DOI: https://doi.org/10.21203/rs.3.rs-2477973/v1
Acute ischemic stroke is a rare neurological complication of mycoplasma (MP) infection in children. We present two children with a MP respiratory infection who experienced posterior cerebral circulation stroke, which is particularly rare, and review the relevant literature. Both cases were pre-school children who initially acquired a respiratory illness then developed neurological signs including coma and seizure. Chest radiography revealed pneumonic infiltration with pleural effusion or pleural response. Anti-MP IgM antibody was positive. MP DNA was detected in the sputum using polymerase chain reaction analysis. Cerebrospinal fluid biochemical and pathological testing and MP DNA analysis were negative. D-dimer concentration was elevated. Neuroimaging showed posterior circulation occlusion and infarction. Clinical symptoms improved after treatment with erythromycin, anticoagulation, and thrombolysis; however, neurological sequelae remained and follow-up imaging revealed permanent effects. In our literature review, we identified 25 patients (including the two presented here) who developed an ischemic stroke as a complication of MP infection, 14 males and 11 females. Median age was six years (range, zero to 13) and average time between respiratory symptoms and stroke onset was 9 days. Nineteen strokes (76%) involved the anterior cerebral circulation; middle cerebral artery stroke was most prevalent (68%). Hemiparesis and seizure were the most common neurologic signs. Evidence of MP infection was found in the cerebrospinal fluid of five children. Coagulopathy affected nearly half. The most common treatments were macrolide antibiotics, immunoglobulin, glucocorticoid, and aspirin. Three patients (11%) died during follow-up, all from early respiratory deterioration. Thirteen children had varying degrees of permanent neurological sequelae. Cerebral infarction is a rare complication of MP infection in children and has a poor prognosis. Early identification of stroke risk factors and early intervention may improve outcomes.
Pneumonia is the most common mycoplasma (MP) infection in hospitalized patients. Extrapulmonary complications occur in approximately 25% of patients with MP pneumonia[1]. Central nervous system involvement is unusual but seen in approximately 7% of cases. Encephalitis, meningoencephalitis, aseptic meningitis, transverse myelitis, acute disseminated encephalomyelitis, and Guillain–Barre syndrome may occur[2]. Cerebral infarction accompanies MP infection in 0.1% of cases[3]. Fewer than 30 cases of MP-related strokes in children have been previously reported and most had an unfavorable outcome. Posterior circulation involvement is exceptionally rare[4–6]. We report two children with MP infection who experienced posterior cerebral artery occlusion and review the relevant literature, focusing on the clinical and pathophysiologic links between MP infection and ischemic stroke.
A 5-year-old boy with no significant medical or family history was admitted to an outside hospital because of a paroxysmal cough with recurrent high fevers. The highest body temperature recorded was 41°C. He improved after treatment with ceftizoxime and bromhexine. However, on the ninth day of illness, he experienced a seizure of 30-minute duration and was transferred to our facility for further care.
The patient was unconscious on arrival with heart rate 120/minute, respiratory rate 30/minute, blood pressure 115/90 mmHg, and body temperature 37.3℃. On neurological examination, pupils were equal, lower extremity muscle tone was increased, and the Babinski sign was present bilaterally. White blood cell count was 11,310/mm3 (neutrophils, 90.1%; lymphocytes, 5.5%). Hemoglobin concentration and platelet count were 12.0 g/dL and 362,000/mm3, respectively. Erythrocyte sedimentation rate was 28 mm/h and C-reactive protein was 8 mg/L (reference range, < 10 mg/L). Procalcitonin level was 0.41 ng/mL (reference range, < 0.5 ng/mL). Biochemical investigations were normal. Fibrinogen concentration was 1.17 g/L(reference range, 1.8-4 g/L) and D-dimer concentration was 1.45 mg/L(reference range, < 0.3 mg/L). MP-specific IgM serum antibodies were strongly positive. Polymerase chain reaction (PCR) testing of sputum for MP showed 8.63 × 104 copies. Lumbar puncture yielded clear cerebrospinal fluid (CSF) with an opening pressure of 90 mm H2O. CSF white blood cell count was 3 × 106/L and red blood cell count was zero. CSF protein and glucose were 2.3 g/L and 4.0 mmol/L, respectively. CSF PCR testing for MP was negative. CSF cultures were sterile. Plain chest radiography showed bilateral pneumonia with right pleural reaction (Fig. 1A). Brain magnetic resonance imaging (MRI) showed abnormal signal in both occipital lobes, corpus callosum, thalamus, midbrain, pons, and both cerebellar hemispheres that suggested infarction (Fig. 1B and C). Magnetic resonance angiography (MRA) suggested occlusion of the basilar artery (Fig. 1D).
Acute cerebral infarction after MP infection was diagnosed. The patient was treated with thrombolysis, subcutaneous low-molecular-weight heparin (dose adjusted to maintain activated partial thromboplastin time twice the control), intravenous erythromycin (30 mg/kg/day), intravenous methylprednisolone (2 mg/kg/day), and intravenous immunoglobulin. He achieved a partial recovery and was discharged 1 week after his transfer to our facility. At the 1-month follow-up, he was hemiplegic and hypotonic.
A 3-year-old girl presented to an outside hospital with high fever and dry cough and was admitted. She was treated with oral erythromycin (30 mg/kg/day) followed by intravenous ceftriaxone (80 mg/kg/day) and methylprednisolone (1 mg/kg/day). Other medical history and family history were unremarkable. Her symptoms did not improve and she developed impaired consciousness on the seventh day after admission. She was then transferred to our hospital for further care.
On arrival, she was unconscious with body temperature 39.2℃, pulse rate 160/minute, respiratory rate 37/minute, and blood pressure 119/63 mmHg. Physical examination showed mild throat congestion, shortness of breath, decreased breath sounds in the right lung, and coarse breathing on the left. Neurological examination showed unequal pupils (left, 5 mm; right, 3 mm) with weak light reflex, increased muscle tone, and hyperactive deep tendon reflexes. Babinski testing was positive bilaterally.
White blood cell count was 11,000/mm3 (67.7% neutrophils, 21.5% lymphocytes). Hemoglobin concentration, platelet count, and erythrocyte sedimentation rate were 11.0 g/dL, 389,000/mm3, and 55 mm/h. C-reactive protein concentration was 9 mg/L (reference range, < 10 mg/L). Serum biochemistry and procalcitonin level were normal. MP IgM antibody titers were positive (1:320). PCR testing for MP in respiratory secretions was positive (2.0 × 105 copies). D-dimer concentration was 18 mg/L (reference range, < 0.3 mg/L). Plain chest radiography showed pneumonia in the right lower lung lobe and a moderate right pleural effusion. (Fig. 2A). Severe MP pneumonia was diagnosed. CSF examination showed the following: nucleated cell count, 3 × 106/L; protein, 0.20 g/L; adenosine deaminase, 1.4 U/L; glucose, 2.99 mmol/L; and chloride, 116 mmol/L. CSF PCR for MP was negative. Blood and CSF cultures were sterile. Brain MRI showed areas of high signal intensity in the thalamus, brainstem, and cerebellar hemispheres on fluid-attenuated inversion recovery and diffusion-weighted imaging.(Fig. 2B and C). MRA showed no filling of the basilar artery (Fig. 2D).
The patient was treated with low-molecular-weight heparin, erythromycin, meropenem, mannitol, glycerol, methylprednisolone, immunoglobulin, and plasma exchange. Her body temperature returned to normal and she gradually regained consciousness. Eventually, the lung inflammation decreased and the pleural effusion was absorbed. She was discharged after 35 days in the hospital. Repeat brain MRI with MRA 4 weeks after discharge showed no significant improvement. One year later, she remained paralyzed, blind, and aphasic but responsive to verbal and painful stimuli.
The PubMed and Embase databases were searched using the terms "cerebral embolism,” “cerebral infarction," "children," and "mycoplasma". We reviewed English-language articles that reported pediatric patients with MP infection confirmed by culture or serologic or PCR testing who developed new neurological symptoms within 4 weeks of infection and had ischemic cerebral infarction confirmed on computed tomography or MRI.
Twenty-two articles reporting 23 patients were identified(Table 1). Therefore, 25 patients were reviewed, including the two patients reported here[2, 4–6, 8–25]. Among these, 14 were male and 11 were female. Age ranged from zero to 13 years. The average time between respiratory symptoms and stroke onset was nine days. At presentation, 22 patients (88%) exhibited respiratory symptoms; three had a recent MP infection without respiratory symptoms. Hemiparesis was the most common neurological sign (13 patients; 52%); among these, aphasia was also present in five and coma in four. Anterior circulation stroke occurred in 19 patients (76%) and posterior circulation in six. MP was detected in the CSF of only five patients (MP antibodies were positive in three and PCR testing in two). Coagulation testing was performed in 21 patients and 11 had coagulation abnormalities (52%). Peripheral thrombosis was detected in two. Antibiotics were administered to all 24 patients for whom clinical data were available, most commonly a macrolide. Glucocorticoids and anticoagulation were administered to 14 and 11 patients, respectively. Plasma exchange was used only in one patient (case 2 of this report). Three patients (11%) died of respiratory failure. Varying degrees of neurological sequelae persisted in 13.
This report describes two children who initially presented with a respiratory infection and findings of pneumonia and pleural effusion on chest radiography that developed cerebral infarction. Both were previously healthy and had no personal or family history of cardiovascular, cerebrovascular, immune system, or hematologic disease. Moreover, neither had a history of trauma or were taking any medication. In both patients, MP infection was confirmed and MRI showed posterior circulation occlusion and infarction.
We also summarized the data of 25 children (including the two reported here) who experienced ischemic stroke associated with MP infection and have been described in previous reports. Median patient age was 6 years and there was a slight male predominance. The median interval between respiratory symptoms and stroke onset was 9 days, which is consistent with previous reports[7]. Although serologic testing for MP infection was positive in all patients, only five showed direct evidence of MP infection in the CSF, which implies an indirect pathogenic mechanism. Anterior circulation infarction was most prevalent, either in the internal carotid or middle cerebral artery (68%). The posterior circulation was involved in only six [4–6, 8].
The pathophysiology of neurologic complications following MP infection is unknown. Different mechanisms have been proposed, including direct invasion, immune-mediated response to injury, hypercoagulable/thrombotic state, vasculitis, and toxin damage (Fig. 3) [7, 26]. These various pathogenic mechanisms are closely linked and discussed below.
MP is highly invasive and has been successfully isolated from CSF. Anti-MP antibodies and MP gene fragments have also been detected in CSF [27]. These suggest a CSF pathway for organism entrance into the central nervous system. Detection of MP-like structures in small intracranial arteries by electron microscopy has also been reported [28], suggesting a vascular pathway as well. In our literature review of 25 children with MP-related stroke, CSF PCR analysis was positive in only two patients, suggesting that direct invasion is not the main mechanism of cerebral infarction in this population. We think that direct invasion is only the initiating factor and propose that the subsequent activation of the immune response with its associated inflammation and hypercoagulability cause cerebral arterial vasculitis and thrombosis, ultimately leading to cerebral infarction.
The "time window" for cerebral infarction after MP infection suggests an autoimmune component. Almost all patients with MP-related cerebral infarction present approximately 1 to 2 weeks after infection. MP infection causes a Th2 cell-based immune response that releases inflammatory mediators such as tumor necrosis factor, gamma interferon, interleukins, and neutrophil chemokines, causing widespread multisystem damage [29]. In addition, the MP cell membrane contains proteins and glycolipid antigens that have an antigenic component similar to those in human brain tissue, which can stimulate autoantibody production and activate the complement system to form antigen–antibody complexes that may cause vascular and neurological damage [30].
MP infection activates coagulation activity and inhibits fibrinolytic activity, causing an increase in fibrinogen and fibrin degradation products and hypercoagulable state [31]. Furthermore, lipoglycans on the MP surface have an antigenic effect and stimulate lymphocytes to produce procoagulant substances with tissue factor activity and activate exogenous coagulation pathways [32]. This procoagulant environment increases the risk of vascular thromboembolism.
Cerebral vasculitis with microthrombosis has been reported in brain biopsy and autopsy specimens from patients with MP encephalitis [33]. These findings are probably related to synthesis of hydrogen peroxide and superoxide radicals by the MP organism. These molecules cause oxidative damage to vascular epithelial cells. Animal experiments have demonstrated that MP can cause multiple cerebral vasculitides. The presence of MP in the bloodstream can induce the release of cytokines and chemokines that affect vascular wall function and cause endothelial damage, which may result in local vasculitis or thrombotic vascular occlusion [34].
M. pneumoniae can produce a virulence factor with pertussis-like toxin structure that can directly cause cellular damage [35]. Intravenous injection of an exotoxin of the A strain of M. neurolyticum causes brain tissue degeneration in mice [36]. Although toxicity may be responsible for in vivo pathogenicity in humans, this has not yet been established and further studies are needed.
Both children in our report had high D-dimer concentration. It is possible that thromboembolism resulting from intravascular coagulation and vasculitis caused arterial blockage and subsequent stroke. In addition, 19 patients had an arterial infarction in the anterior cerebral circulation. Still, only six patients had an ischemic stroke in the posterior cerebral circulation, consistent with the preferred site of cerebral infarction in adults. Therefore, we speculate that this difference in the onset area may be related to anatomical factors.
Because the pathogenesis of cerebral infarction caused by MP infection is uncertain, the appropriate treatment is also uncertain. Antibiotics, corticosteroids, intravenous immunoglobulin, other anti-inflammatory agents, and plasma exchange are all options that can be selected on an individual basis. In our literature review, anticoagulation (including low-dose aspirin or low-molecular-weight heparin) was used in 11 of 25 patients with vascular occlusion, which led to a poor outcome. Three patients died, however, and one had elevated CSF MP antibody concentration; the other two were not treated with immunosuppressive drugs. Therefore, we believe that patients with MP detected in the CSF may be more severely ill and that glucocorticoid therapy may be beneficial. Comprehensive treatment that includes rehabilitation may reduce the incidence of neurological complications. Further study of these issues is warranted.
In conclusion, clinicians should be aware of the risk of ischemic stroke in children with a respiratory MP infection. Hypercoagulability and vasculitis may play a role in the etiology. Due to this type of stroke having an unfavorable prognosis, further treatment research is needed.
Ethics approval and consent to participate：
This study was performed in accordance with the ethical standards as laid down in the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards.The study was approved by the ethics and plan review committee of Nanjing Medical University. Written informed consent was obtained from all participants and from a parent and/or legal guardian.
Consent for publication：Written informed consent was obtained from the parents of the two children for publication of this study and accompanying images. All authors of this paper agree to the publication of this paper
Availability of data and material：Not applicable
Competing interests：All the authors have no competing interests
-Funding：This research was supported by the National Natural Science Foundation of China(81903383), Natural Science Foundation of Jiangsu Province (BK20211009), Nanjing Medical Science and technique Development foundation(No.QRX 17074) and Scientific Research Projects of Jiangsu Health Commission (ZDB2020018).
-Authors' contributions：Patient management and data curation: Jian Li, Dongmei Chen, Jun Wang and Lihui Wu. Data analysis: Lihui Wu and Jian Li. Project administration: Hongjun Miao and Yongjun Fang. Writing—original draft: Jian Li. Writing—review and editing: Yongjun Fang and Lihui Wu. All authors contributed to the article and approved the submitted version.
-Acknowledgements：We acknowledge the Figdraw platform (www.figdraw) for providing material used in figure creation. We thank Liwen Bianji (Edanz) (https://www.liwenbianji.cn) for editing the language of a draft of this manuscript.
Table 1 is available in the Supplementary Files section.