Risk factors for pneumonia in patients with anti-NMDA receptor encephalitis: A single-center retrospective study.

To identify the risk factors of pneumonia in patients with Anti-N-methyl-D-aspartate (Anti-NMDA) receptor encephalitis.This is a retrospective study.Department of Neurology in West China Hospital of Sichuan University.Patients with a definitive diagnosis of anti-NMDA receptor encephalitis.Risk factors associated with pneumonia were examined by bivariate analysis and multivariate logistic regression model.A total of 104 patients were included in this study, of which 41% patients (n = 43) were diagnosed with pneumonia at 7 days (range: 4-40 days) after admission. The occurrence of pneumonia was associated with prolonged hospital stays, a higher rate of poor outcome, and extra healthcare costs. Risk factors associated with pneumonia included Glasgow coma scale score (GCS), abnormal movements and hypokalemia.Pneumonia is a common complication in anti-NMDA receptor encephalitis. In the present study, we found that disorders of consciousness, abnormal movements, and hypokalemia were independent risk factors for pneumonia in inpatients with anti-NMDA receptor encephalitis. Pneumonia prolongs the patients' hospital stay, hospitalization expenditures, and affects the patients' prognosis.

Introduction

Anti-N-methyl-D-aspartate (Anti-NMDA) receptor encephalitis is a newly recognized autoimmune disorder in the central nervous system, associated with abnormal production of autoantibodies to the NR1 subunit of NMDA receptor.[ First described in young women with ovarian teratomas in 2007, is characterized by a progressive clinical course with the potential for effective management and improved outcome.[ Anti-NMDA receptor encephalitis accounts for about 4% of all encephalitis cases,[ of which typical symptoms are psychiatric features, seizure, speech dysfunction, movement disorder, decreased consciousness level and autonomic imbalance.[ The diagnosis of anti-NMDA receptor encephalitis is based on serum and cerebrospinal fluid (CSF) results. Furthermore, symptoms can be alleviated by first-line treatment (corticosteroid, plasma exchange, and immunoglobulin), and second-line treatment (cyclophosphamide and rituximab).[ The mortality of anti-NMDA receptor encephalitis is 8% to 10%,[ which was similar to that among acute encephalitis (8%)[ but much higher than encephalitis or meningitis (2.9%).[ Severe pneumonia has been reported to be the main cause of death in anti-NMDA receptor encephalitis.[ The incidence rate of pneumonia in anti-NMDA receptor encephalitis ranges from 55% to 65%,[ which was similar to that among patients with anti-gamma-aminobutyric-acid B receptor (anti-GABABR) encephalitis[ but higher than general surgical procedures and stroke patients.[ However, the cause of pneumonia in patients with anti-NMDA receptor encephalitis is unclear. To investigate pneumonia among patients with anti-NMDA receptor encephalitis, we conducted this retrospective study to explore the risk factors for pneumonia and to describe the burden and prognosis of pneumonia in patients with anti-NMDA receptor encephalitis.

Methods

Study design and setting

This is a single-center retrospective study. Patients with a definitive diagnosis of anti-NMDA receptor encephalitis [ in the West China Hospital of Sichuan University between October 2012 and June 2017 were enrolled.

Participants

Patients who met the diagnostic criteria of anti-NMDA receptor encephalitis were included.[ Anti-NMDA receptor encephalitis diagnostic criteria were met if:

Anti-NMDA receptor antibody IgG was positive in the cerebrospinal fluid (All samples of each patient were sent to Oumeng Biotechnology Corporation, or Peking Union Medical College Hospital, Beijing, China, to detect the anti-NMDA receptor immunoglobulin G antibodies by indirect immunofluorescence using EU 90 cells as previously described[).

Anti-NMDA receptor antibody IgG was positive in the serum. This is not essential.

One or more of the following major symptoms: seizures, abnormal behavior dysfunction, disturbance of consciousness, language impairment, movement disorder or dyskinesia, memory deficit, autonomic dysfunction or central hypoventilation was present.

The exclusion criteria were:

diagnosis of other diseases according to the clinical data, such as patients diagnosed with infectious encephalitis or etiology unknown encephalitis and

patients with pneumonia prior to admission.

The diagnosis criteria for pneumonia was based on the presence of new or progressive lung infiltrates on chest radiographs and patients had at least 2 of the following clinical signs: fever (>38°C), cough, purulent sputum, leukocytosis (>12,000 WBC /mm3) or leucopenia (<4000 WBC/mm3), shortness of breath, and chest pain.[

Data collection

Data extraction was performed by 2 researchers (PY and LZ) from the medical records system, including incidence of pneumonia (timing of diagnosis, etiological agents, signs/symptoms/laboratory/radiologic), demographic data (age, sex), imaging and blood tests (abnormal EEG, abnormal MRI, hyponatremia, gastrointestinal hemorrhage, hypo-albuminemia, liver dysfunction), 8 major clinical manifestations (psychiatric disorders, seizures, movement disorders, decreased level of consciousness, autonomic dysfunction, speech difficulties, memory deficit, and central hypoventilation), tumor, treatment (methylprednisolone, intravenous immunoglobulin), admission to ICU (Yes/No), nasogastric feeding or not, length of hospital stay and healthcare costs. And participants were regularly followed up by telephone and were evaluated using the modified Rankin scale (mRS) after discharge from hospital in a 3-month interval. A poor outcome was defined by mRS score of 4–6 (severe disability or death)[ at the last follow up. The levels of consciousness of patients were evaluated by Glasgow Coma Scale (GCS) score.[

Ethical considerations

The study was approved by the West China Hospital Institutional Review Board and Ethics Committee. Informed consent was obtained from each participant.

Data analysis

Statistical analysis was performed using IBM SPSS Statistics, version 22.0. Continuous variables with a normal and non-normal distribution were described as means ± standard deviation (SD) and medians, respectively. Continuous variables were analyzed using the Student's t test or the Mann–Whitney test. Count data were expressed as the number of cases (%). The significance levels of the differences in gender, clinical presentations and ancillary examination between the 2 groups were analyzed using the chi-square test. Binary logistic regression models were developed to identify independent risk factors associated with pneumonia. Then factors associated with pneumonia by univariate analysis (P < .05) were entered into a multivariate logistic regression model using a stepwise selection procedure. P values of less than .05 (two-sided) were considered statistically significant.

Results

Study population

Finally, 104 patients were included in this study. The demographic information, clinical information, ancillary examination and treatment were summarized in Table 1. Patients had a median age of 28 (11–79) years and 62 (60%) of them were female.

Table 1

Clinical information and univariable analysis of patients with anti-NMDA receptor encephalitis.

Eighty patients (77%) exhibited seizures, of whom 31 experienced status epilepticus. Ninety-four (90%) presented with psychiatric symptoms, including abnormal behavior, anxiety, paranoia, catatonia, and hallucinations. Twelve (12%) patients were diagnosed with the tumor, 6 of them were with teratoma. The ancillary examination found all patients having anti-NMDA receptor antibody positive in the CSF, and 49 (47%) patients with anti-NMDA receptor antibody positive in the serum. Patients were mainly treated with methylprednisolone and intravenous immunoglobulin. Patients were discovered with other clinical information were summarized in Table 1.

Forty-three (41%) patients were diagnosed with pneumonia 7 (4–40) days after admission (Fig. 1). Altogether, 7 bacteria and 1 yeast were isolated from sputum samples of 9 patients out of the 40 pneumonia cases (22.50%), 5 patients (12.5%) had a single pathogen and other 4 (10%) had 2 pathogens, Gram-negative bacilli were the most common organisms Table 2. The signs/symptoms/laboratory/ radiologic for pneumonia were list in Table 3.

Figure 1

Timing of diagnoses. The median length of hospital stay on which pneumonia was diagnosed was day 7. The 52.5% of cases were diagnosed less than or equal to 7 days and 47.5% more than 7 days.

Table 2

Pathogen for pneumonia.

Table 3

Signs/symptoms/laboratory/radiologic for pneumonia.

Burden of patients with pneumonia in anti-NMDA receptor encephalitis

The length of hospital stay was 28 (3–104) days in patients with pneumonia, longer than patients without pneumonia with 18 (4–69) days (P < .001). The healthcare cost of patients with pneumonia was (28,792 ± 13,943), higher than 18,092 ± 13,995 (¥, RMB) among those without (P = .003). Patients were with a median follow-up duration of 14 (3–48) months after discharge from the hospital. Patients with pneumonia were prone to have a poorer outcome (mRS = 4–6) compared to those without pneumonia (20% vs 3%, P = .013).

Univariable analysis of predictors of pneumonia

Univariate analysis of predictors of pneumonia was reported in Table 1. The demographic information, clinical information, ancillary examination and treatment of the patients were compared according to pneumonia.

Compared with patients without pneumonia, patients with pneumonia had higher frequency of seizures (88% vs 69%, P = .020), disorders of consciousness (P < .001), abnormal movements (63% vs 30%, P = .001), mechanical ventilation (23% vs 2%, P = .001), hypo-albuminemia (30% vs 3%, P < .001), hypokalemia (26% vs 5%, P = .002), gastrointestinal hemorrhage (21% vs 3%, P = .011), methylprednisolone (72% vs 44%, P = .005), nasogastric tube (60% vs 11%, P < .001) and admission to ICU (16% vs 2%, P = .017). No significant difference was found in others clinical information.

Multivariable analysis of risk factors for pneumonia

Multivariable analysis of predictors for pneumonia was shown in Table 4. Variables entered in the multivariate model were: seizures, disorders of consciousness, abnormal movements, hypokalemia, mechanical ventilation, hypo-albuminemia, gastrointestinal hemorrhage, methylprednisolone, nasogastric tube and admission to ICU. In multivariate analysis, factors associated with pneumonia included levels of consciousness (GCS score) (Odds Ratio 0.764, 95% CI: 0.620–0.942, P = .012), abnormal movements (Odds Ratio 3.716, 95% CI: 1.149–12.015, P = .028) and hypokalemia (Odds Ratio 13.473, 95% CI: 1.974–91.967, P = .008) (Table 4).

Table 4

Variables associated with pneumonia in multivariate analysis.

Discussion

In this study, the incidence of pneumonia in 104 in-patients with anti-NMDA receptor encephalitis was 41%. Pneumonia is associated with longer hospital stays, poorer outcome, and more healthcare costs. Disorders of consciousness, abnormal movements, and hypokalemia were identified to be risk factors for pneumonia in patients with anti-NMDA receptor encephalitis.

In our present study, a lower GCS was found to be associated with the occurrence of pneumonia in patients with anti-NMDA receptor encephalitis. This is consistent with previous studies[. Caterina et al[ reported a high incidence of pneumonia (76.79%) in patients with disorders of consciousness.[ A lower GCS score was strongly related to the reduced gag and cough reflexes, indicating that patients with decreased consciousness maybe unable to protect their own airway and were at risk for aspiration.[ It was recommended that patients with a GCS of ≤8 should undergo tracheal intubation to prevent possible airway obstruction, aspiration, or respiratory compromise.[ However, a considerable proportion of those with a GCS ≤8 not intubated had no respiratory complications developed. This indicated that airway management in anti-NMDA receptor encephalitis should be paid more attention and decided by the clinical situation.[

In the present retrospective study, movement disorder was also proving to be associated with the occurrence of pneumonia in patients with anti-NMDA receptor encephalitis. Movement disorders are typical symptoms in patients with anti-NMDA receptor encephalitis. Orofacial and tongue dyskinesia are the most frequent characteristic movement disorder.[ Orofacial and tongue dyskinesia can affect the oral phase of normal swallowing process,[ which may lead to dysphagia and increase the risk of aspiration.[ This maybe the best explanation that abnormal movement increases the incidence of pneumonia in patients with anti-NMDA receptor encephalitis.

Hypokalemia (serum potassium less than 3.5 mmol/L)[ is one of the most common electrolyte disturbances, which was often caused by steroid treatment. Hypokalemia may affect the muscles of respiration, which can lead to reduced protective cough function,[ difficulty in breathing, fast breathing or respiratory failure. Affected gastrointestinal muscles could cause intestinal obstruction with related symptoms of abdominal distension, nausea, and vomiting.[ Symptoms of respiration and gastrointestinal muscles weakness due to hypokalemia may be the cause for aspiration and increase the risk of pneumonia.

In our study, treatment with methylprednisolone (glucocorticoid) is associated with pneumonia, though did not enter the multivariate analysis result. Previous studies have shown long-term use of inhaled corticosteroids increases the risk of pneumonia in COPD,[ and glucocorticoid may be a risk factor for Pneumocystis jirovecii pneumonia infection in patients with autoimmune diseases[ However, Glucocorticoids is recommended as first-line treatments in patients with anti-NMDA receptor encephalitis. This may be one of the reasons for the high rate of pneumonia in patients with anti-NMDA receptor encephalitis.

There were some limitations in our study. First, this is a retrospective study. Second, the sample size was small as our data were collected from a single center. We will strive for the opportunity to collect data in multicenter and validate these variables in different data-set. Third, we were unable to classify the specific types of pneumonia for all patients due to restrictions on the information we obtained. Furthermore, we did not have the same follow-up time after patient discharge, which may affect the evaluation of prognosis.

Conclusion

In the present study, we found that disorders of consciousness, abnormal movements and hypokalemia were independent risk factors for pneumonia in inpatients with anti-NMDA receptor encephalitis. Pneumonia prolongs the patients’ hospital stay, hospitalization expenditures, and affects the patients’ prognosis.

Acknowledgments

The authors thank all the subjects enrolled in this study.

Author Contributions

Conceptualization: Pingqiao Yuan, Rong Yang, Jinmei Li.

Data curation: Pingqiao Yuan, Le Zhang, Xinyue Jiang.

Formal analysis: Xiaohui Miao, Lihong Zhao, Pingqiao Yuan, Hanyu Cao, Hongrui Shi.

Funding acquisition: Rong Yang.

Investigation: Pingqiao Yuan, Xiaohui Miao, Lihong Zhao.

Methodology: Pingqiao Yuan, Xiaohui Miao, Lihong Zhao.

Project administration: Rong Yang, Jinmei Li.

Resources: Rong Yang, Jinmei Li.

Software: Pingqiao Yuan, Xiaohui Miao, Lihong Zhao.

Supervision: Rong Yang, Jinmei Li.

Validation: Pingqiao Yuan, Xiaohui Miao, Lihong Zhao.

Visualization: Pingqiao Yuan, Xiaohui Miao, Lihong Zhao.

Writing – original draft: Pingqiao Yuan, Xiaohui Miao, Lihong Zhao.

Writing – review & editing: Rong Yang, Jinmei Li.