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Clinical Characteristics and Prognosis of Severe Anti-N-methyl-d-aspartate Receptor Encephalitis Patients

  • Yan Zhang
  • Gang Liu
  • Mengdi Jiang
  • Weibi Chen
  • Yanbo He
  • Yingying Su
Original Article

Abstract

Background and purpose

Data concerning the characteristics and duration of the critical manifestations, treatment response, and long-term outcomes of severe anti-N-methyl-d-aspartate receptor (anti-NMDAR) encephalitis patients compared to those of non-severe patients are limited. This observational study was performed to explore the clinical characteristics and long-term outcomes of severe anti-NMDAR encephalitis patients.

Methods

According to their characteristics on admission to the neurology intensive care unit, patients with anti-NMDAR encephalitis were divided into a severe group and a non-severe group. The demographics, clinical manifestations, main accessory examinations, immunotherapy, and outcomes of patients were recorded. Statistical analyses were employed to examine the differences in each observed indicator between the severe and non-severe groups.

Results

This study enrolled 111 patients with anti-NMDAR encephalitis, including 59 males and 52 females with a mean age of 27.7 ± 13.7 years; 39 (35.1%) patients were in the severe group, and 72 (64.9%) patients were in the non-severe group. Compared to the non-severe group, the severe group exhibited a higher proportion of epilepsy, involuntary movement, disturbance of consciousness, autonomic dysfunction, and central hypoventilation. The cerebrospinal fluid (CSF) of all patients was positive for the NMDAR antibody, but only 57 patients (51.4%) tested positive for the NMDAR antibody in the blood. The proportion of patients with a strong positive NMDAR antibody titer in the severe group (48.7%) was higher than that in the non-severe group (29.2%). The proportion of patients receiving intravenous gamma immunoglobulin in the severe group was higher than that in the non-severe group (P = 0.003), and only patients in the severe group received plasma exchange, intravenous rituximab, and cyclophosphamide treatment. No significant difference was observed in the prognosis between the severe group and the non-severe group after 6 months and during long-term follow-up.

Conclusion

Most severe anti-NMDAR encephalitis patients will eventually achieve good long-term prognoses after receiving early, positive and unremitting combined immunotherapy and life support.

Keywords

Anti-N-methyl-d-aspartate receptor encephalitis Critical care Outcome Therapeutic effect 

Introduction

Anti-N-methyl-d-aspartate receptor (anti-NMDAR) encephalitis is one of the most common forms of autoimmune encephalitis. The proportion of severe anti-NMDAR encephalitis patients is high; approximately 60% of patients have the disorder of consciousness, approximately 50% have autonomic nervous dysfunction, and 31.3–45.7% of adult patients have central hypoventilation [1]. Therefore, 75% of patients with anti-NMDAR encephalitis, especially those experiencing the above symptoms, require extensive critical care management and admission into an intensive care unit (ICU) [1]. The incidence of anti-NMDAR encephalitis is high among critically ill patients with encephalitis of uncertain etiology [2]. Patients with severe anti-NMDAR encephalitis are usually in serious condition and need longer hospitalization periods, more complex immunotherapy, and life support [3, 4, 5]. Previous studies have suggested that the prognosis of severe anti-NMDAR encephalitis patients is poor [1, 6], but others have reported that the long-term prognosis is good [7, 8, 9]. In the literature, there are limited data concerning the characteristics and duration of critical manifestations, the treatment response, and the long-term outcomes of severe anti-NMDAR encephalitis patients compared with those of non-severe patients. Therefore, the purpose of our study is to investigate the differences in clinical manifestations and outcomes between severe anti-NMDAR encephalitis patients and non-severe patients in China. This study may help other neurologists and ICU teams to anticipate these patients’ complex critical care needs and prognosis.

Methods

Patient eligibility

In this observational study, anti-NMDAR encephalitis patients consecutively admitted to the Department of Neurology in Xuanwu Hospital of Capital Medical University between January 1, 2012, and June 30, 2017, were enrolled. The inclusion criteria are as follows: (1) the anti-NMDAR encephalitis diagnostic criteria [10]; rapid onset (less than 3 months) of one or more of the six major groups of symptoms, including abnormal (psychiatric) behavior or cognitive dysfunction, speech dysfunction (pressured speech, verbal reduction, and mutism), seizures, movement disorders (dyskinesias or rigidity/abnormal postures), decreased level of consciousness, and autonomic dysfunction or central hypoventilation; the presence of IgG anti-GluN1 antibodies; reasonable exclusion of other disorders; and (2) informed consent from the patient or admission to the neurology intensive care unit (NCU) in severe condition with informed consent from the patient’s family.

Critically ill patients admitted to the NCU met at least one of the following criteria: respiratory failure requiring mechanical ventilation, disturbance of consciousness, or status epilepticus. According to admission to the NCU, patients were divided into the severe group and non-severe group.

Data collection

A unified design form was used to record the patient demographics, medical histories, clinical manifestations, and main accessory examinations. The following information was recorded: gender; age; prodromal symptoms; time of onset; clinical manifestations; presence of teratomas or other tumors; cranial magnetic resonance imaging (MRI); electroencephalogram (EEG); pressure of lumbar puncture; NMDAR antibody titers in serum and cerebrospinal fluid (CSF) (according to the levels of the antibody titer, samples were classified as strong positive [titer of 1:100 and above], positive [1:32], weak positive [1:10], and negative); white blood cell count, glucose, protein, and chloride in CSF; modified Rankin Scale (mRS) [1] before treatment; days between onset and immunotherapy; immunotherapeutic methods; and admission to the NCU. According to the antibody titers in the CSF, patients were divided into the low titer group and the high titer group. The low titer group included patients with negative and weakly positive NMDAR antibody in the CSF. The high titer group included patients with positive and strongly positive NMDAR antibodies in CSF. EEGs performed during the peak stage of the disease (14–60 days after the onset of symptoms) were analyzed [11, 12]. EEG analytic patterns included epileptiform discharges, diffuse slowing, focal slowing, polymorphic delta rhythm, diffuse beta activities, and extreme delta brush [11, 13].

Treatment and prognosis evaluation

All patients received tumor screening, symptomatic supportive treatment, and immunotherapy. All cancer patients received tumor resection. Immunotherapy included intravenous glucocorticoid therapy (1000 or 500 mg methylprednisolone for 3 or 5 days), intravenous gamma immunoglobulin (IVIG; 0.4 g/kg/day for each course for 5 days), plasma exchange (PE; 3–5 times in each course), or immunosuppressants (rituximab, cyclophosphamide, mycophenolate mofetil, or azathioprine). Patients received outcome evaluations every 6 months following immunotherapy. The mRS [1] was used for outcome evaluations. After discharge, the outcome evaluation was performed during a clinical visit to the neurologist or telephone follow-up. The evaluation standards were as follows: a mRS of 0–2 points was a favorable outcome and 3–6 points was an unfavorable outcome. The neurologist who evaluated the outcomes was blinded to the clinical conditions during the patient’s hospitalization to avoid interference with the accuracy of the outcome assessments.

Statistical analysis

Statistical analyses were performed with statistical software SPSS 22.0 (IBM Corporation, Armonk, NY, USA). Data with normal distributions are expressed as the mean ± standard deviation, whereas data with non-normal distributions are expressed as the median (interquartile range, IQR). Student’s t test was used for intergroup comparisons of data with a normal distribution and homogeneous variance, whereas the Mann–Whitney U test was employed for intergroup comparisons of data with a non-normal distribution and heterogeneous variance. Binary data were analyzed using Fisher’s exact test. Univariate analyses were employed to examine the differences in each observed indicator between the severe and non-severe groups. P ≤ 0.05 was deemed statistically significant.

Results

In total, this study enrolled 111 patients with anti-NMDAR encephalitis, including 59 males (53.2%) and 52 females (46.8%) (Table 1). The ages of the patients were between 13 and 72 (mean 27.7 ± 13.7) years. Nine (9/52, 17.3%) female patients had combined ovarian teratoma, and all received teratoma resection within 1 month of admission. No other patients in the study had tumors. Of the 111 patients admitted to the NCU, 39 (35.1%) were in the severe group, and 72 (64.9%) were in the non-severe group. Cranial MRI and lumbar puncture were performed at least once in all 111 patients, and EEG was performed at least once in 84 patients.
Table 1

Demographics, clinical manifestations, and main accessory examinations of patients with anti-NMDAR encephalitis

 

Total (n = 111)

Clinical severity

CSF NMDAR antibody titers

Non-severe group (n = 72)

Severe group (n = 39)

P value

Low-level group (n = 16)

High-level group (n = 95)

P value

Gender (n, %)

 Male

59 (53.2)

38 (52.8)

21 (53.8)

1.000

10 (62.5)

49 (51.6)

0.587

 Female

52 (46.8)

34 (47.2)

18 (46.2)

 

6 (37.5)

46 (48.4)

 

Age (years, mean, range)

27.7 (13–72)

27.4 (13–72)

28.5 (13–68)

0.680

28.3 (13–68)

27.7 (13–72)

0.574

Time of onset (n, %)

 First onset

105 (94.6)

68 (94.4)

37 (94.9)

1.000

15 (93.8)

90 (94.7)

1.000

 Recurrence

6 (5.4)

4 (5.6)

2 (5.1)

 

1 (6.3)

5 (5.3)

 

Tumor comorbidity (n, %)

 Ovarian teratoma

9 (8.1)

3 (4.2)

6 (15.4)

0.064

0 (0)

9 (9.5)

0.353

 No tumor

102 (91.9)

69 (95.3)

33 (84.6)

 

16 (100)

86 (90.5)

 

Prodromal symptoms (n, %)

 No

48 (43.2)

34 (47.2)

14 (35.9)

0.317

9 (56.3)

39 (41.1)

0.286

 Fever

33 (29.7)

17 (23.6)

16 (41.0)

0.081

3 (18.8)

30 (31.6)

0.385

 Headache

15 (13.5)

10 (13.9)

5 (12.8)

1.000

3 (18.8)

12 (12.6)

0.451

 Respiratory symptoms

11 (9.9)

9 (12.5)

2 (5.1)

0.323

1 (6.3)

10 (10.5)

1.000

 Emesis

2 (1.8)

1 (1.4)

1 (2.6)

1.000

0 (0)

2 (2.1)

1.000

 Diarrhea

2 (1.8)

1 (1.4)

1 (2.6)

1.000

0 (0)

2 (2.1)

1.000

Clinical manifestations (n, %)

 Mental behavior disorder

84 (75.7)

51 (70.8)

33 (84.6)

0.164

8 (50.0)

76 (80.0)

0.023

 Epileptic seizure

71 (64.0)

40 (55.6)

31 (79.5)

0.014

9 (56.3)

62 (65.3)

0.570

 Involuntary movement

60 (54.1)

26 (36.1)

34 (87.2)

< 0.001

6 (37.5)

54 (56.8)

0.181

 Disturbance of consciousness

55 (49.5)

20 (27.8)

35 (89.7)

< 0.001

6 (37.5)

49 (51.6)

0.419

 Cognitive impairment

55 (49.5)

33 (47.1)

22 (56.4)

0.426

7 (43.8)

48 (50.5)

0.788

 Language impairment

33 (29.7)

24 (33.3)

9 (23.1)

0.285

4 (25.0)

29 (30.5)

0.774

 Autonomic nervous dysfunction

29 (26.6)

10 (14.3)

19 (48.7)

< 0.001

2 (12.5)

27 (28.4)

0.230

 Central hypoventilation

25 (22.5)

0 (0)

25 (64.1)

< 0.001

1 (6.3)

24 (25.3)

0.114

 Numbness and weakness of the limbs

12 (11.0)

11 (15.3)

1 (2.6)

0.053

2 (12.5)

10 (10.5)

0.683

Electroencephalogram (n, %)

 Normal

4 (3.6)

4 (5.6)

0 (0)

0.295

2 (12.5)

2 (2.1)

0.099

 Epileptiform discharges

15 (13.5)

8 (11.1)

7 (17.9)

0.386

1 (6.3)

14 (14.7)

0.692

 Diffuse slowing

33 (29.7)

16 (22.2)

17 (43.6)

0.029

3 (18.8)

30 (31.6)

0.385

 Focal slowing

12 (10.8)

10 (13.9)

2 (5.1)

0.209

1 (6.3)

11 (11.6)

1.000

 Polymorphic delta rhythm

5 (4.5)

3 (4.2)

2 (5.1)

1.000

1 (6.3)

4 (4.2)

0.548

 Diffuse beta activities

4 (3.6)

2 (2.8)

2 (5.1)

0.612

0 (0)

4 (4.2)

1.000

 Extreme delta brush

11 (9.9)

6 (8.3)

5 (12.8)

0.513

2 (12.5)

9 (9.5)

0.658

Cranial MRI (n, %)

 Normal

47 (42.3)

28 (38.9)

19 (48.7)

0.324

6 (37.5)

41 (43.2)

0.788

 Lesions in cerebral cortex

42 (37.8)

27 (37.5)

15 (38.5)

1.000

8 (50.0)

34 (35.8)

0.404

 Lesions in white matter

13 (11.7)

9 (12.5)

4 (10.3)

1.000

2 (12.5)

11 (11.6)

1.000

 Hippocampal atrophy

9 (8.1)

8 (11.1)

1 (2.6)

0.156

0 (0)

9 (9.5)

0.353

Pressure of lumbar puncture increased (n, %)

34 (30.6)

18 (25.0)

16 (41.0)

0.089

3 (18.8)

31 (32.6)

0.385

CSF pleocytosis (n, %)

70 (63.1)

45 (62.5)

25 (64.1)

1.000

10 (62.5)

60 (63.2)

1.000

CSF protein increased (n, %)

23 (20.7)

17 (23.6)

6 (15.4)

0.340

4 (25.0)

19 (20.0)

0.739

CSF NMDAR antibody titers (n, %)

 Negative

0 (0)

0 (0)

0 (0)

 Weakly positive

16 (14.4)

12 (16.7)

4 (10.3)

0.412

 Positive

55 (49.5)

39 (54.2)

16 (41.0)

0.234

 Strongly positive

40 (36.0)

21 (29.2)

19 (48.7)

0.062

Serum NMDR antibody titers (n, %)

 Negative

54 (48.6)

37 (51.4)

17 (43.6)

0.551

11 (68.8)

43 (45.3)

0.107

 Weakly positive

19 (17.1)

9 (12.5)

10 (25.6)

0.112

4 (25.0)

15 (15.8)

0.471

 Positive

31 (27.9)

20 (27.8)

11 (28.2)

1.000

0 (0)

31 (32.6)

0.005

 Strongly positive

6 (5.4)

5 (6.9)

1 (2.6)

0.663

0 (0)

6 (6.3)

0.591

Anti-NMDAR anti-N-methyl-d-aspartate receptor, CSF cerebrospinal fluid, MRI magnetic resonance imaging

Clinical manifestations were compared between the severe group and the non-severe group (Table 1). Significant differences were observed in epilepsy, involuntary movement, disturbance of consciousness, autonomic nervous dysfunction, and central hypoventilation. Compared with the non-severe group, the severe group exhibited a higher proportion of epilepsy, involuntary movement, disturbance of consciousness, autonomic dysfunction, and central hypoventilation. Of the 71 patients with epilepsy, 5 patients (5/71, 7%) had status epilepticus, and all were in the severe group. Compared to the low titer group, the high titer group exhibited a higher proportion of behavior disorders.

The CSF of all patients (100%) was positive for the NMDAR antibody, but only 57 patients (51.4%) tested positive for the NMDAR antibody in blood. The comparison of the main auxiliary examination results between the severe group and non-severe group (Table 1): the ratio of diffuse slow waves in EEG was higher in the severe group than in the non-severe group. The proportion of patients with a strong positive NMDAR antibody titer in the severe group (48.7%) was higher than that in the non-severe group (29.2%). Additionally, there was a trend toward higher NMDAR antibody titers in the severe group (P = 0.062).

There were several points of comparison for treatments between the severe group and non-severe group (Table 2). The hospitalization time of the severe group was significantly longer than that of the non-severe group (P < 0.001). Median length of stay in the NCU for severe patients was 39 days (interquartile range, IQR 14, 73 days). Before immunotherapy, the ratio of patients with a mRS of 3–5 in the severe group was significantly higher than that in the non-severe group (Fig. 1a). All patients received immunotherapy, 97 (87.4%) received glucocorticoids, 74 (66.7%) received IVIG (1–7 courses), and 19 (17.1%) received plasmapheresis. Among the 26 patients who received immunosuppressive therapy, 12 received mycophenolate mofetil, 2 received mycophenolate mofetil after intravenous rituximab, 5 received azathioprine, 2 received azathioprine after intravenous rituximab, 3 received intravenous cyclophosphamide, and 2 received intravenous rituximab. Intravenous sedatives or anesthetics, such as midazolam, propofol or dexmedetomidine, were only used in the severe group to treat acute symptoms.
Table 2

Treatment and outcomes of patients with anti-NMDAR encephalitis

 

Total (n = 111)

Clinical severity

CSF NMDAR antibody titers

Non-severe group (n = 72)

Severe group (n = 39)

P value

Low-level group (n = 16)

High-level group (n = 95)

P value

Length of hospital stay (days, median, IQR)

19 (14,39)

17 (13,21)

39 (20,73)

< 0.001

16 (12, 25)

20 (14,39)

0.073

Number of days between onset and immunotherapy (mean, range)

41 (5–406)

43 (5–337)

36 (7–406)

0.538

39 (7–144)

41 (5–406)

0.899

Number of days between onset and hormonotherapy (mean, range)

43 (5–406)

44 (5–337)

41 (7–406)

0.880

36 (7–137)

44 (5–406)

0.644

Number of days between onset and IVIG (mean, range)

41 (8–407)

40 (8–165)

43 (8–407)

0.792

41 (10–144)

42 (8–407)

0.967

Number of days between onset and PE (mean, range)

49 (15–83)

0 (0)

49 (15–83)

47 (41–52)

49 (15–83)

0.871

Immunotherapy (n, %)

 Hormonotherapy

97 (87.4)

62 (86.1)

35 (89.7)

0.767

12 (75.0)

85 (89.5)

0.117

 IVIG

74 (66.7)

41 (56.9)

33 (84.6)

0.003

11 (68.8)

63 (66.3)

1.000

 PE

19 (17.1)

0 (0)

19 (48.7)

< 0.001

2 (12.5)

17 (17.9)

0.735

Immunosuppressants

 Mycophenolate mofetil

14 (12.6)

10 (13.9)

4 (10.3)

1.000

3 (18.8)

11 (11.6)

0.422

 Azathioprine

7 (6.3)

2 (2.8)

5 (12.8)

0.182

0 (0)

7 (7.4)

0.591

 Rituximab

6 (5.4)

0 (0)

6 (15.4)

0.001

0 (0)

6 (6.3)

0.591

 Cyclophosphamide

3 (2.7)

0 (0)

3 (7.7)

0.014

0 (0)

3 (3.2)

1.000

Symptomatic treatment (n, %)

 Diazepam

39 (35.1)

19 (26.4)

20 (51.3)

0.12

4 (25.0)

35 (36.8)

0.412

 Phenobarbital sodium

46 (41.4)

18 (25.0)

28 (71.8)

< 0.001

4 (25.0)

42 (44.2)

0.179

 Midazolam

23 (20.7)

0 (0)

23 (59.0)

< 0.001

3 (18.8)

20 (21.1)

1.000

 Propofol

14 (12.6)

0 (0)

14 (35.9)

< 0.001

0 (0)

14 (14.7)

0.214

 Dexmedetomidine

7 (6.3)

0 (0)

7 (17.9)

< 0.001

1 (6.3)

6 (6.3)

1.000

Recurrence (n, %)

7 (6.3)

6 (8.3)

1 (2.6)

0.418

1 (6.3)

6 (6.3)

1.000

mRS before immunotherapy (n, %)

 0–2

40 (36.0)

40 (55.6)

0 (0)

< 0.001

8 (50.0)

32 (33.7)

0.262

 3–5

71 (64.0)

32 (44.4)

39 (100)

 

8 (50.0)

63 (66.3)

 

mRS after 2 months (n, %)

       

 0–2

57 (51.4)

52 (72.2)

5 (12.8)

< 0.001

9 (56.2)

48 (50.5)

0.789

 3–6

54 (48.6)

20 (27.8)

34 (87.2)

 

7 (43.8)

47 (49.5)

 

mRS after 6 months (n, %)

 0–2

89 (80.2)

61 (84.7)

28 (71.8)

0.135

11 (68.8)

78 (82.1)

0.306

 3–6

22 (19.8)

11 (15.3)

11 (28.2)

 

5 (31.3)

17 (17.9)

 

Long-term follow-up mRS (n, %)

 0–2

83 (89.2)

58 (92.1)

25 (83.3)

0.283

13 (81.2)

70 (90.9)

0.368

 3–6

10 (10.8)

5 (7.9)

5 (16.7)

 

3 (18.8)

7 (9.1)

 

Anti-NMDAR anti-N-methyl-d-aspartate receptor, IQR interquartile range, IVIG intravenous gamma immunoglobulin, mRS modified Rankin Scale, PE plasma exchange

Fig. 1

The mRS before and after immunotherapy among patients with anti-NMDAR encephalitis in the severe group and non-severe group. a The mRS before immunotherapy. b The mRS after 2 months. c The mRS after 6 months. d The long-term follow-up mRS (6–64 months)

Outcomes are outlined in Table 2. The mortality rate within 6 months was 4.5% (5/111). In the severe group, two patients died of multiple organ failure during their stay in the NCU. One patient in the severe group showed marked improvement and was discharged but died 1 month after discharge due to liver failure. The remaining 36 patients exhibited improvement following immunotherapy and intensive care support, were transferred from the NCU to general ward, and were ultimately discharged from the hospital. In the non-severe group, two patients showed improvement after immunotherapy and were discharged from hospital but died 1 month after discharge due to comorbidity.

At 2 months after immunotherapy (Fig. 1b), 34 patients (87.2%) had poor outcomes in the severe group; this number was significantly higher than that in the non-severe group (P < 0.001). After 6 months, there was no significant difference in the outcomes between the severe group and non-severe group (Fig. 1c). Subsequently, 96 survivors were followed up once every 6 months, and 18 of these patients were lost to follow-up. The longest follow-up time was 64 months after immunotherapy (Fig. 1d). Twelve patients with weakness of the limbs underwent rehabilitation training and recovered without weakness. The remaining symptoms included cognitive impairment in 25 patients, personality change in 13, epileptic seizure in 2, and involuntary movement in 1.

Discussion

Anti-NMDAR encephalitis is a form of autoimmune encephalitis that can be reversed with early active treatment; it is also a common form of encephalitis in the ICU [1, 2]. In this study, 35.1% of patients were in the severe group and required admission to the ICU. Compared with the non-severe group, the severe group showed a higher proportion of epilepsy, involuntary movement, disturbance of consciousness, autonomic dysfunction, and central hypoventilation.

Epilepsy is a common symptom in anti-NMDAR encephalitis. Of the 111 patients in this study, 71 (64%) had epilepsy, and the incidence of epilepsy in the severe group was significantly higher than that in the non-severe group. Furthermore, five (5/71, 7%) epileptic patients had status epilepticus, and all were in the severe group. Autoimmune encephalitis is the most common cause of new-onset refractory status epilepticus [13]. In addition to epilepsy, involuntary movement is also a common problem for patients with severe anti-NMDAR encephalitis. Among 28 anti-NMDAR encephalitis patients with movement disorders in a previous study, 20 had orofacial–lingual dyskinesia, 11 had tremor, 11 had dystonia, 9 had choreoathetosis, and 3 had ballism [14]. Distinguishing between true seizures and non-seizure-like movements is a challenge both at initial presentation and throughout the hospital course, especially in coma patients [15, 16]. In a previous case report, EEG combined with intracranial pressure monitoring was performed to identify status epilepticus in anti-NMDAR encephalitis patients [15]. In the clinic, anticonvulsant medicines, antipsychotics, continuous-infusion sedatives, and neuromuscular blocking agents are administered to the majority of severe patients, with the aim of limiting seizures or abnormal movements [2, 16]. Patients’ severe oral–lingual–facial dyskinesias and opisthotonic posturing might result in the dislodging and malfunction of airway devices (endotracheal tube and tracheostomies), significantly complicating airway management in the ICU [16].

The proportion of patients with autonomic nervous dysfunction in the severe group was high in this study. Persistent dysautonomias are additional difficult to manage confounders [2]. Autonomic dysfunction includes cardiac dysrhythmias, hyperthermia, unstable blood pressure, and hypersalivation, among other issues [2, 17, 18, 19]. Severe bradycardia might progress to cardiac asystole, necessitating cardiopulmonary resuscitation [17, 18]. Individual patients may need to consider installing a cardiac pacemaker to prevent cardiac arrest [17]. Hypoventilation is also a common symptom in adult severe anti-NMDAR encephalitis [1]. The role of NMDARs in respiratory control is indirectly supported by neurohistological evidence of NMDA expression in multiple brainstem regions that control respiration [20, 21]. This distribution of NMDARs may cause central hypoventilation in patients with anti-NMDAR encephalitis.

The results of this study are consistent with previous research showing that the sensitivity of NMDAR antibody testing is higher in CSF than in serum [22, 23]. In this study, all patients (100%) were positive for the NMDAR antibody in CSF, but only 57 cases (51.4%) were positive for the NMDAR antibody in the blood. Nuria Gresa-Arribas et al. [23] studied patients with a clinical picture characteristic of anti-NMDAR encephalitis but whose serum tested negative in other laboratories. When they examined samples from these patients, they confirmed that the serum samples were negative, but the CSF samples (not examined in other laboratories) were positive by both immunohistochemistry and cell-based assays. These results suggested that in some patients with anti-NMDAR encephalitis, the antibodies are detectable only in the CSF. The mechanism may involve the intrathecal synthesis of antibodies. Patients with severe defects showed limited clinical evidence of blood–brain barrier disruption and low or undetectable serum antibody levels [24]. In addition, there was a trend toward a higher NMDAR antibody titer in severe group (P = 0.062). Therefore, clinical severity and CSF antibody titers might be associated. A previous study also suggested that CSF antibody titers could complement clinical assessments [23].

In this study, the diffuse slow wave was the most common type of EEG presentation in anti-NMDAR encephalitis; this finding was also reported in a previous study [25]. The NMDAR is an ionotropic glutamate receptor; it has many regulatory sites with different structures and ligand-gated channels with high calcium permeability and is distributed throughout all brain tissues. Following the interaction between NMDARs and NMDAR antibodies, cell depolarization is shortened, causing slow waves in the EEG [26]. In addition, encephalitis will cause damage in certain locations, such as the cerebral cortex, cerebral white matter, basal ganglia, and midbrain. Cortical damage or disorders of the ascending reticular activating system will induce the presence of slow waves. According to the different locations of damage, focal slow waves or diffuse slow waves might occur [27]. In this study, patients in the severe group had a higher ratio of diffuse slow waves in EEG than did patients in the non-severe group. However, only 84 of the 111 patients underwent EEG monitoring during the peak stage of the disease, which is a limitation of this study; thus, the clinical significance of this difference should be further observed and studied.

Whether female patients with ovarian tumors had worse conditions or short-term outcomes remains uncertain. In previous studies, female patients with ovarian tumors had good responses to immunotherapy and better outcomes after tumor removal [28, 29]; however, another study found that compared with patients without tumors, female patients with ovarian tumors did not have favorable short-term outcomes or good responses to treatment [14]. In this study, although there was no significant difference between the two groups (P = 0.064), the proportion of the patients with teratoma in the severe group was higher than that in the non-severe group. Female patients with teratoma had severe initial presentations and more chances to receive second-line therapy than did male patients.

Based on our results, although patients in the severe group have longer hospitalization times and more complicated treatment, there is no significant difference in long-term prognosis and recurrence between the severe group and non-severe group. This finding might be associated with more active immunotherapy in the severe group in this study. The main treatments for anti-NMDAR encephalitis are immunotherapy and tumor resection. The commonly used first-line immunotherapy includes high-dose methylprednisolone combined with IVIG or PE, and immunosuppressants are recommended for second-line immunotherapy [1]. The selection of immunotherapeutic methods and the intensity of combined immunotherapy were significantly different between the severe group and non-severe group. The patients in the severe group received more active combined immunotherapy; only patients in the severe group received PE, intravenous rituximab and cyclophosphamide treatment. PE data in pediatric anti-NMDAR encephalitis appear to confirm the trend toward a better outcome when PE is administered early and with steroids [30]. In a recent study [4], the efficacy of intravenous methylprednisolone administered alone or following PE was compared in the treatment of anti-NMDAR encephalitis. The obtained results were clearly in favor of administering steroids only after PE in the studied patient population. Some case reports emphasize the importance of early implementation of therapeutic PE, which is a potentially life-saving therapy [31, 32]. Therefore, aggressive immunotherapy helps control the progression of severe patients [3, 5]. Simultaneously, management of complications is essential and may improve the prognosis of anti-NMDAR encephalitis [6, 33].

Conclusion

In summary, most severe anti-NMDAR encephalitis patients in China will eventually achieve good long-term prognoses after receiving early, positive and unremitting combined immunotherapy and life support despite the disease severity, longer stays in the ICU and difficulties in treatment. Studies examining different populations will allow more accurate conclusions.

Notes

Acknowledgements

We thank Dr Haitao Ren and Dr Yanhuan Zhao from the Department of Neurology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, China, for performing anti-NMDAR antibody assays and for technical support.

Funding

This project was supported by Chinese Natural Science Fund No. 81671037 (to Yingying Su).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature and Neurocritical Care Society 2018

Authors and Affiliations

  • Yan Zhang
    • 1
  • Gang Liu
    • 1
  • Mengdi Jiang
    • 1
  • Weibi Chen
    • 1
  • Yanbo He
    • 1
  • Yingying Su
    • 1
  1. 1.Department of Neurology, Xuanwu HospitalCapital Medical UniversityBeijingChina

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