Demographics and baseline characteristics
The baseline characteristics of all included patients and diagnostic subgroups are shown in Table 1. Overall, 121 patients were enrolled, including 54 males and 67 females. The average age of onset was 32.3±15.1 years. There were 62 patients (51.2%) with fever, 59 patients (48.8%) with abnormal mental behaviour, and 35 patients (28.9%) with consciousness disorder. Forty-five patients (37.2%) had epileptic seizures as the first symptom. Ninety-five patients (78.5%) presented with tonic-clonic seizures, and 27 patients (22.3%) developed status epilepticus. Eighty-six patients (71.1%) had abnormal brain MRI reports, and 41 patients (33.9%) were admitted to the ICU. The vast majority (90.9%) of patients were treated with AEDs during hospitalization, and 57.9% of patients were treated with single AEDs, such as levetiracetam, valproate, and oxcarbazepine, to control their seizures.
According to the diagnosis, there were 54 patients (44.6%) in the viral encephalitis group and 67 patients (55.4%) in the autoimmune encephalitis group. There were no significant differences between the two groups in terms of demographic characteristics, most clinical manifestations in the acute phase, abnormal MRI rate or ICU admission rate.
Compared with the autoimmune encephalitis group, the viral encephalitis group had relatively fewer mental and behavioural abnormalities (P = 0.021), manifested as focal seizures (P = 0.001), and they developed status epilepticus (SE) (P = 0.008) at a lower rate. Nine patients in the viral encephalitis group were not treated with AEDs to control seizures, and fewer patients were treated with AEDs in combination than those in the autoimmune encephalitis group (20.4% vs 43.3%, P = 0.003).
Table 1 Baseline characteristics of acute encephalitis
Characteristics
|
Total
(n=121)
|
Viral encephalitis
(n=54)
|
Autoimmune encephalitis
(n=67)
|
P value
|
Sex (Male)
|
54 (44.6)
|
28(51.9)
|
26(38.8)
|
0.151
|
Age (years)
|
|
|
|
0.064
|
0-17
18-40
40-70
|
26(21.5)
58(47.9)
37(30.6)
|
7(13.0)
26(48.1)
21(38.9)
|
19(28.4)
32(47.8)
16(23.9)
|
|
Fever
|
62(51.2)
|
30(55.6)
|
32(47.8)
|
0.394
|
Consciousness disorder
|
35(28.9)
|
13(24.1)
|
22(32.8)
|
0.291
|
Abnormal mental behaviour
|
59(48.8)
|
20(37.0)
|
39(58.2)
|
0.021*
|
Seizures as the first symptom
|
45(37.2)
|
17(31.5)
|
28(41.8)
|
0.243
|
Types of seizures
|
|
|
|
0.001*
|
Tonic-clonic seizure
|
95(78.5)
|
50(92.6)
|
45(67.2)
|
|
Focal seizure
|
26(21.5)
|
4(7.4)
|
22(32.8)
|
|
SE
|
27(22.3)
|
6(11.1)
|
21(31.3)
|
0.008*
|
Brain MRI abnormal
|
86(71.1)
|
41(75.9)
|
45(67.2)
|
0.291
|
ICU
|
41(33.9)
|
18(33.3)
|
23(34.3)
|
0.908
|
AEDs
|
|
|
|
0.003*
|
One AED
|
70(57.9)
|
34(63.0)
|
36(53.7)
|
|
≥Two AEDs
|
40(33.1)
|
11(20.4)
|
29(43.3)
|
|
No AED
|
11(9.1)
|
9(16.7)
|
2(3.0)
|
|
Immunotherapy
|
|
|
|
<0.001*
|
Only glucocorticoids
|
50(41.3)
|
35(64.8)
|
15(22.4)
|
|
Only immunoglobulin
|
8(6.6)
|
3(5.6)
|
5(7.5)
|
|
Glucocorticoids and immunoglobulin
|
63(52.1)
|
16(29.6)
|
4 7(70.1)
|
|
p values derived from Chi-square test, data presented as n (%). p values < 0.05 are given in *.
SE status epilepticus, MRI magnetic resonance imaging, ICU intensive care unit, AED antiepileptic drug
Immunotherapy
All patients received immunotherapy with first-line drugs. Glucocorticoids were administered to 113 patients (93.3%), of whom 50 (41.3%) were treated alone and 63 (52.1%) with combination immunoglobulin. Only 8 patients (6.6%) received immunoglobulin alone. Compared with autoimmune encephalitis, there were significantly more patients treated with glucocorticoids alone in the viral encephalitis group (64.8% vs 22.4%) and significantly fewer patients treated with glucocorticoids in combination with immunoglobulin (29.6% vs 70.1%). There were statistically significant differences between the two groups in terms of immunotherapy for encephalitis (P < 0.001) (Table 1). Patients in the viral encephalitis group received adjuvant corticosteroids, most of which were dexamethasone, prednisolone, or methylprednisolone <500 mg/day (42/51, 82.4%), and only nine patients received high-dose methylprednisolone. Patients in the autoimmune encephalitis group were mostly treated with intravenous pulses of high-dose methylprednisolone (44/62, 71.0%). The median dose of methylprednisolone was 106 mg/day in the viral encephalitis group and 500 mg/day in the autoimmune encephalitis group (P < 0.001) (Figure 1).
Follow-up results
At the follow-up 6 months after onset, 95 of the 121 patients (78.5%) with encephalitis were seizure-free, 53 (43.8%) continued to take AEDs, and 61 (50.4%) had no seizures after discharge and no seizures after discontinuation of AEDs. There were no statistically significant differences in the seizure-free rate (77.8% vs 79.1%) or AEDs rate (35.2% vs 50.7%) between the viral encephalitis group and the autoimmune encephalitis group (P > 0.05). A total of 61.1% of patients with viral encephalitis achieved discontinuation of AEDs without seizures, which was significantly higher than that of the autoimmune encephalitis group (41.8%) (P = 0.009) (Table 2).
A total of 26 (21.4%) of these patients with encephalitis still had seizures at 6 months after onset (Figure 2a); 19 were still taking AEDs, with a drug taking rate of 73.1%, which was significantly higher than the 35.8% taking rate of 95 patients without seizures (P = 0.001). The same trend was observed in the viral encephalitis and autoimmune encephalitis groups (Figure 2b).
A total of 56.2% of encephalitis patients (including 35 viral encephalitis and 33 autoimmune encephalitis) had withdrawn AEDs at 6 months after onset. The seizure-free rate among these patients was 89.7%, higher than the 64.2% rate among the 53 patients who took AEDs. Moreover, 33 (94.3%) patients with viral encephalitis and 28 (84.8%) patients with autoimmune encephalitis experienced remission of seizures after discharge, and there was no statistically significant difference between the two groups (P > 0.05) (Figure 2c).
Table 2 Seizure control and antiepileptic drug administration during follow-up of acute encephalitis
|
Viral encephalitis
|
Autoimmune encephalitis
|
χ2
|
P value
|
seizure-free
|
6 month
|
42(77.8)
|
53(79.1)
|
0.031
|
0.860
|
12 month
|
42(80.8)
|
57(91.9)
|
3.086
|
0.079
|
χ2
|
34.479
|
-
|
|
|
P value
|
<0.001*
|
a<0.001*
|
|
|
continue AED
|
6 month
|
19(35.2)
|
34(50.7)
|
2.941
|
0.086
|
12 month
|
12(23.1)
|
20(32.3)
|
1.181
|
0.277
|
χ2
|
15.312
|
16.037
|
|
|
P value
|
<0.001*
|
<0.001*
|
|
|
seizure-free and
discontinue AED
|
6month
|
33(61.1)
|
28(41.8)
|
6.756
|
0.009*
|
12 month
|
39(75.0)
|
42(67.7)
|
5.976
|
0.015
|
χ2
|
26.567
|
22.776
|
|
|
P value
|
<0.001*
|
<0.001*
|
|
|
p values derived from Chi-square test. ap values derived from Fisher's test, p values < 0.05 are given in * . data presented as n (%). AED antiepileptic drug.
After 12 months, 4 patients were lost to follow-up, and 3 died of myocardial infarction or accident. In total, 114 patients, including 52 with viral encephalitis and 62 with autoimmune encephalitis, were followed up. Ninety-nine (86.8%) patients with encephalitis were seizure-free. The seizure-free rate of the autoimmune encephalitis group (57 patients, 91.9%) was higher than that of the viral encephalitis group (42 patients, 80.8%), but the difference between the two groups was not statistically significant (P > 0.05). The overall rate of taking AEDs was reduced to 28.1% (32 patients). The rate of taking in the viral encephalitis group (12 patients, 23.1%) was similar to that of the autoimmune encephalitis group (20 patients, 32.3%), and they all took only one AED. In this period, the rate of discontinuation of AEDs without seizures in the viral encephalitis group (75.0%) was higher than that in the autoimmune encephalitis group (67.7%), and the difference was statistically significant (P = 0.015) (Table 2).
By 12 months after onset, the epileptic seizure rate of encephalitis had dropped to 13.2%, 19.2% for viral encephalitis and 8.1% for autoimmune encephalitis (Figure 2a). Of the 15 patients who still had seizures (10 with viral encephalitis and 5 with autoimmune encephalitis), only one (6.7%) patient did not continue to take AEDs. Among those who were seizure-free, the rate of continued use of AEDs was reduced to 18.2% (18 patients), with only 3 (7.1%) patients with viral encephalitis and 15 (26.3%) patients with autoimmune encephalitis continuing to take AEDs (Figure 2b). The seizure-free rate of patients with autoimmune encephalitis and viral encephalitis who stopped taking AEDs was 100% and 97.5%, respectively, both of which were significantly higher than those in the continuing group (Figure 2c).
The seizure-free rates of viral encephalitis and autoimmune encephalitis at 12 months after onset were higher than those at 6 months after onset. The difference in seizures between the two follow-up periods was statistically significant (P < 0.001). Meanwhile, the rate of AED use at 12 months was lower than that at 6 months (P < 0.001). In addition, 6 new patients with viral encephalitis and 14 patients with autoimmune encephalitis achieved discontinuation of AEDs without seizures 12 months after the onset of disease, except for the 61 patients who had no seizures when the drug was stopped at the follow-up 6 months after the onset of the disease. Thus, 81 patients (71.1%) were seizure-free after the drug was stopped, and the drug was successfully withdrawn. There was a statistically significant difference in the seizure-free rate after AED withdrawal between the two follow-up periods (P < 0.001) (Table 2). The prognosis of epileptic seizures at 12 months after onset was better than that at 6 months.
Demographic and acute phase characteristics and prognosis of epileptic seizures in viral encephalitis and autoimmune encephalitis
The relationships between the prognosis of seizures with viral encephalitis and autoimmune encephalitis and demographic information, clinical symptoms in the acute phase, and treatment were assessed (Table 3). Univariate analysis showed that fever in the acute phase (P = 0.026, OR 11.7 95% CI 1.4-101.1) affected the prognosis of epileptic seizures 6 months after the onset of viral encephalitis, while admission to the ICU and glucocorticoid therapy alone were correlated with the prognosis of epileptic seizures at 6 and 12 months (P < 0.05). Immunotherapy was related to the prognosis of epileptic seizures at 6 and 12 months after the onset of autoimmune encephalitis (P < 0.05) (Table 3).
The variables with P < 0.1 in the univariate analysis of the two groups of encephalitis as well as SE and ICU were included in the binary logistic regression analysis. The results showed that fever was the only risk factor for a poor prognosis of epileptic seizures after 6 months of viral encephalitis. Patients with fever were 9.5 times more likely to have seizures 6 months after onset than those without fever (P = 0.043, OR 9.5 95%CI 1.1-84.5). Patients with viral encephalitis treated with glucocorticoid alone had a lower risk of seizures after 12 months than those treated with glucocorticoids combined with immunoglobulin (P = 0.006, OR 0.95% CI 0.0-0.5) (Table 4).
Multivariate regression analysis showed that immunotherapy could affect the outcome of autoimmune encephalitis epileptic seizures. The risk of epileptic seizures in patients treated with glucocorticoids alone at 6 months and 12 months was 5.6 times and 13.5 times higher than that in patients treated with glucocorticoids combined with immunoglobulin, respectively (P = 0.015, OR 5.6 95%CI 1.4-22.4; P = 0.031, OR 13.5 95%CI 1.3-143.6). Patients treated with immunoglobulin alone were 12.6 times more likely to have seizures at 6 months than those treated with glucocorticoid combined with immunoglobulin (P = 0.014, OR 12.6 95%CI 1.7-94.5) (Table 4).
Table 3 Univariate analysis the factors associated with the prognosis of seizures
Variable
|
Viral encephalitis
|
|
Autoimmune encephalitis
|
6 month
|
12 month
|
6 month
|
12 month
|
OR(95%CI) P value
|
OR(95%CI)
|
P value
|
OR(95%CI)
|
P value
|
OR(95%CI)
|
P value
|
Sex (Male)
|
0.6(0.2-2.2) 0.426
|
1.7(0.4-6.7)
|
0.484
|
|
0.8(0.2-2.7)
|
0.727
|
0.9(0.1-5.7)
|
0.889
|
Age>17 yearsa
|
0.8(0.3-2.3) 0.737
|
1.6(0.5-4.5)
|
0.418
|
|
0.7(0.3-1.5)
|
0.325
|
1.4(0.4-4.9)
|
0.629
|
Fever
|
13.3(1.6-112.7) 0.017*
|
4.4(0.8-23.2)
|
0.081
|
|
1.6(0.5-5.3)
|
0.432
|
4.8(0.5-45.4)
|
0.174
|
Consciousness disorder
|
0.6(0.1-3.0) 0.500
|
1.4(0.3-6.3)
|
0.685
|
|
1.2(0.3-4.0)
|
0.797
|
0.5(0.0-4.4)
|
0.503
|
Abnormal mental behaviour
|
0.8(0.2-3.1) 0.763
|
1.8(0.4-7.2)
|
0.408
|
|
2.1(0.6-7.4)
|
0.265
|
3.1(0.3-29.7)
|
0.322
|
Seizures as the first symptom
|
0.4(0.1-1.9) 0.223
|
0.2(0.0-1.7)
|
0.144
|
|
1.1(0.3-3.5)
|
0.928
|
2.1(0.3-13.3)
|
0.447
|
Tonic-clonic
seizures
|
1.2(0.1-12.5) 0.890
|
1.4(0.1-15.6)
|
0.762
|
|
2.5(0.8-8.5)
|
0.131
|
0.5(0.1-5.2)
|
0.595
|
SE
|
0.7(0.1-6.4) 0.730
|
0.8(0.1-7.9)
|
0.866
|
|
0.8(0.2-3.1)
|
0.802
|
0.6(0.1-5.7)
|
0.646
|
Brain MRI abnormal
|
4.4(0.5-37.9) 0.178
|
3.6(0.4-31.6)
|
0.248
|
|
0.9(0.2-2.9)
|
0.797
|
2.0(0.2-19.2)
|
0.548
|
ICU
|
6.4(1.6-25.8) 0.009*
|
8.6(1.8-39.9)
|
0.006*
|
|
0.5(0.1-1.8)
|
0.261
|
0.5(0.0-4.4)
|
0.503
|
AEDs
|
|
|
|
|
0.6(0.2-1.7)
|
0.310
|
0.7(0.1-4.1)
|
0.728
|
≥Two AEDs b
|
2.2(0.5-9.7) 0.296
|
1.8(0.2-17.0)
|
0.618
|
|
|
|
|
|
No AED b
|
0.5(0.1-4.5) 0.523
|
3.4(0.3-40.9)
|
0.330
|
|
|
|
|
|
Only glucocorticoidsc
|
0.2(0.1-0.8) 0.027*
|
0.1(0.0-0.5)
|
0.006*
|
|
5.6(1.4-22.4)
|
0.015*
|
13.5(1.3-143.6)
|
0.031*
|
Only immunoglobulinc
|
0.0(0.0- ) 0.999
|
0.0(0.0- )
|
0.999
|
|
12.6(1.7-94.5)
|
0.014*
|
22.5(1.0-505.8)
|
0.050
|
High-dose methylprednisolone
|
0.3(0.1-1.4) 0.115
|
0.2(0.0-1.0)
|
0.060
|
|
1.5(0.4-6.0)
|
0.556
|
0.8(0.1-8.4)
|
0.862
|
p values < 0.05 are given in *. SE status epilepticus,MRI magnetic resonance imaging,ICU intensive care unit,AED antiepileptic drug .
The reference category of: a,17 years old; b, One AED; c, glucocorticoids combined immunoglobulin.
Table 4 Multivariate analysis the factors associated with the prognosis of seizures
Variable
|
Viral encephalitis
|
|
Autoimmune encephalitis
|
6 month
|
12 month
|
6 month
|
12 month
|
OR(95%CI) P value
|
OR(95%CI)
|
P value
|
OR(95%CI)
|
P value
|
OR(95%CI)
|
P value
|
fever
|
9.5(1.1-84.5) 0.043*
|
-
|
-
|
|
-
|
-
|
-
|
-
|
only glucocorticoidsc
|
-
|
0.1(0.0-0.5)
|
0.006*
|
|
5.6(1.4-22.4)
|
0.015*
|
13.5(1.3-143.6)
|
0.031*
|
only immunoglobulinc
|
-
|
-
|
-
|
|
12.6(1.7-94.5)
|
0.014*
|
-
|
|
p values < 0.05 are given in *.
The reference category of c was glucocorticoids combined immunoglobulin.
Acute immunotherapy programmes and prognosis of epileptic seizures in autoimmune encephalitis
Patients with autoimmune encephalitis received three immunotherapy programmes in the acute phase, and there were differences in the prognosis of epileptic seizures within 12 months of onset. The rate of achieving seizure-free AEDs in patients treated with glucocorticoids alone and immunoglobulin alone in the acute phase was 60.0% (9/15, 6 of the 9 (66.7%) discontinued AEDs) and 40.0% (2/5, 1 of the 2 (50%) discontinued AEDs), respectively, and the rate of seizure-free AEDs in patients who received glucocorticoids combined with immunoglobulin therapy reached 89.4% (42/47, 21 of the 42 (50.0%) discontinued AEDs) (Figure 3a). There were statistically significant differences in seizure-free status among the three different immunotherapies (P = 0.004), and there were no statistically significant differences in AED administration at follow-up among the three immunotherapies (P = 0.657 > 0.05).
At 12 months, the seizure-free rate of patients treated with glucocorticoids alone and immunoglobulin alone was 76.9% (10/13, 7 of the 10 (70.0%) discontinued AEDs) and 66.7% (2/3, 1 of the 2 (50%) discontinued AEDs), respectively, and the seizure-free rate of patients treated with the immunotherapy combination was as high as 97.8% (45/46, 34 of the 45 patients (75.6%) stopped taking antiepileptic drugs) (Figure 3a). There were statistically significant differences in seizure-free status among the three different immunotherapy programmes at 12 months (P = 0.014), and there were no significant differences in the AEDs taken during follow-up among the three immunotherapies (P = 0.143 > 0.05).
Prognosis of epileptic seizures in acute fever and AEDs and viral encephalitis during follow-up
Thirty patients (55.6%) in the viral encephalitis group had fever during the acute period. A total of 63.6% (19/30, 16 of 19 patients (84.2%) discontinued AEDs) of patients with viral encephalitis who had acute fever achieved seizure-free status at 6 months, which was significantly lower than the 95.8% of patients without fever (23/24, 17 of 23 patients (73.9%) did not take AEDs for a long time) (Figure 3b). There was a statistically significant difference in the prognosis of epileptic seizures at 6 months after the onset of disease (P = 0.004), and there was no significant difference in the use of AEDs during follow-up (P = 0.407 > 0.05). A total of 71.4% (20/28, 18 out of 20 (90.0%) of those without AEDs) of patients with fever achieved seizure-free status at 12 months after onset, which was still lower than the 91.7% (22/24, 21 of 22 patients (95.5%) who discontinued AEDs) of patients without fever (Figure 3b). At this time, there was no statistically significant difference in the prognosis of epileptic seizures between patients with fever and those without fever (P = 0.135 > 0.05).