Brazilian consensus recommendations on the diagnosis and treatment of autoimmune encephalitis in the adult and pediatric populations

Dutra, Lívia Almeida; Silva, Pedro Victor de Castro; Ferreira, João Henrique Fregadolli; Marques, Alexandre Coelho; Toso, Fabio Fieni; Vasconcelos, Claudia Cristina Ferreira; Brum, Doralina Guimarães; Pereira, Samira Luisa dos Apóstolos; Adoni, Tarso; Rocha, Leticia Januzi de Almeida; Sampaio, Leticia Pereira de Brito; Sousa, Nise Alessandra de Carvalho; Paolilo, Renata Barbosa; Pizzol, Angélica Dal; Costa, Bruna Klein da; Disserol, Caio César Diniz; Pupe, Camila; Valle, Daniel Almeida do; Diniz, Denise Sisterolli; Abrantes, Fabiano Ferreira de; Schmidt, Felipe da Rocha; Cendes, Fernando; Oliveira, Francisco Tomaz Meneses de; Martins, Gabriela Joca; Silva, Guilherme Diogo; Lin, Katia; Pinto, Lécio Figueira; Santos, Mara Lúcia Schimtz Ferreira; Gonçalves, Marcus Vinícius Magno; Krueger, Mariana Braatz; Haziot, Michel Elyas Jung; Barsottini, Orlando Graziani Povoas; Nascimento, Osvaldo José Moreira do; Nóbrega, Paulo Ribeiro; Proveti, Priscilla Mara; Castilhos, Raphael Machado do; Daccach, Vanessa; Glehn, Felipe von

doi:10.1055/s-0044-1788586

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Brazilian Academy of Neurology • Arq. Neuro-Psiquiatr. 82 (7) • 2024 • https://doi.org/10.1055/s-0044-1788586 linkcopy

Brazilian consensus recommendations on the diagnosis and treatment of autoimmune encephalitis in the adult and pediatric populations

Consenso brasileiro sobre o diagnóstico e o tratamento de encefalites autoimunes nas populações adulta e pediátrica

Authorship SCIMAGO INSTITUTIONS RANKINGS

Abstract

Background Autoimmune encephalitis (AIE) is a group of inflammatory diseases characterized by the presence of antibodies against neuronal and glial antigens, leading to subacute psychiatric symptoms, memory complaints, and movement disorders. The patients are predominantly young, and delays in treatment are associated with worse prognosis.

Objective With the support of the Brazilian Academy of Neurology (Academia Brasileira de Neurologia, ABN) and the Brazilian Society of Child Neurology (Sociedade Brasileira de Neurologia Infantil, SBNI), a consensus on the diagnosis and treatment of AIE in Brazil was developed using the Delphi method.

Methods A total of 25 panelists, including adult and child neurologists, participated in the study.

Results The panelists agreed that patients fulfilling criteria for possible AIE should be screened for antineuronal antibodies in the serum and cerebrospinal fluid (CSF) using the tissue-based assay (TBA) and cell-based assay (CBA) techniques. Children should also be screened for anti-myelin oligodendrocyte glucoprotein antibodies (anti-MOG). Treatment should be started within the first 4 weeks of symptoms. The first-line option is methylprednisolone plus intravenous immunoglobulin (IVIG) or plasmapheresis, the second-line includes rituximab and/or cyclophosphamide, while third-line treatment options are bortezomib and tocilizumab. Most seizures in AIE are symptomatic, and antiseizure medications may be weaned after the acute stage. In anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis, the panelists have agreed that oral immunosuppressant agents should not be used. Patients should be evaluated at the acute and postacute stages using functional and cognitive scales, such as the Mini-Mental State Examination (MMSE), the Montreal Cognitive Assessment (MoCA), the Modified Rankin Scale (mRS), and the Clinical Assessment Scale in Autoimmune Encephalitis (CASE).

Conclusion The present study provides tangible evidence for the effective management of AIE patients within the Brazilian healthcare system.

Keywords
Autoimmune Encephalitis; Anti-N-Methyl-D-Aspartate Receptor Encephalitis; Delphi Technique; Rituximab; Tocilizumab

Diagnostic criteria for possible autoimmune encephalitis in adults (all three of following criteria met):
Subacute onset (rapid progression in fewer than than three months) of working memory deficits (short-term memory loss), altered mental status (decreased level of consciousness, lethargy or personality changes), or psychiatric symptoms At least one of the following: New focal CNS findings Seizures not explained by a previously-known seizure disorder CSF pleocytosis MRI suggestive of encephalitis Reasonable exclusion of alternative causes.
Diagnostic criteria for possible autoimmune encephalitis in the pediatric population (all three of following criteria met):
Onset of neurologic and/or psychiatric symptoms over ≤ 3 months in a previously-healthy child. Two of the following: Altered mental status/level of consciousness, or EEG with slowing or epileptiform activity (focal or generalized) Focal neurologic deficits Cognitive difficulties Acute developmental regression Movement disorder (except tics) Psychiatric symptoms Seizures not explained by a previously-known seizure disorder or other condition Reasonable exclusion of alternative causes, including other causes of CNS inflammation.

Statement		% Agree (n)
1. AIE should be suspected in patients with acute or subacute (< 3 months) onset of focal or diffuse neurological symptoms, psychiatric symptoms, epileptic seizures, movement disorders, or dysautonomia.		100% (25)
2. In adults, the definition of possible AIE follows the criteria proposed by Graus et al., 2016.¹⁰		100% (25)
3. In adults, the definition of probable seronegative AIE follows the criteria proposed by Graus et al.¹⁰.		96% (25)
4. In children, the definition of possible AIE follows the criteria review proposed by Cellucci et al., 2020.¹¹		100% (25)
5. The definition of definite AIE follows the criteria proposed by Graus et al.¹⁰		100% (25)
6. The definition of autoimmune limbic encephalitis follows the criteria proposed by Graus et al.¹⁰		96% (25)
7. All patients meeting the criteria for possible AIE should be tested for autoantibodies in paired serum and CSF samples.		84% (25)
8. In cases of suspected AIE, patients should be investigated with:	Brain MRI	100% (25)
	EEG	96% (25)
	OCBs (in the CSF)	88% (25)
	IgG Index (in the CSF)	84% (25)
	PCR for herpesvirus (in the CSF)	92% (25)
9. The following findings on brain MRI are suggestive of AIE: hyperintensities on T2 and FLAIR sequences restricted to the medial temporal lobe, either unilateral or bilateral; multifocal involvement of white and/or gray matter that is suggestive of demyelination or inflammation.		92% (25)
10. The search for antineuronal antibodies should be performed using the TBA and CBA methodologies.		96% (25)
11. For the detection of anti-MOG and anti-glycine antibodies, the CBA technique should be used.		96% (25)
12. Laboratory findings that should be interpreted with caution	Low titers of anti-GAD anti-GAD antibodies in the serum.	100% (24)
	Anti-TPO antibodies at any titer.	96% (25)
	Low titers of antibodies detected by other methodologies (such as radioimmunoassay).	96% (25)
	Exclusive presence of anti-NMDAR antibodies in the serum.	100% (25)
	Low titers of anti-CASPR-2 antibodies.	87% (23)
13. The detection of antibodies solely in the serum should be interpreted with caution. The determination of pathogenicity should consider the specific antibody detected, the clinical presentation, and discussion with experts in AIE.		100% (25)
14. Antibodies against the VGKC complex should not be requested.		65% (23)
14a. Antibodies against the VGKC complex should not be requested in the investigation of AIE		92% (24)
15. Anti-MOG testing should be requested in children with suspected autoimmune encephalitis, regardless of the findings on brain MRI.		84% (25)

Statement	% agree (n)
1. Treatment should be initiated for patients with criteria for possible or definite AIE.	96% (25)
2. The collection of paired serum and CSF samples for diagnosis should be performed before initiating treatment.	96% (25)
3. Treatment should be considered for patients who meet the criteria for possible AIE following HSV (types 1 and 2) encephalitis.	92% (24)
4. The first-line treatment should preferably be the combination of MP and IVIG or MP and PLX.	100% (25)
5. MP can be administered concomitantly with PLX.	100% (25)
6. IVIG can be prescribed concomitantly with MP.	100% (25)
7. The choice between the combination of MP and PLX or IGIV should be made based on the availability and experience of the attending medical team.	96% (25)
8. In my practice, PLX would be considered the first therapeutic option in the following clinical manifestations: need for ICU admission; autonomic dysfunction; status epilepticus; and rapid progression to severe disease nadir.	52% (25) 52% (25) 68% (25) 72% (25)
9. The second-line treatment should be initiated after 10 to 14 days of the start of the initial treatment if there is no satisfactory clinical response.	88% (25)
10. Satisfactory clinical response is defined as clinical and/or functional improvement within a period of 10 to 14 days after initiating treatment.	96% (25)
11. Treatment response should be monitored using parameters such as seizure control, cognitive symptoms, psychiatric symptoms, level of consciousness, movement disorders, gait and coordination, signs of brainstem dysfunction, and muscle weakness. Currently, there is no structured tool to quantify treatment response.	100% (25)
12. In my clinical practice, if maintenance treatment with immunosuppressive drugs is prescribed, it can be performed with: monthly IVIG infusions; oral corticosteroids; azathioprine; mycophenolate mofetil; and rituximab.	72% (25) 60% (25) 68% (25) 63% (24) 92% (24)
13. The options for second-line treatment are rituximab alone or in combination with cyclophosphamide.	80% (25)
14. The use of rituximab in AIE is associated with improved functional outcomes and lower recurrence rates.	92% (25)
15. The use of cyclophosphamide is indicated for patients older than 16 years of age in cases of refractory AIE, contraindication to or unavailability of rituximab.	96% (25)
16. The options for third-line treatment include tocilizumab and bortezomib.	88% (24)
17. Patients with AIE should not receive long-term immunosuppression (> 6 months) with azathioprine, corticosteroids, methotrexate, or mycophenolate.	36% (25)
32a. As a routine practice, patients with AIE should not receive immunosuppression with azathioprine or mycophenolate, especially in cases of anti-NMDAR encephalitis.	100% (24)
18. AEDs should only be prescribed if the patient presents with epileptic seizures.	92% (25)
19. AEDs should be withdrawn after the treatment of the acute stage, considering the low risk of developing autoimmune epilepsy.	52% (25)
34a. In general, patients with AIE may present with symptomatic epileptic seizures, but most of them do not develop epilepsy in the long term.	100% (23)
20. The drugs of choice for hyperkinetic movements are: benzodiazepines; anticholinergics; valproate; and neuroleptics.	92% (25) 32% (25) 68% (25) 56% (25)
21. The use of neuroleptics should be rationalized due to the potential risk of developing neuroleptic malignant syndrome.	100% (25)
22. Refractory cases of movement disorders that pose a risk to patient care can be managed with propofol, midazolam, or tetrabenazine. After the acute stage, medications should be tapered and discontinued.	88% (25)
23. For symptomatic treatment of Morvan syndrome (peripheral hyperexcitability) the following drugs can be used: Carbamazepine; and Phenytoin.	96% (23) 75% (24)
24. The principles of the treatment for relapses should be similar to those used for the initial manifestation of AIE.	92% (25)

First-line options	Dose/mode of administration
IVIG	2 g/kg for 2–5 days.
IV methylprednisolone	Children: 20–30 mg/kg/day (maximum: 1 g/day) for 3–5 days. Adults: 1,000 mg for 3–5 days.
Plasmapheresis	5–7 sessions over 7–14 days.
Second-line options	Dose/mode of administration
IV rituximab	The following doses are acceptable: 500–1,000 mg (500 mg for < 40 kg, 1,000 mg for > 40 kg) given twice and separated by 2 weeks, or 750 mg/m² (maximum: 1 g), given twice and separated by 2 weeks, or 375 mg/m² (maximum: 1 g) weekly for 4 weeks.
IV cyclophosphamide	500–1,000 mg/m² (maximum: 1,500 mg) monthly pulses.
Third-line options	Dose/mode of administration
IV tocilizumab	Children: 12 mg/kg/dose for < 30 kg, 8 mg/kg/dose for > 30 kg (maximum: 800 mg). Adults: 8 mg/kg/dose (maximum: 800 mg), given monthly.
SC bortezomib	Three cycles of 21 days, each one composed of 1.3 mg/m² on days 1, 4, 8 and 11.

Statement	% agree (N)
1. Screening for neoplasia should be performed in all patients with AIE at the time of clinical presentation.	100% (25)
2. Paraneoplastic screening should be individualized according to the specific antibody identified and its association with neoplasms.	80% (25)
3. In cases of AIE with antibodies frequently associated with neoplasms, screening should be performed every 12 months for 4 years.	76% (25)
4. The initial screening for neoplasms should include contrast-enhanced CT scans of the chest, abdomen, and pelvis. If CT is contraindicated, consider using MRI as an alternative.	92% (25)
5. Children and adults with a typical clinical syndrome of anti-NMDAR antibody encephalitis should be specifically investigated for teratoma using ovarian/testicular ultrasound or abdominal and pelvic MRI.	100% (25)
6. Whole-body FDG-PET can be requested when the initial CT scan is negative or inconclusive.	84% (25)
7. The prognosis is associated with treatment within the first 4 weeks of symptom onset.	92% (25)
8. During follow-up consultations for patients with AIE, it is important to evaluate cognition, psychiatric/behavioral symptoms, frequency of epileptic seizures, presence of abnormal movements, gait and coordination abnormalities, muscle weakness, presence of dysautonomia, and symptoms suggestive of brainstem dysfunction (such as ophthalmoparesis and dysphagia).	100% (25)
9. The performance cognitive screening tests at least semi-annually for ongoing monitoring and assessment of cognitive function is recommended.	92% (25)
10. Cognitive monitoring can be performed using the MoCA scale in adults.	78% (23)
11. Cognitive monitoring can be performed using the MMSE scale in adults.	61% (23)
50a. Cognitive monitoring can be performed using the MMSE scale in adults, considering the limitations of this assessment in cognitive domains such as memory and executive function.	79% (23)
12. Serial measurement of antibody titers is not indicated as a prognostic factor or as an indicator for second-line treatment or maintenance therapy.	92% (25)
13. In cases of anti-MOG-associated encephalitis, antibody titers should be monitored.	52% (25)
52a. In cases of encephalitis associated with anti-MOG antibodies, monitoring of anti-MOG titers can be useful, although there is no clearly-defined clinical relevance.	95.8% (24)

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[TFN1] Abbreviations: CNS, central nervous system; CSF, cerebrospinal fluid; EEG, electroencephalogram; MRI, magnetic resonance imaging.

[TFN2] Note: Adapted from Graus et al.¹⁰ (2016) and Cellucci et al.¹¹ (2020).