A Step by Step Approach to Autoimmune Encephalitis

 

Autoimmune Encephalitis: A Comprehensive Clinical Approach for Recognition, Evaluation, and Management

Dr Neeraj Manikath ,claude.ai

Abstract

Autoimmune encephalitis (AE) encompasses a heterogeneous group of immune-mediated inflammatory disorders of the brain characterized by subacute onset of memory deficits, altered mental status, and psychiatric symptoms frequently accompanied by seizures, movement disorders, or autonomic dysfunction. Early recognition and initiation of immunotherapy are associated with improved neurological outcomes. This review provides a systematic approach to the diagnosis and management of AE based on clinical presentation, evaluation, and current treatment recommendations. We propose a practical framework for clinicians to facilitate timely identification and appropriate management of suspected AE cases.

Keywords: autoimmune encephalitis; paraneoplastic; immunotherapy; antibody-mediated; T-cell-mediated; diagnostic algorithm

Introduction

Autoimmune encephalitis represents a diverse spectrum of neuroinflammatory disorders that cause subacute neurological and psychiatric symptoms due to immune-mediated mechanisms. The understanding of AE has expanded significantly in the past two decades, with the discovery of numerous neural antibodies and improvements in diagnostic techniques.^1,2^ Early recognition remains challenging due to its heterogeneous presentation, which often overlaps with infectious, metabolic, toxic, and primary psychiatric disorders.^3^ However, prompt diagnosis and initiation of immunotherapy are crucial for favorable outcomes.^4^

This review outlines an evidence-based, stepwise approach to suspecting, evaluating, and treating autoimmune encephalitis in clinical practice, addressing the following key questions:

1. When should clinicians suspect autoimmune encephalitis?
2. What is the appropriate initial workup for a patient with suspected AE?
3. How can AE be classified based on pathophysiology and antibody status?
4. What are the established treatment approaches for different subtypes of AE?
5. How should treatment response be monitored and follow-up care organized?

Epidemiology and Classification

The annual incidence of AE has been estimated at approximately 5-10 cases per 100,000 population, though this likely underestimates the true prevalence due to under-recognition.^5^ AE affects all age groups but shows bimodal peaks in young adults and patients over 65 years.^6^ Sex distribution varies by antibody subtype, with some forms (like anti-NMDAR encephalitis) predominantly affecting females.^7^

AE can be broadly classified into three categories based on pathophysiological mechanisms:^8^

1. Antibody-mediated encephalitis: Directed against cell-surface neuronal antigens (e.g., NMDAR, LGI1, CASPR2)
2. Paraneoplastic autoimmune encephalitis: Associated with onconeural antibodies against intracellular antigens (e.g., Hu, Yo, Ma2, CV2/CRMP5, amphiphysin)
3. Seronegative autoimmune encephalitis: Clinically consistent with AE but without identified antibodies

When to Suspect Autoimmune Encephalitis

Step 1: Recognize the Core Clinical Presentation

The clinical presentation of AE typically includes:^9,10^

A. Cognitive/Behavioral Manifestations

• Subacute onset (rapid progression over less than 3 months)
• Working memory deficits
• Altered mental status or encephalopathy
• Psychiatric symptoms (personality changes, psychosis, catatonia, anxiety)

B. Associated Symptoms

• Seizures (focal or generalized)
• Movement disorders (dystonia, chorea, myoclonus, orofacial dyskinesias)
• Sleep disturbances
• Autonomic dysfunction
• Speech disorders
• Decreased level of consciousness

Step 2: Recognize Syndrome-Specific Presentations

Certain symptom clusters should particularly raise suspicion for specific AE subtypes:^11-13^

Anti-NMDAR Encephalitis

• Predominant psychiatric presentation
• Characteristic progression: prodromal phase (headache, fever) → psychiatric symptoms → movement disorders → autonomic instability → decreased consciousness
• Orofacial dyskinesias, choreoathetoid movements
• Common in young females, often associated with ovarian teratomas

LGI1 Antibody Encephalitis

• Faciobrachial dystonic seizures (brief, frequent contractions of face and ipsilateral arm)
• Memory impairment
• Hyponatremia
• Predominantly affects older adults

CASPR2 Antibody Encephalitis

• Neuromyotonia or peripheral nerve hyperexcitability
• Insomnia and other sleep disorders
• Neuropathic pain
• Predominantly affects older men

GABA-A Receptor Encephalitis

• Refractory seizures or status epilepticus
• Characteristic multifocal cortical-subcortical MRI abnormalities

Anti-GAD65 Associated Disorders

• Stiff-person syndrome
• Cerebellar ataxia
• Temporal lobe epilepsy

Paraneoplastic Limbic Encephalitis

• Prominent memory impairment and confusion
• Temporal lobe seizures
• Association with lung, testicular, breast, ovarian, or thymic malignancies

Step 3: Recognize Red Flags That Suggest AE

Several clinical features should prompt consideration of AE in the differential diagnosis:^14,15^

• Psychiatric symptoms unresponsive to antipsychotic medications
• New-onset seizures with psychiatric symptoms
• Unexplained status epilepticus
• CSF pleocytosis of unknown etiology
• Mesial temporal lobe T2/FLAIR hyperintensities on MRI
• Neuropsychiatric symptoms following herpes simplex encephalitis (potential post-infectious AE)
• Neuropsychiatric symptoms with underlying systemic autoimmunity
• New neurological symptoms in patients with cancer

Diagnostic Approach

Step 4: Initial Evaluation

Once AE is suspected, a systematic diagnostic approach is warranted:^16,17^

A. History and Physical Examination

• Detailed neuropsychiatric history with timeline of symptom evolution
• Complete neurological examination
• Targeted screening for underlying malignancy based on age, sex, and risk factors
• Evaluation for systemic autoimmune diseases

B. Brain MRI

• T2/FLAIR sequences may show hyperintense signal abnormalities in:
  • Medial temporal lobes (limbic encephalitis)
  • Cortical and subcortical regions
  • Brainstem
  • Note: Up to 50% of AE cases may have normal initial MRI^18^

C. Electroencephalography (EEG)

• Diffuse or focal slowing
• Epileptiform discharges
• Extreme delta brush pattern (in anti-NMDAR encephalitis)
• Focal temporal abnormalities (in limbic encephalitis)

D. Cerebrospinal Fluid Analysis

• Cell count and differential (mild to moderate lymphocytic pleocytosis)
• Protein (mildly elevated in 50-80% of cases)
• Glucose (typically normal)
• Oligoclonal bands (present in 30-60% of cases)
• IgG index
• Cytology (to exclude malignant cells)
• PCR for infectious etiologies (HSV, VZV, enterovirus)
• CSF-specific oligoclonal bands

Step 5: Autoantibody Testing

A. Serum and CSF Antibody Panels^19,20^

• Cell-surface/synaptic antibodies:
  • NMDAR, LGI1, CASPR2, AMPAR, GABA-A/B receptors, DPPX, mGluR5, IgLON5, neurexin-3α
• Intracellular/onconeuronal antibodies:
  • Hu (ANNA-1), Yo (PCA-1), Ri (ANNA-2), Ma2/Ta, CV2/CRMP5, amphiphysin, SOX1, Zic4, GAD65, GFAP

B. Testing Considerations

• Testing both serum and CSF increases sensitivity
• Some antibodies (e.g., NMDAR) have higher sensitivity in CSF
• Others (e.g., LGI1, CASPR2) may be more reliably detected in serum
• Consider testing for novel antibodies through research laboratories in highly suspicious cases

Step 6: Cancer Screening

Paraneoplastic forms of AE necessitate thorough cancer screening:^21,22^

A. Initial Cancer Screening

• Whole-body CT or PET-CT
• Age and sex-appropriate cancer screening:
  • Mammography/breast MRI in women
  • Testicular ultrasound in men
  • Pelvic ultrasound/CT in women with anti-NMDAR antibodies (to detect ovarian teratomas)
  • Bronchoscopy if lung malignancy is suspected

B. Follow-up Screening

• If initial screening is negative but suspicion for paraneoplastic etiology remains high, repeat cancer screening every 3-6 months for 2-3 years

Diagnostic Criteria

The 2016 diagnostic criteria for possible, probable, and definite autoimmune encephalitis provide a useful framework:^23^

Possible Autoimmune Encephalitis

All three of the following criteria:

1. Subacute onset (rapid progression of less than 3 months) of working memory deficits, altered mental status, or psychiatric symptoms
2. At least one of:
   • New focal CNS findings
   • Seizures not explained by previously known seizure disorder
   • CSF pleocytosis
   • MRI features suggestive of encephalitis
3. Reasonable exclusion of alternative causes

Probable Autoimmune Encephalitis

Diagnostic criteria for possible AE and:

1. Abnormal EEG showing focal or diffuse slow or epileptic activity, or
2. CSF pleocytosis or oligoclonal bands

Definite Autoimmune Encephalitis

1. Histopathological evidence of brain inflammation with lymphocytic infiltrates and exclusion of other causes, or
2. Detection of well-characterized autoantibodies with compatible clinical syndrome, or
3. Fulfillment of diagnostic criteria for specific antibody-defined syndromes

Management Approach

Step 7: Decision to Initiate Empiric Treatment

Consider early empiric immunotherapy when:^24,25^

• Clinical presentation and ancillary testing strongly suggest AE
• Infectious etiologies have been reasonably excluded
• Patient exhibits severe or rapidly progressive symptoms
• Delay in treatment could lead to irreversible neurological damage

Step 8: First-Line Immunotherapy

A. Corticosteroids^26^

• High-dose intravenous methylprednisolone (1g daily for 3-5 days)
• Followed by oral prednisone taper (starting at 1mg/kg/day) over 2-3 months

B. Intravenous Immunoglobulin (IVIG)^27^

• 0.4g/kg/day for 5 days or 1g/kg/day for 2 days
• May be repeated at 2-4 week intervals based on response

C. Plasma Exchange^28^

• 5-7 exchanges over 10-14 days
• Consider in severe cases or when rapid response is needed

Step 9: Second-Line Immunotherapy

For patients with inadequate response to first-line therapy after 2-3 weeks:^29,30^

A. Rituximab

• 375mg/m² weekly for 4 weeks or 1000mg given twice with 2-week interval
• Particularly effective in antibody-mediated AE

B. Cyclophosphamide

• 750mg/m² monthly for 3-6 months
• Consider in severe cases of paraneoplastic AE or those with intracellular antibodies

Step 10: Third-Line and Maintenance Immunotherapy

For refractory cases or maintenance:^31,32^

A. Additional Immunosuppressive Agents

• Mycophenolate mofetil (starting at 500mg twice daily, increasing to 1000-1500mg twice daily)
• Azathioprine (starting at 1mg/kg/day, increasing to 2-3mg/kg/day)
• Tacrolimus or cyclosporine
• Methotrexate

B. Novel Therapies

• Bortezomib (in severe anti-NMDAR encephalitis)
• Tocilizumab (IL-6 receptor antagonist)
• Low-dose interleukin-2 for regulatory T-cell expansion

Step 11: Tumor Treatment in Paraneoplastic AE

• Prompt tumor removal or treatment is essential in paraneoplastic cases^33^
• Ovarian teratoma resection in anti-NMDAR encephalitis improves outcomes
• Combined approach: tumor therapy and immunotherapy

Step 12: Symptomatic Management

A. Seizure Management^34^

• Levetiracetam often preferred (fewer drug interactions and side effects)
• Avoid medications that can worsen psychiatric symptoms (e.g., topiramate, zonisamide)
• Consider benzodiazepines for status epilepticus

B. Psychiatric Symptom Management^35^

• Low-dose atypical antipsychotics (quetiapine, olanzapine) when necessary
• Caution with high-potency antipsychotics due to risk of aggravating symptoms
• Benzodiazepines for anxiety, agitation, or catatonia

C. Autonomic Dysfunction Management^36^

• Careful fluid and electrolyte balance
• Blood pressure management
• Temperature control
• Cardiac monitoring

Monitoring Response and Follow-up

Step 13: Evaluating Treatment Response

A. Clinical Assessment^37^

• Standardized cognitive assessments (Montreal Cognitive Assessment, Modified Rankin Scale)
• Psychiatric symptom scales
• Seizure frequency
• Functional independence measures

B. Laboratory Monitoring^38^

• Repeat CSF analysis (cell count, protein)
• Antibody titers (note: titers may not correlate with clinical improvement)
• EEG improvement

Step 14: Long-term Follow-up

A. Immunotherapy Tapering^39^

• Gradual corticosteroid taper over months
• Maintenance immunosuppression for 6-24 months based on syndrome type
• Longer immunosuppression may be needed for patients with relapses

B. Relapse Monitoring^40^

• Higher relapse risk in certain antibody types (e.g., MOG, NMDAR)
• Clinical monitoring for symptom recurrence
• Consider periodic antibody testing in high-risk patients
• Low threshold for repeat imaging or EEG with new symptoms

C. Cognitive Rehabilitation^41^

• Neuropsychological evaluation
• Targeted cognitive rehabilitation
• Occupational and speech therapy as needed

D. Psychiatric Support^42^

• Long-term psychiatric follow-up
• Cognitive behavioral therapy
• Psychoeducation for patients and families

Special Considerations

Pediatric Autoimmune Encephalitis^43^

• Different phenotypes and antibody distributions
• Higher prevalence of anti-NMDAR encephalitis
• Developmental regression may be prominent
• Consider AE in children with unexplained encephalopathy, movement disorders, or status epilepticus
• Age-appropriate dosing of immunotherapies

Autoimmune Encephalitis in Pregnancy^44^

• Safety considerations for immunotherapy
• Corticosteroids and IVIG generally considered safe
• Rituximab contraindicated in first trimester
• Cyclophosphamide contraindicated throughout pregnancy
• Multidisciplinary approach involving neurology, obstetrics, and neonatology

Post-infectious Autoimmune Encephalitis^45^

• May occur following HSV encephalitis (anti-NMDAR antibodies)
• Clinical worsening after initial improvement in viral encephalitis
• Requires distinction from viral recrudescence
• Early immunotherapy improves outcomes

Conclusion

Autoimmune encephalitis represents a diverse group of immune-mediated disorders with significant diagnostic and therapeutic challenges. A systematic approach to recognition, evaluation, and management can facilitate early diagnosis and treatment, potentially improving neurological outcomes. The field continues to evolve rapidly with the discovery of new antibodies and refinement of treatment protocols. Ongoing research is needed to optimize diagnostic criteria, treatment algorithms, and long-term management strategies for these complex disorders.

References

1. Dalmau J, Graus F. Antibody-mediated encephalitis. N Engl J Med. 2018;378(9):840-851.
2. Graus F, Titulaer MJ, Balu R, et al. A clinical approach to diagnosis of autoimmune encephalitis. Lancet Neurol. 2016;15(4):391-404.
3. Herken J, Prüss H. Red flags: clinical signs for identifying autoimmune encephalitis in psychiatric patients. Front Psychiatry. 2017;8:25.
4. 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. Lancet Neurol. 2013;12(2):157-165.
5. Dubey D, Pittock SJ, Kelly CR, et al. Autoimmune encephalitis epidemiology and a comparison to infectious encephalitis. Ann Neurol. 2018;83(1):166-177.
6. Hermetter C, Fazekas F, Hochmeister S. Systematic review: syndromes, early diagnosis, and treatment in autoimmune encephalitis. Front Neurol. 2018;9:706.
7. Dalmau J, Lancaster E, Martinez-Hernandez E, et al. Clinical experience and laboratory investigations in patients with anti-NMDAR encephalitis. Lancet Neurol. 2011;10(1):63-74.
8. Honorat JA, McKeon A. Autoimmune encephalitis: an evolving field. Brain Pathol. 2022;32(1):e13029.
9. Broadley J, Seneviratne U, Beech P, et al. Diagnostic utility of psychiatric symptoms in autoimmune encephalitis. J Neurol Neurosurg Psychiatry. 2019;90(10):1132-1139.
10. Höftberger R, Titulaer MJ, Sabater L, et al. Encephalitis and GABAB receptor antibodies: novel findings in a new case series of 20 patients. Neurology. 2013;81(17):1500-1506.
11. Liu X, Yan B, Wang R, et al. Seizure outcomes in patients with anti-NMDAR encephalitis: a follow-up study. Epilepsia. 2017;58(12):2104-2111.
12. van Sonderen A, Petit-Pedrol M, Dalmau J, Titulaer MJ. The value of LGI1, Caspr2 and voltage-gated potassium channel antibodies in encephalitis. Nat Rev Neurol. 2017;13(5):290-301.
13. Joubert B, Honnorat J. Autoimmune channelopathies in paraneoplastic neurological syndromes. Biochim Biophys Acta. 2015;1848(10 Pt B):2665-2676.
14. Escudero D, Guasp M, Ariño H, et al. Antibody-associated CNS syndromes without signs of inflammation in the elderly. Neurology. 2017;89(14):1471-1475.
15. Mittal MK, Rabinstein AA, Hocker SE, et al. Autoimmune encephalitis in the ICU: analysis of phenotypes, serologic findings, and outcomes. Neurocrit Care. 2016;24(2):240-250.
16. Hébert J, Gros P, Lapointe S, et al. Searching for autoimmune encephalitis: beware of normal CSF. J Neuroimmunol. 2020;345:577285.
17. Probasco JC, Solnes L, Nalluri A, et al. Abnormal brain metabolism on FDG-PET/CT is a common early finding in autoimmune encephalitis. Neurol Neuroimmunol Neuroinflamm. 2017;4(4):e352.
18. Irani SR, Gelfand JM, Al-Diwani A, Vincent A. Cell-surface central nervous system autoantibodies: clinical relevance and emerging paradigms. Ann Neurol. 2014;76(2):168-184.
19. Zuliani L, Nosadini M, Gastaldi M, et al. Management of antibody-mediated autoimmune encephalitis in adults and children: literature review and consensus-based practical recommendations. Neurol Sci. 2019;40(10):2017-2030.
20. Dalmau J, Geis C, Graus F. Autoantibodies to synaptic receptors and neuronal cell surface proteins in autoimmune diseases of the central nervous system. Physiol Rev. 2017;97(2):839-887.
21. McKeon A. Paraneoplastic and other autoimmune disorders of the central nervous system. Neurohospitalist. 2013;3(2):53-64.
22. Vogrig A, Muñiz-Castrillo S, Joubert B, et al. Central nervous system complications associated with immune checkpoint inhibitors. J Neurol Neurosurg Psychiatry. 2020;91(7):772-778.
23. Graus F, Titulaer MJ, Balu R, et al. A clinical approach to diagnosis of autoimmune encephalitis. Lancet Neurol. 2016;15(4):391-404.
24. Nosadini M, Mohammad SS, Ramanathan S, et al. Immune therapy in autoimmune encephalitis: a systematic review. Expert Rev Neurother. 2015;15(12):1391-1419.
25. Lee WJ, Lee ST, Byun JI, et al. Rituximab treatment for autoimmune limbic encephalitis in an institutional cohort. Neurology. 2016;86(18):1683-1691.
26. Dale RC, Brilot F, Duffy LV, et al. Utility and safety of rituximab in pediatric autoimmune and inflammatory CNS disease. Neurology. 2014;83(2):142-150.
27. Shin YW, Lee ST, Park KI, et al. Treatment strategies for autoimmune encephalitis. Ther Adv Neurol Disord. 2018;11:1756285617722347.
28. DeSena AD, Noland DK, Matevosyan K, et al. Intravenous methylprednisolone versus therapeutic plasma exchange for treatment of anti-N-methyl-D-aspartate receptor antibody encephalitis: a retrospective review. J Clin Apher. 2015;30(4):212-216.
29. Scheibe F, Prüss H, Mengel AM, et al. Bortezomib for treatment of therapy-refractory anti-NMDA receptor encephalitis. Neurology. 2017;88(4):366-370.
30. Lee WJ, Lee ST, Moon J, et al. Tocilizumab in autoimmune encephalitis refractory to rituximab: an institutional cohort study. Neurotherapeutics. 2016;13(4):824-832.
31. Nosadini M, Granata T, Matricardi S, et al. Relapse risk factors in anti-N-methyl-D-aspartate receptor encephalitis. Dev Med Child Neurol. 2019;61(9):1101-1107.
32. Dalmau J, Gleichman AJ, Hughes EG, et al. Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies. Lancet Neurol. 2008;7(12):1091-1098.
33. Lim JA, Lee ST, Jung KH, et al. Anti-N-methyl-d-aspartate receptor encephalitis in Korea: clinical features, treatment, and outcome. J Clin Neurol. 2014;10(2):157-161.
34. Sutter R, Kaplan PW, Marsch S, et al. Early predictors of refractory status epilepticus: an international two-center study. Eur J Neurol. 2015;22(1):79-85.
35. Lejuste F, Thomas L, Picard G, et al. Neuroleptic intolerance in patients with anti-NMDAR encephalitis. Neurol Neuroimmunol Neuroinflamm. 2016;3(5):e280.
36. Titulaer MJ, Soffietti R, Dalmau J, et al. Screening for tumours in paraneoplastic syndromes: report of an EFNS task force. Eur J Neurol. 2011;18(1):19-e3.
37. Varley JA, Webb AJS, Balint B, et al. The movement disorder associated with NMDAR antibody-encephalitis is complex and characteristic: an expert video-rating study. J Neurol Neurosurg Psychiatry. 2019;90(6):724-726.
38. Schimmel M, Bien CG, Vincent A, et al. Successful treatment of anti-N-methyl-D-aspartate receptor encephalitis presenting with catatonia. Arch Dis Child. 2009;94(4):314-316.
39. Gultekin SH, Rosenfeld MR, Voltz R, et al. Paraneoplastic limbic encephalitis: neurological symptoms, immunological findings and tumour association in 50 patients. Brain. 2000;123(Pt 7):1481-1494.
40. McKeon GL, Scott JG, Spooner DM, et al. Cognitive and Social Functioning Deficits after Anti-N-Methyl-D-Aspartate Receptor Encephalitis: An Exploratory Case Series. J Int Neuropsychol Soc. 2016;22(8):828-838.
41. Finke C, Kopp UA, Prüss H, et al. Cognitive deficits following anti-NMDA receptor encephalitis. J Neurol Neurosurg Psychiatry. 2012;83(2):195-198.
42. Schäbitz WR, Rogalewski A, Hagemeister C, et al. VZV brainstem encephalitis triggers NMDA receptor immunoreaction. Neurology. 2014;83(24):2309-2311.
43. Armangue T, Petit-Pedrol M, Dalmau J. Autoimmune encephalitis in children. J Child Neurol. 2012;27(11):1460-1469.
44. Joubert B, García-Serra A, Planagumà J, et al. Pregnancy outcomes in anti-NMDA receptor encephalitis: case series. Neurol Neuroimmunol Neuroinflamm. 2020;7(3):e668.
45. Armangue T, Spatola M, Vlagea A, et al. Frequency, symptoms, risk factors, and outcomes of autoimmune encephalitis after herpes simplex encephalitis: a prospective observational study and retrospective analysis. Lancet Neurol. 2018;17(9):760-772.