Autoimmune encephalitis

Last revised by Rohit Sharma on 11 Mar 2024

Autoimmune encephalitis, also known as autoimmune limbic encephalitis, is an antibody-mediated brain inflammatory process, typically involving the limbic system, although any part of the brain, and central nervous system more broadly, can be involved.

Autoimmune encephalitis can be divided broadly into two groups, based on whether or not antibodies are the result of an underlying tumour: 

  • paraneoplastic limbic encephalitis: usually antibodies are against intracellular antigens, poor response to immunotherapy

  • non-neoplastic autoimmune limbic encephalitis: antibodies are against extracellular antigens, usually with a reversible neuronal dysfunction and better response to immunotherapy 

Unfortunately, there is considerable heterogeneity in how the term limbic encephalitis is used. Most authors limit the term to autoimmune limbic encephalitis, including both paraneoplastic and non-paraneoplastic causes. Some, however, include viral encephalitides (especially HSV encephalitis) under the broad term limbic encephalitis.

For the purpose of this article, we will restrict the term to autoimmune encephalitis, both paraneoplastic and non-paraneoplastic causes. HSV and other viral encephalitides are discussed separately. 

The epidemiology of tumour-related autoimmune encephalitis mimics that of the underlying malignancy. Those with non-tumour related autoimmune encephalitis have a variable epidemiology but are mostly young patients with a female predilection 8.

Various autoimmune encephalitides may be associated with an underlying malignancy or tumour, more commonly in those with antibodies against intracellular antigens 21.

The clinical presentation of autoimmune encephalitis is incredibly varied, with potential manifestations including subacute development of 2,8:

  • seizures and epilepsy, including new-onset refractory status epilepticus (NORSE)

  • mental status change

  • psychiatric symptoms (e.g. psychosis, depression and behaviour disorder)

    • the presence of psychiatric symptoms is particularly helpful in distinguishing limbic encephalitis from herpetic encephalitis, which otherwise can present similarly, albeit usually more acutely 8

  • memory disturbance

  • focal neurological deficits (e.g. cerebellar dysfunction, signs localising to the brainstem)

  • movement disorders

  • sleep disorders

Autoimmune encephalitis can be divided according to the presence or absence of an underlying tumour, or on the type of antibody responsible.

Causes of paraneoplastic autoimmune encephalitis include 8,9:

Causes of non-paraneoplastic autoimmune encephalitis include:

Another way of dividing autoimmune encephalitis is on the grounds of whether the antibodies are against intracellular antigens or cell surface antigens 21. The antibodies, in turn, correlate both to an underlying cause and pattern of involvement 8,9. As a general rule, antibodies targeted to intracellular antigens are more frequently associated with an underlying tumour 9

  • group I - antibodies to intracellular antigens

    • anti-Hu (ANNA-1) antibodies 21

    • anti-Ma (Ta) antibodies 21

    • anti-CV2 (CRMP-5) antibodies 21

    • anti-GAD65 (glutamic acid decarboxylase 65) antibodies 21

      • rarely associated with tumours

      • presents with stiff person syndrome, limbic encephalitis, or cerebellar ataxia

    • anti-amphiphysin antibodies 21

    • anti-Ri (ANNA-2) antibodies 21

    • anti-Yo (PCA1) antibodies 21

    • anti-Tr (DNER) antibodies 21

    • anti-Zic4 antibodies 14

    • anti-KLHL11 (Kelch-like protein 11) antibodies 13,21

    • anti-SOX1 (Sry-like high mobility group box 1) antibodies 21

    • anti-ANNA-3 antibodies 21

    • aneti-PCA-2 (MAP1B) antibodies 24

    • anti-Homer-3 antibodies 23

      • very rare and unclear if there are any associations with underlying tumour or malignancy

      • presents with cerebellar ataxia

    • anti-GFAP (glial fibrillary acid protein) antibodies (autoimmune GFAP astrocytopathy) 15

      • usually not associated with tumours, but ovarian teratoma is most common

      • broad clinical phenotype including meningoencephalitis or meningoencephalomyelitis

    • anti-neurochondrin antibodies 25,26

      • very rare and unclear if there are any associations with underlying tumour or malignancy

      • presents with cerebellar ataxia, rhombencephalitis, chorea, neuropathy, or myelitis

    • anti-ITPR-1 (inositol trisphosphate receptor 1) antibodies 25,27

      • very rare and unclear if there are any associations with underlying tumour or malignancy

      • presents with cerebellar ataxia or neuropathy

    • anti-ARHGAP26 (RhoGTPase-activating protein 26) antibodies 25,28

      • very rare and unclear if there are any associations with underlying tumour or malignancy

      • presents with cerebellar ataxia or psychosis

    • anti-AP3B2 (adaptor protein-3 beta-2) antibodies 25,30

      • very rare and unclear if there are any associations with underlying tumour or malignancy

      • presents with cerebellar ataxia or neuropathy

  • group II - antibodies to cell surface antigens

    • anti-NMDAR (N-methyl-D-aspartic acid receptor) antibodies 21

      • common

      • may be associated with underlying tumours (e.g. ovarian teratoma) in older patients, but younger patients may not have any underlying tumour

      • presents with psychiatric symptoms initially, followed by limbic encephalitis, movement disorders, and dysautonomia

      • mild or often absent imaging changes are common

    • anti-VGKC (voltage-gated potassium channel) antibodies 21

      • common

      • two types:

        • anti-LGI1

          • usually not associated with underlying tumour or malignancy

          • presents with limbic encephalitis with often specific seizure types (e.g. faciobrachial dystonic seizures, autonomic seizures), hyponatraemia

        • anti-CASPR2

    • anti-GABA (gamma-aminobutyric acid) antibodies 21

    • anti-AMPAR (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor) antibodies 21

    • anti-D2R (dopamine-2 receptor) antibodies 21

      • usually not associated with underlying tumour or malignancy

      • presents with parkinsonsim (basal ganglia encephalitis)

    • anti-GlyR (glycine receptor) antibodies 21

      • usually not associated with underlying tumour or malignancy

      • presents with stiff person syndrome, or progressive encephalomyelitis with rigidity and myoclonus (PERM)

    • anti-mGluR1(metabotropic glutamate receptor 1) antibodies 21

    • anti-mGluR5 (metabotropic glutamate receptor 5) antibodies 21

    • anti-GluR3 (glutamate receptor 3) antibodies 22

    • anti-DPPX (dipeptidyl-peptidase–like protein 6) antibodies 16,21

      • usually not associated with underlying tumour or malignancy

      • presents with encephalopathy with hyperekplexia, myoclonus, tremor; often has a prodrome of gastrointestinal upset and weight loss

    • anti-IgLON5 (immunoglobulin LSAMP, OBCAM, neurotrimin 5) antibodies 17,21

      • usually not associated with underlying tumour or malignancy

      • presents with a broad phenotype including sleep disorder, bulbar dysfunction, and cognitive impairment

    • anti-VGCC (voltage-gated calcium channel) antibodies 21

    • anti-AK5 (adenylate kinase 5) antibodies 18

      • very rare and unclear if there are any associations with underlying tumour or malignancy

      • presents with limbic encephalitis

    • anti-SEZ6L2 (seizure-related 6 homolog like 2) antibodies 19

      • very rare and unclear if there are any associations with underlying tumour or malignancy

      • presents with cerebellar ataxia

    • anti-neurexin-3-alpha antibodies 20

      • very rare and unclear if there are any associations with underlying tumour or malignancy

      • presents with a clinical phenotype that may mimic anti-NMDAR encephalitis

    • anti-septin-5 antibodies 25,29

      • very rare and unclear if there are any associations with underlying tumour or malignancy

      • presents with cerebellar ataxia

    • anti-septin-7 antibodies 31

      • very rare and unclear if there are any associations with underlying tumour or malignancy

      • presents with encephalopathy

Many cases have no imaging findings, especially early in the course of the disease. However, MRI with contrast is considered the most sensitive imaging modality, and findings are present in over half of individuals 8.   

As the older term limbic encephalitis implies, the most common location of involvement is the mesial temporal lobes and limbic systems, typically manifested by cortical thickening and increased T2/FLAIR signal intensity of these regions. Bilateral involvement is most common (60%), although often asymmetric 8. The lateral temporal lobe and insula are less commonly involved, whereas the basal ganglia, in contrast, are frequently involved, helpful in distinguishing it from HSV encephalitis which characteristically spares the basal ganglia 8.

In addition to the aforementioned T2/FLAIR changes, patchy areas of enhancement can be seen post-gadolinium ref. True diffusion restriction (i.e. low ADC values) and haemorrhage are not common and suggest alternative diagnoses ref. The presence of haemorrhage on SWI, for example, favours other diagnoses such herpes simplex encephalitis.

Although less common, essentially any part of the central nervous system can be involved in autoimmune encephalitis 9. This is particularly important in autoimmune encephalitides which are not presenting with the classic limbic encephalitis phenotype.

PET-CT may show increased FDG uptake 4

Management is predominantly with immunotherapy, options including high-dose glucocorticoids, intravenous immunoglobulin, plasmapharesis, cyclophosphamide, and rituximab 11,12. Symptomatic management (e.g. of seizures with anti-seizure medications) and neurological rehabilitation are also important therapies 11.

General imaging differential considerations include:

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