Autoimmune Encephalitis

1. AUTOIMMUNE
ENCEPHALITIS
Ade Wijaya, MD – January 2019

2. Introduction
◦ Acute encephalitis
Debilitating
Rapidly
progressive
< 6 weeks
Brain
inflammation
Jmor F, Emsley HC, Fischer M, Solomon T, Lewthwaite P. The incidence of acute encephalitis syndrome in Western industrialised and tropical countries. Virol J. 2008;5:134–46.
Vora NM, Holman RC, Mehal JM, Steiner CA, Blanton J, Sejvar J. Burden of encephalitis-associated hospitalizations in the United States, 1998–2010. Neurology. 2014;82:443–51.
INFECTION Autoimmune

3. Graus F, Titulaer MJ, Balu R, Benseler S, Bien CG, Cellucci T, Cortese I, Dale RC, Gelfand JM, Geschwind M, Glaser CA. A clinical approach to diagnosis of autoimmune encephalitis. The Lancet Neurology. 2016 Apr 1;15(4):391-404.

4. Lancaster E. The diagnosis and treatment of autoimmune encephalitis. Journal of Clinical Neurology. 2016 Jan 1;12(1):1-3.

5. Diagnostic Criteria for
Possible Autoimmune Encephalitis
Diagnosis can be made when all three of the following criteria have been met:
◦ Subacute onset (rapid progression of less than 3 months) of working memory deficits (short-
term memory loss), altered mental status*, or psychiatric symptoms
◦ At least one of the following:
◦ New focal CNS findings
◦ Seizures not explained by a previously known seizure disorder
◦ CSF pleocytosis (white blood cell count of more than five cells per mm3)
◦ MRI features suggestive of encephalitis†
◦ Reasonable exclusion of alternative causes
Venkatesan A, Tunkel AR, Bloch KC, et al. for the International Encephalitis Consortium. Case definitions, diagnostic algorithms, and priorities in encephalitis: consensus statement of the international encephalitis consortium. Clin Infect Dis. 2013;57:1114–28.
Vora NM, Holman RC, Mehal JM, Steiner CA, Blanton J, Sejvar J. Burden of encephalitis-associated hospitalizations in the United States, 1998–2010. Neurology. 2014;82:443–51.
Ball R, Halsey N, Braun MM, et al. for the VAERS Working Group. Development of case definitions for acute encephalopathy, encephalitis, and multiple sclerosis reports to the vaccine: Adverse Event Reporting System. J Clin Epidemiol. 2002;55:819–24.
Sejvar JJ, Kohl KS, Bilynsky R, et al. for the Brighton Collaboration Encephalitis Working Group. Encephalitis, myelitis, and acute disseminated encephalomyelitis (ADEM): case definitions and guidelines for collection, analysis, and presentation of
immunization safety data. Vaccine. 2007;25:5771–92.
Britton PN, Eastwood K, Paterson B, et al. for the Australasian Society of Infectious Diseases (ASID), the Australasian College of Emergency Medicine (ACEM), the Australian and New Zealand Association of Neurologists (ANZAN), and the Public Health
Association of Australia (PHAA) Consensus guidelines for the investigation and management of encephalitis in adults and children in Australia and New Zealand. Intern Med J. 2015;45:563–76.

6. Diagnostic Criteria for Definite
Autoimmune Limbic Encephalitis
Diagnosis can be made when all four* of the following criteria have been met:
◦ Subacute onset (rapid progression of less than 3 months) of working memory deficits, seizures,
or psychiatric symptoms suggesting involvement of the limbic system
◦ Bilateral brain abnormalities on T2-weighted fluid-attenuated inversion recovery MRI highly
restricted to the medial temporal lobes†
◦ At least one of the following:
◦ CSF pleocytosis (white blood cell count of more than five cells per mm3)
◦ EEG with epileptic or slow-wave activity involving the temporal lobes
◦ Reasonable exclusion of alternative causes
Baumgartner A, Rauer S, Mader I, Meyer PT. Cerebral FDG-PET and MRI findings in autoimmune limbic encephalitis: correlation with autoantibody types. J Neurol. 2013;260:2744–53.
Heine J, Prüss H, Bartsch T, Ploner CJ, Paul F, Finke C. Imaging of autoimmune encephalitis - Relevance for clinical practice and hippocampal function. Neuroscience. 2015;309:68–83

7. Diagnostic Criteria for Definite Acute
Disseminated Encephalomyelitis
Diagnosis can be made when all five of the following criteria have been met:
◦ A first multifocal, clinical CNS event of presumed inflammatory demyelinating cause
◦ Encephalopathy that cannot be explained by fever
◦ Abnormal brain MRI:
◦ Diffuse, poorly demarcated, large (>1–2 cm) lesions predominantly involving the cerebral white matter
◦ T1-hypointense lesions in the white matter in rare cases
◦ Deep grey matter abnormalities (eg, thalamus or basal ganglia) can be present
◦ No new clinical or MRI findings after 3 months of symptom onset
◦ Reasonable exclusion of alternative causes
Krupp LB, Tardieu M, Amato MP, et al. for the International Pediatric Multiple Sclerosis Study Group. International Pediatric Multiple Sclerosis Study Group criteria for pediatric multiple sclerosis and immune-mediated central nervous system
demyelinating disorders: revisions to the 2007 definitions. Mult Scler.2013;19:1261–67.

8. Diagnostic Criteria for
Anti-NMDA Receptor Encephalitis
Probable anti-NMDA receptor encephalitis
◦ Diagnosis can be made when all three of the following criteria have been met:
◦ Rapid onset (less than 3 months) of at least four of the six following major groups of symptoms:
◦ Abnormal (psychiatric) behaviour or cognitive dysfunction
◦ Speech dysfunction (pressured speech, verbal reduction, mutism)
◦ Seizures
◦ Movement disorder, dyskinesias, or rigidity/abnormal postures
◦ Decreased level of consciousness
◦ Autonomic dysfunction or central hypoventilation
◦ At least one of the following laboratory study results:
◦ Abnormal EEG (focal or diffuse slow or disorganised activity, epileptic activity, or extreme delta brush)
◦ CSF with pleocytosis or oligoclonal bands
◦ Reasonable exclusion of other disorders
Diagnosis can also be made in the presence of three of the above groups of symptoms accompanied by a systemic teratoma
Definite anti-NMDA receptor encephalitis*
◦ Diagnosis can be made in the presence of one or more of the six major groups of symptoms and IgG anti-GluN1 antibodies,† after reasonable exclusion of other disorders
Graus F, Titulaer MJ, Balu R, Benseler S, Bien CG, Cellucci T, Cortese I, Dale RC, Gelfand JM, Geschwind M, Glaser CA. A clinical approach to diagnosis of autoimmune encephalitis. The Lancet Neurology. 2016 Apr 1;15(4):391-404.

9. Diagnostic Criteria for
Bickerstaff’s Brainstem Encephalitis
Probable Bickerstaff’s brainstem encephalitis
◦ Diagnosis can be made when both of the following criteria have been met:
◦ Subacute onset (rapid progression of less than 4 weeks) of all the following symptoms:
◦ Decreased level of consciousness
◦ Bilateral external ophthalmoplegia
◦ Ataxia
◦ Reasonable exclusion of alternative causes
Definite Bickerstaff’s brainstem encephalitis
◦ Diagnosis can be made in the presence of positive IgG anti-GQ1b antibodies even if bilateral
external ophthalmoplegia is not complete or ataxia cannot be assessed, or if recovery has
occurred within 12 weeks after onset
Koga M, Kusunoki S, Kaida K, et al. Nationwide survey of patients in Japan with Bickerstaff brainstem encephalitis: epidemiological and clinical characteristics. J Neurol Neurosurg Psychiatry. 2012;83:1210–15.

10. Diagnostic Criteria for
Hashimoto’s Encephalopathy
Diagnosis can be made when all six of the following criteria have been met:
◦ Encephalopathy with seizures, myoclonus, hallucinations, or stroke-like episodes
◦ Subclinical or mild overt thyroid disease (usually hypothyroidism)
◦ Brain MRI normal or with non-specific abnormalities
◦ Presence of serum thyroid (thyroid peroxidase, thyroglobulin) antibodies*
◦ Absence of well characterised neuronal antibodies in serum and CSF
◦ Reasonable exclusion of alternative causes
Castillo P, Woodruff B, Caselli R, et al. Steroid-responsive encephalopathy associated with autoimmune thyroiditis. Arch Neurol. 2006;63:197–202

11. Criteria for Autoantibody-Negative but
Probable Autoimmune Encephalitis
Diagnosis can be made when all four of the following criteria have been met:
◦ Rapid progression (less than 3 months) of working memory deficits (short-term memory loss), altered
mental status, or psychiatric symptoms
◦ Exclusion of well defined syndromes of autoimmune encephalitis (eg, typical limbic encephalitis,
Bickerstaff’s brainstem encephalitis, acute disseminated encephalomyelitis)
◦ Absence of well characterised autoantibodies in serum and CSF, and at least two of the following
criteria:
◦ MRI abnormalities suggestive of autoimmune encephalitis*
◦ CSF pleocytosis, CSF-specific oligoclonal bands or elevated CSF IgG index, or both*
◦ Brain biopsy showing inflammatory infiltrates and excluding other disorders (eg, tumour)
◦ Reasonable exclusion of alternative causes
Graus F, Titulaer MJ, Balu R, Benseler S, Bien CG, Cellucci T, Cortese I, Dale RC, Gelfand JM, Geschwind M, Glaser CA. A clinical approach to diagnosis of autoimmune encephalitis. The Lancet Neurology. 2016 Apr 1;15(4):391-404.

12. Differential Diagnosis
◦ CNS infections
◦ Septic encephalopathy
◦ Metabolic encephalopathy
◦ Drug toxicity
◦ Cerebrovascular disease
◦ Neoplastic disorders
◦ Creutzfeldt-Jakob disease
◦ Epileptic disorders
◦ Rheumatologic disorders (e.g., lupus, sarcoidosis, other)
◦ Kleine-Levin
◦ Reye syndrome (children)
◦ Mitochondrial diseases
◦ Inborn errors of metabolism (children)
Graus F, Titulaer MJ, Balu R, Benseler S, Bien CG, Cellucci T, Cortese I, Dale RC, Gelfand JM, Geschwind M, Glaser CA. A clinical approach to diagnosis of autoimmune encephalitis. The Lancet Neurology. 2016 Apr 1;15(4):391-404.

13. Treatment
◦ 1st line: steroid, IVIg, plasmapheresis
◦ 2nd line:
Rituximab (often 375 mg/m2 weekly for 4 weeks)
Cyclophosphamide (750 mg/m2 IV monthly until improvement is noted)
or both.
Huijbers MG, Querol LA, Niks EH, Plomp JJ, van der Maarel SM, Graus F, et al. The expanding field of IgG4-mediated neurological autoimmune disorders. Eur J Neurol 2015;22:1151–1161.

14. Summary
◦ Encephalitis is a severe inflammatory disorder of the brain with many possible causes and a
complex differential diagnosis
◦ Advances in autoimmune encephalitis research in the past 10 years have led to the identification
of new syndromes and biomarkers that have transformed the diagnostic approach to these
disorders
◦ Immunotherapy