Mycoplasma pneumoniae has been associated with a wide variety of infectious and postinfectious neurologic illnesses. The agent almost certainly causes neurologic disease; however, many aspects of its association with central and peripheral nervous system injury remain controversial. Possible mechanisms of injury include direct infection, postinfectious (ie, autoimmune) events, and vascular compromise. In this article, the author reviews the pathogenesis, clinical features, diagnosis, and treatment of this disorder.
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• The role of Mycoplasma pneumoniae as an agent causing neurologic disease has been controversial, both because the organism is difficult to isolate and because elevated titers of antibody against M pneumoniae may be detected in patients with neurologic conditions due to other infectious agents.
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• Two major groups of neurologic conditions have been associated with the agent: meningoencephalitis with Mycoplasma organisms or DNA recovered from CSF, and conditions that appear to be postinfectious and caused by host immune response. In addition, in a minority of patients, a syndrome of CNS cerebrovascular thrombosis involving large or small vessels has been reported in association with M pneumoniae infection.
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• A second Mycoplasma organism, M hominis, may occasionally cause meningitis or brain abscess in infants.
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• Because Mycoplasma species lack a cell wall, penicillins, cephalosporins, and vancomycin are ineffective. Erythromycin and tetracyclines have traditionally been used to treat cases of acute M pneumoniae meningitis or encephalitis, although a variety of other antibiotics have been used in individual patients. Tetracyclines are avoided in children because of their effects on developing teeth and bones.
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• There are no controlled studies of immunosuppressive or immunomodulatory treatment for postinfectious neurologic complications of Mycoplasma infection. In individual cases, improvement of symptoms has followed treatment with methylprednisolone, plasma exchange, and intravenous immunoglobulin G.
Historical note and terminology
Following the introduction of sulfonamides and antibiotics, clinicians identified cases of pneumonia in which organisms could not be identified and that did not respond to usual antibiotic therapy. These cases came to be termed “primary atypical pneumonia.” In 1944, Eaton discovered that sputum and lung tissue from such cases contained an agent that could pass through 45 µm filters, which were permeable to viruses but not bacteria, and he learned that this filtered agent could cause focal pulmonary infiltrates in rodents (46). Eaton, along with others, subsequently demonstrated that convalescent sera from patients with primary atypical pneumonia could neutralize this agent. Soon thereafter, Finland and colleagues demonstrated that sera from approximately 70% of such patients could agglutinate red blood cells at cold temperatures (52). Transmission of the agent to human volunteers was accomplished in 1946, followed by growth of the agent in tissue culture and then in cell-free media. Confirmation that the “Eaton agent” was in fact the cause of primary atypical pneumonia came only later, in the 1960s, with transmission of pneumonia to human volunteers using organisms isolated in cell-free culture (71; 13).
Early descriptions of primary atypical pneumonia noted accompanying headaches and myalgias, and the first association of primary atypical pneumonia infection with neurologic symptoms was observed in 1943 (32). Over the years, individual case reports have described a wide variety of complications associated with Mycoplasma pneumoniae infection, including cases with neurologic complications in the absence of systemic symptoms and cases that appear to be postinfectious rather than being caused directly by the organism (81; 80). Despite many case reports over many years, however, the extent to which M pneumoniae is involved in the causation of human neurologic disease remains uncertain (40). Three reasons have existed for this uncertainty. First, mycoplasma are frequent laboratory contaminants, with an accompanying risk of falsely positive studies: this was of particular concern in some early case reports. Second, actual isolation of M pneumoniae is technically demanding, with handling and culture requirements that are more exacting than those in routine use; this is now circumvented through the use of polymerase chain methods (09). Third, serological testing for mycoplasma is imprecise in its diagnostic utility because of false negatives and, of significant importance for neurologists, because patients with neurologic involvement due to other agents may sometimes develop elevated antibody titers to M pneumoniae (24; 61).
Over time, 2 major overlapping patterns of neurologic involvement have been associated with M pneumoniae infection: cases which appear to represent direct CNS invasion by the agent, and cases in which neurologic injury is thought to occur through autoimmune, “postinfectious” mechanisms (113; 105; 103; 66; 09; 72; 101; 108; 159; 160). In the former group, organisms may be detected in CSF by culture or polymerase chain reaction methods. The latter, apparently postinfectious group is comprised in large part of cases in which diagnosis was made by serological methods or PCR detection of the organism in oropharyngeal samples, without detection of the organism in CSF (50; 51; 43; 105; 103; 66; 09; 72; 101; 108; 159; 160). In a minority of these cases, however, M pneumoniae has been identified in CSF by culture or polymerase chain reaction methods (109; 110; 113; 103; 72; 101; 108).
Less frequently, other species of Mycoplasma may cause neurologic disease; these will be discussed separately, below.