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2 juin 2011 4 02 /06 /juin /2011 08:06
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 pathogenChlamydophila (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.]

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 recently been reviewed in some detail by Chuck Stratton and myself [Stratton CW, Wheldon DB. Multiple sclerosis: an infectious syndrome involving Chlamydophila pneumoniaeTrends 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, 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 a secondary progressive phase for which there was no treatment, and that the illness must be expected to take its course.

I’m much more interventional than he — this goes with the territory of my being a medical microbiologist — and 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 she 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 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.

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