Multiple Sclerosis

Disease Burden

The impact of MS is best summarized by one of the experts in infectious MS, Dr. Charles W. Stratton, in his recent review article entitled “A Review of Multiple Sclerosis as an Infectious Syndrome”.

“Multiple sclerosis (MS) is a chronic neuroinflammatory disease that is characterized by progressive, inflammatory, and multifocal demyelination of the brain and spinal cord. MS affects approximately 2.5 million people worldwide, with women being afflicted twice as frequently as men. Importantly, young adults are the primary groups afflicted with MS: the average age of diseases onset is 30 years, with half of these patients requiring a wheelchair within 25 years of their diagnosis. The onset and progression of MS in young adults places a considerable economic burden on these patients, their families, as well as on health and social resources.”

Dr. David Wheldon: Halting MS

Dr. Wheldon successfully treated his wife’s MS with antibiotics.  This video chronicles her treatment, the research that backs this treatment protocol and the barriers that exist in the medical community.  Cases like this demand attention and highlight a valid, long-overdue question:

How many MS cases are treatable with antibiotics?

Expert Opinion

In the conclusion of his comprehensive review, Dr. Stratton states:
“Regardless of which infectious triggers may be involved, MS should be considered to be an infectious syndrome that involves a neurodegenerative process resulting in an autoimmune disease.  Identification of each potential infectious trigger described in this review early in the course of MS might allow appropriate antimicrobial intervention as has been done with at least one of these triggers, C. pneumoniae.  Future studies in MS should identify each of these potential infectious triggers early in the course of MS.  Such identification might then allow appropriate antimicrobial therapy.  Moreover, stratification of MS based on specific infectious triggers would allow specific clinical trials that are focused on each pathogen.”

Take Action

With such a debilitating disease, why not continue to test this established concept of infectious causation?  Much like the landscape in Alzheimer’s Disease, large antimicrobial trials are called for based upon current literature.  The biggest issue is funding as the therapies to address infection, regardless of the pathogen, are largely generic.  Even chemotherapeutic agents have been investigated in the treatment of MS.  This highlights the severity of the disease when the risk-benefit ratio tips the scales in favor of chemo.  Clearly, there is an unmet need, and few would argue the relative safety of antimicrobial therapy (be it antibiotics or antivirals) compared with chemotherapeutics.  There is one thing we can all agree on: MS is a horrific disease and we owe it to patients to leave no stone unturned in the quest to find a cure.

Research Studies

Detection of Chlamydial Bodies and Antigens in the Central Nervous System of Patients with Multiple Sclerosis
n= 20 MS cases and 12 other Neurological Diseases (OND), The Journal of Infectious Diseases, 2005.
Methods- post-mortem brain tissue and CSF from MS and OND cases analyzed for the presence of Chlamydia pneumoniae using Immunohistochemistry (IHC), electron microscopy, and PCR.
Results- Chlamydia pneumonaie was confirmed via IHC, electron microscopy and PCR in a significant number of MS cases.
Conclusion- though this does not definitely prove causation between C. pneumoniae and MS, Chlamydial antigens may prove to be a trigger to MS leading to auto-immune involvement.

Infection with Chlamydia pneumoniae and risk of multiple sclerosis.
Nested, case-control analysis, n=62,548 women (141 with MS), Epidemiology, 2003.
Methods- serum samples assessed for Cpn-specific immunoglobulin G antibodies is MS cases versus two healthy, age-matched controls.
Results- Cpn IgG seropositivity was positively associated with risk of MS.  The association with relapsing-remitting MS was moderate while the association with progressive MS was strong.
Conclusion- These results prove a positive association between CpN infection and progressive MS.

PCR analysis of Cerebrospinal fluid, n=27, Multiple Sclerosis, 2008.

Methods- CSF samples obtained by lumbar puncture performed with appropriate clinical indications from 12 patients with MS and 15 controls previously analyzed for C. pneumoniae DNA and PCR positive for either major outer membrane protein (MOMP) or 16s rRNA chlamydial genes.  The control group had other inflammatory or non-inflammatory neurologic disorders.
Results- PCR evidence of Chlamydia-like organisms in CSF was observed in two relapsing–remitting MS patients with clinical and MRI disease activity.
Conclusion- These findings suggest a possible association between CpN and Chlamydia-like organism brain infections as a cofactor in MS development.

Pilot study to examine the effect of antibiotic therapy on MRI outcomes in RRMS
Randomized, double-blind, placebo-controlled, parallel group study in patients with recently diagnosed MS, n= 8, Journal of Neurological Sciences, 2005.
Methods- RRMS (relapsing-remitting) patients with an EDSS of < 4.5, a positive PCR signal for C. pneumoniae in CSF and at least one enhancing lesion on a brain MRI at entry were enrolled.  Placebo vs Rifampin 300mg BID plus Azithromycin 500mg every other day for 6 months with monthly MRIs.
Results- There was no statistical difference in either the number or the volume of the enhancing lesions noted when comparing the three different epochs (pre-treatment, on treatment and post-treatment); the primary outcome measure of the study was not met. Three of four patients who received antibiotics showed a decrease in the volume of enhancing lesions, while in the fourth patient in whom there was no decrease.  However, there was a significant difference in brain parenchymal fraction loss favoring those patient receiving antibiotics compared with PBO ( p≤ 0.02).
Conclusion- The reduction in atrophy in patients receiving antibiotics must be viewed with caution, due to the small number of patients studied.  In spite of the small number,  this preliminary study suggests unexpected stabilization in brain atrophy. These results mirror the results of a study done with RRMS and scheduled pulsed intravenous methylprednisolone (IVMP).  A larger trial is needed to determine the potential benefit of antimicrobial therapy.

Increased prevalence of and gene transcription by Chlamydia pneumoniae in cerebrospinal fluid of patients with relapsing-remitting multiple sclerosis
Pilot study using nested PCR to detect ompA gene sequences of C. pneumoniae in CSF, n=84 with definitive MS and 87 with other neurologic diseases (OND), Journal of Neurology 2004.
Methods- nested polymerase chain reaction (PCR) to detect ompA gene sequences of C. pneumoniae. In subjects with positive PCR, probed for chlamydial heat shock protein 60-mRNA and 16S-rRNA by reverse transcriptase (rt)-PCR.
Results- C. pneumoniae (CpN)specific DNA was more often detected in MS patients (50 %) than in all OND patients combined (28.1 %, p = 0.003) and in OND patients with normal CSF (24.2 %, p = 0.003) but not than in OND patients with pathological CSF (37 %, p = 0.24). In relapsing-remitting MS (n = 55), the prevalence of CpN DNA was higher (66.7 %) than in both OND subgroups (p ≤ 0.05). In MS patients (n = 20), chlamydial heat shock protein 60-mRNA (75 %) and 16S-rRNA (70 %) were more often detected than in OND patients (n = 16; 18.8 %; p < 0.005)
Conclusion- Although more often detected in remitting-relapsing MS, CpN DNA in CSF is not specific for MS, it also has a high prevalence in OND controls. However, the higher rate of gene transcription suggests a more active metabolism of C. pneumoniae in MS patients.  An interesting thought given these results is what role CpN plays in the OND control group disease pathology, and how these results would compare with CSF of healthy volunteers (free of neurologic disease).

CCSVI is associated with multiple sclerosis
Meta-analysis of fourteen published studies on prevalence of CCSVI in MS patients, Neurological Research, 2013.
Methods- revised methodology and results from all 14 trials on CCSVI in MS.
Results- great variability in prevalence of CCSVI in MS in previous studies, however, a recent meta-analysis showed a >13 times prevalence in MS.  Global hyoperfusion, reduced CSF dynamics, and higher post-mortem findings of intraluminal defects in the main extracranial vein in MS compared to controls.
Conclusions- CCSVI can be added to the list of factors in MS pathogenesis based upon these data.

Review Papers

A Review of Multiple Sclerosis as an Infectious Syndrome
Abstract-“Multiple sclerosis (MS) is a chronic neuroinflammatory disease of the central nervous system (CNS) that is generally considered to be an autoimmune myelitis of unknown etiology. Epidemiological studies suggest that infection may act as a trigger on a predisposing genetic background. A number of causative agents have been considered. This review will focus on the pathogenesis of MS and link this pathophysiology to infectious agents that have been implicated as possible co-factors. By doing so, MS will be viewed as an infectious syndrome that involves a CNS infection that results in a neurodegenerative process as well as an autoimmune disease. Early detection of infectious triggers could allow appropriate intervention and thus improved outcomes.”

Role of Chlamydophila pneumoniae in the Pathogenesis of Chronic Cerebrospinal Venous Insuffiency in Patients with Multiple Sclerosis
Abstract- “Although the aetiology of Multiple Sclerosis (MS) is unknown, genetic and environmental factors including infectious agents may play a role in the development of this disease. Recent studies have demonstrated chronic cerebrospinal venous insufficiency (CCSVI) as a potential factor in the pathogenesis of clinically defined MS but current evidence does not support a substantial role of CCSVI in the pathogenesis of the classic MS lesions. As the association of Chlamydophila pneumoniae with vascular infections and endothelial dysfunction due to inflammation is well known, C. pneumoniae could be implicated in the development of CCSVI. This hypothesis is based on the ability of this pathogen to infect venous endothelial cells that could contribute to an inflammatory-autoimmune process in venous tissue leading to the venous anomalies (venous stenosis/occlusions) described in CCSVI. In fact, besides the recognized infection by C. pneunoniae of a large variety of cells including alveolar epithelial cells, macrophages, dendritic cells, B and T-cells, neuronal glia and neuronal ependymal cells, this pathogen may also infect vascular endothelial cells in venous tissues. Such an infection/inflammation of venous vascular tissues could contribute to the inflammatory-autoimmune disease causing the venous abnormalities described in the so-called CCSVI.”

Multiple sclerosis: an infectious syndrome involving Chlamydophila pneumoniae.
Abstract- “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.”