Mycoplasma pneumoniae ecephalitis

Mycoplasma pneumoniae Encephalitis Ari Bitnun, MD, Elizabeth Ford-Jones, MD, FRCPC, Susan Blaser, MD and Susan Richardson, MD Mycoplasma pneumoniae causes between 5 and 10 percent of acute childhood encephalitis in Europe and North America. Encephalitis due to this organism may be caused by direct infection of the brain, immune-mediated brain injury or thromboembolic phenomenon. The prognosis is guarded with 20 to 60 percent suffering neurologic sequelae. The diagnosis of M. pneumoniae encephalitis should be based on strong evidence of M. pneumoniae infection that includes detection of the organism in culture or using molecular detection techniques in addition to serology and exclusion of other potential etiologies. Antibiotic therapy should be considered for all children with suspected M. pneumoniae encephalitis; antibiotics with good central nervous system (CNS) penetration such as ciprofloxacin, doxycycline, chloramphenicol or azithromycin are appropriate under most circumstances. Immune modulating therapies, such as corticosteroids, intravenous immune globulin or plasmapharesis, should be considered in those with immune-mediated syndromes such as acute disseminated encephalomyelitis. © 2003 Elsevier Inc. All rights reserved.

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entral nervous system (CNS) complications of Mycoplasma pneumoniae infection were described first nearly 50 years ago,1-3 but the association was confirmed by the successful isolation of the organism from brain tissue4 and cerebrospinal fluid (CSF).5-9 Until recently, the lack of standardized, accurate, and readily accessible diagnostic testing hampered efforts to define more accurately the role of M. pneumoniae in CNS disease. Most large series relied exclusively on serology for diagnosis,10-16 despite the known lack of specificity of such assays.17-22 With the advent of highly sensitive and specific molecular diagnostic techniques, such as the polymerase chain reaction (PCR), and the comprehensive nature of the microbiologic investigations being performed in many of the more recent prospective studies, the role of M. pneumoniae in childhood encephalitis and other neurologic syndromes is being defined more precisely.23-27 The purpose of this review is to provide a comprehensive overview of current knowledge pertaining to M. pneumoniae encephalitis and related syndromes.

From the Division of Infectious Diseases, Department of Pediatrics, the Department of Diagnostic Imaging, and the Department of Pediatric Laboratory Medicine, The Hospital for Sick Children and The University of Toronto, Toronto, Ontario, Canada. Address correspondence to E. Lee Ford-Jones, MD, FRCPC, Division of Infectious Diseases, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, M5G 1X8, Canada; e-mail: [email protected] © 2003 Elsevier Inc. All rights reserved. 1045-1870/03/1402-0005$30.00/0 doi:10.1053/spid.2003.127226

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Microbiology M. pneumoniae is a bacterium of the class Mollicutes, the smallest free-living class of organisms known. Their small genome size results in a biological niche more parasitic than free-living. Their ecological niche is the mucosal surfaces of various mammals, where they may exist as colonizers or pathogens, rarely invading beyond the mucosa. Unlike other bacteria, Mollicutes do not possess a cell wall, thus rendering them very susceptible to adverse environmental conditions such as heat or drying, resistant to cell-wall active antimicrobial agents such as the beta-lactam antibiotics, and resistant to staining with the Gram stain. They are very fastidious in their growth requirements, rendering their in vitro isolation difficult, time-consuming and expensive. Preformed nucleic acid precursors, sterols, growth factors, metabolic substrates, and optimal pH all are critical factors in the isolation of these organisms.28

Diagnosis Culture. M. pneumoniae, like other mycoplasmas, replicates slowly, requiring as long as 4 weeks for its isolation in vitro. The isolation of M. pneumoniae by conventional culture requires special, rigorously quality-controlled medium that is not readily available commercially. The use of transport media to prevent loss of viability, followed by culture in broth and on agar media, is necessary. Labor-intensive aspects of culture for M. pneumoniae include culture of serial dilutions of the original specimen (to overcome growth inhibitory factors), regular blind subculture of all broths (because of the lack of turbidity produced by growth of the organism), a 3-week incubation period, and confirmatory

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Mycoplasma pneumoniae Encephalitis identification tests.28 Despite rigorous quality control of the entire process, the sensitivity of detection of culture is no greater than 102 to 106 CFU/mL of respiratory secretions.29 Given the much lower concentration of organisms in nonrespiratory sites, such as cerebrospinal fluid (CSF), one is not surprised that culture from such sites rarely is positive. PCR. PCR has superseded culture for the diagnosis of M. pneumoniae infections largely because of its rapid turnaround time and sensitivity of detection. Many assays have been described, but none is available commercially. Most PCR primers target either the P1 adhesin gene or ribosomal RNA, although primers developed against other M. pneumoniae-specific DNA sequences and the beta-globin gene have been described.30-34 The in vitro sensitivity of most assays is between 0.0006 to 119 colony-forming units. In clinical respiratory samples, PCR is as much as 300 percent more sensitive than is culture.30-33 With respect to M. pneumoniae-associated central nervous system (CNS) disease, molecular testing has been particularly useful. Before the availability of PCR, only a handful of culture-confirmed M. pneumoniae CNS infections were reported in the literature.4-9 At least 50 additional cases have been reported since the advent of reliable PCR assays.23,25,27,35-41 Most patients with culture-negative PCR-positive respiratory specimens have positive serology and a compatible clinical presentation, suggesting that positive PCR results are reliable. Nevertheless, as is the case for evaluating most tests with regard to whether they are more sensitive than is the existing standard, one must consider the possibility of falsepositive results. Hence, an imperative is that vigorous quality control be practiced. Serology. Serology has been the cornerstone of the diagnosis of M. pneumoniae infections and remains so in most institutions that do not have molecular testing available to them. Traditionally, the complement fixation (CF) test has been used. It utilizes a crude methanol-chloroform lipid extract that contains glycolipids that cross-react with antigens in other bacteria, plants, and human tissue.29 Significant changes in CF titer, mainly IgM, have been demonstrated in patients with acute pancreatitis and bacterial meningitis.19,22 In the context of pneumonia, the sensitivity and specificity of the CF test (as defined by a four-fold rise in CF titer between acute and convalescent sera) are quite good. However, in the setting of nonrespiratory disease, for which the pretest likelihood that M. pneumoniae is the cause is low, the specificity of the CF test declines substantially. Immunoglobulin M complement-fixing antibodies usually precede the IgG response by approximately 5 days and can be detected after approximately 1 week of illness,42 rendering them more useful in the early diagnosis of M. pneumoniae infections. The peak IgM titer occurs between 10 and 30 days and usually falls to undetectable levels 3 to 6 months after the onset of symptoms,43 although in some cases it may persist for years.44 Children tend to have higher IgM levels in acute infection, whereas adults may have undetectable IgM levels and higher IgG levels, probably reflecting the immunologic response to reinfection.43 A variety of other serologic assays have been developed, the most useful of which are those that have focused on establishing a diagnosis of acute respiratory tract infection

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using a single specimen taken at the time of clinical presentation. Enzyme immunoassays or microparticle agglutination assays using nonlipid antigens to detect IgM or IgA appear to be the most promising techniques, with reported sensitivities of 87 to 100 percent and specificities of greater than 90 percent.45-48 As is the case for the CF test, these assays are less specific in the context of nonrespiratory disease. Making definitive comparisons among the various assays is difficult because of the lack of a highly sensitive and specific gold standard assay. Reproducible sensitivity and specificity of PCR techniques will need to be established before they can become the gold standard against which serologic assays are measured.

Epidemiology and Transmission M. pneumoniae infections occur in children of all ages, but lower respiratory tract disease is seen principally in schoolaged children and young adults.49-51 In studies conducted in the U.S. during the 1960s, the highest attack rate was seen in the 5- to 9-year-old age group.51,52 In Japan, 2 decades later, the incidence was highest in children 3 to 4 years of age.53 The differences between these 2 studies may be related, at least in part, to the younger age of daycare/ preschool entry in the latter population at the time the studies were conducted.51 Many M. pneumoniae infections are subclinical, a finding that is particularly common in children younger than 5 years of age.49,54,55 The proportion of pneumonia cases attributable to M. pneumoniae increases with age from approximately 20 percent in children 10 to 16 years of age to approximately 50 percent in young adults.56-59 Recurrent infections, which occur within 2 to 10 years of a previous infection, are coincident with waning of naturally acquired immunity.60 Epidemics of M. pneumoniae respiratory disease, which occur every 3 to 7 years, are superimposed on a low-level, constant, endemic infection rate.51,56 No seasonal predilection is discernible in longterm epidemiologic studies.56 M. pneumoniae is transmitted by the respiratory route. Shedding of the organism, in symptomatic as well as asymtomatic subjects, typically persists for several weeks but may last as long as 4 months in some cases.54,61,62 Transmission is enhanced by prolonged close contact such as occurs within households, college dormitories, or military barracks.51,54,57,59 In one study that evaluated infection and transmission rates in the family setting, 84 percent of children younger than 15 years of age and 44 percent of those 15 years of age or older acquired the infection; transmission was enhanced by the presence of young children (ⱕ10 years) in the household.54 Transmission between schoolmates appears to occur much less commonly.54 Several studies have suggested that children serve as an important reservoir of infection.54,55 The incubation period for respiratory illness, based on studies within families, appears to be between 11 and 25 days, with a mode of 20 to 23 days.54,61 CNS disease is estimated to occur in 1 to 10 percent of serologically confirmed M. pneumoniae infections deemed severe enough to require hospitalization.2,14,63 However, the overall incidence of CNS complications for all M. pneumoniae

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infections likely is less than 0.1 percent.1 As is the case for respiratory disease, M. pneumoniae encephalitis tends to be an epidemic disease.13,64 M. pneumoniae is one of the leading causes of encephalitis among children in Europe and North America.10,23,24 In most prospective long-term studies, the proportion of acute encephalitis cases attributable to M. pneumoniae is between 5 and 10 percent.12,23,63 In 1 of these studies, 41 of 462 children (8.9%) diagnosed with encephalitis during a 20year period had serologic evidence of M. pneumoniae infection.12 In our institution, approximately 7 percent of encephalitis cases diagnosed between January 1994 and December 1999 were attributed to M. pneumoniae (based on detection of the organism in CSF by PCR or by detection of the organism in the throat by PCR in conjunction with positive serology).23 Comparatively, only 2.4 percent of children had conclusive evidence of HSV infection, as determined by positive CSF PCR; a further 6 percent had serologic evidence, in serum, suggestive of acute herpes simplex virus (HSV) infection. CNS complications of M. pneumoniae infection appear to occur more commonly in children than in adults.13,63 In a study involving 560 patients with encephalitis in Finland, 15 of the 27 patients who had serologically confirmed M. pneumoniae infections were children; 13 were between 1 and 9 years of age.63 In another prospective study from the same country, children accounted for 44 of 61 M. pneumoniae infections that were associated with CNS disease.13 The mean age of presentation among children in prospective studies is between 6 and 8 years of age.12,23 The incidence of M. pneumoniae CNS disease appears to be similar for males and females.12,13,15,23,63

Pathophysiology Pathogenesis of M. pneumoniae-Induced Neurologic Injury M. pneumoniae CNS disease may result from direct invasion of the brain parenchyma by the organism or as a consequence of M. pneumoniae-induced autoimmune or thromboembolic phenomena. Neurotoxin-mediated CNS disease has been documented in mice infected with Mycoplasma neurolyticum and in turkeys infected with Mycoplasma gallisepticum, but no such toxin has been demonstrated for M. pneumoniae.65-67 Direct invasion of the CNS by M. pneumoniae undoubtedly is responsible for a significant proportion of M. pneumoniaeinduced neurological disease.4,5,7-9,23,25,27,35-39,68-71 The organism was isolated in culture from the brain of a previously healthy 30-year-old patient who died of disseminated M. pneumoniae infection4 and was detected by nucleic acid hybridization in another subject who died with bilateral pneumonia and encephalitis.68 In the former case, M. pneumoniae was cultured from the trachea, lung, kidney, and cerebral cortex; postmortem serologic studies for M. pneumoniae were negative. M. pneumoniae also has been cultured from or detected by PCR in the CSF of approximately 50 patients with encephalitis.5-8,23,25,27,35-41 Other Mycoplasma species also have been shown to invade the CNS directly and cause neurologic injury in animals and

humans.72-75 The rodent pathogen Mycoplasma pulmonis has been isolated in culture from the brain of naturally as well as experimentally (intranasal inoculation) infected rats,74 and the swine pathogens Mycoplasma hyorhynis and Mycoplasma hyopneumoniae have been shown to infect ependymal cells and cause cytopathological effects similar to those seen in respiratory epithelial cells.75 In humans, Mycoplasma hominis and Urea urealyticum have been implicated as causes of meningitis, encephalitis, and brain abscess principally during the neonatal period.72,73,76 In one recent report, M. hominis was isolated in culture from a brain abscess of a 3-week-old term infant and speciated using 16S ribosomal RNA sequencing.72 M. pneumoniae also has been implicated in the development of immune-mediated neurologic syndromes such as acute disseminated encephalomyelitis (ADEM), postinfectious hemorrhagic leukoencephalitis, Guillain-Barre´ syndrome, and transverse myelitis.15,23,40,41,77-88 The mechanisms of neurologic injury in such cases are understood incompletely but likely stem from similarities of M. pneumoniae antigens and human neuronal tissues.20,80,89,90 Antineuronal antibodies have been demonstrated in patients with and without CNS disease and serologically confirmed M. pneumoniae infection as well as in healthy controls in the absence of serologic evidence M. pneumoniae infection.14,20,80,89 In 1 study, complement-fixing antineuronal IgM and IgG antibodies were demonstrated in 39 percent of patients with CNS disease and 16 percent of those without CNS disease and serologically confirmed M. pneumoniae infection (P ⫽ 0.023).89 In another study, antigalactocerebroside antibodies, detected by enzyme-linked immunosorbent assay (ELISA), were demonstrated in 100 percent of patients with CNS disease and serologically confirmed M. pneumoniae infection, 25 percent of patients with isolated M. pneumoniae respiratory tract infection, and 3.8 percent of healthy controls.80 The findings of these studies suggest that although antineuronal antibodies occur more frequently in CNS disease, they may not always be pathogenic or that susceptibility to such antibodies may differ among individuals, or both. Antineuronal antibodies first appear during the second week of respiratory illness and peak two to four weeks into the illness,20 corresponding to the time of onset of most immune-mediated M. pneumoniae-associated neurologic syndromes. Differences in the duration of prodromal symptoms (defined as any illness that preceded neurologic symptoms) between patients with and without microbiological evidence of CNS infection support the concept that direct infection, as well as autoimmunity, plays an important pathophysiologic role in the development of M. pneumoniae CNS disease. In the first studies that addressed this issue, M. pneumoniae was detected in the serum and CSF significantly more often in patients with prodromal symptoms of 7 or fewer days compared with those with more prolonged prodromal symptoms.25,26 In our institution, a similar pattern was noted; 5 of 6 children in whom M. pneumoniae was detected in the CSF but not the throat had prodromal symptoms of 5 or fewer days duration, whereas all 5 children in whom M. pneumoniae was detected in the throat but not the CSF had prodromal symptoms 7 or more days.23 In a third study, M.

Mycoplasma pneumoniae Encephalitis pneumoniae was isolated in culture of the CSF more commonly in those with a shorter duration of respiratory symptoms.36 Taken together, these studies support the concept of an autoimmune mechanism of CNS disease principally, but not exclusively, for that subset of patients who have had a more prolonged illness before the onset of encephalitis. Thromboembolic phenomena also have been implicated as a potential mechanism of M. pneumoniae-mediated CNS disease.23,35,91-99 In some of these cases, M. pneumoniae infection was confirmed by PCR detection of the organism in CSF.23,35,91 The pathophysiology of such events remains incompletely understood. The possibility that the so-called cold hemagglutinins, autoantibodies directed at the I-antigen of the erythrocyte membrane, could be responsible for such events seems unlikely because this agglutination process occurs only at temperatures of 4°C or less. A procoagulatory state has been implicated in some95,99 but not all cases of M. pneumoniae-associated stroke. M. pneumoniae also has been associated with the development of a systemic vasculitis, and such a process conceivably could lead to thromboembolic events.100

Coinfections and Selected Immunologic Aspects of M. pneumoniae Infections Evidence of coinfection with M. pneumoniae and at least 1 other microbe has been documented in prospective studies of community-acquired pneumonia101 as well as encephalitis.12,23,24 In a large prospective study of community acquired pneumonia, 7 of 17 children with IgM class antibodies to M. pneumoniae had evidence of coinfection with respiratory viruses.101 With respect to encephalitis, the incidence of coinfection ranges from 22 to 64 percent in various studies.12,23,24 The strongest evidence for coinfections comes from nonserologic proof of infection with more than 1 agent. In our institution, 7 of 11 children with encephalitis and PCR-confirmed M. pneumoniae infection also had evidence of infection with at least 1 other microbe;23 most of these coinfections involved respiratory or herpes group viruses, diagnosed using antigen detection assays or PCR, respectively. Cytotoxic damage to respiratory epithelium induced by respiratory viruses possibly predisposes to bloodstream invasion by M. pneumoniae. With regard to the herpes group viruses, neither patient with M. pneumoniae-HSV CNS coinfections in our cohort manifested a four-fold rise or fall in HSV serologic titer, suggesting that M. pneumoniae may have led to reactivation of latent HSV infection. The possibility that many serologically diagnosed coinfections are not true coinfections also must be considered. M. pneumoniae has been shown to induce nonspecific T-celldependent production of IgM and IgG antibodies to various viral antigens in lymphocyte cultures of healthy subjects who had evidence of prior immunity to these viruses.102,103 Similar responses were observed in unstimulated lymphocyte cultures of patients with serologically confirmed M. pneumoniae pneumonia.102,103 This propensity of M. pneumoniae to induce nonspecific polyclonal B-cell activation may explain, in part, the high frequency with which M. pneumoniae infections are associated with serologic evidence of coinfections.

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Increasing evidence suggests that cell-mediated immunity plays an important role in the pathogenesis of M. pneumoniae pneumonia.104-106 The severity of pneumonia (defined radiologically) has been shown to correlate positively with the size of the cutaneous reaction to a purified M. pneumoniae antigen preparation.104 In addition, the pattern of pulmonary infiltrate correlates with purified protein derivative (PPD) responsiveness; nodular opacities with a centrilobular pattern are found more commonly in those with negative tuberculin skin tests (⬍10 mm), whereas a localized consolidation with an air bronchogram is found more commonly in those with positive tuberculin skin tests (ⱖ10 mm).106 In mice, IL-2 administration, starting 3 days after intranasal inoculation with M. pneumoniae, is associated with increased peribronchial and perivascular lymphocyte cuffing.105 In contrast, transient cutaneous anergy to tuberculin has been observed in patients with M. pneumoniae pneumonia,107,108 and, in vitro, M. pneumoniae has been shown to cause transient hyporesponsiveness of lymphocytes to PPD as well as other antigens.107,109 Although further studies in this area are needed, these findings suggest that differences in the host cell-mediated immune response may have significant bearing on the development and progression of CNS disease.

Clinical Manifestations The vast majority of M. pneumoniae infections are restricted to the respiratory tract.110 Many such infections are asymptomatic, particularly in children younger than 5 years of age. M. pneumoniae pneumonia typically presents as a febrile illness associated with a dry nonproductive cough; commonly associated symptoms include headache, malaise, chills, and sore throat. Unilateral or bilateral crackles and, to a lesser extent, wheezes are common auscultatory findings in children with M. pneumoniae pneumonia.111 Pleural effusions occur in a minority of cases. A protracted cough associated with tracheobronchial involvement, in the absence of pneumonia, and bullous myringitis also can occur. Rare but potentially life-threatening nonneurologic extrapulmonary complications include erythema multiforme major and myocarditis. Neurologic syndromes that have been associated with M. pneumoniae infection include aseptic meningitis, encephalitis, meningoencephalitis, acute bilateral striatal necrosis, cerebellar ataxia, ADEM, postinfectious hemorrhagic leukoencephalitis, transverse myelitis, Guillain-Barre´ syndrome and thromboembolic stroke.2,4-9,12,14,15,23,25,35-41,63,68,69,71,73,77-88,91-93,100,112-115 In the past, many reports linking M. pneumoniae with these syndromes were viewed with skepticism because of their reliance solely on serology for diagnosis.18 More recently, the link between M. pneumoniae and neurologic disease has been strengthened by the use of molecular diagnostic techniques such as PCR.23,25,27,35-41,69,88 Most, but not all, children with M. pneumoniae encephalitis have a history of recent or concurrent respiratory symptoms.14,15,23,26,63 In those with respiratory symptoms, pneumonia is seen in a minority13-15,23,26,63; most have mild upper respiratory symptoms, principally cough and sore

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throat. In our institution, 7 of 11 children with M. pneumoniae encephalitis, defined by detection of the organism in the CSF by PCR/culture or detection of the organism in the throat by PCR/culture and positive serology, had respiratory symptoms; 4 of them had pulmonary infiltrates on chest x-ray.23 Fever, headache, and vomiting were common prodromal symptoms in those who lacked respiratory symptoms. Interestingly, respiratory symptoms occurred in all 5 children in whom M. pneumoniae was detected by PCR in the throat but not the CSF but in only 2 of 6 in whom the organism was detected in the CSF but not the throat. Other researchers have demonstrated a significantly higher rate of M. pneumoniae detection by PCR in serum among patients with M. pneumoniae CNS disease without pneumonia.26 Thus, M. pneumoniae should be considered in the differential diagnosis of any child with encephalitis, irrespective of the presence or absence of respiratory symptoms. Furthermore, the absence of respiratory symptoms appears to be more characteristic of patients whose neurologic disease is caused by direct invasion of the CNS rather than by immunologic or thromboembolic phenomena.23,26 Despite serologic evidence to the contrary, the common assumption is that M. pneumoniae infections are unusual occurrences in children younger than 5 years of age. However, in our cohort, 4 of 11 children with PCR-confirmed M. pneumoniae CNS infections were in this age group.23 Two of these 4 children were younger than 2 years of age. Several other case reports of M. pneumoniae encephalitis in children younger than 5 years of age (12 months and 3 years) have been published.25,71 Therefore, the possibility of M. pneumoniae being a potential cause of encephalitis in all children, irrespective of age, is an important consideration. The clinical manifestations as well as the CSF, electroencephalographic (EEG), and neuroimaging abnormalities of M. pneumoniae encephalitis are indistinguishable from those seen with viral encephalitis.24 The classic triad of fever, headache, and encephalopathy cannot always be elicited in children with acute encephalitis, irrespective of the etiology. Encephalopathic features may include lethargy, stupor, coma, extreme irritability, or a significant change in personality or behavior. Other common clinical manifestations that have been seen in M. pneumoniae-associated encephalitis include focal or generalized seizures, ataxia, psychosis, and focal neurologic deficits such as hemiparesis and cranial nerve palsies.12,13,23,36,63 The signs and symptoms associated with M. pneumoniae-induced ADEM typically are indistinguishable from those of acute encephalitis.40,77,78,81,84,85 Optic neuritis is seen in conjunction with ADEM in some cases.23,77 Those with transverse myelitis present with a flaccid paralysis, absence of deep tendon reflexes, loss of bowel and bladder control, and a sensory level.82,83,86-88 CSF abnormalities occur in approximately 60 percent of children with culture- or PCR-confirmed M. pneumoniae encephalitis.23,36 The CSF leukocyte count is elevated in 40 to 60 percent of cases12-15,23,36 and typically is in the range of 10 to 200 cells/␮L5,7,8,12-15,23,25,36,37,88 but occasionally may be as high as several thousand cells/␮L.9,36,40 A predominance of lymphocytes is seen in 90 percent of those with pleocytosis.14,23 CSF fluid protein is elevated (⬎40 mg/dL) in 35 to

50 percent of cases,23,36 whereas the CSF glucose level almost always is normal. In those with ADEM or transverse myelitis, the CSF protein may be particularly high, in the range of 100 to 250 mg/dL.40,77,85-87 As one would expect, the CSF Gram stain and routine bacterial cultures are universally negative. Approximately 80 percent of patients with M. pneumoniae encephalitis or ADEM have EEG abnormalities.13,23 Generalized or focal slowing and epileptiform activity are the most common findings, occurring in approximately 65 percent and 25 percent of cases, respectively.8,23,25,36-39,71,84,85,88 Less common abnormalities include periodic lateralizing epileptiform discharges (PLEDs), frontal intermittent rhythmic delta activity (FIRDA), or occipital intermittent rhythmic delta activity (OIRDA).23 Neuroimaging abnormalities are quite variable. Those with acute onset encephalitis developing in the absence of or after a short prodromal illness often have no detectable finding on CT.15,23,69 MRI is more sensitive than is CT in the detection of subtle lesions but may still be normal if obtained early. Focal or generalized edema of the cortex, lobe, or hemisphere may be seen (Figs 1 and 2).23,36,38 Bilateral signal intensity increase of the hippocampi also has been reported. Patchy asymmetric or diffuse signal change of gray and white matter is characteristic of patients presenting with an ADEM response to M. pneumoniae (Fig 3).23,40,85,88 MRI typically demonstrates multifocal, asymmetric foci of high signal intensity on FLAIR and T2-weighted images.40,78 Focal ischemic lesions and vascular occlusions are rare occurrences but have been reported23,35,91,94,96; such lesions, however, are not the predominant neuroimaging abnormality seen in most patients presenting with M. pneumoniae-related hemiparesis or stroke like symptoms. In contrast to the relatively benign course of M. pneumoniae meningitis,13,14,63 the prognosis for children with M. pneumoniae encephalitis is guarded. Well-documented fatalities have been reported,4,36,38,68 but such cases appear to be relatively uncommon. The 5 to 10 percent mortality rate reported in several studies of serologically confirmed M. pneumoniae encephalitis in Finland12,13,63 has not been confirmed in other studies.14,15,23,36 In our series, no deaths occurred, but significant neurologic sequelae, including seizures, hemiparesis, expressive dysphasia, and dysarthria, developed in 7 of 11 children with PCR-confirmed M. pneumoniae encephalitis (mean follow-up of 1.8 years).23 In other prospective studies and case series that relied on serology to establish a diagnosis, 20 to 60 percent of subjects had severe neurologic sequelae.12-15,63 Mild cognitive impairments, such as difficulties with concentration, memory, reading, and word finding, also have been described.15,23

Diagnosis The neurologic manifestations and CSF, EEG, and neuroimaging findings of M. pneumoniae encephalitis are nonspecific,10-12,14,23 and pneumonia occurs in only 10 to 40 percent of cases.13-15,23,26,63 Routine laboratory tests such as the peripheral leukocyte count, erythrocyte sedimentation rate,

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Figure 1. Neuroimages of an 8-year-old girl who presented with acute left-sided hemiplegia subsequent to a 5-day history of fever, headache, and vomiting; M. pneumoniae was detected in the CSF by PCR. (A) Magnetic resonance angiogram shows prominence of the vessels of the right middle cerebral artery distribution in keeping with loss of autoregulation (arrows). The caliber of the arteries in the left middle cerebral artery distribution is normal. (B) T2-weighted coronal image (TR ⫽ 5,700, TE ⫽ 90) shows extensive cortical swelling and increased signal intensity within the gray matter of the right frontal and temporal lobes. The white matter is relatively spared.

and chest radiograph are not helpful in establishing a definitive diagnosis of M. pneumoniae infection. Cold hemagglutinins are seen in only 30 to 50 percent of those with M. pneumoniae disease,17 and their presence is nonspecific; positive results may occur with many viral infections, including those caused by influenza viruses, respiratory syncytial virus, adenoviruses, mumps virus, Ebstein-Barr virus, and cytomegalovirus,17,90 as well as with collagen vascular diseases and a variety of other systemic diseases.17 Serology has long been the mainstay of diagnosis for M. pneumoniae infections. In one large study of community acquired pneumonia, the sensitivity, specificity, positive predictive value and negative predictive value of a positive CF test were 90, 94, 58, and 97 percent, respectively.29 Numerous other serologic assays, none of which is clearly superior to the others, are available commercially.17,116-119 As with any test, the probability that a positive test result is truly indicative of disease is dependent on the pretest probability (prevalence) of disease. For example, the pretest probability that M. pneumoniae is the cause of “walking pneumonia” in a 10-year-old child is relatively high, and a positive serologic result would reinforce such a diagnosis. However, because M. pneumoniae is a less common cause of acute encephalitis, interpretation of a positive serologic test is

more problematic. Thus, the post-test probability that M. pneumoniae is the cause of encephalitis in a given individual, assuming an assay sensitivity and specificity of 90 and 94 percent, respectively,29 and a disease prevalence of 1 to 10 percent (pretest probability that M. pneumoniae is the cause of encephalitis)10-12,14,23 would be between 13 and 62 percent. As a result, relying solely on serology to establish a diagnosis of M. pneumoniae-CNS disease should be discouraged. In addition, negative serologic results have been documented in culture- and PCR-confirmed CNS infections. Because of the difficulties associated with M. pneumoniae culture and serology, PCR is being utilized increasingly to establish a diagnosis of M. pneumoniae infection.23,25-27,32,88,118,120-125 The sensitivity, specificity, positive predictive value, and negative predictive value of PCR for the diagnosis of pneumonia using culture as the gold standard are 92 to 100 percent, 98 to 100 percent, 98 to 100 percent, and 99 to 100 percent, respectively.23,32 Clearly, detection of M. pneumoniae in the CSF or brain tissue by PCR (or culture) provides strong evidence of causality. Detection of M. pneumoniae in the throat but not the CSF provides reasonably good evidence of causality for those patients without convincing evidence of another infectious etiology, particularly when the clinical presentation is con-

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Bitnun et al. been associated temporally with antibiotic therapy in some5,7,8,15,27,36,37,40,79-81,88 but not all reports of children with M. pneumoniae encephalitis.14,15,36,38,63,69,80-82,84 Some children have made full recoveries without antibiotic therapy.9,25,80,85 Antibiotics with significant in vitro and in vivo activity against M. pneumoniae include the macrolides (erythromycin, clarythromycin, azithromycin), tetracyclines (tetracycline, doxycycline), chloramphenicol, quinolones (ciprofloxacin, ofloxacin, levofloxacin, sparfloxacin, grepafloxacin), ketolides, and streptogramins. Of these, the macrolides are considered the first-line agents for most pediatric M. pneumoniae infections. The principle disadvantage of the macrolides, in the context of CNS disease, is their inability to traverse the blood brain barrier and achieve therapeutic levels within the CNS.126 Azithromycin is a noted exception in that it has been shown, albeit in only 1 study, to achieve high concentration in brain tissue (several hundred-fold higher than serum levels), though not in CSF or aqueous humor.127 Most of the other antibiotics listed above have been shown to achieve therapeutic levels within the CNS;

Figure 2. Magnetic resonance image demonstrating pronounced edema of the cortical gray matter in the left hemisphere with extension to involve the subjacent white matter. The ventricles are large, but there is no periventricular edema. This 14-month-old female presented with a right-sided focal seizure and encephalopathy following a respiratory illness of 7 days’ duration. Mycoplasma pneumoniae was implicated as the likely etiology on the basis of a complement fixation titer of ⬎1:128. sistent with immune-mediated disease or a thromboembolic stroke. A chronic M. pneumoniae carrier state does not occur in immunocompetent individuals, but throat cultures may remain positive for as long as 10 to 16 weeks after the onset of respiratory illness.51,54,61 Unfortunately, prospective studies designed to assess the duration of PCR positivity have not been published to date. Ultimately, the diagnosis of M. pneumoniae CNS disease requires a certain degree of clinical judgment and should be based on consideration of the clinical context and results of microbiologic investigations. In general, culture and/or PCR evidence of M. pneumoniae infection is essential for a reliable diagnosis.

Treatment The role of antibiotic therapy in the management of M. pneumoniae encephalitis remains undefined because of the lack of controlled trials assessing such therapy, uncertainties regarding the pathophysiology and natural history of CNS disease, and the small number of children who have received such therapy. Clinical improvement has

Figure 3. Magnetic resonance image of a 10-year-old female with Mycoplasma pneumoniae-induced ADEM. On this T2-weighted axial (TR ⫽ 2,800, TE ⫽ 90) image, multiple foci of increased signal intensity within deep gray structures and white matter are present. Upper respiratory symptoms of 2 weeks’ duration had resolved 1 to 2 weeks before the onset of encephalitis. M. pneumoniae was implicated on the basis of positive serology (positive IgM by enzyme immunoassay and acute/convalescent CF titers of 1:128/1:512) and detection of the organism by PCR in the throat.

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Table 1. General Features and Therapeutic Approach to the Major Clinical Syndromes Associated with Encephalopathy and Mycoplasma pneumoniae Infection Syndromes

Pathophysiology

Clinical Clues*

Proposed Therapy†

Encephalitis or meningoencephalitis

Direct invasion‡

● Prodrome ⬍7 days ● Respiratory symptoms often absent or mild; pneumonia distinctly uncommon ● CSF: normal or lymphocytic pleocytosis ● Neuroimaging: normal or focal/diffuse edema ● Positive CSF and negative throat culture/PCR

Antibiotic therapy: ciprofloxacin, doxycycline, azithromycin, or chloramphenicol

ADEM

Autoimmune‡

● Prodrome ⱖ7 days ● Respiratory symptoms usually present, pneumonia relatively common ● CSF: significantly elevated protein ● Neuroimaging: patchy asymmetric or diffuse white and gray matter signal change ● Positive throat and negative CSF culture/PCR

Antibiotic therapy: a. Positive CSF PCR— ciprofloxacin, doxycycline, azithromycin, or chloramphenicol b. Negative CSF PCR— azithromycin or another macrolide§ AND Immune modulating therapy: a. Corticosteroids and/or b. IVIG and/or c. Plasmapharesis

Stroke syndromes

Thromboembolic

● Unifocal neurologic deficit ● Neuroimaging: focal infarction ● Positive throat and negative CSF culture/PCR

Antibiotic therapy: a. Positive CSF PCR— ciprofloxacin, doxycycline, azithromycin, or chloramphenicol b. Negative CSF PCR— azithromycin or another macrolide§ AND Stroke management

*Significant overlap in clinical and laboratory manifestations may occur between syndromes. †See text for more details; doxycycline should not be used in children younger than 8 years of age. ‡Substantial overlap may occur with autoimmune processes occurring in encephalitis/meningoencephalitis and direct infection occurring in autoimmune disease. §Ciprofloxacin, doxycycline, or chloramphenicol also may be used in this setting.

the CSF/blood ratios for ciprofloxacin, doxycycline, and chloramphenicol are approximately 26, 26, and 30 to 50 percent, respectively.128-131 Notwithstanding the lack of conclusive evidence in favor of antibiotic therapy, such therapy should be considered for all children with M. pneumoniae encephalitis, principally because of the poor prognosis associated with this disease.14,15,23,63 The choice of antimicrobial agent should be based on the predicted antimicrobial susceptibilities of the organism, consideration of the pathophysiology of the neurologic syndrome being treated, and the age of the patient. Children who likely have direct CNS invasion, based on clinical presentation and/or detection of the organism in the CSF by PCR or culture, should receive an antibiotic that traverses the blood-brain-barrier and achieves therapeutic levels within the CNS. Ciprofloxacin, chloramphenicol, or azithromycin are arguably the most appropriate therapeutic options for such children who are younger than 8 years

of age. In selecting chloramphenicol, one needs to balance the need for therapy, as defined by the severity of disease, with the risk of idiosyncratic bone marrow aplasia. Doxycycline is a reasonable alternative for those 8 years of age or older. The need for CNS penetration may not be as important for those with immune-mediated syndromes such as ADEM or transverse myelitis. However, one must bear in mind that immune-mediated disease does not preclude the possibility of direct CNS infection.35,40,88 Consequently, initial therapy, before availability of culture and/or PCR results, should include an antibiotic with good CNS penetration. For those with negative CSF culture and/or PCR results, administration of a macrolide, such as erythromycin, may be appropriate. In the absence of comparative studies, the role of intravenous versus oral antibiotic therapy is undefined. We would recommend the intravenous route for those in whom optimal CNS penetration is desired. The oral route may be reasonable for those patients

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able to tolerate such therapy who have immune-mediated syndromes and negative CSF PCR. The potential benefit of immune-modulating therapies such as corticosteroids, intravenous immune-globulin, and plasma exchange in the management of immune-mediated neurologic syndromes associated with M. pneumoniae remains undefined. Corticosteroids have been associated temporally with clinical improvement in some patients with M. pneumoniae-associated ADEM,15,23,40,80,81,84 transverse myelitis,41,86 and Guillain-Barre´ syndrome.6,77 Similar results have been documented with the administration of intravenous immune globulin40,79,84 and plasma exchange.77,112,113 In many of these reports, multiple concurrent therapies were being administered, rendering the attribution of clinical improvement solely to any 1 particular intervention difficult. Furthermore, some patients with M. pneumoniaeassociated ADEM and transverse myelitis have made full and near-full recoveries without receiving any immunemodulating therapies.41,78,85,88 On balance, considering the significant morbidity and small, but finite, risk of death associated with ADEM and other immune-mediated syndromes, a reasonable consideration is the use of immune-modulating therapies in children whose clinical presentation, CSF findings, and/or neuroimaging abnormalities are suggestive of M. pneumoniae-induced autoimmune disease. Corticosteroids are appropriate for the initial management of ADEM and transverse myelitis; such therapy has been used widely for these syndromes and noted to shorten the duration of neurologic symptoms in some cases.132-134 Intravenous immune globulin should be used for Guillain-Barre´ syndrome and considered for patients with ADEM, particularly those who fail to respond to corticosteroids.135-138 In some cases of ADEM, intravenous immune globulin has been associated with rapid resolution of symptoms.135 Plasmapheresis is not available readily but may be considered for patients with severe disease, particularly those who have failed to respond to corticosteroids and/or intravenous immune globulin.139

Conclusions M. pneumoniae is one of the most common causes of acute childhood encephalitis, accounting for between 5 and 10 percent of cases in Europe and North America (Table 1). M. pneumoniae should be considered a potential culprit in all children with acute encephalitis, irrespective of age, presence or absence of respiratory symptoms, and regardless of neurologic manifestations. The diagnosis should be based on a thorough evaluation of the clinical context, including the presence or absence of a prodromal illness, neurologic symptoms, CSF abnormalities, and neuroimaging findings in conjunction with results of serologic assays, cultures, and molecular diagnostic tests such as PCR. Direct CNS invasion is the likely mechanism of disease in children with a shorter prodrome (ⱕ5 days), whereas autoimmunity, thromboembolic phenomena, or both are more likely in those with a more prolonged prodrome (ⱖ7 days). Antibiotic therapy should be considered for all children with suspected M. pneumoniae encephalitis; antibiotics with good CNS penetration such as ciprofloxacin, doxycycline, chlor-

amphenicol, or azithromycin are appropriate in most circumstances. Azithromycin or another macrolide may be a reasonable alternative for patients with immune-mediated disease and negative CSF PCR culture. Immune-modulating therapies, such as corticosteroids, intravenous immune globulin, or plasmapheresis, should be considered for patients with immune-mediated syndromes such as ADEM.

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