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Autoimmune encephalitis (AE) is an autoimmune-mediated neurological disease produced by the action of antineuronal antibodies, with clinical manifestations of impaired consciousness, memory deficits, behavioral disorders, and seizures, and some patients are associated with
tumorigenesis.
Immunotherapy is an important measure of AE therapy, and patients with AE associated with neuronal surface antibodies are usually more likely to respond
to immunotherapy.
This article summarizes the progress of drug treatment of AE in conjunction with the Expert Consensus on the Diagnosis and Treatment of Autoimmune Encephalitis in China (2022 Edition) [1], which is used for reference
in clinical treatment.
Note: N-methyl-D-aspartate receptor (NMDAR), leucine-rich glioma inactivated 1 protein (LGI1), contact protein-associated protein 2 (Caspr2), γ-GABABR B receptor.
children and young adults.
Patients with this disease are usually hospitalized with mental behavior abnormalities, and if properly treated, they can be cured without sequelae, and their prognosis depends on early diagnosis and treatment
.
Early treatment (less than 1 month) is an important factor in a good prognosis, and the use of immunotherapy in the early onset of encephalitis is associated
with lower recurrence rates.
Studies have shown that 94% (472/501) of patients receive first-line immunotherapy clinically, 84% (421/501) of patients take steroids, and 69% (346/501).
patients received intravenous immunoglobulin (IVIg), and 40% of patients used both steroids and IVIg (202/501); About one third of patients receive second-line immunotherapy, including rituximab (101/501, 20%), cyclophosphamide (81/501, 16%), and other immunotherapies (azathioprine, methotrexate, or tacrolimus).
[2]
。
Symptomatic treatment of this condition usually focuses on sedation and improving the sleep-wake cycle, but it should be noted that patients taking antipsychotics have a high
incidence of adverse events.
.
Studies have shown that about 97% (42/43) of patients with this disease received immunotherapy at the first onset of the disease, and first-line immunotherapy drugs include steroids, IVIg; Rarely, second-line immunotherapies such as rituximab, cyclophosphamide, mycophenolate mofetil, azathioprine, and tacrolimus
are used.
Patients initially treated with both steroids and IVIg have a better prognosis and a higher recovery rate than those initially treated with steroids alone [3].
There are no large-scale clinical studies of second-line immunotherapy, but patients have been reported to respond rapidly to rituximab and recover completely [4].
79% (30/38) of patients with anti-LGI1 antibody-associated encephalitis had a significant response to immunotherapy, and most patients had a recurrence rate of 35% and a 2-year case fatality rate of 19%
in the later stage (> 2 years).
.
Common clinical manifestations of anti-Caspr2 antibody encephalitis patients include neuropathic muscle rigidity, neuropathic pain, insomnia and other symptoms
.
The study showed that most patients received immunotherapy, 85.
7% of patients received first-line immunotherapy, of which 61.
9% received steroid therapy, 38.
1% received IVIg therapy, and 14.
3% received plasma exchange therapy; Second-line immunotherapy is used in 28.
6 percent of patients, including rituximab, cyclophosphamide, mycophenolate mofetil, and cyclosporine [5].
Patients receiving immunotherapy recovered well
.
In general, the number of anti-Caspr2 antibody encephalitis cases currently known is still small and needs to be studied in depth
.
.
Up to 80% of patients with anti-GABABR antibody encephalitis detect tumors, especially small cell lung cancer
.
The study showed that most patients with this disease received immunotherapy, and 79.
1% of patients received first-line immunotherapy, including steroid therapy (64.
2%), IVIg therapy (43.
3%), and plasma exchange (19.
4%)
。 Only a minority of patients received second-line immunotherapy such as rituximab (6.
0%), cyclophosphamide (4.
5%), mycophenolate mofetil (3.
0%), and azathioprine (1.
5%)
。
Most patients who received immunotherapy showed significant improvement in symptoms, but no significant improvement in those who did not receive immunotherapy (P = 0.
005); In addition, 23.
1 percent of patients died after receiving immunotherapy, compared with three thirds of those who did not receive immunotherapy (three-thirds, 100 percent) [6].
Glucocorticoids: generally using glucocorticoid pulse therapy, methylprednisolone 1000mg/d, continuous intravenous drip for 3d, and then changed to 500mg/d, intravenous drip for 3d
.
Then the dose can be reduced to 40~80mg/d, intravenous drip for 2 weeks; or change to oral prednisone acetate 1mg/(kg·d) for 2 weeks (or oral methylprednisolone, according to 5mg prednisone acetate = 4mg methylprednisolone); After that, 5 mg
is reduced every 2 weeks.
For mild cases, oral hormones
can be used directly without shock therapy.
The total course of oral hormones is generally 6 months
.
In the process of stopping hormones, it is necessary to assess the activity of encephalitis, pay attention to fluctuations and recurrence
of the disease.
2.
IVIg: According to the patient's body weight, according to the total amount of 2g/kg, divided into 3~5d intravenous drip
.
For critically ill patients, it is recommended to use IVIg in combination with hormones, and IVIg
can be repeated every 2~4 weeks.
Repeated or multiple rounds of IVIg are indicated for patients with severe AEs and patients
with recurrent AEs.
3.
Plasma exchange: For patients with severe AE who are positive for serum antibodies, plasma exchange
can be considered.
Among them, immunosorbent is a special therapeutic plasma exchange technique that specifically adsorbs and removes pathogenic antibodies
from the blood through the adsorption column.
Plasma exchange can be used
in combination with hormones.
If IVIg is used concomitantly, plasma exchange should be given before IVIg therapy
.
4.
Rituximab: the conventional scheme is 375mg/m2 (body surface area) intravenous drip, once a week, a total of 3~4 times
.
The tapering regimen is 600 mg (100 mg intravenously on day 1 and 500 mg intravenously on day 2) or 400 mg (100 mg once a week for 4 doses).
If there is no significant response to first-line therapy, rituximab
may be considered for about 2 weeks thereafter.
5.
Intravenous injection of cyclophosphamide: according to 750mg/m2, dissolved in 100ml of normal saline, intravenous drip, time more than 1h, once every 4 weeks
.
Discontinue
after 6 consecutive applications or after remission.
6.
Mycophenolate mofetil: conventional oral dose of 1000~2000mg/d, divided into 2~3 oral administrations, at least 1 year
.
The dose of induction period can be used to 2500~3000mg/d; Dynamic detection of peripheral hemolymphocyte subsets with IgG levels contributes to the individualization
of dose.
Mainly used in patients with relapse; It can also be used as an add-on immunotherapy
for refractory AEs.
The drug has a high risk of teratogenicity, and pregnant women should use
it with caution.
7.
Azathioprine: oral dose of 100mg/d, at least 1 year
.
For the prevention of relapse
.
8.
Tocilizumab: mainly used in patients with refractory severe AE.
According to the patient's body weight, 8 mg/kg intravenous infusion, once every
4 weeks.
For patients with a high risk of adverse reactions such as infection, a dose reduction regimen (2~6mg/kg)
can be used as appropriate.
9.
Intrathecal injection of methotrexate: use methotrexate 10mg (instructions for use of intrathecal injection of products, diluted into 10ml with normal saline) and dexamethasone sodium phosphate injection 10mg (2ml), once a week, 3~4 weeks
in a row.
During the treatment cycle, it is necessary to closely monitor the neurological symptoms and signs of patients, and pay attention to adverse reactions
such as acute chemical arachnoiditis, spinal radiculopathy, and leukoencephalopathy.
10.
Bortezomib: 21d per course of treatment, a single dose of 1.
3mg/m 2 subcutaneous injection, injection 2 times a week, continuous injection for2 weeks (that is, injection on days 1, 4, 8, 11), and then stop for 10d (i.
e.
from day 12 to day 21).
Each time in combination with dexamethasone 20 mg
.
Generally, 1~6 courses
are used.
11.
Low-dose interleukin-2 (IL-2): no domestic use has been reported
.
The course of treatment lasts 9 weeks
.
Week 1: 1.
5 million IU/d subcutaneously for 5 days; Week 3: 3 million IU/d subcutaneously for 5 days; Week 6 and Week 9 usage is the same
as week 3.
Where can I see more neurological medication knowledge?
Come to the "Doctor Station" and take a look 👇
Consensus summary, fast collection!
Autoimmune encephalitis (AE) is an autoimmune-mediated neurological disease produced by the action of antineuronal antibodies, with clinical manifestations of impaired consciousness, memory deficits, behavioral disorders, and seizures, and some patients are associated with
tumorigenesis.
Immunotherapy is an important measure of AE therapy, and patients with AE associated with neuronal surface antibodies are usually more likely to respond
to immunotherapy.
This article summarizes the progress of drug treatment of AE in conjunction with the Expert Consensus on the Diagnosis and Treatment of Autoimmune Encephalitis in China (2022 Edition) [1], which is used for reference
in clinical treatment.
Note: N-methyl-D-aspartate receptor (NMDAR), leucine-rich glioma inactivated 1 protein (LGI1), contact protein-associated protein 2 (Caspr2), γ-GABABR B receptor.
01
Anti-NMDAR antibody encephalitis
children and young adults.
Patients with this disease are usually hospitalized with mental behavior abnormalities, and if properly treated, they can be cured without sequelae, and their prognosis depends on early diagnosis and treatment
.
Early treatment (less than 1 month) is an important factor in a good prognosis, and the use of immunotherapy in the early onset of encephalitis is associated
with lower recurrence rates.
Studies have shown that 94% (472/501) of patients receive first-line immunotherapy clinically, 84% (421/501) of patients take steroids, and 69% (346/501).
patients received intravenous immunoglobulin (IVIg), and 40% of patients used both steroids and IVIg (202/501); About one third of patients receive second-line immunotherapy, including rituximab (101/501, 20%), cyclophosphamide (81/501, 16%), and other immunotherapies (azathioprine, methotrexate, or tacrolimus).
[2]
。
Symptomatic treatment of this condition usually focuses on sedation and improving the sleep-wake cycle, but it should be noted that patients taking antipsychotics have a high
incidence of adverse events.
02
Anti-LGI1 antibody-associated limbic system encephalitis
.
Studies have shown that about 97% (42/43) of patients with this disease received immunotherapy at the first onset of the disease, and first-line immunotherapy drugs include steroids, IVIg; Rarely, second-line immunotherapies such as rituximab, cyclophosphamide, mycophenolate mofetil, azathioprine, and tacrolimus
are used.
Patients initially treated with both steroids and IVIg have a better prognosis and a higher recovery rate than those initially treated with steroids alone [3].
There are no large-scale clinical studies of second-line immunotherapy, but patients have been reported to respond rapidly to rituximab and recover completely [4].
79% (30/38) of patients with anti-LGI1 antibody-associated encephalitis had a significant response to immunotherapy, and most patients had a recurrence rate of 35% and a 2-year case fatality rate of 19%
in the later stage (> 2 years).
03
Anti-Caspr2 antibody encephalitis
.
Common clinical manifestations of anti-Caspr2 antibody encephalitis patients include neuropathic muscle rigidity, neuropathic pain, insomnia and other symptoms
.
The study showed that most patients received immunotherapy, 85.
7% of patients received first-line immunotherapy, of which 61.
9% received steroid therapy, 38.
1% received IVIg therapy, and 14.
3% received plasma exchange therapy; Second-line immunotherapy is used in 28.
6 percent of patients, including rituximab, cyclophosphamide, mycophenolate mofetil, and cyclosporine [5].
Patients receiving immunotherapy recovered well
.
In general, the number of anti-Caspr2 antibody encephalitis cases currently known is still small and needs to be studied in depth
.
04
ANTI-GABABR ENCEPHALITIS
.
Up to 80% of patients with anti-GABABR antibody encephalitis detect tumors, especially small cell lung cancer
.
The study showed that most patients with this disease received immunotherapy, and 79.
1% of patients received first-line immunotherapy, including steroid therapy (64.
2%), IVIg therapy (43.
3%), and plasma exchange (19.
4%)
。 Only a minority of patients received second-line immunotherapy such as rituximab (6.
0%), cyclophosphamide (4.
5%), mycophenolate mofetil (3.
0%), and azathioprine (1.
5%)
。
Most patients who received immunotherapy showed significant improvement in symptoms, but no significant improvement in those who did not receive immunotherapy (P = 0.
005); In addition, 23.
1 percent of patients died after receiving immunotherapy, compared with three thirds of those who did not receive immunotherapy (three-thirds, 100 percent) [6].
05
Expert consensus [1] recommends specific drug regimens for the treatment of AEs
1.
Glucocorticoids: generally using glucocorticoid pulse therapy, methylprednisolone 1000mg/d, continuous intravenous drip for 3d, and then changed to 500mg/d, intravenous drip for 3d
.
Then the dose can be reduced to 40~80mg/d, intravenous drip for 2 weeks; or change to oral prednisone acetate 1mg/(kg·d) for 2 weeks (or oral methylprednisolone, according to 5mg prednisone acetate = 4mg methylprednisolone); After that, 5 mg
is reduced every 2 weeks.
For mild cases, oral hormones
can be used directly without shock therapy.
The total course of oral hormones is generally 6 months
.
In the process of stopping hormones, it is necessary to assess the activity of encephalitis, pay attention to fluctuations and recurrence
of the disease.
2.
IVIg: According to the patient's body weight, according to the total amount of 2g/kg, divided into 3~5d intravenous drip
.
For critically ill patients, it is recommended to use IVIg in combination with hormones, and IVIg
can be repeated every 2~4 weeks.
Repeated or multiple rounds of IVIg are indicated for patients with severe AEs and patients
with recurrent AEs.
3.
Plasma exchange: For patients with severe AE who are positive for serum antibodies, plasma exchange
can be considered.
Among them, immunosorbent is a special therapeutic plasma exchange technique that specifically adsorbs and removes pathogenic antibodies
from the blood through the adsorption column.
Plasma exchange can be used
in combination with hormones.
If IVIg is used concomitantly, plasma exchange should be given before IVIg therapy
.
4.
Rituximab: the conventional scheme is 375mg/m2 (body surface area) intravenous drip, once a week, a total of 3~4 times
.
The tapering regimen is 600 mg (100 mg intravenously on day 1 and 500 mg intravenously on day 2) or 400 mg (100 mg once a week for 4 doses).
If there is no significant response to first-line therapy, rituximab
may be considered for about 2 weeks thereafter.
5.
Intravenous injection of cyclophosphamide: according to 750mg/m2, dissolved in 100ml of normal saline, intravenous drip, time more than 1h, once every 4 weeks
.
Discontinue
after 6 consecutive applications or after remission.
6.
Mycophenolate mofetil: conventional oral dose of 1000~2000mg/d, divided into 2~3 oral administrations, at least 1 year
.
The dose of induction period can be used to 2500~3000mg/d; Dynamic detection of peripheral hemolymphocyte subsets with IgG levels contributes to the individualization
of dose.
Mainly used in patients with relapse; It can also be used as an add-on immunotherapy
for refractory AEs.
The drug has a high risk of teratogenicity, and pregnant women should use
it with caution.
7.
Azathioprine: oral dose of 100mg/d, at least 1 year
.
For the prevention of relapse
.
8.
Tocilizumab: mainly used in patients with refractory severe AE.
According to the patient's body weight, 8 mg/kg intravenous infusion, once every
4 weeks.
For patients with a high risk of adverse reactions such as infection, a dose reduction regimen (2~6mg/kg)
can be used as appropriate.
9.
Intrathecal injection of methotrexate: use methotrexate 10mg (instructions for use of intrathecal injection of products, diluted into 10ml with normal saline) and dexamethasone sodium phosphate injection 10mg (2ml), once a week, 3~4 weeks
in a row.
During the treatment cycle, it is necessary to closely monitor the neurological symptoms and signs of patients, and pay attention to adverse reactions
such as acute chemical arachnoiditis, spinal radiculopathy, and leukoencephalopathy.
10.
Bortezomib: 21d per course of treatment, a single dose of 1.
3mg/m 2 subcutaneous injection, injection 2 times a week, continuous injection for2 weeks (that is, injection on days 1, 4, 8, 11), and then stop for 10d (i.
e.
from day 12 to day 21).
Each time in combination with dexamethasone 20 mg
.
Generally, 1~6 courses
are used.
11.
Low-dose interleukin-2 (IL-2): no domestic use has been reported
.
The course of treatment lasts 9 weeks
.
Week 1: 1.
5 million IU/d subcutaneously for 5 days; Week 3: 3 million IU/d subcutaneously for 5 days; Week 6 and Week 9 usage is the same
as week 3.
References
[1] Neuroinfectious Diseases and Cerebrospinal Fluid Cytology Group, Neurology Branch of Chinese Medical Association.
Expert consensus on diagnosis and treatment of autoimmune encephalitis in China(2022 edition)[J].
Chinese Journal of Neurology2022,55(9):931-949.
)
[2] Titulaer MJ，McCracken L，Gabilondo I，et al.
Treatment and prognostic factors for long-term outcome in patients with anti-NMDA receptor encephalitis:An observational cohort study[J].
Lancet Neurol，2013，12（2）:157-165.
[3] Shin YW，Lee ST，Shin JW，et al.
VGKC-complex/LGI1-antibody encephalitis:Clinical manifestations and response to immunotherapy[J].
J Neuroimmunol，2013，265（1-2）:75-81.
[4] Markovic I，Basic S，Devedjija S.
Aggressive anti-LGI1 encephalitis defeated by one cycle of intravenous rituximab-A case report[J].
Neurol Sci，2020，41（7）:1949-1950.
[5] MAO Ningning, ZHANG Qiaoman, WANG Chengze, et al.
Clinical analysis of 13 cases of anti-contact protein-associated protein-2 antibody positive autoimmune encephalitis[J].
Chinese Journal of Practical Diagnosis and Therapy,2021,35(6):618-620.
)
[6] Zeng W，Cao L，Zheng J，et al.
Clinical characteristics and long-term follow-up of seven cases of antiGABABR encephalitis in patients of Han Chinese descent[J].
Neurol Sci，2020，41（2）:373-378.
Where can I see more neurological medication knowledge?
Come to the "Doctor Station" and take a look 👇
