Association between clinical factors and orofacial dyskinesias in anti‐N‐methyl‐D‐aspartate receptor encephalitis

Abstract Background and Purpose We aimed to determine whether demographic information, clinical characteristics, laboratory tests, and imaging features are associated with orofacial dyskinesias (OFLD) in patients with anti‐N‐methyl‐D‐aspartate receptor (NMDAR) encephalitis. Methods In this retrospective study, patients who were diagnosed with anti‐NMDAR encephalitis were enrolled. All patients’ factors, including demographic information, clinical characteristics, laboratory tests, and imaging features, were obtained at the time of hospitalization. The neurological function was assessed using the modified Rankin scale (mRS). Univariate and multivariate logistic regressions were used to examine the associations between clinical factors and OFLD. Results In total, 119 patients (median age: 28.0 [19.0–41.0] years; 67 females) were recruited. Of 119 patients, 44 (37.0%) had OFLD. OFLD was associated with increased mRS at admission, serum sodium, lumbar puncture pressure, female biologic sex, fever, psychiatric symptoms, seizures, impaired consciousness, autonomic dysfunction, and central hypoventilation in univariate logistic regression, respectively. Multivariate regression analysis revealed that female biologic sex (odds ratios [OR], 4.73; 95% confidence interval [CI], 1.27–17.64; p = .021), increased mRS at admission (OR, 2.09; 95% CI, 1.18–3.71; p = .011), psychiatric symptoms (OR, 7.27; 95% CI, 1.20–43.91; p = .031), and seizures (OR, 5.11; 95% CI, 1.22–21.43; p = .026) were associated with OFLD, after adjusting for confounding factors. Conclusions Our analysis suggests that the following clinical factors are associated with OFLD: female biologic sex, increased mRS at admission, psychiatric symptoms, and seizures.


INTRODUCTION
1 and 2, and herpes zoster virus); (3) an immunosuppressed state (including long-term immunosuppressive therapy due to chemotherapy or organ transplantation); and (4) thyroid disease, a recent history of thyroid hormone replacement, or a lack of test results on thyroid function and antibodies. This study was approved by the Ethics Com-mittee of the Affiliated Brain Hospital of Nanjing Medical University.
All the patients provided written consent forms.

Demographic information and clinical characteristics
The demographic information of all the patients, including age and sex, was collected from the electronic medical record system. A neurologist analyzed clinical characteristics at hospitalization. The presence or absence of headaches, fever, cognitive decline, psychiatric symptoms, MDs, seizures, impaired consciousness, autonomic dysfunction, speech disturbance, central hypoventilation, and sleep disturbance was evaluated, respectively. The category and diagnosis of MDs that included OFLD, tremors, dystonias, stereotypies, chorea, myoclonus, catatonia, and parkinsonism were assessed according to previous studies (Damato et al., 2018;Varley et al., 2019). Moreover, the time from the onset to admission (TOA), time from the onset to diagnosis (TOD), and length of stay were recorded for all the patients. The neurological function of all the patients at admission was independently evaluated by two physicians with consensus using the modified Rankin scale (mRS) (van Swieten et al., 1988).

Laboratory tests, electroencephalography, and imaging examination
All the patients underwent laboratory tests, including standard biochemistry, AE-related antibodies (Dalmau & Graus, 2018;Hang et al., 2020), thyroid function, rheumatic indicators, syphilis, tumor biomarkers, autoantibodies, and other laboratory tests. The patients also underwent both CSF and serum examinations. The blood and CSF AE-related antibodies were detected by indirect immunofluorescence testing based on cell-based assay as previously published (Dalmau et al., 2017). The lumbar puncture pressure (LPP), CSF cell count, and CSF protein were measured. All the patients underwent brain magnetic resonance imaging (MRI), routine electroencephalography (EEG), and abdominal ultrasonography examinations. Thyroid function abnormalities included continuous thyroid function test measurements (abnormal concentrations of thyrotropin and FT4), or thyroid peroxidase antibody positivity, or thyroglobulin antibody positivity.
Abnormal EEG was defined as extreme delta brush, focal or diffuse slow or disorganized activity, or epileptic activity (Graus et al., 2016).
The T2/T2-fluid attenuated inversion recovery hyperintensities in the unilateral or bilateral limbic system, or other areas, or multiple cortical or basal ganglia were considered as abnormal brain MRI (Graus et al., 2016).

Differences in demographic information, clinical characteristics, laboratory tests, and imaging features between the OFLD and non-OFLD groups
There were 103 MD cases in the present study, of which 44 (42.7%) were confirmed as OLFD based on the presence of the characteristic movements of chewing, jaw opening, sucking, and lip-smacking. No significant differences were found in other clinical characteristics, laboratory tests, imaging features, and age between the two groups (all p ≥ .05). Table 1 presents the results of comparisons between the two groups.   differences in MDs are insufficiently studied and poorly understood (Meoni et al., 2020). Sex hormones in women, such as estrogens, may justify some differences, implicating their crucial role in the MDs (Rabin et al., 2014). An underlying explanation could account for this association: estrogen may aggravate hyperkinetic states (such as chorea) (Meoni et al., 2020). The pathophysiological mechanisms of sex-related differences in MDs should be investigated in future studies.

Associations of demographic information, clinical characteristics, laboratory tests, and imaging features with OFLD
Symptom severity was assessed with the mRS at admission of the disease in the present study. We found that increased mRS at admission was independently associated with OFLD in patients with anti-NMDAR encephalitis. There is growing evidence that mRS can be used to evaluate neurological outcomes in anti-NMDAR encephalitis (Titulaer et al., 2013;Xu et al., 2019). However, the relationship between the mRS and OFLD has not been reported previously to the best of our knowledge. Therefore, our findings indicated that it is valuable to assess the neurological status at admission.
We observed that psychiatric symptoms are significantly associated with OFLD. It is widely accepted that both psychiatric symptoms and MDs are predominant manifestations in anti-NMDAR encephalitis (Dalmau et al., 2017;Irani et al., 2010). Although the relationship between psychiatric symptoms and OFLD was not clear, most previous studies proposed that abnormalities in glutamatergic receptor functions play a crucial role in the pathogenesis of psychosis and MDs (Iizuka et al., 2008;Laruelle, 2014). Therefore, we speculate that this neurobiological phenomenon may explain why these two conditions coexist clinically in anti-NMDAR encephalitis. However, further prospective studies are required to elucidate the underlying mechanism of the relationship.

CONCLUSION
The present study showed that clinical factors, such as female biologic sex, increased mRS at admission, psychiatric symptoms, and seizures, were independently associated with OFLD. Our findings suggest that it is valuable to evaluate the demographic and clinical characteristics to characterize the risk of OFLD and may even warrant more closely monitored symptom progression and development.

ACKNOWLEDGMENT
This work was supported by the grants of National Natural Science

CONFLICT OF INTEREST
The authors declare no conflict of interest.

AUTHOR CONTRIBUTIONS
Conceptualization (

DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from the corresponding author upon reasonable request.