long term treatment protocols of anti NMDAR and anti LGI1 receptor encephalitis.

1. LONG TERM TREATMENT PROTOCOL OF
ANTI-NMDA AND ANTI-LGI1 RECEPTOR
ENCEPHALITIS
Dr Sumeet Singh
Senior Resident Neurology
GMC, Kota

2. INTRODUCTION
Acute encephalitis - rapidly progressive encephalopathy(usually in <6 weeks)
caused by brain inflammation.
 Most frequently recognized causes of encephalitis are infectious.
 Past 10 years increasing number of non-infectious, mostly autoimmune
encephalitis cases identified
Diagnostic mimics of autoimmune encephalitis are far more prevalent than
autoimmune encephalitis, including toxic/metabolic encephalopathies, functional
neurological disorders, primary psychiatric disease, neurodegenerative disorders,
neoplasms, and epilepsy.

3. AUTOIMMUNE ENCEPHALITIS
Antibodies against intra cellular, neuronal cell-surface or synaptic
proteins.
Can resemble infectious encephalitis
Difficult clinical diagnosis - similarities in clinical, imaging and
laboratory findings of many forms of autoimmune and infectious
encephalitis
Vincent A, Bien CG, Irani SR, Waters P. Autoantibodies associated with diseases of the CNS: new developments and future
challenges. Lancet Neurol 2011; 10:759

4. CLUES TO AN AUTOIMMUNE ETIOLOGY
• Change in baseline neurologic function
• Subacute onset (days to weeks) & fluctuating course
• Systemic markers of autoimmunity : elevatedANAor TPO
antibodies
• History of or concurrent malignancy

5. CLUES TO AN AUTOIMMUNE ETIOLOGY
• CSF studies : elevated WBC (<100 cells/µl), protein
(<100mg/dl), Ig G index, oligoclonal bands.
• EEG : Focal abnormalities, epileptiform discharges, slowing,etc
• MRI : T2/FLAIR abnormalities in temporal lobes or other part of brain
• PET Brain : areas of hypo/hypermetabolism
• Response to immunosuppression
• Identification of a neural autoantibody

6. • Diagnosis of possible autoimmune encephalitis can be made when all three of the following
criteria have been met:
• 1 Subacute onset (rapid progression of less than 3 months) of working memory deficits (short-
term memory loss), altered mental status, and/or psychiatric symptoms
• 2 At least one of the following:
◇ New focal central nervous system findings
◇ Seizures not explained by a previously known seizure disorder
◇ CSF pleocytosis (white blood cell count of more than 5 cells/mm3)
◇ MRI features suggestive of encephalitis
• 3 Reasonable exclusion of alternative causes
Prüss H, Dalmau J, Harms L, et al. Retrospective analysis of NMDA receptor antibodies in encephalitis of unknown origin.
Neurology 2010; 75:1735.

7. • Diagnosis of definite autoimmune encephalitis can be made when all four of the following
criteria have been met:
• 1 Subacute onset (rapid progression of less than 3 months) of working memory deficits,
seizures, and/or psychiatric symptoms suggesting involvement of the limbic system
• 2 Bilateral brain abnormalities on T2-weighted FLAIR MRI highly restricted to the mesial
temporal lobes
• 3 At least one of the following:
 CSF pleocytosis (white blood cell count of more than 5 cells/mm)
 EEG with epileptic or slow-wave activity involving the temporal lobes
Antibody positivity in serum or CSF
• 4 Reasonable exclusion of alternative causes
Graus F, Titulaer MJ, Balu R, et al. A clinical approach to diagnosis of autoimmune encephalitis. Lancet Neurol 2016; 15:391.

8. Red Flags in Autoimmune Encephalitis Diagnosis
Clinical
• Insidious onset
• Multiplecomorbiditiesthatcausecognitivedeficitssuch as
polypharmacy, chronic pain, fibromyalgia, sleep disorders
• Examination results consistent witha functionalneurologic
disorder
• Featuresofmitochondrialdisease present
• Normalneuropsychologicaltest results
Magnetic Resonance Imaging of the Head
• Normal
• Progressive atrophywithoutsignalabnormalitiesor
enhancement
• Lesion(s)continuingtoexpanddespiteimmunotherapy
Cerebrospinal Fluid
• Noninflammatory

9. Serology
• TPO antibodies of anytiter
• Lowtiter–positive GAD65antibodies
• Voltage-gated potassium channel complex antibodies negative forLGI1/CASPR2
• Low-titer antibodypositives by oldergenerationtechniques (eg, RIA)
• IsolatedserumNMDARantibodynegativeinCSF
• Immunoblotorlineblotantibodypositivityinisolation
• Lowtiter positive–CASPR2 antibodies
• Antibodydetectioninnoncertifiedlaboratories
Abbreviations: CASPR2, contactin-associated protein-like 2;
CSF, cerebrospinal fluid; GAD65, glutamic acid decarboxylase 65;
LGI1, leucine-rich-glioma-inactivated-1; NMDAR, N-methyl-D-aspartate receptor; RIA, radioimmunoprecipitation assay;
TPO, thyroid peroxidase.

11. Anti-NMDAR Encephalitis

12. DIAGNOSTIC CRITERIA FOR ANTI-NMDA RECEPTORS
ENCEPHALITIS
Probable anti-NMDA receptor encephalitis
Diagnosis can be made when all three of the following criteria have been met
1. Sub acute onset (less than 3 months ) of at least 4 of the 6 major group of symptoms
• Abnormal (psychiatric) behaviour or cognitive dysfunctions
• Speech dysfunctions(pressured speech ,verbal reduction, mutism)
• Seizures
• Movement disorders , dyskinesis or rigidity/abnormal posture
• Decreased level of consciousness
• Autonomic dysfunction and central hypoventilation

13. 2. At least one of the following laboratory study results
• Abnormal EEG(focal pr diffuse slow or disorganised activity, epileptic activity or extreme delta
brush)
• CSF with pleocytosis or oligoclonal band
3.Reasonable exclusion of other disorders
• Diagnosis can also be made in the presence of 3 of the above group of symptoms
accompanied by systemic teratoma

14. Definite anti-NMDA receptor encephalitis
• Diagnosis can be made in the presence of 1 or more of the 6 major group of symptoms and
IgG anti-GluN1 antibodies( antibody testing must include CSF)
• If only serum is available confirmatory tests like tissue immunohistochemistry in addition to
cell based assay.
• Exclusion of recent history of Herpes simplex virus encephalitis or Japanese B encephalitis,
which might result in relapsing immune mediated neurological symptoms.
Dalmau J, Armangué T, Planagumà J, Radosevic M, Mannara F, Leypoldt F, Geis C, Lancaster E, Titulaer MJ,
Rosenfeld MR, Graus F. An update on anti-NMDA receptor encephalitis for neurologists and psychiatrists: mechanisms
and models. The Lancet Neurology. 2019 Nov 1;18(11):1045-57.

15. Anti-NMDAR (NR1) encephalitis
Dalmau J, Rosenfeld MR. Paraneoplastic syndromes of the CNS. Lancet Neurol 2008; 7:327.

16. Management of Anti-NMDAR Encephalitis
• The diagnosis of anti-NMDA receptor encephalitis is confirmed by the detection of IgG
antibodies to the GluN1 (also known as NR1) subunit of the NMDA receptor in CSF (serum is
less reliable)
• After treatment or in advanced stages of the disease, the CSF antibodies usually remain
elevated if there is no clinical improvement, while serum antibodies may be substantially
decreased by treatments
• The titer of CSF antibodies appears to correlate more closely with the clinical outcome than
serum titers
• Cerebrospinal fluid (CSF) lymphocytic pleocytosis or oligoclonal bands
• EEG with infrequent epileptic activity, but frequent slow, disorganized activity that does not
correlate with most abnormal movements
Titulaer MJ, McCracken L, Gabilondo I, et al. Treatment and prognostic factors for longterm outcome in patients with anti-NMDA
receptor encephalitis: an observational cohort study. Lancet Neurol 2013; 12:157.

17. • Ovarian teratomas revealed by USG, MRI and computed tomography (CT) of the abdomen
and pelvis
• Brain MRI that is often normal or shows transient fluid-attenuated inversion recovery (FLAIR)
or contrast-enhancing abnormalities in cortical (brain, cerebellum) or subcortical
(hippocampus, basal ganglia, white matter) regions
• Positron emission tomography (PET) reportedly shows a characteristic increase in the frontal-
occipital gradient of cerebral glucose metabolism, which correlates with disease severity
Basu S, Alavi A. Role of FDG-PET in the clinical management of paraneoplastic neurological syndrome: detection of the underlying
malignancy and the brain PET-MRI correlates. Mol Imaging Biol 2008; 10:131

18. Acute and long term treatment plan
• First line treatment:
• Treatment consists of immunosuppression and tumor resection when indicated
• Intravenous methylprednisolone ( e.g. 1 gram daily for five days in an adult)
• Intravenous immunoglobulin G (IVIG; e.g. 400 mg/kg per day for five days) or plasma
exchange
• Second line therapies :
• Rituximab (either 375 mg/m weekly for 4 weeks, or 1 g twice two weeks apart)
• Cyclophosphamide (500-1000 mg/m2 monthly for 4 to 6 months depending on results), or
both.
• An alternative approach to stepwise escalation of immunotherapy is to use rituximab in
combination with steroids and IVIG or plasma exchange as initial therapy
Nosadini M, Eyre M, Molteni E, et al. Use and Safety of Immunotherapeutic Management of N-Methyl-d-Aspartate Receptor
Antibody Encephalitis: A Meta-analysis. JAMA Neurol 2021; 78:1333.

19. Maintenance therapy
• Corticosteroids are typically continued after the induction phase if a response has occurred
as 1-g IV methylprednisolone infusion every 7 to 14 days with gradually increasing intervals
as allowed by the clinical course.
• Daily oral prednisone at 1mg/kg may also be used if IV preparations are not easily accessible
and tapered after 3 month over a period of 6-12 months.
• If IVIg was used in induction and was deemed effective, it can be continued with gradually
increasing inter dose intervals while response is monitored, most commonly monthly over
the following 6 to 12 months.
• Dose of IVIg is 0.4g/kg .
• If Rituximab was used at induction, and a response was determined to have been achieved, it
usually needs to be readministered every 6 months to prevent relapse, given that B cells will
regenerate eventually and antibody production will resume. During this time, CD19 levels can
be monitored to assess for B-cell recovery.
• Dose of Rituximab 375mg/m2
Nosadini M, Mohammad SS, Ramanathan S, et al. Immune therapy in autoimmune encephalitis: a systematic review. Expert Rev
Neurother 2015; 15:1391.

20. • If Cyclophosphamide was used during the initial treatment phase, it is typically continued as
part of the maintenance therapy for 6 months .
• Dose 1-2mg/kg/day or 500-1000mg/m2 iv per month.
• Mycophenolate mofetil and azathioprine are sometimes used, if a response to induction
therapy was achieved, to maintain remission and facilitate eventual discontinuation of first-
line therapies.
• .
Dalmau J, Armangué T, Planagumà J, Radosevic M, Mannara F, Leypoldt F, Geis C, Lancaster E, Titulaer MJ,
Rosenfeld MR, Graus F. An update on anti-NMDA receptor encephalitis for neurologists and psychiatrists:
mechanisms and models. The Lancet Neurology. 2019 Nov 1;18(11):1045-57.

21. • Mycophenolate mofetil orally 500mg/day for 2 weeks followed by 1000mg per day for 3-5 years
• Measure Blood cell counts, renal and liver function tests at baseline, weekly for 1 month, every other
week for 2 months then monthly.
• Oral azathioprine 2-3 mg/kg/d once daily or in divided doses 3-5 years.
• Measure thiopurine S-methyltransferase enzyme activity before initiation; blood cell counts, renal
function and liver function at baseline then weekly for 1 month, every other week for 2 months, and
monthly thereafter.
• They are also used to prevent relapses, which can occur in 35% of patients with autoimmune
encephalitis.
• They have also been used to augment induction therapy in some cases.
• The use of these medications has not been established for any of these indications in prospective trials
to date.
• The duration of treatment is also unclear

22. Long term Seizure control protocol
• Immunotherapy controls seizure in 50% of patients
• Rest are controlled with anti seizure medications
• Higher responder rates have been reported with sodium channel blockers, particularly
carbamazepine and Lacosamide compared with levetiracetam.
• Seizures usually resolve after resolution of anti–NDMA receptor encephalitis, eventually
allowing successful antiseizure medication discontinuation.
• Long-term antiseizure medication administration is not always necessary in many patients
after resolution of acute encephalitis, and discontinuation can be considered after 6 months
or a greater period of seizure cessation.
de Bruijn MAAM, van Sonderen A, van Coevorden-Hameete MH, et al. Evaluation of seizure treatment in anti-LGI1, anti-NMDAR,
and anti-GABABR encephalitis. Neurology 2019; 92:e2185.

23. Relapse
• More common among
1. Who did not receive immunotherapy with the initial presentation .
2. Adolescent presentation has also been associated with increased risk for relapse
Treatment
 Treated similarly to the approach in newly diagnosed patients,
 Lower threshold to initiate second-line therapies early in the course of the relapse

24. NEOS score
• Anti NMDAR encephalitis one year functional status score
Patient characteristic Neos score
ICU admission required 1
No clinical improvement after 4 weeks of treatment 1
No treatment after 4 week of symptom onset 1
Abnormal MRI 1
CSF WBC count >20 cells/ul 1
Interpretation: maximum the score poor the functional status outcome at one year
and patient will require 2nd or 3rd line immunomodulator therapy.
Peng Y, Dai F, Liu L, Chen W, Yan H, Liu A, Zhang X, Wang X, He J, Li Y, Li C. Validation of the
NEOS score in Chinese patients with anti-NMDAR encephalitis. Neurology-Neuroimmunology
Neuroinflammation. 2020 Sep 1;7(5).

27. Conclusion
• In this series of patients, 84.8% showed clinical improvement within 4 weeks after beginning
immunotherapy
• 80.7% and 85.7% exhibited substantial recovery (i.e., mild or no residual symptoms) at 12
and 24 months, respectively.
• The overall prognosis continued to improve through 42 months after onset.
• The median baseline mRS was 4, and only 15% were admitted to the ICU. Moreover, different
populations with varied genetic backgrounds and other external factors (e.g., lifestyle,
metabolism, and diet) might also respond differently to treatment.
• Therefore, more research is required to understand the mechanisms underlying disease
initiation, aggravation, and progression in different populations

29. Conclusion
• Overall, 219 (99.5%) patients received first-line immunotherapy
• in most cases a combined regimen of repeated steroids and IVIG.
• A total of 208 (94.5%) patients received steroids, of whom 103 (46.8%) received pulsed IV
methylprednisolone.
• IVIG was administered to 199 (90.5%) patients, and 7 (3.2%) patients underwent PE.
• Second-line immunotherapy was administered to only a small proportion of the patients, Twelve (5.5%)
patients received RTX, and 4 (1.8%) received CTX.
• Long-term immunotherapy was administered mainly in patients who were enrolled later, as an add-on
therapy for severe or refractory patients in the acute phase, or as maintenance therapy to prevent and
manage relapses.
• In general, MMF was administered in 109 (49.5%) patients, 55 of whom at onset and 54 after relapse, and
AZA was administered in 8 (3.6%) patients.
• In addition, intrathecal MTX was given to 8 (3.6%) severe patients.
• During the first 12 months, 207 (94.1%) patients experienced improvement, 8 (3.6%) were stable, and 5
(2.3%) patients died.
• All survival patients were followed for at least a year (range 12–72 months). At 12-month follow-up, 204
(92.7%) patients had attained satisfactory neurologic function.

30. Largest study till date…..
• The largest single study on treatment and outcomes in anti-NMDA receptor encephalitis is a
retrospective study of 577 patients that included 501 patients for whom treatment effects and outcome
were assessable [8].
• Nearly all patients (94 percent) were treated with tumor removal and first-line immunotherapy,
including steroids, IVIG, and/or plasma exchange. Half of patients improved within the first four weeks
of first-line therapy.
• Of these, 97 percent had a good outcome at 24-month follow-up.
• Of the 221 patients who did not improve within the first four weeks of first-line therapy, 125 (57
percent) received rituximab, cyclophosphamide, or both. Patients who received second-line therapy
had a higher likelihood of a good outcome (modified Rankin Scale [mRS] 0 to 2) than those who did not
(odds ratio [OR] 2.7, 95% CI 1.2-5.8). Response rates were similar in adults and children.
• By 24 months, approximately 80 percent of patients achieved a good outcome (mRS 0 to 2) and 30
patients had died. Outcomes continued to improve for up to 18 months after symptom onset
• Twelve percent of patients relapsed within the first two years of the initial episode. Patients without a
tumor and those who did not receive second-line immunotherapy were at increased risk for relapse.
Titulaer MJ, McCracken L, Gabilondo I, et al. Treatment and prognostic factors for longterm outcome in patients with anti-NMDA
receptor encephalitis: an observational cohort study. Lancet Neurol 2013; 12:15

31. Lee WJ, Lee ST, Moon J, et al. Tocilizumab in Autoimmune Encephalitis Refractory to Rituximab: An
Institutional Cohort Study. Neurotherapeutics 2016; 13:824.

32. • .
Bortezomib is a proteasome inhibitor and antineoplastic agent that is used in
treatment of refractory multiple myeloma and certain lymphomas.
For patients who do not appear to respond to first- and second-line therapies, other agents such
as bortezomib reported to provides benefit
Cordani R, Micalizzi C, Giacomini T, et al. Bortezomib-Responsive Refractory Anti-NMethyl-d-Aspartate Receptor Encephalitis.
Pediatr Neurol 2020; 103:61

33. Bad Prognostic Markers….
1. Lack of clinical improvement within the first four weeks of treatment
2. Requirement for intensive care unit admission
3. Extremes of age (≤2 or ≥65 years of age)
4. Extreme delta brush pattern on EEG,
5. Lack of immunotherapy within the first 30 days of disease onset
6. In children, an abnormal brain MRI and sensorimotor deficits at presentation have also
been associated with worse outcome

34. Anti-LGI1 Encephalitis

35. Clinical profile
• VGKC- complex antibodies mediated encephalitis
• Memory disturbances
• Confusion
• Facio brachial dystonic seizures(most specific)
• Hyponatremia
• Rapid eye movement (REM) sleep behavior disorder.
• MRI usually shows findings typical of limbic encephalitis (eg, medial temporal lobe
hyperintensity)
• EEG may show no ictal findings even during focal seizures in anti-LGI1 encephalitis or may
show temporal epileptic discharges or slowing.
• CSF is often normal or only shows oligoclonal bands.
• Only 5 to 10 percent of cases are associated with cancer; the most common associated tumor
is thymoma.

37. Pathophysiology and Diagnosis
• The associated antibodies mostly IgG4 class target the LGI1 protein, a secreted neuronal
protein that functions as a ligand for two epilepsy-related proteins, ADAM22 and ADAM23 .
• The binding of the antibodies to LGI1 disrupts pre- and postsynaptic LGI1 signalling, resulting
in neuronal hyperexcitability.
• The gold standard for diagnosis is a positive LGI1 antibody in serum or CSF.
• Sensitivity was higher in CSF as compared to serum
• After recovery serum LGI1 antibodies may remain positive.
Jacob S, Irani SR, Rajabally YA, et al. Hypothermia in VGKC antibody-associated limbic encephalitis. J Neurol Neurosurg Psychiatry
2008; 79:202

39. • This [18F]fluorodeoxyglucose (FDG) PET study evaluates the accuracy of semiquantitative
measurement of Putaminal hypermetabolism in identifying anti–leucine-rich, glioma–
inactivated-1 (LGI1) protein autoimmune encephalitis (AE)
• Semiquantitative measurement of Putaminal hypermetabolism with FDG-PET may be used to
distinguish LGI1-AE from other pathologies
• Metabolic abnormalities in LGI1-AE also extend beyond putamen and MTL into other
subcortical and cortical regions
• FDG-PET may be used in evaluating disease evolution in LGI1-AE.
• Patients with good short-term outcome (mRS ≤ 2) at the time of follow-up PET showed a
reduction in MTL hypermetabolism .
Rissanen E, Carter K, Cicero S, Ficke J, Kijewski M, Park MA, Kijewski J, Stern E, Chitnis T, Silbersweig D, Weiner HL.
Cortical and subcortical dysmetabolism are dynamic markers of clinical disability and course in anti-LGI1 encephalitis.
Neurology-Neuroimmunology Neuroinflammation. 2022 Mar 1;9(2).

41. Acute and long term treatment plan
• First line treatment:
• Treatment consists of immunosuppression and tumor resection when indicated
• Intravenous methylprednisolone (eg, 1 gram daily for five days in an adult)
• Intravenous immunoglobulin G (IVIG; eg, 400 mg/kg per day for five days) or plasma
exchange
• Second line therapies :
• Cyclophosphamide (500-1000 mg/m2 monthly for 4 to 6 months depending on results)
• An alternative approach to stepwise escalation of immunotherapy is to use rituximab in
combination with steroids and IVIG or plasma exchange as initial therapy
• Significant clinical improvement in 70 to 80 percent of patients.
Wong SH, Saunders MD, Larner AJ, et al. An effective immunotherapy regimen for VGKC antibody-positive limbic encephalitis. J
Neurol Neurosurg Psychiatry 2010; 81:1167.

44. Conclusion
• Early adequate immunotherapy has positive implications for the improvement of clinical
symptoms of anti-LGI1 encephalitis.
• The outcome for patients with anti-LGI1 encephalitis is mostly favorable, although cognitive
dysfunction does persist in some patients.
• The treatment of severe, refractory, and/or recurrent anti-LGI1 encephalitis has yet to be
investigated.
• Although recurrence was uncommon in this study, physicians should be aware that disease
relapse is possible, even years after disease onset.
• Therefore, long-term follow-up is essential. Further research, using more robust study
designs and extended follow-up periods, is necessary

45. Early initiation of immunotherapy in patients with facio brachial dystonic seizures may
prevent the development of cognitive impairment and improve long-term outcomes

46. Experience with rituximab as an add-on therapy in patients with anti-LGI1
encephalitis is limited

47. Prognosis and long term outcome
• Relapses occur in up to one-third of patients
• The median time to relapse after initial presentation is around 36 months.
• Cognitive deficits and disability persist in many patients
• Evidence of hippocampal atrophy on MRI which were done in follow up.
• The risk of long-term epilepsy appears to be low in the absence of disease relapse.
• Long-term antiseizure medication administration is not always necessary in many patients
after resolution of acute encephalitis, and discontinuation can be considered after 6 months
or a greater period of seizure cessation.
• Maintenance oral or iv steroids can be given at increasing intervals over 6-12 month duration.
Ariño H, Armangué T, Petit-Pedrol M, et al. Anti-LGI1-associated cognitive impairment: Presentation and long-term outcome.
Neurology 2016; 87:759.

48. References
• Bradley 8th edition
• Continuum journal
• Dalmau J, Rosenfeld MR. Paraneoplastic syndromes of the CNS. Lancet Neurol 2008; 7:327.
• Titulaer MJ, McCracken L, Gabilondo I, et al. Treatment and prognostic factors for longterm
outcome in patients with anti-NMDA receptor encephalitis: an observational cohort study.
Lancet Neurol 2013; 12:15
• Lawn ND, Westmoreland BF, Kiely MJ, et al. Clinical, magnetic resonance imaging, and
electroencephalographic findings in paraneoplastic limbic encephalitis. Mayo Clin Proc 2003;
78:1363.

49. THANKYOU