Chlamydia and Multiple Sclerosis
Wise Young PhD MD
August 11, 2012
Infections have long been suspected to be part of the pathogenesis of multiple sclerosis (MS) , from psittacosis  to sexually transmitted diseases . In 1983, Permutter and Darvish  proposed a possible relationship of Chlamydia to MS. However, the data for such a relationship was largely correlational and controversial .
In 1999, Sriram  studied 17 patients with relapsing-remitting MS, 20 patients with chronic progressive MS, and 27 patients with other neurological diseases. They found Chlamidia pneumoniae (C. pneuomoniae) in 64% of the MS patients versus 11% of other neurological diseases. An even higher 86% percentage of MS patients had increased cerebrospinal fluid (CSF) antibodies to C. peneumoniae. They suggested that C pneumoniae may represent a cause of MS but pointed out that it may also be a secondary infection and proposed a therapeutic trial aimed at eliminating C pneumoniae from the central nervous system.
In 2000, several groups failed to detect C. pneumoniae in the CSF [7, 8] or brains [9, 10] of patients with MS and another group found CSF C. pneumoniae in oly 5 of 10 patients with MS. In 2001, Tsai, et al.  reported no significant association of C. pneumoniae and MS but Ikejima, et al.  used a more sensitive polymerase test to detect C. pneumoniae DNA in 68% of patients with MS., suggesting that commercial kits are not sufficiently sensitive. Yao, et al.  suggested that interferon beta (IFN-beta) therapy of MS may be beneficial because it prevented the inflammatory effects of C. pneumoniae.
Bang, et al.  did a meta-analysis of 26 studies assessing the relationship between Chlamydia and MS. These studies involved 1332 patients and 1464 controls. They found that that people with MS do have a significantly greater risk of having detectable levels of Chlamydia (Cpn) DNA in their intrathecal fluid, as well as increased intrathecal immunoglobulins, compared to other neurological diseases. However, there is no evidence of increased serum levels of immunoglobulins. Correction for gender effects increased the association of MS with Cpn DNA. The authors concluded that the presence of Cpn is more likely in MS patients but the data are insufficient to establish a cause-effect relationship.
Pohl, et al.  reported a case of a 12 year old male patient who had three attacks of optic neuritis within 3 months and had C. pneumoniae in the cerebrospinal fluid. After treatment with the antibiotic rifampin, he experienced no further attacks during a followup period of 6 years. In 2006, Stratton and Wheldon  pointed out that the traditional explanation of MS being autoimmune myelinopathy is problematical because vasculitis is often seen in the MS brain, both within lesions and in adjacent normal appearing white matter. They suggested that an oligodendrocyte infection by C. pneumoniae (or other infectious agents) could trigger demyelination in a subject of patients with MS. C. pneumoniae is known to cause vasculitis in other parts of the body.
On the other hand, C. pneumoniae is a sexually transmitted disease and, if it caused MS, there should be differences in sexual practice and a higher incidence of other sexually transmitted diseases in women with MS. In 2008, Lidegaard, et al.  studied the sexual habits of women before MS. A total of 604 women with MS and 619 women without MS filled out questionaires. They found no difference between women with and without MS, regarding years of schooling, oral herpes infections, genital herpes, blood transfusion, age at sexual debut, age at coital debut, number of sexual partners before and after age 20, anal sex, condyloma attack, or chlamydia infection. A total of 68% and 72% of women with MS and controls had oral sex sometimes or often before the 20th year. They concluded that the data argue against MS being a sexually transmitted disease.
Krone, et al.  pointed out that there is an association of MS with Epstein-Barr virus infection in childhood. So, they studied 152 German children with MS and looked for other infections that might be associated with MS. Serological studies of the children showed a significantly higher prevalence of IgM in C. pneumoniae while the other diseases resulted in a higher prevelance of IgG antibodies. This distinction is of interest because IgM is more frequently associated with innate immunity and autoimmune disorders than IgG. The observation that C. pneumoniae in children with MS is the only infectious disease associated with IgM increase supports a possible etiological role of C. pneumoniae in children.
Parratt, et al.  examined the frequency of C. pneuomoniae-specific immune complexes in patients with MS, patients with other neurological diseases, and healthy controls. They found C. pneumoniae immune complexes in 24% of MS patients, 16% of patients with other diseases, and 15% of normal controls. In people with recently diagnosed MS, the odds ratio for having C. pneumoniae was 4.33 (p=0.001). These data suggest strongly that systemic C. pneuomoniae infection is more common in patients with MS than patients with other neurological diseases or normal people. It also suggested that C. pneumoniae infections are much more common early in the course of MS. These data support an etiological role of C. pneumoniae in MS.
Contini, et al.  re-examined the CSF of 27 patients who had previously been reported to have C. pneumonia DNA in their CSF. Of these patients, 12 had MS and the rest had other neurological conditions. The repeat examination revealed C. pneumonia DNA in only two patients, both of whom has MS. In the rest, the C. pneumoniae was no longer present. This suggests that patients who do not develop MS clear out the C. pneuomoniae from their CSF while some patients who have MS do not clear out the C. pneumoniae from their CSF.
With such an accumulation of evidence implicating C. pneumoniae in MS, one wonders why the original suggestion by Sriram, et al.  to do a therapeutic trial had not been heeded. Wang, et al.  reported that macrolide antibiotics aggravate experimental autoimmune encephalomyelitis and inhibits inducible nitric oxide synthease. They suggested a comparison of other anti-chlamydial antibiotics in MS. Several common antibiotic used to treat chlamydial infections may have deleterious effects in patients with MS [21, 22]. Several antibiotics are known to modulate immune function [23, 24].
In 2005, Sriram, et al.  did a pilot study to examine the effects of antibiotic therapy on patients who have positive Chlamydia presence in their CSF. MRI outcomes in relapsing-remitting MS were obtained. After a 3 month run-in trial, patients were randomized to rifampin (300 mg twice daily) and azithromycin (500 mg every other day) for 6 months or placebo. While three of four patients treated with the antibiotic cleared the C. pneumoniae from their CSF compared to only one of four patients given placebo, there was no reduction in MRI lesions although the treated patients had less cerebral atrophy.
In the meantime, Contini, et al.  proposed that monocytes may traffic C. pneuomoniae across the blood brain barrier, shed the organism in the central nervous system, induce neuroinflammation, and contribute to a chronic persistent brain infection that plays a role not only in MS but in schizophrenia, autism, and Alzheimer’s disease. Other organisms that cause atypical pneumonias may also have CNS effects, including legionella  and of course Lyme’s disease. These diseases, however, do not present with MS. At the present, two clinical trials are recruiting subjects with MS to a trial to assess minocycline (NCT00666887, NCT01073813).
In summary, many studies suggest an association between MS and C. pneumoniae. While convincing evidence for an etiological (causative) role of C. pneuomoniae have not yet been achieved, the fact that several studies have shown that half or more of patients with MS have evidence of actual or previous C. pneumoniae infection in the cerebrospinal fluid, much more than people with other neurological diseases and healthy controls, indicate that it may play a significant role. C. pneumonia infections seem to be much more prevalent in patients that have just been diagnosed with MS. Finally, some tantalizing preliminary evidence suggest that antibiotics may reduce cerebral atrophy. This needs to be confirmed on a larger multicenter trial.
1. Pawate S and Sriram S (2010). The role of infections in the pathogenesis and course of multiple sclerosis. Annals of Indian Academy of Neurology 13: 80-6. Department of Neurology, Vanderbilt University Medical Center, Nashville, TN, USA. firstname.lastname@example.org. Interplay between susceptibility genes and environmental factors is considered important player in the genesis of multiple sclerosis (MS). Among environmental factors, a role for an infectious pathogen has long been considered central to the disease process. This opinion has support both from epidemiological data and the findings of immunological abnormalities in spinal fluid that reflect an immune response to an as yet undetermined antigen, possibly a pathogen, in the cerebrospinal fluid. Our review will outline the current understanding of the role of infection in the causation and progression of MS. We will review the data that point to an infectious cause of MS and consider the specific agents Chlamydophila (Chlamydia) pneumoniae, Human Herpes Virus 6, and Epstein-Barr Virus, that are implicated in either the development or progression of MS.
2. Le Gac P, Wulffaert F and Arquie E (1966). [The psittacosis virus in the etiology of multiple sclerosis]. Comptes rendus hebdomadaires des seances de l'Academie des sciences. Serie D: Sciences naturelles 263: 1793-5.
3. Lidegaard O and Svendsen AL (2008). Sexual habits before multiple sclerosis: a national case-control study. Multiple sclerosis 14: 67-72. Gynaecological Clinic 4232, Rigshospitalet, Copenhagen O, Denmark. Lidegaard@dadlnet.dk. The trigging off agent for multiple sclerosis (MS) is despite intensive epidemiological and biomedical research still unknown. The disease is typically diagnosed in reproductive age and recent findings have suggested that MS could be a sexually transmitted disease. AIM: To assess the influence of different sexual practices in young age on the risk of developing MS, and specifically to explore the possible impact of oral sex and oral sperm exposure on this risk. DESIGN: National case-control study. METHODS: Inclusion: Danish women with a first time MS discharge diagnosis from a neurological department at most 40 years old during the period 1998-2005, and an age and geographically matched control group. The response rate to our postal questionnaires was 75% for cases and 61% for controls. A total of 604/619 completed case/control questionnaires were included in the analysis. Data underwent logistic regression analysis. RESULTS: We found no difference between women with and without MS for years of schooling, oral herpes infections, genital herpes, blood transfusions, age at sexual debut, age at coital debut, number of sexual partners before and after age 20 years, anal sex, condyloma attack or chlamydia infections. Family disposition with an affected father, mother or sibling, increased the risk of MS 9.1, 6.9 and 4.1 times, respectively. A total of 68% of cases and of 72% of controls had oral sex sometimes or often before their 20th year. Among women entertaining oral sex, 53%, respectively, 54% had experienced oral sperm exposure. Also oral sex after 20 years was similar in women with and without MS. CONCLUSION: Neither oral sex in early reproductive age, oral sperm exposure, oral sex after 20 years, sexual debut, nor number of sexual partners had any association to the risk of later developing MS. This study does not support the hypothesis that MS is a sexually transmitted or acquired disease.
4. Perlmutter LJ and Darvish M (1983). Possible relationship of Chlamydia to multiple sclerosis. Medical hypotheses 12: 95-8. Multiple sclerosis is an acquired disease of the central nervous system, probably due to a transmissible factor, and characterized by pathological changes in the white matter of the brain and cord. These changes consist of loss of the myelin covering of the axons in the form of demyelinative plaques. Based on a review of the following studies, Chlamydia may indeed be one of the agents involved in the pathophysiology of multiple sclerosis.
5. Gilden DH (1999). Chlamydia: a role for multiple sclerosis or more confusion? Annals of neurology 46: 4-5.
6. Sriram S, Stratton CW, Yao S, Tharp A, Ding L, Bannan JD and Mitchell WM (1999). Chlamydia pneumoniae infection of the central nervous system in multiple sclerosis. Annals of neurology 46: 6-14. Department of Neurology, Vanderbilt School of Medicine, Nashville, TN, USA. Our identification of Chlamydia pneumoniae in the cerebrospinal fluid (CSF) of a patient with multiple sclerosis (MS) led us to examine the incidence of this organism in the CSF from 17 patients with relapsing-remitting MS, 20 patients with progressive MS, and 27 patients with other neurological diseases (OND). CSF samples were examined for C pneumoniae by culture, polymerase chain reaction assays, and CSF immunoglobulin (Ig) reactivity with C pneumoniae elementary body antigens. C pneumoniae was isolated from CSF in 64% of MS patients versus 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. Infection of the central nervous system with C pneumoniae is a frequent occurrence in MS patients. Although the organism could represent the pathogenetic agent of MS, it may simply represent a secondary infection of damaged central nervous system tissue. A therapeutic trial directed at eliminating C pneumoniae from the central nervous system may provide additional information on its role in MS.
7. Boman J, Roblin PM, Sundstrom P, Sandstrom M and Hammerschlag MR (2000). Failure to detect Chlamydia pneumoniae in the central nervous system of patients with MS. Neurology 54: 265. Department of Virology, Umea University, Sweden.
8. Pucci E, Taus C, Cartechini E, Morelli M, Giuliani G, Clementi M and Menzo S (2000). Lack of Chlamydia infection of the central nervous system in multiple sclerosis. Annals of neurology 48: 399-400.
9. Ke Z, Lu F, Roblin P, Boman J, Hammerschlag MR and Kalman B (2000). Lack of detectable Chlamydia pneumoniae in brain lesions of patients with multiple sclerosis. Annals of neurology 48: 400.
10. Hammerschlag MR, Ke Z, Lu F, Roblin P, Boman J and Kalman B (2000). Is Chlamydia pneumoniae present in brain lesions of patients with multiple sclerosis? Journal of clinical microbiology 38: 4274-6. Chlamydia Research Laboratory, Department of Pediatrics, Division of Infectious Diseases, SUNY Health Science Center at Brooklyn, Brooklyn, New York, USA. We investigated the presence of Chlamydia pneumoniae in 81 normal and pathological specimens obtained from postmortem brain tissues of patients with multiple sclerosis and with other neurological or nonneurological diseases. The assays used included PCR amplification of all DNA samples in the initial study. Culture and a second PCR amplification of the organism in a subset of 19 brain specimens were also performed in two separate laboratories. All results were negative. Thus, this study on a large number of brain tissues suggests that C. pneumoniae is not involved in inflammatory demyelination.
11. Tsai JC and Gilden DH (2001). Chlamydia pneumoniae and multiple sclerosis: no significant association. Trends in microbiology 9: 152-4. Dept of Microbiology and the Neuroscience Graduate Group, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA. The cause of multiple sclerosis (MS) is unknown. Despite indications from epidemiological and identical-twin studies that MS is infectious, no virus or other infectious agent has been tightly linked to disease. The isolation of Chlamydia pneumoniae from the cerebrospinal fluid (CSF) of MS patients and the detection of both Chlamydia-specific DNA and antibody in MS CSF have been reported. Other analyses of brain and CSF have shown no significant difference in C. pneumoniae-specific DNA or antibody between MS and control subjects. Recent work has revealed intrathecal production of C. pneumoniae-specific IgG in only 24% of MS patients compared with 5% of control patients. More importantly, the major CSF oligoclonal bands from MS patients did not react to C. pneumoniae.
12. Ikejima H, Haranaga S, Takemura H, Kamo T, Takahashi Y, Friedman H and Yamamoto Y (2001). PCR-based method for isolation and detection of Chlamydia pneumoniae DNA in cerebrospinal fluids. Clinical and diagnostic laboratory immunology 8: 499-502. Department of Medical Microbiology and Immunology, University of South Florida College of Medicine, Tampa, Florida 33612, USA. Since current studies indicate the possible involvement of Chlamydia pneumoniae in the pathogenesis of multiple sclerosis (MS), demonstration of C. pneumoniae in the cerebrospinal fluid (CSF) of patients with MS is highly desirable. However, there is controversy concerning the detection of C. pneumoniae in CSFs from MS patients due to the lack of a standard protocol for extraction and detection of C. pneumoniae DNA. In this regard, we attempted to establish a highly effective extraction protocol for C. pneumoniae DNA from CSFs utilizing a commercial kit and a PCR detection method. The extraction and PCR detection protocol established in this study succeeded in detecting as few as 20 C. pneumoniae organisms in 200 microl of mock CSF. The use of this protocol to detect C. pneumoniae DNA in CSFs revealed that 68% of CSF samples obtained from patients with MS were positive (11 out of 16 samples) for chlamydia DNA. Thus, the protocol established here is sensitive enough to detect chlamydia DNA from CSFs and can be used by other laboratories for evaluation of the presence of chlamydiae in CSFs because the protocol is based on the use of a commercial kit.
13. Yao SY, Ljunggren-Rose A, Stratton CW, Mitchell WM and Sriram S (2001). Regulation by IFN-beta of inducible nitric oxide synthase and interleukin-12/p40 in murine macrophages cultured in the presence of Chlamydia pneumoniae antigens. Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research 21: 137-46. Department of Neurology, Vanderbilt University School of Medicine, Nashville, TN 37212, USA. Chlamydia pneumoniae has been demonstrated in the cerebrospinal fluid (CSF) of patients with multiple sclerosis (MS). Interferon-beta (IFN-beta) has favorable effects on the clinical course of MS. We investigated whether the beneficial effects of IFN-beta in MS may involve its role in regulating nitric oxide (NO) and interleukin-12 (IL-12) in macrophages, as these immune modulators form part of the innate immune response to intracellular pathogens, such as C. pneumoniae. Murine macrophages in cultures exposed to elementary body antigens or recombinant major outer membrane protein (rMOMP) of C. pneumoniae demonstrate a significant increase in NO as well as production of IL-12/p40 in culture supernatants compared with basal levels. Addition of murine IFN-beta increased NO activity in murine macrophages cultured with chlamydial antigens. Addition of neutralizing anti-IFN-beta antibody prevented the NO increase. In contrast to its effect on inducible NO synthase (iNOS), IFN-beta reduced induction of IL-12/p40 following culture with either elementary body antigens or rMOMP. Inhibition was reversed with anti-IFN-beta antibody. If C. pneumoniae infection is responsible for the inflammatory response in the pathogenesis of MS, the beneficial effects of IFN-beta in MS may be due to its enhancing intracellular NO activity while inhibiting secretion of the proinflammatory cytokine, IL-12.
14. Bagos PG, Nikolopoulos G and Ioannidis A (2006). Chlamydia pneumoniae infection and the risk of multiple sclerosis: a meta-analysis. Multiple sclerosis 12: 397-411. Department of Cell Biology and Biophysics, Faculty of Biology, University of Athens, Panepistimiopolis, Athens, 15701, Greece. email@example.com. We conducted a meta-analysis of studies comparing the presence of Chlamydia pneumoniae (Cpn) between multiple sclerosis (MS) patients and other neurological diseases patients or healthy controls. We identified 26 studies with 1332 MS patients and 1464 controls. Using random-effects methods, MS patients were found more likely to have detectable levels of Cpn DNA (OR = 3.216; 95% CI: 1.204, 8.585) in their cerebrospinal fluid, and intrathecally synthesized immunoglobulins (OR = 3.842; 95% CI: 1.317, 11.212), compared to other patients with neurological diseases. There is no evidence for increased levels of serum immunoglobulins (OR = 1.068; 95% CI: 0.745, 1.530), even though this result is confounded by the presence of studies using normal subjects as controls. Similarly, there is no evidence for association of immunoglobulins against Cpn in the cerebrospinal fluid (OR = 3.815; 95% CI: 0.715, 20.369). Up to 59.7% of the between-studies variability could be explained by the inappropriate matching of cases and controls for gender. In random-effects meta-regressions, adjusting for the confounding effect of gender differences results in stronger and statistically significant associations of MS with detectable levels of Cpn DNA, intrathecally synthesized immunoglobulins and immunoglobulins in the cerebrospinal fluid. Even though the presence of Cpn is clearly more likely in MS patients, these findings are insufficient to establish an etiologic relation.
15. Pohl D, Rostasy K, Gieffers J, Maass M and Hanefeld F (2006). Recurrent optic neuritis associated with Chlamydia pneumoniae infection of the central nervous system. Developmental medicine and child neurology 48: 770-2. Department of Paediatrics and Paediatric Neurology, Georg August University Gottingen, Germany. It has been suggested that Chlamydia pneumoniae (C. pneumoniae) is involved in the pathogenesis of diverse diseases of the central nervous system (CNS), including multiple sclerosis. We report the case of a 12-year-old male with isolated recurrent optic neuritis and an associated CNS infection with C. pneumoniae. The patient presented with three attacks of optic neuritis within 5 months. A positive polymerase chain reaction for C. pneumoniae in the cerebrospinal fluid led to the diagnosis of a CNS infection with C. pneumoniae. After treatment with the antibiotic rifampicin, he experienced no further attacks during the follow-up period of 6 years. These findings suggest the possibility of a C. pneumoniae infection as a contributing factor or even causative event for the development of optic neuritis.
16. Stratton CW and Wheldon DB (2006). Multiple sclerosis: an infectious syndrome involving Chlamydophila pneumoniae. Trends in microbiology 14: 474-9. Department of Pathology, Vanderbilt University Medical Center, Nashville, TN 37232, USA. firstname.lastname@example.org. The concept of autoimmune myelinopathy as the primary pathology in multiple sclerosis (MS) is problematic. Vasculitis is seen in the MS brain, both within lesions and in adjacent normal-appearing white matter. The first observation in acute relapse is the sudden, orderly death of oligodendrocytes; inflammatory removal of unsupported myelin seems to be a secondary process. An alternative explanation for these findings is that oligodendrocyte infection might trigger an inflammatory response. Many pathogens, including Chlamydophila (Chlamydia) pneumoniae, have been associated with MS. MS might be an infectious syndrome in which C. pneumoniae has a role in a subset of patients. Mechanisms by which such a cryptic infection could engender relapsing-remitting and, ultimately, progressive disease patterns are discussed.
17. Krone B, Pohl D, Rostasy K, Kahler E, Brunner E, Oeffner F, Grange JM, Gartner J and Hanefeld F (2008). Common infectious agents in multiple sclerosis: a case-control study in children. Multiple sclerosis 14: 136-9. Department of Virology, Georg August University Goettingen,Germany. email@example.com. Environmental factors, in particular infections, have been linked with the risk of developing multiple sclerosis (MS). The association of Epstein-Barr virus infection with childhood onset of MS has been recently recognized. As other infections characteristically experienced during childhood have not yet been studied in larger cohorts of paediatric MS, we conducted a study on 152 German children with MS (age at onset <16 years) and matched controls in the hope of gaining evidence for their possible aetiological role in MS. Patterns of antibody responses were determined to a range of infections which, in prior studies principally on adult patients, had revealed possible associations with MS. In this study on children the serology of several infections showed associations with MS. In the exceptional case of Chlamydia pneumoniae there was a significantly higher prevalence of IgM antibody but, more typically, as in the case of influenza A, measles, parainfluenza 2, varicella/zoster viruses and particularly to the herpes simplex virus type 2 (HSV-2) lysate antigen, there were significantly higher concentrations of IgG antibody. Additional investigations, however, make it highly unlikely that a relevant number of children have experienced infections with HSV-2. In general this study supports and emphasizes a complex infectious and immunologic background of MS.
18. Parratt J, Tavendale R, O'Riordan J, Parratt D and Swingler R (2008). Chlamydia pneumoniae-specific serum immune complexes in patients with multiple sclerosis. Multiple sclerosis 14: 292-9. Department of Neurology, University of Sydney, Blackburn Building, Camperdown, Sydney, NSW 2006, Australia. firstname.lastname@example.org. The significance of Chlamydia pneumoniae infection in patients with multiple sclerosis (MS) is unclear. We determined the frequency of serum C. pneumoniae-specific immune complexes in patients with MS, neurological (OND) and healthy controls in a blinded, cross-sectional study. C. pneumoniae immune complexes were detected in 24% (38/156) of MS patients, 16% (11/69) of OND and 15% (77/499) of healthy controls. The odds ratio for all MS patients was 3.95 (95% CI: 2.15 to 7.24; P < 0.0001) accounting for the covariates: sex, age, socio-economic status and area of residence. The odds ratio for recently diagnosed MS patients was 4.33 (95% CI: 1.76 to 10.64; P = 0.001). Systemic C. pneumoniae infection is more frequent in MS patients than the healthy population and occurs early in the course of the disease.
19. Contini C, Seraceni S, Cultrera R, Castellazzi M, Granieri E and Fainardi E (2008). Molecular detection of Parachlamydia-like organisms in cerebrospinal fluid of patients with multiple sclerosis. Multiple sclerosis 14: 564-6. Section of Infectious Diseases, Department of Clinical and Experimental Medicine, University of Ferrara, Ferrara, Italy. email@example.com. The presence of Chlamydia-like organism DNA was investigated by polymerase chain reaction (PCR) in cerebrospinal fluid (CSF) samples from 27 patients previously found positive for Chlamydia pneumoniae DNA: 12 with multiple sclerosis (MS), grouped according to clinical and magnetic resonance imaging (MRI) evidence of disease activity, 8 with other inflammatory neurological disorders and 7 with non-inflammatory neurological disorders. PCR evidence of Chlamydia-like organisms in CSF was observed only in two relapsing-remitting MS patients with clinical and MRI disease activity. These findings suggest a possible association between C. pneumoniae and Chlamydia-like organism brain infections as a cofactor in MS development.
20. Wang D, Lu Z, Hu L, Zhang Y and Hu X (2009). Macrolide antibiotics aggravate experimental autoimmune encephalomyelitis and inhibit inducible nitric oxide synthase. Immunological investigations 38: 602-12. Department of Neurology, The Third Affiliated hospital of Sun Yat-sen University, Guangzhou, China. Recent studies have implicated Chlamydia pneumoniae (C. pneumoniae) is present in a subset of patients with multiple sclerosis (MS) in which C. pneumoniae could act as a cofactor in the development of the disease. Macrolide antibiotics are most widely used anti-chlamydial agents and have immunomodulatory effect independently of their anti-bacterial activity. To investigate their effects on experimental autoimmune encephalomyelitis (EAE), EAE was induced by immunization with MBP68-86 peptide emulsified in complete Freund's adjuvant (CFA). Clarithromycin (CM) or azithromycin (AM, 50 mg/100 g body weight) was administrated daily from day 2 before immunization. All rats developed and survived EAE, but the groups administrated CM or AM had more severe symptoms. On day 11 post-immunization, mononuclear cells (MNCs) were prepared from the spleen of control group and cultured with or without macrolide antibiotics (10mug/ml). We evaluated nitric oxide (NO) production in the serum and culture supernatant. Inducible nitric oxide synthase (iNOS) mRNA and protein expression in the spinal cords and cultured MNCs were measured. The results showed that CM and AM similarly inhibited NO production and iNOS mRNA and protein expression in vivo and in vitro. Macrolide antibiotics may aggravate EAE by inhibiting iNOS mRNA and protein expression. Further studies are needed to investigate the effect of macrolide antibiotics on MS and to compare the effect of different anti-chlamydial antibiotics on MS.
21. Holdiness MR (1987). Neurological manifestations and toxicities of the antituberculosis drugs. A review. Medical toxicology 2: 33-51. The neurological manifestations and toxicities of 12 antituberculosis drugs [isoniazid, rifampicin (rifampin), ethambutol, p-aminosalicylic acid, pyrazinamide, streptomycin, kanamycin, ethionamide, cycloserine, capreomycin, viomycin and thiacetazone] are reviewed. Their effects upon the central nervous system, cranial nerves, peripheral nerves and the neuromuscular junction are examined, and drug interactions of neurological concern are briefly discussed. Isoniazid is well known to increase the concentrations of gamma-aminobutyric acid in neural tissues. Although conflicting data have been published, isoniazid may play a limited future role in reducing the degree of adventitious movements noted in certain neurological diseases such as multiple sclerosis, spasmodic torticollis, and other segmental dystonic syndromes. With rifampicin neurological complications have been observed infrequently. Rifampicin penetrates into the CSF and has been shown to have useful activity against various micro-organisms in the CSF, including certain viruses; however, contrary to earlier suggestions, it appears to have no role in the treatment of subacute sclerosing panencephalitis. A number of studies have indicated that isoniazid is associated with a large number of accidental and intentional poisonings. The highest incidence has been observed with Southwestern American Indians in which this agent was involved in 7% of all suicide attempts and 19% of the suicide deaths. Degeneration of the optic chiasma and nerve is a well-known adverse effect of ethambutol; toxicity is manifested by impairment of visual acuity, marked loss of colour discrimination, constricted visual fields, and central and peripheral scotoma. Ototoxicity is a well known problem caused by streptomycin, kanamycin, capreomycin and viomycin. The use of streptomycin in pregnant mothers is associated with congenital deafness in newborns in certain cases. The aminoglycoside antibiotics are also associated with flaccid paralysis following neuromuscular blockade. Adverse reactions to cycloserine are mainly dose-related with neurological and psychiatric syndromes noted in up to 50% of patients. Recent data indicate that isoniazid, rifampicin, ethambutol, pyrazinamide, streptomycin, kanamycin, ethionamide, and cycloserine appear in measurable quantities in the cerebrospinal fluid. Five of these compounds (isoniazid, rifampicin, ethambutol, kanamycin, cycloserine) pass to some degree through non-inflamed meninges. Other than discontinuation of the therapeutic regimen and general supportive measures, very few methods are described in the literature for treatment of acute intoxications with antituberculosis drugs.
22. Noguera-Pons R, Borras-Blasco J, Romero-Crespo I, Anton-Torres R, Navarro-Ruiz A and Gonzalez-Ferrandez JA (2005). Optic neuritis with concurrent etanercept and isoniazid therapy. The Annals of pharmacotherapy 39: 2131-5. Rheumatology Section, Hospital General Universitario de Elche, Alicante, Spain. OBJECTIVE: To report a case of optic neuritis associated with concurrent etanercept and isoniazid therapy. CASE SUMMARY: A 55-year-old man diagnosed as having rheumatoid arthritis had received treatment with nonsteroidal antiinflammatory drugs, sulfasalazine, oral methotrexate, leflunomide, and deflazacort. Four months prior to admission, he had a Disease Activity Score of 6.06; treatment with etanercept was considered. Three months prior to admission, because of evidence of latent tuberculosis, isoniazid 300 mg once daily and pyridoxine 50 mg once daily were prescribed. Treatment with subcutaneous etanercept 25 mg twice weekly was started 5 days after isoniazid was initiated. Two weeks prior to admission, the patient developed blurred vision in his left eye. Ten days later, his vision worsened and he was hospitalized. The visual acuity in both eyes was 0.7, and a campimetric examination was compatible with optic neuritis. Magnetic resonance imaging of the brain revealed lesions suggesting demyelinating lesions. The clinical course was consistent with bilateral optic neuritis. Etanercept was stopped, and isoniazid was replaced with rifampin 600 mg once daily. The patient was treated with intravenous methylprednisolone hemisuccinate 1 g/day for 5 days followed by oral prednisolone, resulting in a minor subjective improvement in left eye visual acuity. He then received oral prednisone for 3 weeks, slowly tapering to discontinuation. DISCUSSION: No physiologic factors could have predisposed this patient to develop optic neuritis. He was not diagnosed with a demyelinating disease or underlying systemic condition. The optic neuritis was unlikely to be an early manifestation of multiple sclerosis based on the clinical course and the negative results of the imaging tests. Furthermore, there was a close temporal correlation between the drug exposure and the onset of symptoms. After discontinuation of etanercept and isoniazid therapy, the patient's general condition improved. Use of the Naranjo probability scale indicated a possible relationship between optic neuritis and combined etanercept-isoniazid therapy. CONCLUSIONS: Patients initiated on etanercept and isoniazid should be closely monitored for the development of adverse neurologic signs and effects. If optic neuritis is determined, etanercept and isoniazid should be discontinued immediately.
23. Herrmann I, Kellert M, Spreer A, Gerber J, Eiffert H, Prinz M and Nau R (2007). Minocycline delays but does not attenuate the course of experimental autoimmune encephalomyelitis in Streptococcus pneumoniae-infected mice. The Journal of antimicrobial chemotherapy 59: 74-9. Department of Neurology, Georg August University, D-37075 Gottingen, Germany. OBJECTIVES: Experimental autoimmune encephalomyelitis (EAE), the animal model of multiple sclerosis (MS), can be aggravated by a mild Streptococcus pneumoniae infection. This study was performed to assess whether treatment with antibiotics inhibiting bacterial protein synthesis reduces the detrimental effect of infection on the course of EAE. METHODS: In vitro, release of proinflammatory pneumococcal products was studied by enzyme immunoassay and western blot. Seven days after induction of EAE (prior to the onset of symptoms) mice were infected intraperitoneally with S. pneumoniae and treated either with the inhibitors of bacterial protein synthesis minocycline or rifampicin, or with the beta-lactam ceftriaxone. RESULTS: During bacterial killing in vitro, minocycline and rifampicin released lower quantities of proinflammatory bacterial products from S. pneumoniae than ceftriaxone. Mice treated with minocycline developed symptoms of EAE 1 day later than mice treated with ceftriaxone. Neither minocycline nor rifampicin therapy, however, reduced the severity of EAE in comparison with ceftriaxone treatment. CONCLUSIONS: Although statistically significant (P = 0.04), a delay of 1 day in the onset of symptoms of EAE after minocycline treatment is of minor clinical relevance. These data do not support the hypothesis of superiority of a bacterial protein synthesis inhibitor over a beta-lactam antibiotic for the treatment of concomitant infections during the latent phase of EAE or MS.
24. Tauber SC and Nau R (2008). Immunomodulatory properties of antibiotics. Curr Mol Pharmacol 1: 68-79. Department of Neurology, Georg-August-University, Gottingen, Germany. There is growing evidence that certain antibiotics exert their beneficial effects not only by killing or inhibiting the growth of bacterial pathogens but also indirectly by immunomodulation. This review aims at giving an overview of the immunomodulatory properties of antibiotics in different diseases: The antiinflammatory properties of macrolides in chronic inflammatory pulmonary disorders were recognized more than 15 years ago and have been well documented in the last decade. Recent data suggest that several antibiotics such as tetracyclines and cephalosporins may have a beneficial immunomodulatory or neuroprotective effect on neuroimmunological and neurodegenerative diseases including multiple sclerosis and amyotrophic lateral sclerosis. Moreover, the non-bacteriolytic but bactericidal antibiotics rifampicin, clindamycin and aminoglycosides kill bacteria without releasing high quantities of proinflammtory cell wall components. The use of bactericidal, non-bacteriolytic protein synthesis inhibitors reduces mortality and long-term sequelae in experimental bacterial sepsis, plague and meningitis. Clinically, macrolides have been well established as an adjunctive treatment to beta-lactam antibiotics in pulmonary diseases. For other indications, appropriate clinical trials are necessary before using the immunomodulatory properties of antibiotics in clinical practice.
25. Sriram S, Yao SY, Stratton C, Moses H, Narayana PA and Wolinsky JS (2005). Pilot study to examine the effect of antibiotic therapy on MRI outcomes in RRMS. Journal of the neurological sciences 234: 87-91. Department of Pathology, Vanderbilt University Medical Center, Nashville, TN 37212, USA. firstname.lastname@example.org. This trial examined the safety and possible MRI and clinical effects of anti-chlamydial antibiotic therapy in relapsing-remitting MS (RRMS). Newly diagnosed MS patients were selected to participate if they showed Chlamydia pneumoniae gene in their CSF and had one or more enhancing lesions on brain magnetic resonance imaging (MRI). After a 4-month run in phase of monthly MRI, patients were randomized to receive rifampin (300 mg twice daily) and azithromycin (500 mg every other day) for 6 months or placebo (PBO). Patients then had monthly MRI on therapy and two additional scans on months 12 and 14. Lumbar punctures were repeated between months 7 and 8 and within 2 weeks of termination of the study. Data on 4 patients on treatment and 4 on PBO were available for analysis. The primary outcome measure of showing a beneficial effect on enhancing lesions was not met. However, there was a significant difference in brain parenchymal fraction loss favoring those patient receiving antibiotics compared with PBO (p< or =0.02). Three of the four patients on antibiotic therapy cleared the organism from the CSF by month 12; in the PBO group one patient cleared the organism. The reduction in atrophy in patients receiving antibiotics must be viewed with caution, due to the small number of patients studied.
26. Contini C, Seraceni S, Cultrera R, Castellazzi M, Granieri E and Fainardi E (2010). Chlamydophila pneumoniae Infection and Its Role in Neurological Disorders. Interdisciplinary perspectives on infectious diseases 2010: 273573. Section of Infectious Diseases, Department of Clinical and Experimental Medicine, University of Ferrara, Via Fossato di Mortara, 23, 44100 Ferrara, Italy. Chlamydophila pneumoniae is an intracellular pathogen responsible for a number of different acute and chronic infections. The recent deepening of knowledge on the biology and the use of increasingly more sensitive and specific molecular techniques has allowed demonstration of C. pneumoniae in a large number of persons suffering from different diseases including cardiovascular (atherosclerosis and stroke) and central nervous system (CNS) disorders. Despite this, many important issues remain unanswered with regard to the role that C. pneumoniae may play in initiating atheroma or in the progression of the disease. A growing body of evidence concerns the involvement of this pathogen in chronic neurological disorders and particularly in Alzheimer's disease (AD) and Multiple Sclerosis (MS). Monocytes may traffic C. pneumoniae across the blood-brain-barrier, shed the organism in the CNS and induce neuroinflammation. The demonstration of C. pneumoniae by histopathological, molecular and culture techniques in the late-onset AD dementia has suggested a relationship between CNS infection with C. pneumoniae and the AD neuropathogenesis. In particular subsets of MS patients, C. pneumoniae could induce a chronic persistent brain infection acting as a cofactor in the development of the disease. The role of Chlamydia in the pathogenesis of mental or neurobehavioral disorders including schizophrenia and autism is uncertain and fragmentary and will require further confirmation.
27. Cunha BA (2006). The atypical pneumonias: clinical diagnosis and importance. Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases 12 Suppl 3: 12-24. Infectious Disease Division, Winthrop-University Hospital, Mineola, New York 11501, USA. The most common atypical pneumonias are caused by three zoonotic pathogens, Chlamydia psittaci (psittacosis), Francisella tularensis (tularemia), and Coxiella burnetii (Q fever), and three nonzoonotic pathogens, Chlamydia pneumoniae, Mycoplasma pneumoniae, and Legionella. These atypical agents, unlike the typical pathogens, often cause extrapulmonary manifestations. Atypical CAPs are systemic infectious diseases with a pulmonary component and may be differentiated clinically from typical CAPs by the pattern of extrapulmonary organ involvement which is characteristic for each atypical CAP. Zoonotic pneumonias may be eliminated from diagnostic consideration with a negative contact history. The commonest clinical problem is to differentiate legionnaire's disease from typical CAP as well as from C. pneumoniae or M. pneumonia infection. Legionella is the most important atypical pathogen in terms of severity. It may be clinically differentiated from typical CAP and other atypical pathogens by the use of a weighted point system of syndromic diagnosis based on the characteristic pattern of extrapulmonary features. Because legionnaire's disease often presents as severe CAP, a presumptive diagnosis of Legionella should prompt specific testing and empirical anti-Legionella therapy such as the Winthrop-University Hospital Infectious Disease Division's weighted point score system. Most atypical pathogens are difficult or dangerous to isolate and a definitive laboratory diagnosis is usually based on indirect, i.e., direct flourescent antibody (DFA), indirect flourescent antibody (IFA). Atypical CAP is virtually always monomicrobial; increased IFA IgG tests indicate past exposure and not concurrent infection. Anti-Legionella antibiotics include macrolides, doxycycline, rifampin, quinolones, and telithromycin. The drugs with the highest level of anti-Legionella activity are quinolones and telithromycin. Therapy is usually continued for 2 weeks if potent anti-Legionella drugs are used. In adults, M. pneumoniae and C. pneumoniae may exacerbate or cause asthma. The importance of the atypical pneumonias is not related to their frequency (approximately 15% of CAPs), but to difficulties in their diagnosis, and their nonresponsiveness to beta-lactam therapy. Because of the potential role of C. pneumoniae in coronary artery disease and multiple sclerosis (MS), and the role of M. pneumoniae and C. pneumoniae in causing or exacerbating asthma, atypical CAPs also have public health importance.