.]
MRI improvement in antibiotic-treated patients with early
disease in a small but fastidious double-blind trial of non-immunomodulatory
antibiotics [Sriram
S, Yao SY, Stratton C, Moses H, Narayana PA, Wolinsky JS. Pilot
study to examine the effect of antibiotic therapy on MRI outcomes
in RRMS. J Neurol Sci. 2005 Jul 15;234(1-2):87-91.]
MRI improvement,
with reduction of the number of Gd-enhancing lesions, in a second
treatment study with minocycline [Metz LM, Zhang Y, Yeung M, Patry DG,
Bell RB, Stoian CA, et al. Minocycline reduces gadolinium-enhancing
magnetic resonance imaging lesions in multiple sclerosis. Ann
Neurol. 2004 May;55(5):756.]
An association of
C. pneumoniae in the CNS with MS is demonstrated by immunohistochemical,
molecular and ultrastructural methods. [Sriram S, Ljunggren-Rose A, Yao SY,
Whetsell WO Jr. Detection of chlamydial bodies and antigens in
the central nervous system of patients with multiple sclerosis.
J Infect Dis. 2005;192(7):1219-28.]
C. pneumoniae
occurs in a persistent and metabolically active state in the
CSF and peripheral blood monocytes of persons with active MS
[Chlamydophila
pneumoniae DNA and mRNA transcript levels in peripheral blood
mononuclear cells and cerebrospinal fluid of patients with multiple
sclerosis. Contini C, Seraceni S, Castellazzi M, Granieri E,
Fainardi E. Neurosci Res. 2008 Sep;62(1):58-61.]
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The evidence for a causal association
of C. pneumoniae with majority subsets of MS has been
garnered by a surprisingly diverse array of methods; cultural,
molecular (both DNA and RNA based), immunohistological, serological
(blood and CSF based), animal model, ultrastructural and therapeutic
trial. It is this very diversity of methodology which makes the
evidence compelling. The subject has been reviewed in some detail
by Chuck Stratton and myself [Stratton CW, Wheldon DB. Multiple sclerosis:
an infectious syndrome involving Chlamydophila pneumoniae.
Trends Microbiol. 2006 Nov;14(11):474-9.]
The results of antichlamydial
treatment have been very promising, particularly in early disease.
It should be stressed at the
outset that this bacterium is not sexually transmitted. It causes
respiratory infection and is spread by droplet infection
coughing and sneezing.
Sarah's story
Sarah, my wife, an artist of considerable ability, was given
a diagnosis of MS in July 2003. Her illness in fact stretched
back to 1989, when she experienced a sudden weakness of the right
arm. After a fortnight she recovered its function completely.
A few years later she experienced a slight greying of vision
in one eye; this resolved over a few weeks. Occasional relapses
followed, all with a complete recovery. In 1999 the remissions
started to become less complete. Right foot-drop began insidiously
and did not resolve. Then, in 2001, shortly after a prolonged
upper respiratory infection which led to mild new-onset asthma,
Sarah began to enter a new, rapidly progressive stage of the
illness. Within two years she was unable able to stand unaided,
had to hold furniture, was unable to hold or use a pencil or
paint-brush with her right hand, and she felt giddy. She said
that she seemed to live in a mental fog: indeed, in the evenings
she would fall into a half-sleep from which she obtained no rest.
Her speech was becoming slurred. There was a continual sense
of flickering and worsening neurological deficit. She suffered
tinnitus, hearing the continual sound of distant machinery. She
developed L'hermitte's sign, manifested as an electric-shock-like
pain down the back on bending the head forward and signifying
damage to the cervical spinal cord.
An MRI scan showed many typical active lesions, visible as variably-sized
bead-like hyperintensities in the white matter of the brain.
The neurologist told Sarah
that she had Multiple Sclerosis; the disease had entered an aggressive
secondary progressive phase for which there was no treatment,
and that the illness must be expected to take its course. He
took me to one side and told me that her days of creativity were
finished. (He said this with a despairing pass of his hands.)
He advised me to make preparations and find a nursing home.
Im much more interventional than he this goes with
the territory of my being a consultant medical microbiologist
and I quickly found the Vanderbilt paper which first described
the association of C. pneumoniae infection and MS. [Sriram S, Stratton
CW, Yao S, Tharp A, Ding L, Bannan JD, Mitchell WM. Chlamydia
pneumoniae infection of the central nervous system in multiple
sclerosis. Ann Neurol. 1999 Jul;46(1):6-14.]
Then the problem of treating
a chronic infection with C. pneumoniae had to be solved.
Many medical microbiologists working in the field believe that
this infection cannot be adequately treated. Using the Internet
I quickly found a US patent taken out by two Vanderbilt doctors,
Mitchell WM and Stratton, CW to record the intellectual priority
of their discovery: [http://www.patentstorm.us/patents/6884784.html]. Using the information in this patent
as a basis for treatment I recommended the following oral antichlamydial
regimen:
doxycycline 200mg once daily
roxithromycin 300mg once daily (azithromycin 250mg three days
a week is an alternative.)
Short courses of metronidazole will later be added to this regimen.
We started the doxycycline first, as it was immediately available.
The results were astonishing. For five days Sarah suffered a
worsening of her symptoms; this was accompanied by a flu-like
illness, with headache round the eyes, pains in the large joints
(hips and shoulders) and night-sweats. This is a typical Herxheimer-like
reaction; it is caused when a large bacterial load is broken
up by antibiotics or other agents. After five days she lost the
mental fog: indeed, she said she felt mentally clearer than for
two years. The roxithromycin was added three weeks later, when
it became available.
This information
has been made available at Sarah's request. It has to be said
that, despite all the research which has been published in the
scientific literature, the existence let alone the therapeutics
of chronic infection with C. pneumoniae is barely
understood by the medical community.
Updates
on progress may be found here
Article
in Hospital Doctor here (graphic - 629Kb)
Evidence that Chlamydia
pneumoniae has a causal association with Multiple Sclerosis:
a brief review.
C pneumoniae is known to patchily parasitize the
cells which line small blood-vessels, causing episodes of vasculitis.
This is a local inflammatory process characterised by tiny punctures
in the vessel walls and leakage of blood-components into the
surrounding tissue space. It can be visualized directly in the
retinal veins, where the vessels appear to be coated with a thin
greyish sheath. This sheath is comprised of T lymphocytes. A
very similar pathology takes place in the brain in early MS.
The association between sheathing of retinal veins and MS was
first made in 1944. The anatomical distribution of lesions within
the brain in MS is often centred on small veins; elongated plaques
may follow the sinuous curves of the vessels they surround. [Esiri MM, ed. Oppenheimer's
Diagnostic Neuropathology, 2nd edition, 1996 Blackwell: 256-9.] Vasculitic phemomena were recognised
surprisingly early: in 1873 Rindfleisch commented: "If one
looks carefully at freshly altered parts of the white matter
in the brain, one sees with the naked eye a red point or line
in the middle of each individual focus, the transversely or obliquely
cut lumen of a small vessel engorged with blood. . . All vessels
running inside the foci, but also that traverse the immediately
surrounding but still intact parenchyma are in a state of chronic
inflammation." Rindfleisch had recognized, over 130 years
ago, that inflammation of small vessels vasculitis
precedes neural damage. A recent study has indeed shown
that C. pneumoniae can be seeded within the brain via
vascular infection [De
Pietro M, et al. Could past Chlamydial vascular infection promote
the dissemination of Chlamydia pneumoniae to the brain? J Biol
Regul Homeost Agents 2013 27(1) 155-164.]
Examination of the eye reveals retinal vasculitis in about a
third of persons with early MS, but it is probably present in
far more. It is especially common following optic neuritis (a
common precursor of MS), and is characterised by leakage of dye
in a fluorescein dye test, blood cells, and cuffing of the vessel
walls by inflammatory cells. Where it is seen, there is a raised
likelihood that MS will follow. I have noted that episcleritis
(an inflammatory condition of the connective tissue between the
conjunctiva and sclera involving vasculitic features) is also
a frequent finding in those with MS. (Unpublished data.)
MS is currently considered an autoimmune demyelinating disease.
Myelin is an insulating lipoprotein; its sudden local loss causes
the acute MS relapse. But this myelin loss may well be a secondary
phenomenon. The very fact that retinal vasculitis is commonly
associated with MS casts considerable doubt on myelinopathy being
the root cause of MS; myelin, and the oligodendrocyte cells which
produce it, are not found in the retina, and the earliest pathological
manifestations of MS are in blood-vessels, not nerves and glial
cells. Demyelination has recently been shown to be a secondary
phenomenon in the acute, typical lesion of MS: the first visible
event in a newly-forming fatal MS lesion is the sudden, orderly,
non-inflammatory local mass death of oligodendrocytes, the cells
which make and support myelin. [Barnett MH, Prineas JW. Relapsing and remitting
multiple sclerosis: pathology of the newly forming lesion. Ann
Neurol. 2004; 55(4): 458-68.] This
casts further doubt on the notion of MS as a primary autoimmune
disease. The removal of unsupported myelin by inflammatory cells
may well be a secondary 'housekeeping' activity. We may be witnessing
the beginning of a sea-change in thought. [Chaudhuri A, Behan PO. Multiple sclerosis:
looking beyond autoimmunity. J Roy Soc Med 2005; 98: 303-306.]
These authors cite ten
important considerations about MS which cannot be explained by
the concept of a myelin-specific autoimmune process.
The epidemiology of MS has been well studied in the Faroe Islands,
where MS was unknown until the Second World War. It suggests
a communicable factor acquired in early adolescence, starting
at about the age of 11. [Kurtzke JF, Heltberg A. Multiple sclerosis in
the Faroe Islands: an epitome. J Clin Epidemiol. 2001
Jan;54(1):1-22.] This is
the age when seroconversion to C pneumoniae often begins.
Two other organisms posited to initiate MS - Human Herpes Virus
6 and the Epstein-Barr virus - would seem unlikely candidates
when this evidence is considered. HHV-6 is acquired by almost
all individuals by the age of three. Seroconversion to the Epstein-Barr
virus occurs in two peaks; one in very young children and the
second in later adolescence and adulthood. Furthermore, Kurtzke's
Faroese data suggest an agent which caused outbreaks at 13 year
intervals: EBV, due to its close and personal mode of spread,
rarely causes outbreaks. The agent which caused MS in the Faroese
seemed to be rather ineffectively spread; this is consistent
with infection caused by C pneumoniae, which is known
to be inefficiently transmitted and thus causes patchy outbreaks.
In 2000 there were areas of the Faroes free of MS. [Kurtzke JF. Multiple
sclerosis in time and space - geographic clues to cause. J
Neurovirol. 2000;6 Suppl 2:S134-40.] Niki and Kishimoto, with regard to C pneumoniae
outbreaks, note that 'transmission occurs only after repeated
and close contact. Small outbreaks may occur in households and
schools where persons have prolonged close contact. Unlike acute
viral infections, it may spread slowly.' [Niki Y, Kishimoto T. Epidemiology
of intracellular pathogens. Clin Microbiol Infect. 1996
Mar;1 Suppl 1:S11-S13.] In
an urban environment the situation is different from that of
island populations: C pneumoniae is ubiquitous; infection
is endemic and outbreaks are correspondingly difficult to delineate.
C pneumoniae has been linked to relapsing-remitting forms
of disease elsewhere in the body, including asthma, reactive
arthritis and coronary artery disease. Causal associations have
been made by isolation of the organism and by detection of diagnostically
raised antibody levels which subside on treatment. MS can be
considered an analogue of these conditions; it is, for instance,
characterized by lipid peroxidation, elevated serum homocysteine
and antioxidant depletion a pathology characteristic of
chronic chlamydial disease and one likely to be due to local
endotoxin activity but, because it represents an intracerebral
infection, shielded from the general circulation, high circulating
antibodies are not to be expected. Actually, C pneumoniae
serology is notoriously difficult to interpret.
A historic study was published by workers at the Vanderbilt School
of Medicine in 1999. CSF samples from 17 patients with relapsing-remitting
MS, 20 patients with progressive MS, and 27 patients with other
neurological diseases (OND) were examined by culture, by PCR
and by antibody detection. C pneumoniae was isolated from
CSF in 64% of MS patients against 11% of OND controls. Polymerase
chain reaction assays demonstrated the presence of C pneumoniae
MOMP gene in the CSF of 97% of MS patients versus 18% of OND
controls. Finally, 86% of MS patients had increased CSF antibodies
to C pneumoniae elementary body antigens as shown by enzyme-linked
immunosorbent assay absorbance values that were 3 SD greater
than those seen in OND controls. The specificity of this antibody
response was confirmed by western blot assays of the CSF, using
elementary body antigens. Moreover, CSF isoelectric focusing
followed by western blot assays revealed cationic antibodies
against C pneumoniae. [Sriram S, Stratton CW, Yao S, Tharp A, Ding
L, Bannan JD, Mitchell WM. Chlamydia pneumoniae infection
of the central nervous system in multiple sclerosis. Ann Neurol.
1999 Jul;46(1):6-14.] It
should be noted that the methodology used by the Vanderbilt workers
is fastidious. In tissue-culture isolation, for instance, repeated
centrifugation and prolonged incubation was carried out; this
is very important as in chronic infection the organism may produce
few of the spore-like elementary bodies, and those that are produced
may be damaged. (It is interesting to note that the discovery
of Helicobacter pylori was made possible by extending
traditional incubation times.)
Episodes of relapse in MS patients are associated with new respiratory
infections with C pneumoniae; [Buljevac D, Verkooyen RP, Jacobs BC,
Hop W, van der Zwaan LA, van Doorn PA, Hintzen RQ. Chlamydia
pneumoniae and the risk for exacerbation in multiple sclerosis
patients. Ann Neurol. 2003 Dec;54(6):828-31.] The relapse is evidence of host collateral
damage.
At a population level antibodies to C pneumoniae rise
as the disease becomes progressive [Munger KL, Peeling RW, Hernán
MA, Chasan-Taber L, Olek MJ, Hankinson SE, Hunter D, Ascherio
A. Infection with Chlamydia pneumoniae and risk of multiple
sclerosis. Epidemiology 2003 14:2 141-147.]
These
three seminal papers triangulate the evidence that C pneumoniae
plays a pathogenic role in the evolution of Multiple Sclerosis.
A question-and-answer page examining the natural history of Chl
pneumoniae infections is given on page
3
A schedule of treatment.
This is one schedule that strikes all stages of the organism's
life-cycle. Other equally good schedules are possible. It is
important that a committed care-giver (for instance, spouse,
partner or parent) should ensure that medication is given, and
swallowed, consistently.)
Doxycycline 100mg orally once daily is taken with
plenty of water.When this is well tolerated,
Azithromycin 250mg orally, three times a week should
be added. Roxithromycin, 150mg twice daily, is an equally
effective alternative. (The availability of these two macrolides
depends on the country of residence. Roxithromycin is not available
in the US and is not routinely available in the UK, but is widely
prescribable in Europe, Israel, Australia and New Zealand.)
When these are well tolerated,
the dose of Doxycycline is increased to 200mg daily.The reason
for this slow, step-wise introduction of antichlamydials is to
minimize any reactions caused by bacterial die-off. These can
be unpleasant.
NOTE: in rapidly progressive MS it may be prudent
to offset the benefits of stopping progression against the risk
of reactions, giving full doses of azithromycin and doxicycline
from the beginning.
This combination is taken continuously.
Two or three months into the treatment regimen three-weekly cycles
of intermittent oral Metronidazole are added. During the
first cycle metronidazole is given only for the first day. When
metronidazole is well tolerated the period of administration
in each cycle is increased to five days. There is no reason for
the intermittent use of metronidazole other than acceptability:
if someone undergoing treatment is able to take longer cycles
of metronidazole then it seems reasonable that they should do
so. The dosage of metronidazole is 400mg three times a day. If
it is suspected that a patient may have a heavy chlamydial load
a smaller daily dose may be given initially.
N-acetyl cysteine (NAC) 600mg daily - 1,200mg twice a day,
should be taken continuously. This is a commonly-taken dietary
supplement, available at health-food stores. It is an acetylated
sulphur-containing amino-acid, and may be expected to cause chlamydial
EBs to open prematurely, killing them. NAC should be started
at the lower dose of 600mg daily; the dose should be doubled
when well-tolerated. NAC offers liver protection; this may be
useful, as rapid bacterial die-off may compromise hepatic function.
If a trial NAC produces unpleasant reactions, its administration
may be delayed until antibiotics are well tolerated. Doxycycline
and azithromycin may be expected to slowly deplete the chlamydial
EB load by destroying them as they enter host cells.
The period of continuous treatment
needs to be of the order of a year. This is very important,
as the organisms are extremely difficult to remove from certain
cell-types. The recommendations for acute infection (typically
2 - 6 weeks monotherapy with doxycycline or a macrolide) are
totally insufficient. The organism is not killed by such
treatment, but is instead driven deeper into a persistent state.
This is recognised but not widely appreciated. [See: Woessner R, Grauer MT, Frese
A et al., Long-term Antibiotic Treatment with Roxithromycin in
Patients with Multiple Sclerosis. Infection. 2006; 34(6): 342-4.] Roxithromycin alone for three 6-week
periods did not help these patients; this outcome was predictable.
The difficulties of treating persistent chlamydial infections
with traditional antimicrobial schedules are ably discussed by
Villareal and co-authors [Villareal C, Whittum-Hudson JA, Hudson AP. Persistent
Chlamydiae and chronic arthritis. Arthritis Res. 2002;4(1):5-9.] Effective treatment needs to address
all stages of the organism's life-cycle.
The eventual aim is to give
all three agents intermittently so that there is some respite
from antibiotics. This, the final leg of treatment, may entail
a 14 day course of doxycycline and roxithromycin, with a five
day course of metronidazole in the middle. This course is given
once a month. After several months the intervals between the
antibiotics may be cautiously extended. Rifampicin is not suitable
for intermittent use, and azithromycin may be given instead.
Here is a graphic representation of a possible course of treatment.
Biotin
Biotin is a water-soluble vitamin.
It is thought to be a cofactor in the synthesis of fatty acids,
including myelin. A 2015 pilot study of high-dose supplementation
in persons with progressive MS showed a surprising improvement
in function in those with cord lesions. The authors comment:
"Sixteen patients out of 18 (89%) with prominent spinal
cord involvement were considered as improved as confirmed by
blinded review of videotaped clinical examination in 9 cases."
They note that improvement took some time (2 - 8 months) to become
manifest. [Sedel
F, Papeix C, Bellanger A, et al. High doses of biotin in chronic
progressive multiple sclerosis: A pilot study. Mult Scler
Relat Disord 2015; 4: 159-169]
The dose used was 100 - 300
milligrams daily. Larger trials are in progress.
Given that biotin is harmless,
it would seem prudent to act on these preliminary findings. Pure
high grade biotin in 10mg tablets is available. The tablets are
small and easily swallowed. Only the pure form, unmixed with
other supplements, should be taken.
Here is a comprehensive review:
[Sedel
F, Bernard D, Mock DM, Tourbah A. Targeting demyelination and
virtual hypoxia with high-dose biotin as a treatment for progressive
multiple sclerosis. Neuropharmacology. 2016 Nov;110(Pt B):644-653]
Added 25th
Jan 2017
Adjuncts
The brain has extraordinary
powers of repair, but must be provided with the building-blocks
by which to do it. This infection is intracellular; the organism
interferes with mitochondria, the cells' powerhouses. Many of
the symptoms of the disease - particularly the fatigue - may
be due to mitochondrial exhaustion. Toxins known as free radicals
are released as various synthetic pathways are disrupted. If
this oxidative stress continues unchecked for too long irreversible
mitochondrial damage may occur. A combined dietary supplementation
of antioxidants is strongly recommended.
Vitamin C 1G daily
E 800iu daily
Omega 3 fish oil daily
Evening primrose oil 1G daily
Acetyl L-Carnitine 500mg daily
Alpha Lipoic acid 150mg daily
Ubiquinone (Coenzyme Q10) 200mg daily
Selenium 200 micrograms daily.
N-acetyl cysteine 600mg twice daily
melatonin 1.5mg at night may be considered.
This may seem like polypharmacy,
but there are good reasons to consider these agents. This is
because the mitochondrial membrane is the bottle-neck for numerous
key cellular reactions, and it is exactly here that chlamydiae
hover as they control the host cell and steal its vital molecules
via tiny projections. These agents are available at health food
stores and are obtainable on-line.
More
details on how antioxidants can act synergistically to enhance
their effects, and to regenerate each other can be found on page 7.
Apart
from mitochondrial support, Vitamin D is needed. There is evidence
that a relative Vitamin D deficiency is common in MS, and may
allow the disease process to begin. High dose supplementation
- 4000iu is recommended. (less may be needed in infections other
than MS) This is discussed on page
11.
In addition, B complex, Magnesium, 300mg and Calcium 500mg supplements
should be taken. (Calcium salts should be taken remote from doxycycline
as it can interfere with absorption.)
High-dose sublingual Vitamin B12 (methylcobalamin) should be
taken; initially 4000 - 5000 micrograms several times a day,
reducing to once daily after three months. This is to flood the
system with methylcobalamin as there is often a functional B12
deficit, as evidenced by raised serum methylmalonate or homocysteine.
Vitamin B12 (together with B6 and folate) counteracts the hyperhomocysteinaemia
which frequently accompanies chronic Chl pneumoniae infection
and which is thought to cause connective tissue damage. Excess
homocysteine is a potent neurotoxin with activity against cortical
and hippocampal neurones. [1. Kruman II, Culmsee C, Chan SL, et al., Homocysteine
elicits a DNA damage response in neurons that promotes apoptosis
and hypersensitivity to excitotoxicity. J Neurosci 2000;20:6920-6:]
[2. Den Heijer T, Vermeer SE, Clarke R, Oudkerk M, Koudstaal
PJ, Hofman A, et al. Homocysteine and brain atrophy on MRI of
non-demented elderly. Brain 2002;126:170-5:] [3. Leblhuber
F, Walli J, Artner-Dworzak E, Vrecko K, Widner B, Reibnegger
G, et al. Hyperhomocysteinemia in dementia. J Neural Tansm
2000;107:1469-74.] An
excellent review of Vitamin B12 and multiple sclerosis can be
recommended here: [Miller
A, Korem M, Almog R, Galboiz Y. Vitamin B12, demyelination, remyelination
and repair in multiple sclerosis. J Neurol Sci 2005 Jun
15;233(1-2):93-7.]
Regular Lactobacillus acidophilus, daily, either as a
supplement or in capsules. This is to maintain bowel flora in
the face of antibiotic treatment. Tablets of Lactobacillus
sporogenes spores may be considered. These have the advantage
of getting into the small bowel in large numbers.
It would be wise to avoid foods
containing artificial trans-fats. These are hard fats made from
unsaturated oils which, after heating under pressure, are hydrogenated
in the presence of a catalyst. They are widely used because they
have a long shelf life and are inexpensive. With certain exceptions
hydrogenated fats are not found in nature, and are metabolized
with difficulty in the body. They alter cell and mitochondrial
membrane functions. Two studies in animal models have found that
artificial trans-fats affect mitochondrial efficiency as measured
by a reduction of ATP synthesis. [Blomstrand R, Svensson L. The effects
of partially hydrogenated marine oils on the mitochondrial function
and membrane phospholipid fatty acids in rat heart. Lipids.
1983 Mar;18(3):151-70; De Schrijver R, Privett OS. Energetic
efficiency and mitochondrial function in rats fed trans fatty
acids. J Nutr. 1984 Jul;114(7):1183-91.] Dietary intake of trans-fats increases systemic
inflammatory markers in humans. [Mozaffarian D, Pischon T, Hankinson
SE, et al. Dietary intake of trans-fatty acids and systemic inflammation
in women. Am J Clin Nutr. 2004;79:60612.; Baer DJ,
Judd JT, Clevidence BA, Tracy RP. Dietary fatty acids affect
plasma markers of inflammation in healthy men fed controlled
diets: a randomized crossover study. Am J Clin Nutr. 2004;79:96973.] If the words 'hydrogenated oil' or
'partially hydrogenated oil' appear in a list of ingredients
then trans-fats are likely to be present. (It may be noted that
dairy products and animal fats also contain a small proportion
of trans-fats, but these naturally occurring trans-fats are digestible
and were beneficial in animal studies; evidence is less clear-cut
in humans. [reviewed
by Wang Y, Jones PJ. Dietary conjugated linoleic acid and body
composition. Am J Clin Nutr. 2004 Jun; 79(6 Suppl): 1153S
- 1158S.])
Turmeric, the yellow spice used in Indian cooking, may be very
useful. The active ingredient, curcumin, moderates the pro-inflammatory
effects of bacterial endotoxin, probably by restraining the activation
of nuclear factor-kappa B. 'Nuclear factor kappa B has been implicated
in autoimmune and inflammatory diseases, infection, cell survival,
and cell transformation with subsequent promotion of cancer.'
[Reviewed
by Holmes-McNary M. Nuclear factor kappa B signaling in catabolic
disorders. Curr Opin Clin Nutr Metab Care. 2002 May;5(3):255-63.] Turmeric is by itself poorly absorbed;
piperine greatly improves absorption. Combinatory formulations
are available.
A cautionary note must be sounded.
All this is very new and much of it is speculative. It is linking
up the work of others. But an empirical trial of antibiotic treatment
is surely worthwhile: it would be attempted in any other disease
were there even indirect evidence of a treatable pathogen. As
an example, one might consider culture-negative endocarditis,
where long-term antibiotics are given (often successfully) in
the absence of a demonstrable pathogen. MS, as it progresses,
can be just as devastating and antibiotics are very cheap by
the standards of conventional treatment. In comparison with other
drugs they are relatively (but not completely) risk-free.
Other Potential Pathogens
In treating the disease, it
makes sense to use a schedule of antimicrobial agents which is
effective against other potential pathogens of the CNS including
Borrelia garini and B burgdorferi. These spirochaetes
have been known to cause a serologically negative MS-like illness
with white-matter MRI changes. Chronic infections with these
organisms are generally difficult to detect serologically; the
EIA test is particularly prone to giving false negative results.
Chronic borreliosis may be much more prevalent than is now believed;
B. burgdorferi has been identified in avian ticks infesting
songbirds [Morshed
MG, Scott JD, et al., Migratory songbirds disperse ticks across
Canada, and first isolation of the Lyme disease spirochete, Borrelia
burgdorferi, from the avian tick, Ixodes auritulus.
J Parasitol. 2005 Aug;91(4):780-90.]
and has been posited as a reservoir of borrelial infection in
Europe [Comstedt
P, Bergstrom S, Olsen B, et al., Migratory passerine birds as
reservoirs of Lyme borreliosis in Europe. Emerg Infect Dis. 2006
Jul;12(7):1087-95.] Given
the likelihood of chronic C pneumoniae infection causing
a decreased efficiency of host systems, one might speculate that
chronic C pneumoniae infection may prevent resolution
of borreliosis. It would also make sense to cover for Rickettsiae
and Mycoplasma sp. and cell-wall deficient forms. MS and
other initially relapsing-remitting but ultimately progressive
diseases may have a polymicrobial phase: the punctured vasculitis
caused by Chl pneumoniae would provide an easy portal
of tissue-entry for blood-borne organisms. Microbiologists are
beginning to recognise that, in many chronic infections, an altered
host physiology provides a niche for a host of secondary organisms:
an obvious example is chronic HIV disease, where the pathogen
which initiates the disease is rarely the pathogen which causes
the final event which results in death.
There seem to be a number of
factors which need to be in place before MS develops, including
chronic C. pneumoniae infection and a genetic inheritance
which determines a certain kind of response to this infection.
Some people have a disease-form which is primarily driven by
the infection; it is characterised by rapid progression and intoxication
with bacterial metabolites. Untreated it results in a swift decline;
it is rapidly fatal. This is the form that Sarah had. Paradoxically,
it seems very responsive to treatment. Other people seem to have
a disease-form where the host reaction predominates; the infection
is slow, bacterial numbers are probably few. This form seems
to be less amenable to antibacterial treatment, and the disease
may remain active until the remains of the dead bacteria (endotoxins)
are removed. This may be problematic in an enclosed area like
the brain. One might speculate that there are even some disease
forms where autoimmunity persists autonomously. I think that
most people with MS fall somewhere within these extremes. My
own experience from advising many people with MS is that those
with relapsing-remitting disease and early progressive disease
can do well. Patients with later progressive disease respond
less well, though this is not always the case. Generally speaking,
the earlier that treatment is begun the better the result and
the more complete the resolution.
People with dense neurological deficits which have been in place
for many years and which are situated in confined anatomical
bottlenecks such as the cord or cerebellar peduncles may recover
little function, but treatment may halt disease progression.
Concluding remarks
In appreciating the work cited above, and in considering treatment,
one must make an analysis of risk versus benefit. I believe that
an empirical trial of twelve months' doxycycline plus roxithromycin
/ azithromycin is worthwhile even in late disease, metronidazole
being added if benefits occur and / or progression is halted.
It is important to go into the trial without undue expectation.
Nothing at all can be guaranteed.
A televised discussion
An ABC Television science programme,
Catalyst, investigated the association of C. pneumoniae
and Multiple Sclerosis. It was written and presented by Dr Maryanne
Demasi. It is highly recommended. Here is the link: http://www.abc.net.au/catalyst/stories/3572695.htm
About the author
I'm a consultant medical microbiologist.
As this term may be unfamiliar to many people I thought I'd explain
my raison d'etre in the medical world.
I read Medicine at Bristol University, and, on graduating, was
a house surgeon at Yeovil and house physician at Frenchay and
Cossham Hospitals. I studied pathology as a junior doctor at
the Radcliffe Infirmary, Oxford; I had a particular interest
in neuropathology and microbiology. I remained at the Radcliffe
as registrar and senior registrar, and, in the latter post, was
on the teaching staff of the University and gave lectures on
bacterial infections of the central nervous system. I studied
virology at the Churchill Hospital, Oxford. I was appointed the
Consultant in Medical Microbiology at Bedford Hospital in 1980.
Medical microbiology is a branch of pathology. What does a medical
microbiologist do from day to day? He or she is responsible for
the identification of bacterial and viral infections in individual
patients, sitting at the bench with the laboratory staff and
reading the plates. The greatest priorities are cultures revealing
septicaemias and meningitis cases. I would visit patients on
the wards and discuss treatment with the clinician. A medical
microbiologist deals with outbreaks, and, together with a specialist
nurse, will make strategies for the containment of hospital infection.
Many microbiologists are clinically minded; I would visit the
Intensive Care Unit on a daily basis as many ICU patients are
highly vulnerable and are at risk of infection. Another area
of specialization is the regulation of antibiotic use in the
hospital: if used inappropriately there is a risk of resistance
developing. A consultant microbiologist will also have a teaching
role and will often participate in research.
I hope this gives a brief insight into a medical microbiologist's
world.
I have now retired from the NHS and am working on my creative
writing. I am the author of four philosophical novels. The
Viaduct was published by The Bodley Head in 1983; it won
The Triple First Award, the final judges of which were Graham
Greene and William Trevor. This novel was shortlisted for the
Whitbread Award. The Course of Instruction, A Vocation and
At the Quay followed. Six of my short stories have been published
recently.
The Vigil The Woven Tale Press in 2017
Who Shave Have the Choir Seat? The Woven Tale Press in
2018
The Automaton Nightjar Press in 2017
Six Lost Plots Confingo Publishing in 2017
The Seat of Consciousness Confingo Publishing in 2017
Medusa's Metaphors Confingo Publishing 2018
Here is a link to my own take on what has
happened to the NHS.
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These pages were made with
the intention of helping persons with MS. I certainly make no
money from them.
(When I was working as a Resident
Pathologist at the Radcliffe Infirmary, Oxford, I was given a
most unusual room in the doctors' quarters: the one with the
round window in the pediment of the facade. This beautiful building,
dating from 1770, is no longer a hospital but a part of the University)
photo by Fr. Lawrence
Lew, O.P.
First uploaded 29th November 2003; last updated 9th May 2018
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