key: cord-007325-g8ke9rfg authors: Koskiniemi, Marjaleena title: CNS Manifestations Associated with Mycoplasma pneumoniae Infections: Summary of Cases at the University of Helsinki and Review date: 1993-08-17 journal: Clin Infect Dis DOI: 10.1093/clinids/17.supplement_1.s52 sha: doc_id: 7325 cord_uid: g8ke9rfg CNS manifestations appear in one of 1,000 patients with Mycoplasma pneumoniae-associated infections. Encephalitis is the most frequent manifestation, but cases of meningitis, myelitis, and polyradiculitis, as well as many other symptoms (e.g., coma, ataxia, psychosis, and stroke), have been reported. The onset of these manifestations is usually acute, with lowered consciousness, convulsions, pareses, and other neurological signs. Severe, even fatal, cases are known. The pathophysiology of CNS manifestations is unknown. To our knowledge, M. pneumoniae has never been isolated from brain tissue, but instead it has been recovered from CSF specimens in at least seven cases. Besides direct invasion of M. pneumoniae into the brain, neurotoxic or autoimmune reaction within the brain tissue is suspected. At neuropathological examination, edema, demyelination, and microthrombi have been described. Improved diagnostic methods may reveal the pathophysiology of CNS manifestations associated with M. pneumoniae infection. antibody to M. pneumoniae was observed in 10 further patients in whom encephalitis apparently was associated with another microbe (coxsackie virus B in five and various microbes in five). The routine schema for examining the patients included blood and urine analysis, CSF examination, electroencephalogram (EEG) recording, and electroneuromyography, if needed. Neuroradiological examinations, including computed tomography (CT) of the brain since the late 1970s and magnetic resonance imaging (MRI) of the brain since the early 1980s, were performed if needed. Screening for antibody was done by the CF test with 15-17 different antigens. These antigens included adenovirus, coronavirus (until 1982), coxsackie virus B5, cytomegalovirus, hepatitis B virus (since 1970), herpes simplex virus, influenza A and B viruses, parainfluenza 1 and 3 viruses, poliovirus, respiratory syncytial virus, rotavirus (since 1976), varicella zoster virus, Chlamydia group antigen, M. pneumoniae, and Toxoplasma gondii. Screening for arbovirus was dropped in the early 1980s because no cases were found. Acute encephalitis. All pediatric patients (45) had encephalitis. Of the adult patients, 10 (63%) had encephalitis (figure 2). Most patients (78%) had meningeal symptoms and signs: headache, nausea or vomiting, and neck stiffness (table 1) . Many patients had high temperatures, though some patients' temperatures were normal. One-half of the patients had convulsions on admission or during their stay in the hospital. More than two-thirds of the patients were unconscious or somnolent on admission. In addition, focal neurological signs appeared, e.g., ataxia, deviation of the eye, hemiparesis, or paresthesia. More than one-third (38%) of the patients had an associated pneumonia or other respiratory disease. In some patients, carditis or Reye's syndrome was present. The symptoms were usually acute; in one-half of the cases, they lasted day (figure 3). A large proportion (30%) of the patients needed intensive care, usually for a long period (mean period, 12 days). The hospital stay ranged from 1 day to 3 months (mean stay, 2-3 weeks). Other diseases. Besides encephalitis, adult patients had meningitis, myelitis, and polyradiculitis, two cases of each (figure 2). Cases of meningitis were mild, resembling the clinical course of a usual case of serous meningitis. One patient with myelitis became tetraplegic; plasma exchange was done, and after 2 months she was able to walk. The other patient with myelitis had transverse involvement at the T-8 level; this patient recovered in 1 month with minor sequelae. Both patients with polyradiculitis became tetraplegic; one was treated with plasma exchange, and the other was not. Both of these patients recovered in 6 weeks. Findings of electroneuromyography were consistent with polyradiculitis, while the protein concentration in the CSF was only slightly increased. In our series, 60% of cases had normal findings for CSF (white blood cell count, 0-230 X 10 6/L; protein concentration, 180-1,640 mg/L) at the onset of the manifestation. Most samples were taken on the first 3 days, and if results of CSF analysis were normal, specimens were not obtained later. Thus these findings are relevant to the beginning but not to the later course of the disease. Enterovirus was cultured concomitantly from feces from two patients, and herpes simplex virus antigen was detected in throat specimens from three patients. Results of EEG recording were usually severely (51%) or moderately (27%) disturbed during the first week of neurological illness, and the disturbance was often seen for weeks after the onset. Findings of CT/MRI were unremarkable in our cases, though these tests were performed for one-third of the patients. Evidence of edema, but not of focal lesions, was seen on some patients' scans. Five patients (8%) died. Fourteen patients (23%) had severe sequelae: mental retardation, choreoathetosis, convulsions, an.lmovement disorders. The duration of neurological symptoms before hospital admission was not associated with the outcome. Long-lasting unconsciousness was associated with poor outcome, though even after 8 days one patient recovered from unconsciousness. If an abnormality revealed by EEG recording was present for >4 weeks, sequelae were more common than on average [17] . M. pneumoniae-associated CNS manifestations are variable (table 2) . Encephalitis seems to be the main type in children [17, 18] ; in adults the clinical picture is more diverse [19] [20] [21] . Encephalitis may be diffuse or focal [22] , often expansive [23, 24] . It may resemble encephalitis lethargica [25] . This manifestation may concentrate in the cerebellum or pons regions [26, 27] and may cause hydrocephalus [28] . Sometimes encephalitis may be recurrent [29] . Meningitis is usually a mild manifestation [11, 30] . Myelitis may appear in different forms: diffuse, transverse [1 9 11, 31, 32], or poliolike [33] . In addition, there are descrip- [38] [39] [40] . Neuropathy in cranial or peripheral nerves and myositis have been described as well [41] . The primary diagnosis of M. pneumoniae-associated disease is clinical. The first serology available was the test for cold agglutinins in 1941 [42] . This test, however, is positive in only one-or two-thirds of cases. Titers of CF antibodies may decline on admission to the hospital because often the patient has had the disease for some time. Throat cultures are positive in 65% of cases [43] . Antibody titers in the serum as well as those in the CSF may be nonspecific [44] apparently because of differences between antigens; lipid-containing antigen may be cross-reactive with brain antigens, making the results uncertain [45] [46] [47] . A CT scan may reveal hypodensity in parietal areas [48] M. pneumoniae has been isolated from CSF specimens in at least seven cases [51] [52] [53] [54] [55] , but isolation will never be the [11] . Isolation of the organism from the CSF suggests that M. pneumoniae invades the CNS. However, to our knowledge, M. pneumoniae has never been isolated from brain tissue. Thus the theory of direct invasion of M. pneumoniae into brain tissue is somewhat loose. The RNA hybridization test (Gen-Probe, San Diego) has been diagnostic for throat specimens, tracheal aspirates, and lung tissue [56] , but whether it is for CSF or brain tissue is unknown. As a new approach, the polymerase chain reaction is a promising method [57] [58] [59] [60] , although no reports on determinations of CSF have been published yet. Both erythromycin and tetracycline are effective against M. pneumoniae in vitro and in vivo [61] . The results, however, are variable, and antibiotic therapy may be beneficial [50] or have no effect [5, 11, 22] . In CNS diseases associated with M. pneumoniae, the problem of therapy is unresolved. Corticosteroids, anti-inflammatory drugs, and antidiuretics have been used as well as antibiotics [22, 24, 62] . Plasma exchange has been reported in at least one case, and it appeared to be beneficial [63] . In our series, plasma exchange was done for one patient with myelitis and one with polyradiculitis, and both patients recovered; however, the other two patients with myelitis and polyradiculitis who did not undergo plasma exchange recovered as well. The pathophysiology behind the CNS symptomatology in M. pneumoniae-associated diseases remains hypothetical [64, 65] . M. pneumoniae itself may invade the CNS (in the CSF at least) because the organism has been isolated from CSF [52] [53] [54] [55] . Still, involvement in brain tissue remains uncertain. Some neurotoxin may be released or there may be an autoimmune complex or vasculopathy (table 3) At neuropathological examination, the brain may be edematous throughout or on basal parts, and scattered areas of hemorrhages may be seen [49] . There may also be perivascu-lar infiltration, microthrombi, and areas of demyelination [24, 49] . It is evident that CNS manifestations associated with M. pneumoniae infections are real, but exact diagnostic methods are rarely available. Diagnostic difficulties include crossreactivity of the antigen [46, 47, 68] . Newer technology may help us to make specific diagnoses. M. pneumoniae may be a concomitant or predisposing factor [69] . The pathophysiology of M. pneumoniae-associated CNS manifestations is largely unknown. In spite of the diagnostic problems associated with titers of CF antibody, we argue for the existence of CNS manifestations in association with M. pneumoniae infections. In our large series, M. pneumoniae accounted for 13% of known or suggested etiologies in childhood encephalitides [70] and 7% in adult encephalitides [71] . Our present series of 61 patients with diagnostic or high titers of antibody to M. pneumoniae showed clinical diseases similar to those previously reported. The age spectrum of patients who have neurological diseases associated with M. pneumoniae infection seems to be a little higher than that of patients with respiratory diseases caused by M. pneumoniae [4, 12, 72 ]. The death rate and sequelae we observed resemble those observed by other investigators [3] . These results, many signs of persistent syndromes [25, 27] , persistent brain stem dysfunction [50] , and prolonged immunologic response [62] all emphasize the need for further study of M. pneumoniae-associated CNS manifestations. 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