Clinical of autonomic dysfunction in children with anti-N-methyl-D aspartic receptor encephalitis

doi:10.21203/rs.3.rs-4628973/v1

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Clinical of autonomic dysfunction in children with anti-N-methyl-D aspartic receptor encephalitis

https://doi.org/10.21203/rs.3.rs-4628973/v1

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Background

Anti-N-methyl-D-aspartic receptor encephalitis (Anti-NMDAR encephalitis) is the most prevalent form of autoimmune encephalitis in pediatric patients. Autonomic dysfunction is a frequent symptom of Anti-NMDAR encephalitis, yet it often goes unnoticed by pediatricians. Studies have indicated that pediatric patients with autonomic dysfunction exhibit a poorer prognosis compared to those without. To date, research on autonomic dysfunction in encephalitis has predominantly focused on adults, with no studies conducted on pediatric populations. This analysis examines the clinical features of pediatric patients with Anti-NMDAR encephalitis complicated by autonomic dysfunction.

Methods

We performed a retrospective analysis of patients diagnosed with Anti-NMDAR encephalitis at the Department of Neurology, Children's Hospital Capital Institute of Pediatrics, from June 2017 to June 2023. Patients were categorized based on the presence or absence of autonomic dysfunction during their illness. We summarized and compared the clinical features of children with autonomic dysfunction and analyzed the risk factors for its development in pediatric Anti-NMDAR encephalitis patients.

Results

A total of 56 children were included in this study. Twenty-two (39.3%) exhibited autonomic nervous dysfunction. The most prevalent symptom of autonomic dysfunction was arrhythmia (19/56, 33.9%), with the specific manifestations being sinus tachycardia (8 cases), ventricular premature beats (2 cases), atrioventricular block (2 cases), atrial premature beats (3 cases), and sinus bradycardia (4 cases). Other symptoms included increased salivation (16/56, 28.6%), central hypopnea (3/56, 5.4%), central fever (3/56, 5.4%), hyperhidrosis (3/56, 5.4%), urinary retention (2/56, 3.6%), hypertension (1/56, 1.8%), and cardiac arrest (1/56, 1.8%). Compared to the group without autonomic dysfunction, the group with dysfunction showed significantly higher rates of prodrome infection, tumor complications (all ovarian teratoma), consciousness disturbance, elevated cerebrospinal fluid protein, initiation of second-line and long-term immunotherapy, length of hospital stay, and hospitalization costs (P < 0.05).

Conclusion

Among pediatric patients with Anti-NMDAR encephalitis, arrhythmia is the most common form of autonomic dysfunction. Those with autonomic dysfunction have a worse prognosis and longer hospital stays. Active initiation of second-line and long-term immunotherapy is recommended.

Anti-NMDAR encephalitis

Autonomic dysfunction

Pediatric patients

Encephalitis

Anti-NMDAR encephalitis is the most common autoimmune encephalitis in children, accounting for approximately 54-80% of cases ^[1]. The disease presents with prodromal symptoms such as fever and headache or events of central nervous system infection. Main symptoms include abnormal mental behavior, cognitive impairment, seizures, dysphasia, dyskinesia, consciousness disturbances, and autonomic nervous dysfunction. Common manifestations of autonomic nervous dysfunction include sinus tachycardia, sinus bradycardia, increased salivation, hypotension, central fever, and central hypoventilation ^[2]. Despite its frequency, autonomic nervous dysfunction in Anti-NMDAR encephalitis is often overlooked by pediatricians, leading to underestimation of associated risks. Currently, studies on Anti-NMDAR encephalitis with autonomic dysfunction are limited to adults, with none focused on pediatric patients. This analysis aims to enhance understanding and recognition of Anti-NMDAR encephalitis with autonomic nervous dysfunction in children by investigating its clinical features and differences between groups with and without this complication.

Study population

This study included pediatric patients diagnosed with anti-NMDAR encephalitis at the Children's Hospital Capital Institute of Pediatrics from June 2017 to June 2023. The inclusion criteria were based on the diagnostic framework proposed by Graus ^[2] in 2016, requiring that patients meet all three of the following conditions: A, B, and C. Condition A necessitates one or more of six main symptoms: (1) abnormal mental behavior or cognitive impairment, (2) speech disorder, (3) seizures, (4) dyskinesia/involuntary movement, (5) decreased level of consciousness, and (6) autonomic nervous dysfunction or central hypopnea. Condition B confirms Anti-NMDAR antibody positivity, with cerebrospinal fluid CBA antibody positivity being prevalent. Condition C involves the reasonable exclusion of other causes. Additionally, patients must have had a follow-up period of more than 3 months. The exclusion criterion was the presence of incomplete clinical data. This study received approval from the Ethics Committee of the Capital Institute of Pediatrics (Ethics number: SHERLLM2024017), which exempted guardians from providing informed consent.

Data collection and grouping

Data were collected on demographic details, clinical symptoms, and results of ancillary tests for patients with anti-NMDAR encephalitis. The information gathered included age, sex, prodromal symptoms, main symptoms, presence of concomitant tumors, routine biochemical and cytological tests of cerebrospinal fluid, detection of anti-NMDAR antibodies in both blood and cerebrospinal fluid, use of mechanical ventilation, results of head magnetic resonance imaging, hospitalization costs, the Glasgow Coma Score (GCS), the modified Rankin Scale (mRS) at admission, the maximum duration of disease, and the status at three months post-discharge.

Patients were categorized based on the presence or absence of autonomic dysfunction during their illness. Autonomic dysfunction encompassed a range of symptoms including arrhythmias (such as sinus tachycardia, sinus bradycardia, atrioventricular block, sinus atrial block, atrial premature beat, ventricular premature beat, atrial tachycardia, and ventricular tachycardia), hypersalivation, hypotension, hypertension, urinary retention, cardiac and respiratory arrest, central fever, central hypopnea, and constipation. Conditions such as underlying diseases causing arrhythmia were excluded. Manifestations not attributable to other causes like fever, crying, or shock were considered indicative of autonomic dysfunction.

Clinical symptoms were classified into several categories: abnormality of mental behavior or cognitive impairment, speech disorders, seizures, dyskinesia/involuntary movement, consciousness disorders, and ataxia. The number of clinical symptoms per patient was tallied. The count also included patients experiencing epileptic status, defined as seizure activity lasting more than 30 minutes. Mechanical ventilation was noted for patients requiring ventilator assistance post-intubation or tracheotomy. The GCS was utilized to assess the state of consciousness. Treatment modalities were recorded as follows: first-line treatments included human immunoglobulin, glucocorticoids, and plasma exchange; second-line treatments covered rituximab and cyclophosphamide; and long-term immunotherapy involved agents like mycophenolate mofetil and mercaptopurine.

Statistical Analysis

The data were analyzed using SPSS26.0 statistical software. Count data were represented by the number of cases and percentage (%), with comparisons made using the Chi-square test or Fisher's exact test as appropriate. The Shapiro-Wilk test was employed to assess the normality of the measurement data. For data adhering to a normal distribution, results were expressed as mean ± standard deviation, and comparisons between groups were conducted using the independent sample T-test. Measurement data not conforming to a normal distribution were represented by the median and interquartile range (M(Q1-Q3)), with group comparisons performed using the non-parametric Mann-Whitney U rank sum test. A significance level was set at p < 0.05.

Clinical manifestations and demographic characteristics of autonomic nervous dysfunction in anti-NMDAR encephalitis complicated with autonomic nervous dysfunction

The study included 56 children diagnosed with Anti-NMDAR encephalitis, 22 of whom exhibited symptoms of autonomic dysfunction while 34 did not, resulting in an incidence rate of autonomic dysfunction of 39.3%. The onset of autonomic dysfunction ranged from the 3rd to the 21st day of the disease course, with a median onset time of 9 days. Arrhythmia was the most frequent symptom of autonomic dysfunction (19/56), detailed as follows: sinus tachycardia in 8 patients, ventricular premature beats in 2 patients, atrioventricular block in 2 patients, atrial premature beats in 3 patients, and sinus bradycardia in 4 patients. Other symptoms included increased salivation (16/56), central hypopnea (3/56), central fever (3/56), hyperhidrosis (3/56), urinary retention (2/56), hypertension (1/56), and cardiac arrest (1/56) as shown in Table 1.

Table 1

Clinical manifestation and incidence of autonomic nervous dysfunction
Autonomic dysfunction	patients(n = 22)	percent(%)
Arrhythmia	19	86
Increased salivation	16	73
central hypopnea	3	14
central feve	3	14
hyperhidrosis	3	14
urinary retention	2	9
hypertension	1	5
cardiac arrest	1	5

Arrhythmia include sinus tachycardia (n = 8), ventricular premature beats (n = 2), atrioventricular block (n = 2), atrial premature beats(n = 3), and sinus bradycardia (n = 4) .

2. Comparison of clinical features between patients with and without autonomic dysfunction

As detailed in Table 2, there were no significant differences in sex and age between patients with and without autonomic dysfunction. In the group with autonomic dysfunction, 4 patients had tumors (all ovarian teratomas) and 14 patients exhibited prodromal symptoms. Conversely, no patients in the group without autonomic dysfunction had tumors, and 11 had prodromal symptoms. The presence of prodromal symptoms and tumors was higher in the group with autonomic dysfunction. Although the number of major symptoms was similar between the two groups, there were notable differences in the disturbance of consciousness. In the group with autonomic dysfunction, 18 patients experienced disturbances in consciousness, with a median GCS score of 9 (interquartile range: 7.75–11.25). In contrast, in the group without autonomic dysfunction, 14 patients experienced consciousness disturbances, with a median GCS score of 15 (interquartile range: 10–15). This indicates that the group with autonomic dysfunction had a higher incidence and a more severe degree of consciousness disorder. Regarding auxiliary examinations, there were no significant differences between the two groups in cerebrospinal fluid white blood cell count, MRI abnormalities, blood anti-NMDAR antibody titer, or cerebrospinal fluid anti-NMDAR antibody titer. In terms of treatment, patients with autonomic dysfunction received first-line treatments, second-line treatments, and long-term immunotherapy. The rates of mechanical ventilation, length of hospital stay, and hospitalization costs were greater in the group with autonomic dysfunction. Furthermore, the highest mRS score, mRS score at discharge, and mRS score three months post-discharge were higher in the group with autonomic dysfunction, indicating a poorer prognosis.

3. Multivariate Firth Logistic regression analysis of the associated risk of anti-NMDAR encephalitis with autonomic dysfunction

Using the presence of autonomic nervous dysfunction as the dependent variable (0 = good prognosis, 1 = poor prognosis), a Multivariate Firth Logistic Regression analysis was conducted. The analysis included factors identified as significant in univariate analysis (history of preinfection, disturbance of consciousness, GCS score, duration of consciousness disturbance, tumor presence, highest modified mRS score, cerebrospinal fluid protein). A significant correlation was found between the highest modified mRS score and autonomic dysfunction (P < 0.05), as shown in Table 3.

Results Improved mRS Score (highest) was an independent risk factor for autonomic dysfunction, with a 4.583-fold increase in risk for each 1-point increase

Anti-NMDAR encephalitis is the most prevalent form of autoimmune encephalitis, with autonomic dysfunction occurring in approximately 45.5–69% of patients ^[3–6]. Sinus tachycardia is the most frequent symptom of autonomic dysfunction, followed by hypertension and constipation. A minority of patients ^{[3, 7]} may also experience cardiac arrest, necessitating the use of temporary pacemakers. Symptoms of autonomic dysfunction often resolve following immunotherapy ^[8–9]. Anti-NMDAR encephalitis with autonomic dysfunction is severe, characterized by a high incidence of teratomas, seizures, involuntary movements, and consciousness disorders, as well as a high rate of complications such as lung infections. The short-term prognosis for these patients is poor, and treatment typically requires the use of multiple immunosuppressants. Such patients often need more proactive admission to the intensive care unit ^{[3, 6, 10]}. However, while previous studies have focused on Anti-NMDAR encephalitis in adults, there are fewer studies involving children. Reports indicate that autonomic dysfunction is more commonly observed in adults, whereas convulsive neurological symptoms are more prevalent in children. Consequently, in clinical settings, doctors and nurses often overlook symptoms of autonomic dysfunction in children, leading to delays in recognition and treatment ^{[4, 11]}. This study specifically targeted pediatric patients and found that more than one-third of children with Anti-NMDAR encephalitis experienced autonomic nervous dysfunction, highlighting that this is not an uncommon occurrence. Results from this study revealed that the most common manifestations of autonomic dysfunction were arrhythmias, particularly tachycardia and bradycardia, followed by increased salivation, aligning with findings from previous studies. Additionally, a small number of patients also presented with severe complications such as prolonged cardiac arrest and Takotsubo cardiomyopathy, requiring the use of temporary pacemakers ^{[3, 12]}. Among the 56 children in this study, one case involved a sudden long-term cardiac arrest that resulted in death despite resuscitation efforts, while the symptoms in other children resolved following immunotherapy.

The etiology of autonomic dysfunction in patients with anti-NMDAR encephalitis remains unclear. Some studies have suggested that this dysfunction may be associated with factors such as cerebrospinal fluid glucose levels, anti-NMDAR antibody titers, types of immunotherapy, and temporal lobe lesions ^[7–8]. However, Byun et al. ^[5] compared patients with anti-NMDAR encephalitis to those with herpes simplex encephalitis and found that autonomic nervous dysfunction in anti-NMDAR encephalitis was not related to temporal lobe lesions. Instead, it might be linked to damage within the sympathetic nerve circuit. Anti-NMDAR antibodies are thought to affect both the output of the vagus nerve in the brainstem and the regulation of sympathetic nerve output in the hypothalamus, thus impacting the function of both the vagus and sympathetic nerves and leading to symptoms of autonomic nervous dysfunction. Experimental studies have also shed light on the potential mechanisms. For instance, injecting N-methyl-D-aspartate into the paraventral nucleus of the hypothalamus in rats has been shown to induce sympathetic excitation, increasing blood pressure and heart rate ^[13]. Conversely, administering ketamine, a non-competitive antagonist of NMDAR, can cause autonomic dysfunction ^[14], suggesting a direct relationship between NMDA receptors and autonomic nervous function. Although the precise mechanisms underlying autonomic dysfunction in anti-NMDAR encephalitis are yet to be fully understood, these studies indicate a potential link to damage at the autonomic nervous center. In this study, through multivariate logistic regression analysis, only the highest mRS score was identified as an independent risk factor for autonomic nervous dysfunction, while the modified mRS score served as a method for evaluating neurological function in patients. The presence of autonomic nervous dysfunction could lead to an increased mRS score, suggesting a reciprocal causal relationship between the two. The absence of other related independent risk factors in this analysis is thought to be due to the small sample size of the study.

Children with autonomic dysfunction exhibited a poorer prognosis, longer hospital stays, and higher hospitalization costs, aligning with findings from previous studies. Autonomic dysfunction has been identified as a risk factor for a poor prognosis in anti-NMDAR encephalitis ^[15]. This correlation may be due to a range of factors; autonomic dysfunction can lead to hypopnea and increased salivation, which are linked to higher rates of pulmonary infections and mechanical ventilation, all of which significantly impact prognosis. In this study, all children with autonomic dysfunction were initiated on second-line immunotherapy, reflecting the severity and treatment complexity associated with their condition. Additionally, the cerebrospinal fluid protein levels were higher in the group with autonomic dysfunction than in those without, suggesting more severe neuronal damage in the former group. Despite these differences, there were no significant disparities in the number of white blood cells in the cerebrospinal fluid, head magnetic resonance imaging abnormalities, or anti-NMDAR antibody titers in both blood and cerebrospinal fluid between the two groups. This indicates that while autonomic dysfunction significantly affects clinical outcomes, it may not be directly reflected in these specific biomarkers.

The treatment of autonomic nervous dysfunction in anti-NMDAR encephalitis primarily involves symptomatic management. Medications such as beta-blockers, alpha-2 blockers, or acetylcholinesterase inhibitors may be used to manage sympathetic agitation. For conditions like bradycardia, cardiac arrest, or conduction blocks, temporary pacemakers should be installed. Respiratory issues like hypopnea require close monitoring; tracheal intubation or tracheotomy should be performed promptly, followed by mechanical assisted ventilation. Notably, symptoms related to autonomic dysfunction often resolve following immunotherapy.

In summary, over one-third of children with anti-NMDAR encephalitis experience autonomic nervous dysfunction, with arrhythmia being the most common form. This dysfunction not only exacerbates the severity of anti-NMDAR encephalitis but can also lead to life-threatening conditions such as cardiac arrest. Therefore, it is crucial to monitor for the onset of autonomic symptoms closely. Children with anti-NMDAR encephalitis and autonomic dysfunction often have a high incidence of consciousness disorders, prolonged duration of these disorders, poor prognosis, and extended hospital stays, underscoring the necessity of promptly initiating second-line immunotherapy.

Table 2

Comparison of clinical features between patients with and without autonomic dysfunction

Group without autonomic dysfunction(n = 34)

Group with autonomic dysfunction(n = 22)

t/z/x²

Sex

Male,n(%)

Femal,n(%)

15(44.12)

19(55.88)

8(36.36)

14(63.64)

0.322

0.565

Age,mean ± SD, mouth

82.88 ± 41.89

92.73 ± 43.86

-0.84

0.403

Disturbance of consciousness,n(%)

14(41.18)

18(81.82)

9.009

0.003

Duration of disturbance of consciousness(day)

0.00(0.00-20.25)

33.50(23.25–52.50)

-3.819

< 0.001

GCS score

15.00(11.00–15.00)

9.00(7.75–11.25)

3.566

< 0.001

Number of symptom types

3.00(2.00–3.00)

3.00(2.00–4.00)

-0.566

0.572

Epilepsy,n(%)

21(61.76)

13(59.09)

0.040

0.841

Status epilepticus,n(%)

9(26.47)

9 (40.91)

1.277

0.259

WBC count of CSF(10⁶/L)

14.00(4.75–35.50)

17.00(4.75-52.00)

-0.260

0.794

Protein of CSF(mg/L)

188.55(132.23-267.45)

246.15(167.4-382.38)

-2.064

0.039

Tumour,n(%)

0(0%)

4(18.18)

0.02

Blood anti-NMDAR antibody titer

10.00(0.00–32.00)

0.151

0.88

CSF anti-NMDAR antibody titer

100.00(32.00-100.00)

0.447

0.655

mechanical ventilatio,n(%)

1 (2.94)

4 (18.18)

0.072

MRI abnormalities,n(%)

11 (32.35)

9 (40.91)

0.426

0.514

The highest mRS score

4.00(4.00-4.25)

5.00(4.75-5.00)

-4.019

< 0.001

mRS score at discharge

2.00(1.00-2.25)

3.50(3.00–4.00)

-4.887

< 0.001

mRS score three months post-discharge

1.00(0.00–1.00)

3.50(3.00–4.00)

-4.438

< 0.001

length of hospital stay(day)

23.00(18.00-30.50)

35.00(25.25-42.00)

-2.742

0.006

Hospitalization costs(yuan)

Numbers of immunotherapies

Prodromal symptoms,n(%)

50544.00(31521.50-92796.50)

2.00(2.22-3.00)

11(32.65

126845.00(65096.75-229278.75)

3.00(3.00–3.00)

14(63.64)

-3.608

-3.073

5.29

< 0.001

0.002

0.021

GCS,Glasgow Coma Score;CSF, cerebrospinal flfluid;NMDAR, N-methyl-d-aspartate receptor; MRI, magnetic resonance imaging; WBC, white blood cell count; mRS, modifified Rankin scale.

Table 3 Multivariate Firth Logistic regression analysis of the associated risk of anti-NMDAR encephalitis with autonomic dysfunction

	β	SE	OR	95%CI	χ2	P
Prodromal symptoms	1.048	0.663	2.853	0.755-12.342	2.381	0.123
Disturbance of consciousness	-0.674	1.082	0.509	0.049-4.318	0.373	0.541
GCS score	-0.075	0.171	0.928	0.632-1.369	0.155	0.694
Duration of disturbance of consciousness	0.002	0.020	1.002	0.961-1.061	0.008	0.928
Tumour	1.396	1.481	4.040	0.287-584.099	0.965	0.326
highest modified mRS score	1.720	0.823	5.583	1.055-41.484	4.223	0.040
CSF protein	0.004	0.002	1.004	0.999-1.009	2.658	0.103

Results Improved mRS Score (highest) was an independent risk factor for autonomic dysfunction, with a 4.583-fold increase in risk for each 1-point increase

NMDAR Anti-N-methyl-D-aspartic receptor

GCS Glasgow Coma Score

mRS The modified Rankin Scale

CSF Cerebrospinal flfluid

MRI Magnetic resonance imaging

WBC White blood cell count

Ethics approval and consent to participate

This study was performed in line with the principles of the Declaration of Helsinki. This study received approval from the Ethics Committee of the Capital Institute of Pediatrics (Ethics number: SHERLLM2024017), which exempted guardians from providing informed consent.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no conflicts of interest.

Data availability

The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

Competing interests

The authors declare that they have no conflicts of interest.

Funding

Not applicable.

Author contributions

JZZ contrubutes to the conception of the study and revised the manuscript. DQL recruited patients and provided clinical data, analyzed the data, drafted the initial manuscript, and reviewed and revised the manuscript. SJ,GNL,MS,YJ collected data and conducted the initial analyses. All authors read and approved the final manuscript.

Acknowledgements

Not Applicable.

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You are reading this latest preprint version

Clinical of autonomic dysfunction in children with anti-N-methyl-D aspartic receptor encephalitis

Status:

Version 1

Abstract

Background

Methods

Results

Conclusion

Introduction

Methods

Study population

Data collection and grouping

Statistical Analysis

RESULTS

2. Comparison of clinical features between patients with and without autonomic dysfunction

Discussion

Conclusions

Abbreviations

Declarations

References

Status:

Version 1