Anti-NMDAR encephalitis with euthyroid sick syndrome and lateral ventricle lesions predicts a poor prognosis

doi:10.21203/rs.3.rs-1591714/v1

Background

The aim of this study was to clarify the role of thyroid dysfunction in anti-NMDAR encephalitis (ANE) patients.

Methods

The clinical and laboratory characteristics of 42 ANE patients were analyzed, including 24 ANE patients with normal thyroid function and 18 ANE patients with thyroid dysfunction (12 ANE patients with euthyroid sick syndrome (ESS); 6 ANE patients with thyroid dysfunction but not ESS). Cranial magnetic resonance imaging (MRI) findings, cerebrospinal fluid (CSF) parameters, clinical symptoms, antibodies, and admission and discharge modified Rankin scale (mRS) scores were evaluated.

Results

ANE patients with thyroid dysfunction had more serious consciousness disorders (p = 0.008), motor disorders (p = 0.005) and status epilepticus than those without thyroid dysfunction (p = 0.007). The conditions of ANE patients with ESS were more serious than those of ANE patients without ESS in terms of language disorders (p = 0.035), status epilepticus (p = 0.001), motor disorders (p < 0.007) and consciousness disorders (p = 0.001). Moreover, the admission mRS scores of ANE patients with ESS were higher than those of ANE patients without ESS (p = 0.030). ANE patients with ESS with lateral ventricle lesions (p = 0.017) had higher discharge mRS scores than those without lateral ventricle lesions (p = 0.045).

Conclusion

The conditions of ANE patients with thyroid dysfunction were more serious than those of ANE patients without thyroid dysfunction. The conditions of ANE patients with ESS were more serious than those of ANE patients without ESS, and these patients had poorer prognoses. The lateral ventricles were not common sites of lesions in autoimmune encephalitis patients, but they might predict a worse prognosis in ANE patients with ESS. Such patients should be given more attention. However, interventions for ESS are still controversial. Prospective randomized controlled trials should be performed to further explore the possible mechanisms of ESS in ANE.

Euthyroid sick syndrome

Anti-N-methyl-D-aspartate receptor encephalitis

Autoimmune encephalitis

Retrospective study

Thyroid dysfunction

Anti-N-methyl-d-aspartate receptor (anti-NMDAR) encephalitis (ANE), which is one of the most common types of autoimmune encephalitis (AIE), accounts for approximately 80% of the AIE cases. The course of ANE progresses rapidly. The clinical characteristics of ANE are cognitive disorders, behavior and mental disorders, language disorders, seizures, status epilepticus, motor disorders, consciousness disorders, sleep disorders, autonomic meridian dysfunction and central ventilation insufficiency (Josep, 2019; David, 2018; Qianyi, 2020). Ever since ANE was officially named in 2008, its etiology has not been clarified. Although previous studies have shown that 81% of ANE patients have a good prognosis, 86% of ANE patients still have long-term neurological defects, such as consciousness disorders, behavior and mental disorders, and seizures. Moreover, 5–11% of the critically ill ANE patients/drug-resistant ANE patients die. Therefore, the early identification of the patients with anti-NMDA encephalitis and poor prognosis is still an important issue (James, 2019; Ursitti, 2021).

Euthyroid sick syndrome (ESS), also known as low T3 syndrome, is a condition in which a patient has no basic thyroid diseases, but due to serious systemic diseases, their levels of thyroid hormones are abnormal. In recent years, thyroid dysfunction has been closely related to the progression of critical diseases and poor prognosis and should be given more attention (Fliers, 2021). If ANE patients have thyroid dysfunction, would they be in more danger? Researchers have begun to explore the clinical, laboratory and magnetic resonance imaging (MRI) features of ANE patients with thyroid dysfunction; however, because there were few enrolled patients in these previous studies, a conclusion could not be clearly drawn (Qianhui, 2021; Zhongyun, 2021; Emilia2021). Therefore, more studies should be conducted to further verify these findings. Our study evaluated the differences in the clinical, laboratory and MRI parameters of ANE patients with/without thyroid dysfunction.

Patients Our retrospective study included 103 patients who were diagnosed with AIE in the Department of Neurology (Xinqiao Hospital, Army Medical University, Chongqing, China) from September 2014 to June 2021. The inclusion criteria were as follows: 1. Clinical manifestations: acute or subacute onset (< 3 months), with one or more of the following neurological and psychiatric symptoms or clinical syndromes. (1) limbic system symptoms: recent memory impairment, seizures, abnormal mental behavior, and one or more of the following three symptoms. (2) encephalitis syndrome: clinical manifestation of diffuse or multifocal brain damage. (3) clinical manifestations are present and there is involvement of basal ganglia and/or diencephalon/hypothalamus. (4) mental disorder, and the mental psychology specialty believes that the patient’s mental disease is not due to an nonorganic disease; 2. auxiliary examination: one or more of the following auxiliary examination findings were present or the findings were combined the presence of tumors; (1) abnormal cerebrospinal fluid: cerebrospinal fluid analysis shows leukocytosis (> 5 × 10⁶/L); lymphocytic inflammation or positivity for oligoclonal bands in the CSF; (2) neuroimaging or electrophysiological abnormalities: abnormal signals in the limbic system, unilateral or bilateral, on flare or T2 images on MRI, or abnormal signals in other regions on T2 or flair (excluding nonspecific white matter changes and stroke); or hypermetabolism in the limbic system on a PET examination, or hypermetabolism in multiple cortex and/or basal ganglia; or electroencephalogram abnormalities: focal epilepsy or epileptiform discharges (located outside the temporal lobe or temporal lobe), or diffuse or multifocal slow wave rhythm; (3) specific types of tumors associated with AIE, such as marginal encephalitis with small cell lung cancer and ANE with teratoma; and 3. confirmation test: the autoantibody against neuron surface antigen is positive.

The diagnostic criteria were as follows: possible AIE and confirmed AIE: possible AIE: met items 1, 2 and 4 of the above diagnostic criteria; confirmed AIE: met the above diagnostic criteria 1–4. Among the 103 patients considered to be diagnosed with AIE, 18 patients were excluded due to have negative autoimmune antibody serum and CSF tests. Seventeen patients were excluded because autoimmune antibodies in the serum and CSF was not checked. Twenty-six patients were positive for autoimmune antibodies in the serum and CSF but were not positive for anti-NMDAR antibodies.

The exclusion criteria were as follows: (1) patients with other nervous system disorders (such as viral encephalitis, other types of AIE, or Hashimoto encephalopathy). ① Viral encephalitis: In the acute phase of viral encephalitis, the serum and CSF is negative for anti-nerve cell antibody related to AIE, so the positive antibody related to AIE can exclude viral encephalitis. ② Hashimoto encephalopathy: Hashimoto encephalopathy is associated with a significantly increased serum antithyroid antibody, so Hashimoto encephalopathy can be rule out in patients with normal thyroid antibodies. Hashimoto encephalopathy can be ruled out in patients with elevated thyroid antibodies and positive anti nerve cell antibodies related to AIE. ③ AIE of other antibody types: Patients with AIE of other antibody types were positive for AIE antibodies, did not have anti NMDAR antibodies, and were positive for anti LGI1 antibody, anti GABABR antibody, anti CASPR2 antibody, etc. If the other encephalitis antibodies were positive, the patient was excluded. (2) Patients with a previous history of thyroid disease were excluded.

Our study did not employ any treatment measures in the clinical interventions, and this study was therefore a minimal study risk. Throughout the whole study period, all data obtained were routine data for the diagnosis or treatment of patients, and data were statistically analyzed anonymously. Therefore, the ethics committee of Xinqiao Hospital confirmed that no ethical approval was needed.

Research designs The purpose of this study was to explore changes in the clinical and laboratory characteristics of ANE patients with thyroid dysfunction. We made multiple patient comparisons, and patient grouping information is shown in Fig. 1B. The research design is shown in Fig. 2.

Part I: Forty-two patients were divided into two groups according to whether thyroid function was normal. There were 24 ANE patients with normal thyroid function and 18 ANE patients with thyroid dysfunction. The aim was to clarify the role of thyroid dysfunction in ANE patients.

Part II: We compared 12 ANE patients with ESS with 24 ANE patients with normal thyroid function, and we explored the clinical and laboratory features of ANE patients with ESS.

Part III: We compared 6 ANE patients with thyroid dysfunction but not ESS with 24 ANE patients with normal thyroid function, and we explored the clinical and laboratory features of ANE patients with thyroid dysfunction but not ESS.

Part IV: We compared 12 ANE patients with ESS with 6 ANE patients with thyroid dysfunction but not ESS, and we explored differences in clinical and laboratory features between the two groups of ANE patients with thyroid dysfunction.

Clinical Data Collection All patients underwent cranial MRIs (except 2 patients with severe endotracheal intubation with contraindications for cranial MRI) and lumbar puncture. We also assessed the severity of the disease by taking blood samples at the patient’s admission and discharge and by determining the patient’s mRS (mRS was determined by two neurology clinicians with more than 10 years of experience). Other data included age, sex, the time from symptom onset to treatment initiation, and treatment received.

Auxiliary examinations The serum thyroid hormone levels that were analyzed included free triiodothyronine (FT3, 2.43–6.01 pmol/L), free thyroxine (FT4, 9.01–19.05 pmol/L), thyroid stimulating hormone (TSH, 0.35–4.94 mIU/L), triiodothyronine (T3, 0.98–2.33 nmol/L) and thyroxine (T4, 62.68-150.84 nmol/L). The measurement kit was a free triiodothyronine test kit (Abbott, chemiluminescence particle immunoassay). CSF and serum were collected to detect NMDAR antibodies using a commercial kit (Shaanxi Mybiotech Co., Ltd.). The tumor screening included tests for serum tumor markers such as ferritin, carcinoembryonic antigen, carbohydrate antigen (CA) 125, CA153, CA199, squamous cell carcinoma antigen, and so on; chest computed tomography (CT) (Siemens, Berlin, Germany); and gynecologic color Doppler ultrasound. The liver function tests were performed on a HITACHI 7080 automated analyzer (Tokyo, Japan).

MRI analysis Cranial MRIs were performed at 3.0 T (Signa HDXT). The thickness of the axial scanning layer was 5 mm. The following conventional MRI protocol was used for all patients: T1 (TE: 240, TR: 2000, POV: 24.0, slice thickness: 5.0, spacing: 1.5), T2 (TE: 110, TR 3380, POV: 24.0, slice thickness: 5.0, spacing: 1.5), and T2 FLAIR (TE: 110, TR: 3380, POV: 24.0, slice thickness: 5.0, spacing: 1.5).

Statistical analyses All statistical analyses were performed through Windows (SPSS Inc., Chicago, Illinois, USA) using the SPSS 21.0 software package. This study was mainly descriptive, so the data were summarized and are presented in the form of percentages or median values, with the quartile range for continuous variables and classified variables. Continuous data are expressed as the mean ± standard deviation (SD) or median (lower quartile, upper quartile). Continuous data were compared by Student's test or the Mann–Whitney U test. Nominal variables were analyzed by the chi square test or Fisher’s exact test.

Part I: To compare the clinical and laboratory characteristics of ANE patients with/without thyroid dysfunction.

The aim was to clarify the role of thyroid dysfunction in ANE patients. Among the 42 ANE patients, 25 patients were male. The mean age was 38 ± 16 years. Status epilepticus (p = 0.007), motor disorders (p = 0.005), and consciousness disorders (p = 0.008) were more severe in ANE patients with thyroid dysfunction than in those without thyroid dysfunction (Fig. 3A). For details of patients with abnormal cranial MRI findings, see Fig. 3B. ANE patients with thyroid dysfunction also had abnormal low-density lipoprotein (p = 0.034), albumin/globulin (p = 0.046), globulin (p = 0.018) and triglycerides (p = 0.019) compared with those without thyroid dysfunction (Table 1).

Table 1

clinical and laboratory characteristics of anti NMDAR encephalitis patients with/without thyroid dysfunction
	anti NMDAR encephalitis patients with thyroid dysfunction (n = 18)	anti NMDAR encephalitis patients without thyroid dysfunction (n = 24)	p
Demographics
Age (years)	39.56 ± 14.23	37.38 ± 18.19	0.676
Gender			0.856
Female (% of cases)	7 (41.2)	10 (58.8)
Male (% of cases)	11 (44.0)	14 (56.0)
Hospital duration (days)	18.00 [10.50–20.75]	15.00 [10.25–19.75]	0.779
ICU duration (days)	0.00 [0.00–12.75]	0.00 [0.00–0.00]	0.221
Onset to hospitalization duration (days)	23.00 [10.00–45.00]	20.00 [10.00–30.00]	0.277
Antibody grading in CSF			0.304
- (% of cases)	2 (100.0)	0 (0.0)
+ (% of cases)	4 (50.0)	4 (50.0)
++ (% of cases)	7 (43.8)	9 (56.3)
+++ (% of cases)	5 (31.3)	11 (68.8)
Antibody grading in serum			0.112
- (% of cases)	9 (60.0)	6 (40.0)
+ (% of cases)	3 (75.0)	1 (25.0)
++ (% of cases)	4 (26.7)	11 (73.3)
+++ (% of cases)	2 (25.0)	6 (75.0)
mRS score at admission			0.060
2 (% of cases)	0 (0.0)	1 (100.0)
3 (% of cases)	2 (15.4)	11 (84.6)
4 (% of cases)	10 (52.6)	9 (47.4)
5 (% of cases)	6 (66.7)	3 (33.3)
Discharge mRS score (Superior: 0–2; Inferior: 3–5)			0.289
Superior (% of cases)	4 (30.8)	9 (69.2)
Inferior (% of cases)	14 (48.3)	15 (51.7)
Recrudescence (% of cases)	5 (55.6)	4 (44.4)	0.385
CSF
Abnormal CSF (% of cases)	9 (37.5)	15 (62.5)	0.418
CSF pressure (mm H₂O)	150.00 [110.00–182.50]	127.50 [110.00–177.50]	0.500
WBC in CSF (n ×10⁶/L)	8.00 [2.50–59.50]	22.50 [7.00–79.00]	0.144
CSF protein (g/L)	0.27 [0.21–0.66]	0.30 [0.22–0.53]	0.809
CSF glucose (mmol/L)	3.98 [3.54–4.37]	3.60 [3.31–4.75]	0.274
CSF chloride (mmol/L)	127.55 [122.90–130.10]	125.65 [123.75–128.13]	0.286
Liver function test
Hepatitis B virus infection (% of cases)	9 (47.4)	10 (52.6)	0.591
Liver dysfunction (% of cases)	18 (47.4)	20 (52.6)	0.069
ALT (U/L)	18.10 [11.73–31.60]	18.20 [11.40–25.78]	0.839
AST (U/L)	14.25 [11.57–27.10]	17.50 [14.13–30.93]	0.069
Triglyceride (mmol/L)	1.33 [0.87–4.22]	0.98 [0.73–1.22]	0.019*
Lipoprotein (mmol/L)	148.50 [100.25–266.00]	134.00 [71.00–219.75]	0.684
Apolipoprotein A1 (g/L)	1.18 [0.90–1.45]	1.13 [0.95–1.21]	0.476
Apolipoprotein E (g/L)	3.61 [2.66–5.15]	3.11 [2.29–4.34]	0.509
Apolipoprotein B (g/L)	0.86 ± 0.24	0.74 ± 0.21	0.097
High density lipoprotein (mmol/L)	1.03 [0.91–1.53]	1.05 [0.89–1.21]	0.809
Low density lipoprotein (mmol/L)	2.55 ± 0.67	2.04 ± 0.79	0.034*
Blood sugar (mmol/L)	4.95 [4.41–7.23]	4.70 [4.17–5.18]	0.297
Total protein (g/L)	65.51 ± 6.04	63.49 ± 6.14	0.295
Albumin (g/L)	40.67 ± 4.73	41.55 ± 4.89	0.558
Globulin (g/L)	24.84 ± 4.56	21.98 ± 2.95	0.018*
Albumin/Globulin (%)	1.70 ± 0.39	1.92 ± 0.31	0.046*
Prealbumin (g/L)	245.67 ± 116.33	218.46 ± 74.23	0.361
Total cholesterol (mmol/L)	3.85 ± 1.59	3.71 ± 1.30	0.755
Homocysteine (umol/L)	10.51 ± 2.17	11.28 ± 2.94	0.356
Immunotherapy
Dexamethasone (% of cases)	2(28.6)	5(71.4)	0.403
Methylprednisolone (% of cases)	15(46.9)	17(53.1)	0.347
Plasma exchange (% of cases)	7(36.8)	12(63.2)	0.474
Immunoglobulin (% of cases)	8(47.1)	9(52.9)	0. 098

Part II: To compare the clinical and laboratory characteristics of ANE patients with normal thyroid function with those of ANE with ESS

The aim was to explore the clinical and laboratory features of ANE patients with ESS. Among 36 ANE patients, 20 patients were male. The mean age was 40 ± 16 years. Language disorders (p = 0.035), status epilepticus (p = 0.001), motor disorders (p < 0.007) and consciousness disorders (p = 0.001) were more serious in ANE patients with ESS than in those with normal thyroid function (Fig. 4A). The mRS scores at admission of ANE patients with ESS were higher than those of ANE patients with normal thyroid function, implying that their conditions were more serious (Table 2). There were 19 patients with abnormal cranial MRI findings. Lesions of the lateral ventricle were more common in ANE patients with ESS than in those with normal thyroid function (Fig. 4B). Specific MRI images of 5 ANE patients with ESS are shown in Fig. 5. Their mRS scores were ≥ 4 at admission and ≥ 3 at discharge. ANE patients with ESS with lateral ventricle lesions had poorer prognoses. The admission mRS score (p = 0.030), AST (p = 0.016), triglycerides (p = 0.022), globulin (p = 0.014), albumin/globulin (p = 0.025), and low-density lipoprotein (p = 0.031) were abnormal in ANE patients with ESS (Table 2).

Table 2

clinical and laboratory characteristics of anti NMDAR encephalitis patients with normal thyroid function or with euthyroid sick syndrome (ESS)
	anti NMDAR encephalitis patients with Euthyroid sick syndrome (ESS) (n = 12)	anti NMDAR encephalitis patients without thyroid dysfunction (n = 24)	p
Demographics
Age (years)	44.50 ± 7.97	37.38 ± 18.19	0.206
Gender			0.635
Female (% of cases)	6 (37.5)	10 (62.5)
Male (% of cases)	6 (30.0)	14 (70.0)
Hospital duration (days)	11.50 [9.50–19.50]	15.00 [10.25–19.75]	0.568
ICU duration (days)	0.00 [0.00–15.50]	0.00 [0.00–0.00]	0.268
Onset to hospitalization duration (days)	30.00 [10.00–77.50]	20.00 [10.00–30.00]	0.216
Antibody grading in CSF			0.373
- (% of cases)	1 (100.0)	0 (0.0)
+ (% of cases)	3 (42.9)	4 (57.1)
++ (% of cases)	5 (35.7)	9 (64.3)
+++ (% of cases)	3 (21.4)	11 (78.6)
Antibody grading in serum			0.180
- (% of cases)	6 (50.0)	6 (50.0)
+ (% of cases)	2 (66.7)	1 (33.3)
++ (% of cases)	3 (21.4)	11 (78.6)
+++ (% of cases)	1 (14.3)	6 (85.7)
mRS score at admission			0.030*
2 (% of cases)	0 (0.0)	1 (100.0)
3 (% of cases)	0 (0.0)	11 (100.0)
4 (% of cases)	8 (47.1)	9 (52.9)
5 (% of cases)	4 (57.1)	3 (42.9)
Discharge mRS score (Superior: 0–2; Inferior: 3–5)			0.066
Superior (% of cases)	1 (10.0)	9 (90.0)
Inferior (% of cases)	11 (42.3)	15 (57.7)
Recrudescence (% of cases)	3 (42.9)	4 (57.1)	0.551
CSF
Abnormal CSF (% of cases)	8 (34.8)	15 (65.2)	0.806
CSF pressure (mm H₂O)	144.00 [102.50–167.50]	127.50 [110.00–177.50]	0.906
WBC in CSF (n ×10⁶/L)	10.50 [3.75–87.75]	22.50 [7.00–79.00]	0.650
CSF protein (g/L)	0.29 [0.20–0.71]	0.30 [0.22–0.53]	0.973
CSF glucose (mmol/L)	4.01 [3.50–4.57]	3.60 [3.31–4.75]	0.275
CSF chloride (mmol/L)	128.75 [123.22–131.60]	125.65 [123.75–128.13]	0.185
Liver function test
Hepatitis B virus infection (% of cases)	7 (41.2)	10 (58.8)	0.345
Liver dysfunction (% of cases)	12 (37.5)	20 (62.5)	0.134
ALT (U/L)	18.10 [16.25–28.90]	18.20 [11.40–25.78]	0.737
AST (U/L)	12.80 [11.93–20.50]	17.50 [14.13–30.93]	0.016*
Triglyceride (mmol/L)	1.33 [0.92–3.89]	0.98 [0.73–1.22]	0.022*
Lipoprotein (mmol/L)	165.50 [131.25–294.00]	134.00 [71.00–219.75]	0.347
Apolipoprotein A1 (g/L)	1.14 [0.94–1.43]	1.13 [0.95–1.21]	0.534
Apolipoprotein E (g/L)	3.61 [2.51–4.67]	3.11 [2.29–4.34]	0.638
Apolipoprotein B (g/L)	0.87 ± 0.26	0.74 ± 0.21	0.115
High density lipoprotein (mmol/L)	1.06 [1.00–1.75]	1.05 [0.89–1.21]	0.481
Low density lipoprotein (mmol/L)	2.65 ± 0.73	2.04 ± 0.79	0.031*
Blood sugar (mmol/L)	5.06 [4.34–7.32]	4.70 [4.17–5.18]	0.365
Total protein (g/L)	65.12 ± 6.69	63.49 ± 6.14	0.471
Albumin (g/L)	39.73 ± 4.74	41.55 ± 4.89	0.293
Globulin (g/L)	25.39 ± 4.98	21.98 ± 2.95	0.014*
Albumin/Globulin (%)	1.63 ± 0.41	1.92 ± 0.31	0.025*
Prealbumin (g/L)	272.42 ± 119.35	218.46 ± 74.23	0.104
Total cholesterol (mmol/L)	4.01 ± 1.82	3.71 ± 1.30	0.576
Homocysteine (umol/L)	9.73 ± 1.44	11.28 ± 2.94	0.095
Immunotherapy
Dexamethasone (% of cases)	1(16.7)	5(83.3)	0.343
Methylprednisolone (% of cases)	10(37.0)	17(63.0)	0.414
Plasma exchange (% of cases)	6(33.3)	12(66.7)	1.000
Immunoglobulin (% of cases)	8(47.1)	9(52.9)	0.098

Part III: To compare the clinical and laboratory characteristics of ANE with normal thyroid function with those of ANE with thyroid dysfunction but not ESS

The aim was to explore the clinical and laboratory features of ANE patients with thyroid dysfunction but not ESS. Among 30 ANE patients, 19 patients were male. The mean age was 36 ± 18 years. There were no significant differences between the two groups (Fig. 6A). ANE patients with thyroid dysfunction but not ESS had significantly more lesions in the cingulate gyrus than those with thyroid dysfunction but not ESS (p = 0.042) (Fig. 6B). ANE patients with thyroid dysfunction but not ESS were relatively mild compared with those with ESS (Table 3).

Table 3

clinical and laboratory characteristics of anti NMDAR encephalitis patients combine with normal thyroid function and thyroid dysfunction without Euthyroid sick syndrome (ESS).
	anti NMDAR encephalitis patients with thyroid dysfunction without Euthyroid sick syndrome (ESS) (n = 6)	anti NMDAR encephalitis patients without thyroid dysfunction (n = 24)	p
Demographics
Age (years)	29.67 ± 19.29	37.38 ± 18.19	0.366
Gender			0.256
Female (% of cases)	1 (9.1)	10 (90.9)
Male (% of cases)	5 (26.3)	14 (73.7)
Hospital duration (days)	20.00 [16.50–28.50]	15.00 [10.25–19.75]	0.145
ICU duration (days)	0.00 [0.00–19.50]	0.00 [0.00–0.00]	0.373
Onset to hospitalization duration (days)	19.50 [13.75–34.50]	20.00 [10.00–30.00]	0.754
Antibody grading in CSF			0.255
- (% of cases)	1 (100.0)	0 (0.0)
+ (% of cases)	1 (20.0)	4 (80.0)
++ (% of cases)	2 (18.2)	9 (81.8)
+++ (% of cases)	2 (15.4)	11 (84.6)
Antibody grading in serum			0.365
- (% of cases)	3 (33.3)	6 (66.7)
+ (% of cases)	1 (50.0)	1 (50.0)
++ (% of cases)	1 (8.3)	11 (91.7)
+++ (% of cases)	1 (14.3)	6 (85.7)
mRS score at admission			0.651
2 (% of cases)	0 (0.0)	1 (100.0)
3 (% of cases)	2 (15.4)	11 (84.6)
4 (% of cases)	2 (18.2)	9 (81.8)
5 (% of cases)	2 (40.0)	3 (60.0)
Discharge mRS score (Superior: 0–2; Inferior: 3–5)			0.576
Superior (% of cases)	3 (25.0)	9 (75.0)
Inferior (% of cases)	3 (16.7)	15 (83.3)
Recrudescence (% of cases)	2 (33.3)	4 (66.7)	0.361
CSF
Abnormal CSF (% of cases)	1 (6.3)	15 (93.8)	0.044*
CSF pressure (mm H₂O)	180.00 [140.00–258.75]	127.50 [110.00–177.50]	0.119
WBC in CSF (n ×10⁶/L)	2.50 [0.00–25.75]	22.50 [7.00–79.00]	0.022*
CSF protein (g/L)	0.27 [0.17–0.52]	0.30 [0.22–0.53]	0.586
CSF glucose (mmol/L)	3.83 [3.52–4.23]	3.60 [3.31–4.75]	0.586
CSF chloride (mmol/L)	122.80 [123.22–128.50]	125.65 [123.75–128.13]	0.897
Liver function test
Hepatitis B virus infection (% of cases)	2 (16.7)	10 (83.3)	0.709
Liver dysfunction (% of cases)	6 (23.1)	20 (76.9)	0.283
ALT (U/L)	17.10 [8.00–79.73]	18.20 [11.40–25.78]	0.917
AST (U/L)	22.90 [10.33–65.00]	17.50 [14.13–30.93]	0.979
Triglyceride (mmol/L)	3.10 ± 3.16	1.00 ± 0.39	0.002***
Lipoprotein (mmol/L)	90.50 [53.75–295.00]	134.00 [71.00–219.75]	0.534
Apolipoprotein A1 (g/L)	1.21 [0.62–1.50]	1.13 [0.95–1.21]	0.622
Apolipoprotein E (g/L)	3.97 [2.54–5.80]	3.11 [2.29–4.34]	0.534
Apolipoprotein B (g/L)	0.84 ± 0.21	0.74 ± 0.21	0.336
High density lipoprotein (mmol/L)	0.94 [0.54–1.49]	1.05 [0.89–1.21]	0.551
Low density lipoprotein (mmol/L)	2.34 ± 0.55	2.04 ± 0.79	0.391
Blood sugar (mmol/L)	4.95 [4.02–6.42]	4.70 [4.17–5.18]	0.468
Total protein (g/L)	66.28 ± 4.97	63.49 ± 6.14	0.312
Albumin (g/L)	42.55 ± 4.48	41.55 ± 4.89	0.654
Globulin (g/L)	23.73 ± 3.72	21.98 ± 2.95	0.226
Albumin/Globulin (%)	1.83 ± 0.33	1.92 ± 0.31	0.543
Prealbumin (g/L)	192.17 ± 97.57	218.46 ± 74.23	0.471
Total cholesterol (mmol/L)	3.54 ± 1.08	3.71 ± 1.30	0.766
Homocysteine (umol/L)	12.07 ± 2.67	11.28 ± 2.94	0.554
Immunotherapy
Dexamethasone (% of cases)	1(16.7)	5(83.3)	0.819
Methylprednisolone (% of cases)	5(22.7)	17(77.3)	0.536
Plasma exchange (% of cases)	1(7.7)	12(92.3)	0.141
Immunoglobulin (% of cases)	3(25.0)	9(75.0)	0.576

Part IV: To compare the clinical and laboratory characteristics of ANE with thyroid dysfunction with/without ESS

The aim was to explore differences in clinical and laboratory features between two groups of ANE patients with thyroid dysfunction. Among 18 ANE patients, 11 patients were male. The mean age was 40 ± 14 years. Status epilepticus (p = 0.010), motor disorders (p = 0.007), and consciousness disorders (p = 0.013) were more severe in ANE patients with thyroid dysfunction with ESS at admission than in those without ESS (Fig. 7A). ANE patients with ESS also had higher discharge mRS scores, implying a poor prognosis (p = 0.045, Table 4).

Table 4

clinical and laboratory characteristics of anti NMDAR encephalitis patients combine with thyroid dysfunction with/without Euthyroid sick syndrome (ESS)
	anti NMDAR encephalitis patients with Euthyroid sick syndrome (ESS) (n = 12)	anti NMDAR encephalitis patients with thyroid dysfunction without Euthyroid sick syndrome (ESS) (n = 6)	p
Demographics
Age (years)	44.50 ± 7.97	29.67 ± 19.29	0.032*
Gender			0.171
Female (% of cases)	6 (85.7)	1 (14.3)
Male (% of cases)	6 (54.5)	5 (45.5)
Hospital duration (days)	15.00 ± 8.64	22.33 ± 12.63	0.164
ICU duration (days)	0.00 [0.00–15.50]	0.00 [0.00–19.50]	0.911
Onset to hospitalization duration (days)	30.00 [10.00–77.50]	19.50 [13.75–34.50]	0.637
Antibody grading in CSF			0.915
- (% of cases)	1 (50.0)	1 (50.0)
+ (% of cases)	3 (75.0)	1 (25.0)
++ (% of cases)	5 (71.4)	2 (28.6)
+++ (% of cases)	3 (60.0)	2 (40.0)
Antibody grading in serum			0.950
- (% of cases)	6 (66.7)	3 (33.3)
+ (% of cases)	2 (66.7)	1 (33.3)
++ (% of cases)	3 (75.0)	1 (25.0)
+++ (% of cases)	1 (50.0)	1 (50.0)
mRS score at admission			0.104
2 (% of cases)	0 (0.0)	2 (100.0)
3 (% of cases)	8 (80.0)	2 (20.0)
4 (% of cases)	4 (66.7)	2 (33.3)
Discharge mRS score (Superior: 0–2; Inferior: 3–5)			0.045*
Superior (% of cases)	1 (25.0)	3 (75.0)
Inferior (% of cases)	11 (78.6)	3 (21.4)
Recrudescence (% of cases)	3 (60.0)	2 (40.0)	0.710
CSF
Abnormal CSF (% of cases)	8 (88.9)	1 (11.1)	0.046*
CSF pressure (mm H₂O)	136.67 ± 37.01	194.17 ± 69.31	0.033*
WBC in CSF (n ×10⁶/L)	10.50 [3.75–87.75]	2.50 [0.00–25.75]	0.110
CSF protein (g/L)	0.29 [0.20–0.71]	0.27 [0.17–0.52]	0.743
CSF glucose (mmol/L)	4.01 [3.50–4.57]	3.83 [3.52–4.23]	0.399
CSF chloride (mmol/L)	127.73 ± 4.87	125.78 ± 3.08	0.387
Liver function test
Hepatitis B virus infection (% of cases)	7 (77.8)	2 (22.2)	0.317
ALT (U/L)	18.10 [16.25–28.90]	17.10 [8.00–79.73]	0.779
AST (U/L)	12.80 [11.93–20.50]	22.90 [10.33–65.00]	0.303
Triglyceride (mmol/L)	1.33 [0.92–3.89]	2.20 [0.57–5.78]	0.925
Lipoprotein (mmol/L)	165.50 [131.25–294.00]	90.50 [53.75–295.00]	0.206
Apolipoprotein A1 (g/L)	1.19 ± 0.32	1.10 ± 0.47	0.628
Apolipoprotein E (g/L)	3.85 ± 1.76	4.01 ± 1.75	0.855
Apolipoprotein B (g/L)	0.87 ± 0.26	0.84 ± 0.21	0.772
High density lipoprotein (mmol/L)	1.26 ± 0.44	0.95 ± 0.52	0.197
Low density lipoprotein (mmol/L)	2.65 ± 0.73	2.34 ± 0.55	0.367
Blood sugar (mmol/L)	5.06 [4.34–7.32]	4.95 [4.40–6.42]	1.000
Total protein (g/L)	65.12 ± 6.69	66.28 ± 4.97	0.712
Albumin (g/L)	39.73 ± 4.74	42.55 ± 4.48	0.243
Globulin (g/L)	25.39 ± 4.98	23.73 ± 3.72	0.484
Albumin/Globulin (%)	1.63 ± 0.41	1.83 ± 0.33	0.316
Prealbumin (g/L)	272.42 ± 119.35	192.17 ± 97.57	0.175
Total cholesterol (mmol/L)	4.01 ± 1.82	3.54 ± 1.08	0.570
Homocysteine (umol/L)	9.73 ± 1.44	12.07 ± 2.67	0.026*
Immunotherapy
Dexamethasone (% of cases)	1(50.0)	1(50.0)	0.596
Methylprednisolone (% of cases)	10(66.7)	5(33.3)	1.000
Plasma exchange (% of cases)	6(85.7)	1(14.3)	0.171
Immunoglobulin (% of cases)	8(72.7)	3(27.3)	0.494

In our study, 28.6% of ANE patients had ESS, 9.5% were thyroid antibody-positive, 2.4% had increased TSH (also known as subclinical hypothyroidism), and 2.4% had increased T4. The changes in thyroid function were very obvious in ANE patients, implying the importance of the relationship between thyroid function and the severity/prognosis of ANE. In our study, ANE patients with thyroid dysfunction had more serious symptoms than those without thyroid dysfunction. ANE patients with ESS had poorer prognoses than those without ESS.

The relationship among thyroid function, autoimmune diseases and ANE has not been clearly described. In our study, ANE patients with ESS had higher mRS at admission than those without ESS, implying that their conditions were more serious. ESS is indeed a good indicator of the prognosis of ANE but not the severity of ANE. The patients with ANE, mRS ≥ 3 and ESS not only likely have a poorer prognosis, but also it should be considered that these patients are more serious than patients with normal thyroid function. At the same time, these factors can also guide clinicians to actively give these patients plasma exchange and/or intravenous injections of human immunoglobulin while giving glucocorticoid therapy. In clinical practice, some patients with ANE were only administered glucocorticoid therapy instead of plasma exchange and/or intravenous injections of human immunoglobulin. Timely intervention of these positive treatment methods may be more conducive to the prognosis of patients. We hope clinicians will pay attention to ANE patients with ESS because they have poor prognoses.

In this study, the 2016 diagnostic criteria were mainly adopted for the diagnosis of ANE (Dubey, 2017; Dubey, 2018). Antibody positivity still plays an important role in diagnosis and treatment. However, some ANE patients were negative for antibodies. On the other hand, the antibody titers were not completely related to the patient’s clinical symptoms. The diagnosis should be mainly based on the patient’s clinical symptoms combined with auxiliary examinations rather than relying solely on antibody testing (Ursitti, 2021; Nicola, 2020; Linda, 2016; Hao, 2015). In our study, among the 42 ANE patients, 20 (52.6%) had brain lesions on MRI. The ANE patients with ESS were more prone to abnormal cranial MRI findings than those without ESS. The cranial MRI lesions in AIE patients are commonly found in the hippocampus, parahippocampal gyrus, corpus callosum and brain lobes (Megan, 2022; Julien, 2021; Elia, 2021). However, lateral ventricle lesions were more common in the ANE patients with ESS than in those without ESS in our study. The lateral ventricle is not a common site of lesions in AIE patients but is a common lesions site in patients with leukoaraiosis, subcortical arteriosclerotic encephalopathy and lacunar cerebral infarction. Therefore, insufficient attention has been given to lateral ventricle lesions in AIE. In our study, it was found that lateral ventricle lesions were more common in ANE patients with thyroid dysfunction. The lateral ventricle is not a common site of cranial MRI lesions in patients with AIE. Lateral ventricle lesions are common in patients with leukoaraiosis, subcortical arteriosclerotic encephalopathy and lacunar cerebral infarction. Subcortical arteriosclerotic encephalopathy is a diffuse demyelinating encephalopathy of cerebral white matter. The cranial MRIs in these patients show irregular abnormal changes in the anterior and posterior angles and around the lateral ventricles, as well as multiple lacunar cerebral infarction and encephalatrophy. The clinical manifestations were a decline in comprehension, memory, judgment, and even dementia accompanied by dyskinesia, increased muscle tension, abnormal gait, and even limb paralysis; speech disorders; and extrapyramidal symptoms. Leukoaraiosis is a demyelinating disease of nerve conduction fibers caused by diffuse cerebral ischemia. The cranial magnetic resonance lesions are mainly around the lateral ventricle and the center of the semicircular oval. The main clinical manifestations are cognitive disorders and motor disorders. In general, lateral ventricle lesions can cause obvious and serious cognitive, speech, and motor dysfunctions, extrapyramidal lesions and so on. AIE with euthyroid sick syndrome can also cause cranial ventricular lesions. When ANE is accompanied by lateral ventricular lesions, the clinical symptoms of patients such as cognitive disorders, speech/motor dysfunctions and extrapyramidal system are more obvious, suggesting serious condition and poor prognosis. However, the mechanism of lateral ventricular lesions caused by thyroid dysfunction is unclear (no research report has been found at present). We need more cases for research and some basic experimental research in the future. However, this condition has not attracted attention in previous clinical studies. Among the 42 ANE patients, 5 of the patients had lateral ventricle lesions. Their mRS scores were ≥ 4 at admission and ≥ 3 at discharge. The ANE patients with ESS had poorer prognoses if they had lateral ventricle lesions. Such patients should be treated in a timely manner to improve their prognosis.

The clinical and laboratory characteristics of 42 ANE patients were analyzed. The conditions of the ANE patients with thyroid dysfunction were more serious than those of the ANE patients without thyroid dysfunction. The ANE patients with ESS had poorer prognoses than those without ESS. Lesions were not commonly found in the lateral ventricles of the AIE patients. However, the ANE patients with ESS had poorer prognoses if they had lateral ventricle lesions. Such patients should be treated in a timely manner to improve their prognosis. There is still controversy about the artificial interventions for ESS. Prospective randomized controlled trials should be performed to further explore the possible interventions or treatment for ESS in patients with ANE.

AIE

autoimmune encephalitis

ANE

Anti-N-methyl-d-aspartate receptor (anti-NMDAR) encephalitis

ESS

euthyroid sick syndrome

MRI

magnetic resonance imaging

mRS

modified Rankin scale

Ethical Approval and Consent to participate

This is an observational study. The ethics committee of Xinqiao Hospital had confirmed that no ethical approval was required. Written informed consent was not required for this retrospective study.

Consent for publication

Not applicable

Availability of data and materials

All data generated or analyzed during this study are included in this published article or in the supplementary information.

Competing interests

The authors declared they had no financial interests.

Funding

Not applicable

Authors' contributions

The Author G.W., X.L. and XY. conceived the study, designed research, analyzed the data and wrote the manuscript; J.L., and CS.Y. performed research, and analyzed the data; X.Z., and HY.W. were involved in data generation. X.L. and G.W. conceived the study and revised the manuscript. XS.Y. supervised experimental design and revised the manuscript. All authors reviewed the manuscript.

Acknowledgements

American Journal Experts is gratefully acknowledged for editing the manuscript.

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No competing interests reported.

Anti-NMDAR encephalitis with euthyroid sick syndrome and lateral ventricle lesions predicts a poor prognosis

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