Chronic Bacterial and Viral Infections in Neurodegenerative and Neurobehavioral Diseases

Garth L. Nicolson, PhD

Disclosures

Lab Med. 2008;39(5):291-299. 

In This Article

Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is an adult-onset, idopathic, progressive neurodegenerative disease affecting both central and peripheral motor neurons. Patients with ALS show gradual progressive weakness and paralysis of muscles due to destruction of upper motor neurons in the motor cortex and lower motor neurons in the brain stem and spinal cord, ultimately resulting in death, usually by respiratory failure.[19,20] The overall clinical picture of ALS can vary, depending on the location and progression of pathological changes found in nervous tissue.[21]

In ALS, the role of chronic infections has attracted attention with the finding of enterovirus sequences in a majority of spinal cord samples by polymerase chain reaction (PCR).[22,23] This finding is not without controversy, since others failed to detect enterovirus sequences in spinal cord samples from patients with or without ALS.[24,25] Nonetheless, infectious agents that penetrate the CNS may play a role in the etiology of ALS, although evidence for a transmission of an infectious agent or transfer of an ALS-like disease from man-to-man or man-to-animal has not been demonstrated.[26]

The presence of systemic mycoplasmal infections in ALS patients has been investigated with PCR methods.[27,28] Our studies indicated that 100% of Gulf War veterans diagnosed with ALS (N=8 from 3 different nations) had systemic mycoplasmal infections.[27] All but 1 patient had Mycoplasma fermentans, and 1 veteran from Australia had a systemic M. genitalium infection. In approximately 80% of nonmilitary (unrelated to military patients) ALS patients from the United States, Canada, and Great Britain (N=28), blood mycoplasmal infections were also found.[27] Of the mycoplasma-positive civilian patients who were further tested for M. penetrans, M. fermentans, M. hominis, and M. pneumoniae, most were positive for M. fermentans (59%), but other Mycoplasma species, such as M. hominis (31%) and M. pneumoniae infections (9%), were also found. Some of the civilian ALS patients had multiple mycoplasmal infections; however, multiple mycoplasmal infections were not found in the military patients with ALS.[27] In another study in Mexico, 10 of 20 ALS patients showed evidence of systemic Mycoplasma species by analysis of their blood by PCR.[28]

Another chronic infection that is commonly found in ALS patients who live in certain areas is Borrelia burgdorferi, the principal etiologic agent of Lyme disease (LD). For example, ALS patients who live in New York, an LD-intense area, were examined for B. burgdorferi infections, and over one-half were found to be seropositive for Lyme Borrelia compared with 10% of matched controls.[29] In addition, some patients diagnosed with ALS were subsequently diagnosed with neuroborreliosis.[30] A survey of the literature indicates that spirochetal forms have been observed for some time in the CNS tissue of ALS and other neurodegenerative diseases.[31] Thus, a byproduct of LD may be progression to ALS, but this is probably only possible in some LD patients who have the genetic susceptibility genes for the neurodegenerative disease and who have other toxic exposures.[32,33]

Amyotrophic lateral sclerosis patients also have other chronic infections, including human herpesvirus-6 (HHV6), Chlamydia pneumoniae, and other infections.[34,35] A suggestion that retroviruses might be involved in ALS and other motorneuron diseases[36] prompted McCormick and colleagues[37] to look for reverse transcriptase activity in serum and cerebrospinal fluid (CSF) of ALS and non-ALS patients. They found reverse transcriptase serum activity in one-half of ALS cases but in only 7% of controls (P <0.008). Interestingly, only 1 of 25 ALS CSF samples contained reverse transcriptase activity.[37]

The exact role that infections play in the pathogenesis or progression of ALS is not known. They could be cofactors in ALS pathogenesis, or they could simply be opportunistic infections that cause morbidity in ALS patients, such as the respiratory and rheumatic symptoms and other problems often found in ALS patients. They could also be involved in the progression of ALS rather than in its inception. Although the exact cause of ALS remains unknown, there are several hypotheses on its pathogenesis: (a) accumulation of glutamate causing excitotoxicity; (b) autoimmune reactions against motor neurons; (c) deficiency of nerve growth factor; (d) dysfunction of superoxide dismutase due to mutations; and (e) chronic infection(s).[22,23,24,27,28,29,31,32,33,34] None of these hypotheses is exclusive, and ALS may have a complex pathogenesis involving multiple factors.[34] Future studies should determine more precisely the role of chronic bacterial and viral infections in the pathogenesis and progression of ALS.

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