Anti-NMDA Receptor Autoimmune Encephalitis: Diagnosis and Management Strategies

Figures & data

Table 1 Summary of Clinical Characteristics, Ancillary Testing, Treatments and Outcomes in Studies with Large Cohort (>200) of Anti-NMDAR Encephalitis Patients

	Titulaer et al (n=577)^Citation9	Xu et al (n=220)^Citation10	Gong et al (n=244)^Citation11	Guang et al (n=386)^Citation19
Location	Individuals seen at University of Pennsylvania (USA) and University of Barcelona (Spain) or whose samples were sent to these institutions (from 200 centers in 35 countries)	Individuals seen at Peking Union Medical College Hospital (China)	Individuals seen at West China Hospital (China)	Pediatric patients seen at Xiangya Hospital of Central South University, Children’s Hospital of Chongqing Medical University, Peking University First Hospital, Beijing Children’s Hospital, Children’s Hospital of Fudan University, and Capital Institute of Pediatrics (China)
Years of study	2007–2012	2011–2017	2011–2019	2011–2018
Age (median, years)	21 (range 9 months to 85 years)	21 (range 5–72)	26 (IQR 9–78)	8.00 (IQR 4.83–10.90)
Age <18	–	15 (range 5–17) (n=69)	16 (IQR 9–18) (n=43)	–
Age ≥18	–	26 (range 18–72) (n=151)	29 (IQR 19–78) (n=201)	–
Female gender	468 (81.1%)	143 (65.0%)	128 (54.5%)	224 (58.0%)
Admission to ICU	435 (75.4%)	68 (30.9%)	35 (14.3%)	57 (14.8%)
Abnormal MRI	180 (33.3%) (n=540)	79 (35.9%)	104 (42.6%)	190 (49.2%)
Abnormal EEG	432 (89.6%) (n=482)	113 (51.4%)	188 (77.0%)	306 (79.3%)
Slow activity	398 (82.6%) (n=482)	102 (46.4%)	178 (73.0%)	–
Epileptic discharges	115 (23.9%) (n=482)	14 (6.4%)	52 (21.3%)	–
Abnormal CSF	418 (78.6%) (n=532)	–	–	183 (47.4%)
Pleocytosis	402 (75.6%) (n=532)^a	52 (81.3%) (n=64)^a	124 (50.8%)^d	–
Elevated protein	93 (17.5%) (n=532)^a	19 (29.7%) (n=64)^b	66 (27.1%)^a	–
Positive oligoclonal bands	–	16 (25.0%) (n=64)^c	–	–
Elevated opening pressure	–		64 (26.2%)^a	–
Tumor	220 (38.1%), with 207 being ovarian teratomas	43 (19.5%), with 42 being ovarian teratomas	38 (15.6%), with 26 being ovarian teratomas	4 (1.0%), with 2 with teratoma
Time from onset until treatment (median)	21 (IQR 14–46) days	2 (IQR 1–4) weeks	29 (range 6–82) days	–
Length of hospital stay (median, days)	26 (IQR 14–42)	26 (IQR 14–42)	24 (IQR 16–30) females, 22 (IQR 13–30) males	–
First-line treatment	462 (92.2%) (n=501)	219 (99.5%)	234 (95.9%)	386 (100.0%)
Steroids	421 (84.0%) (n=501), with 202 in combination with IVIG	208 (94.5%), of whom 103 received IV methylprednisolone	163 (66.8%), with 125 in combination with IVIG	15 (3.9%) steroids only, 341 (88.3%) in combination with IVIG and 18 (4.7%) in combination with PLEX
IVIG	346 (69.1%) (n=501), with 202 in combination with steroids	199 (90.5%)	205 (84.0%), with 125 in combination with steroids	10 (2.6%) IVIG only, 341 (88.3%) in combination with steroids
PLEX	163 (32.5%) (n=501)	7 (3.2%)	–	18 (4.7%)
Second-line treatment	134 (26.7%) (n=501)	16 (7.3%)	22 (9.0%) used second-line treatment and/or plasma exchange	73 (18.9%), including 16 who had repeated first-line treatments
Rituximab	101 (20.2%) (n=501)	12 (5.5%)	–	–
Cyclophosphamide	81 (16.2%) (n=501)	4 (1.8%)	–	–
Other immunotherapy	31 (6.2%) (n=501)	–	–	–
Mycophenolate mofetil	–	109 (49.5%), with 55 given at onset and 54 given at relapse	–	16 (4.1%)
Azathioprine	–	8 (3.6%)	–	3 (0.8%)
Intrathecal methotrexate	–	8 (3.6%)	–	–
Poor response to treatment at week four	221 (46.8%) (n=472)	16 (7.3%)	37 (15.2%)	–
Mortality	30 (6.0%) (n=501)	5 (2.3%)	17 (7.0%)	6 (1.6%) (n=381)
mRS 0 at follow up	–	144 (65.5%) at 12 months	–	270 (71.9%) (n=381)
mRS ≤2 at follow up	203 (80.6%) (n=252) at 24 months	204 (92.7%) at 12 months	197 (80.7%) at 12 months 209 (85.7%) at 24 months	360 (94.5%)
Relapse at follow up	45 (12.2%) (n=367) had relapse within 24 months	80 (36.4%) had relapse, with 38 within 12 months and 64 within 24 months.	39 (15.9%) had relapse, with 32 within 24 months.	27 (7.0%)

Notes: ^aAbnormal threshold not specified in paper. ^bProtein ≥ 45 g/L. ^c≥ 1 unique CSF oligoclonal bands. ^d> 5 cells/mm³. IQR, interquartile range. ICU, intensive care unit. IVIG, intravenous immunoglobulin. PLEX, plasma exchange. mRS, modified Rankin Scale.

Table 2 Summary of Treatment Options

Treatment	Type of Use	Mechanism of Action	Side Effects	Regimen
IV methylprednisolone	First-line immunotherapy	Bind to intracellular glucocorticoid receptors and suppress transcription of multiple proinflammatory genes (eg, cytokines, chemokines) Affect synthesis of anti-inflammatory proteins Reduce T-cell circulation and Th1 differentiation Restore blood brain barrier integrity and control brain edema	Insomnia, agitation, hypertension, hyperglycemia, gastrointestinal ulceration/bleed, increased appetite, weight gain, cushingoid features, reactive leukocytosis, cataracts, increased infection risk, osteoporosis, delayed wound healing, avascular necrosis	30 mg/kg (max 1000 mg, divided over 1–2 doses) for 3–5 days
Oral prednisone	First-line immunotherapy: taper after IV steroids Prolonged first-line immunotherapy			2 mg/kg/d (max 60 mg/day) for 1 week, then gradually taper
IVIG	First-line immunotherapy	Neutralize autoantibody Affect complement system by solubilization and clearance of immune complex deposits and/or inhibition of binding of activated complement components^Citation44 Block activating FcγRs and/or upregulate inhibitory FcγRIIB on innate immune cells and reduce their immune complex-mediated activation^Citation30,Citation31 Saturate neonatal Fc receptor, a homeostatic regulator of IgG catabolism, and increase clearance of endogenous IgG^Citation44 Inhibit the proliferation and antigen-presenting functions of B-cells^Citation44 Alter regulatory T-cells^Citation44	Flu-like symptoms, dermatological adverse effects (eg, urticaria, eczema, spot papules), arrhythmia and hypotension, headache, aseptic meningitis, renal impairment, thrombotic events, hemolysis, neutropenia, pulmonary edema	2 g/kg over 3–5 days
	Prolonged first-line immunotherapy			1–2 g/kg over 1–5 days, monthly
PLEX	First-line immunotherapy	Remove autoantibodies Remove cytokines Remove immune complexes with enhanced macrophage/monocyte function^Citation45 Alter immune system by changing lymphocyte numbers and their distribution, T-suppressor cell function, and T-helper cell phenotypes^Citation45 Increase proliferation of antibody-producing cells, sensitizing them to immunosuppressants^Citation45	Catheter related infections or complications, hypotension, electrolyte imbalance, perioral/sensory abnormalities and muscle cramps due to hypocalcemia, reduced serum coagulation factors leading to increased bleeding, pruritus and urticaria due to replacement fluid	1 session every other day for 5–7 cycles
Rituximab	Second-line immunotherapy	Deplete naïve and memory CD20+ B-cells through antibody-mediated cellular toxicity, complement activation, and induction of apoptosis^Citation46 Does not target long-lived mature plasma cells, so there will be prolonged presence of antibodies albeit at lower level^Citation46	Infusion reaction, increased infection risk, body aches, nausea, tiredness, cytopenia, hypogammaglobulinemia, reactivation of hepatitis B and tuberculosis	375 mg/m^2 (max 1000 mg) weekly IV infusion for 4 weeks 500–1000 mg (500 mg for <40 kg, 1000 mg for >40 kg) given twice separated by 2 weeks 375–750 mg/m^2 (max 1000 mg) given twice separated by 2 weeks
	Maintenance (> 6 months) immune suppression			Redose when repopulation of CD19 occurs or about 6 months after first course
Cyclophosphamide	Second-line immunotherapy	Alkylating agent that inhibits cell proliferation Suppress cell-mediated and humoral immunity through its actions on T-cells and B-cells	Myelotoxicity, increased infection risk, nausea, vomiting, alopecia, mucositis, agranulocytosis, infertility, hemorrhagic cystitis, increased risk of tumors (eg, bladder cancer, skin cancer, myeloid leukemia)	500–1000 mg/m2 (max 1500 mg) monthly pulses for 3–6 months
Tocilizumab	Escalation second-line	Bind to membrane bound and soluble IL-6 receptor, inhibiting IL-6 from binding to its receptors, leading to blockade of IL-6 mediated inflammatory cascade IL-6 is involved in inducing B-cell proliferation and differentiation into antibody-producing cells, differentiation of CD8+ cytotoxic T-cells, differentiation of naïve CD4+ helper T-cells into IL-17-producing T-helper cells, and inhibiting differentiation of those cells into regulatory T-cells, which all contribute to autoimmune tissue damage^Citation47	Increased infection risk, blunted fever response and C-reactive protein elevation, neutropenia, thrombocytopenia, elevated liver enzymes, hyperlipidemia	12 mg/kg/dose (<30 kg), 8 mg/kg/dose (≥30 kg) (max 800 mg) given monthly over 6 months or more
Bortezomib	Escalation second-line	Proteasome inhibitor that reduces plasma cell production	Increased infection risk, fever, gastrointestinal symptoms, headache, dizziness, paresthesia, neuralgia, fatigue, cytopenia, hypotension, dyspnea, herpes zoster and hepatitis B reactivation, rash, elevated liver enzymes, hypotension, injection site reaction, peripheral neuropathy, posterior reversible encephalopathy syndrome	Subcutaneous injections 0.3 mg/m^2 with 20 mg IV dexamethasone, twice weekly for 2 weeks (days 1, 4, 8, and 11), followed by a 10-day rest
Azathioprine	Maintenance (>6 months) immune suppression	Antagonist of purine synthesis and consequently DNA/RNA production for proliferation of white blood cells	Fever, malaise, myalgias, gastrointestinal symptoms, rash, infection, hypersensitivity reaction, cytopenia, myelotoxicity, increased infection risk, pancreatitis, elevated liver enzymes, increased risk of tumors (eg, lymphoma and skin cancers)	Initially 1–1.5 mg/kg once daily or divided twice daily, target 2–3 mg/kg/day
Mycophenolate mofetil	Maintenance (>6 months) immune suppression	Inhibitor of purine metabolism, mainly acting on lymphocytes	Gastrointestinal symptoms (nausea, diarrhea, abdominal cramps), hypertension, creatinine elevation, edema, teratogenicity, myelotoxicity, increased infection risk, increased risk of tumors (eg, lymphoma and skin cancers)	600 mg/m^2/dose (max 1000 mg) twice daily or initially 500 mg twice daily, target 1000 mg twice daily

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