Student guest post by Raj Nair.
Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease that affects the central nervous system (CNS) consisting of the brain and the spinal cord . It is thought to be an autoimmune disease since individual’s immune system attacks their own healthy tissues . However, studies to ascertain triggering factors such as genetic, environmental, and infectious causes are still in progress . So one wonders “Who is more susceptible to develop MS” Literature reveals that typically people between 20 and 50 years of age are commonly diagnosed with MS, affects more women than men, and Caucasians of Northern European ancestry are more prone to develop this disease [1, 2]. Knowledge on the pathophysiology of this disease is that immune system attacks myelin, which forms a protective coat surrounding the nerve fibers of the brain and the spinal cord . The myelin sheath can be compared to insulation around an electrical wire. Loss of this protective layer impedes transmission of nerve signals . Consequences of this damaged connection are the spectrum of symptoms seen in MS. Some of these symptoms are blurred vision, loss of balance, poor coordination, extreme fatigue, tremors, loss of sensation or odd sensations (pin and needle sensations), slurred speech, blindness, difficulty concentrating, poor memory and judgment, and in severe cases paralysis . However, every person is wired differently and so these symptoms are not consistently seen in all patients with MS . Considering all of the above facts my guess is symptoms may vary depending on a person’s immune system and the external or other internal factors governing their immune system. The disease is rarely fatal and most of the people are only mildly affected. Moreover, most of the affected people remit spontaneously .
Why should anyone care…. Because MS is unpredictable [1,3], there is no universal cure for the disease , can be a chronic condition , possibility of disease recurrence , and the most important being ‘a single cause’ for the disease has not been identified. As in all diseases with multiple interacting causes, in MS too there is no single pathogen or environment to complete its disease triad. Evidence has it that the disease is more common in Northern America and Canada demonstrating a north-south gradient . Migration studies have established that risk for acquiring MS remains unchanged for those who move from a high prevalence area after age 15, while risk decreased for those who moved at an earlier age . In addition, the genetic angle has been studied by conducting twin studies and studies on specific types of genes. Results yielded prove that genetics can lead to an increase in MS susceptibility but probably not cause MS . In order to make more sense of all the above susceptibility factors and with my interest in infectious causes of diseases, I decided to probe into existing infectious perspectives on MS.
History has it that in 1868, Jean Marie Charcot described the first human demyelinating disease, Multiple Sclerosis. It was postulated then that the disease was a result of exposure to dampness or injuries or emotional stress. However, in the era of microbiological advances, one of Charcot’s students postulated an infectious etiology for MS . Moreover, the CNS pathology and presence of IgG antibodies and oligoclonal bands are known to be consistent with an infectious or immune mediated neurological disorder . Several infectious agents such as Epstein Barr virus, Canine Distemper virus (CDV), measles virus, Chlamydia pneumoniae, Varicella, Human Herpesvirus-6 (HHV-6), and mumps virus have been associated with MS. Viruses win hands down against bacteria in having a strong association with MS. Studies have a tilt towards a viral cause of MS due to the following reasons: low concordance of MS in monozygotic twins similar to what was seen in paralytic poliomyelitis (also a viral infection), spontaneous viral models of CNS demyelination, and increased titers of viral antibodies in MS patients (particularly measles virus). However, these associations can only be strengthened using criteria such as consistency of association across studies, biological plausibility, temporal association, specificity and dose -response relation (epidemiologists know these are the Bradford-Hills criteria!) I will briefly attempt to establish the causal role of CDV in development of MS. Reason I chose this virus? I lost my pet dog to Old Dog Encephalitis (ODE) due to chronic CDV infection. Now I am left thinking ‘Am I or any of my family member’s ideal candidates for developing MS later in life?”
CDV is an RNA virus belonging to the family of Paramyxoviridiae, is closely related to the measles virus in humans and is the most neurotropic form of morbillivirus. As observed in the measles virus, CDV can jump species  and causes fatal CNS demyelination in animals including primates . However, the catch-22 is that there has not been one virus (measles or CDV) consistently detected in samples from MS patients to prove its causal role. To make things worse, there is a possibility of cross-reaction in testing for CDV and measles virus using molecular techniques in samples obtained from MS patients [10, 13]. Neutralization assay used to identify viral antibodies in patients have shown considerable variation in the CDV/measles antibodies ratio [10, 11]. This implies that there is a potential for CDV to produce undiagnosed or subclinical human infections . To explain MS on the basis of owning dogs per se, several studies have observed that significantly higher proportion of dogs were kept indoors in the colder northern United States as compared to the southern and western region . This may explain the north-south gradient noted in the prevalence of MS. So logically, greater exposure to dogs before onset of neurological symptoms was expected. However, this phenomenon could not be studied well using case-control studies owing to the higher exposure of humans to dogs in Western countries particularly the United States .
An interesting aspect studied was exposure to CDV infected dogs. Most of these studies yielded significant exposure to dogs with distemper-like illness at least 5-10 years before development of MS [12, 14]. Historically other studies have shown significant increase in MS incidence rates preceded by a CDV epidemic in locations such as Newfoundland , Key West , Sitka , and the Faroe Islands. One of the most interesting readings was a study conducted to determine environmental changes implemented that may have lead to a reduction in MS incidence in Key West . An animal shelter on the island which was used to dump euthanized dogs was shut down. This change was said to have attributed to reduction in the MS incidence on the island.
With all of the above evidence and in context with the Hills criteria, I will conclude that there is biological plausibility of CDV playing a causal role in development of MS owing to the demyelinating nature of illness caused by this virus. In addition, this virus still causes disease in dogs despite the widespread use of vaccines . This reinforces the possibility of contracting the virus via exposure to infected dogs (zoonotic disease). However, temporal association could not be established between the virus and occurrence of MS. This may be due to the fact that there are other viruses too causing demyelinating diseases such as measles and HIV, which have a well established role in human diseases. Similar symptoms of demyelinating diseases caused due to viruses other than CDV may have resulted in incorrect estimation of MS prevalence or incidence. There is some consistency among case-control studies which demonstrate exposure to CDV or dogs before the development of MS. However, owing to chronic nature of the CDV these studies do not really make a concrete argument for the role of this virus in MS causation. There does not seem to be any study conducted to examine a dose-response relation of the virus with respect to development of MS. In lieu of the above evidence, a criterion of specificity has been wasted and is best overlooked.
So one real conclusion from observations made so far is that CDV may be responsible for the causation of MS. However, it is definitely not the only factor in the causal pathway. This implies that CDV may be a necessary factor in the development of MS as could be other infectious agents (bacterial or viral). However, an individual’s environment, genetics and immune system are other sufficient factors crucial in disease causation. Also I take this opportunity to highlight the cause ‘Take good care of your pet dog and yourself’. It is the rule of nature, “What goes around, comes around”.
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