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 tumor:
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
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Terminology
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.
Epidemiology
The epidemiology of tumor-related autoimmune encephalitis mimics that of the underlying malignancy. Those with non-tumor related autoimmune encephalitis have a variable epidemiology but are mostly young patients with a female predilection 8.
Associations
Various autoimmune encephalitides may be associated with an underlying malignancy or tumor, more commonly in those with antibodies against intracellular antigens 21.
Clinical presentation
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
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psychiatric symptoms (e.g. psychosis, depression and behavior 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 localizing to the brainstem)
movement disorders
sleep disorders
Pathology
Autoimmune encephalitis can be divided according to the presence or absence of an underlying tumor, or on the type of antibody responsible.
Associated tumors
Causes of paraneoplastic autoimmune encephalitis include 8,9:
small cell lung cancer (classic cause): e.g. anti-Hu antibodies
testicular germ cell tumor: e.g. anti-Ma antibodies
ovarian tumors (e.g. ovarian carcinoma and ovarian teratoma)
hematological malignancies (e.g. Hodgkin lymphoma)
gastrointestinal malignancies
Causes of non-paraneoplastic autoimmune encephalitis include:
specific antibodies (see below)
systemic autoimmune conditions, e.g. systemic lupus erythematosus (SLE)
Specific antibodies
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 tumor 9.
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group I - antibodies to intracellular antigens
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anti-Hu (ANNA-1) antibodies 21
most common
associated with small cell lung cancer (in 75% of cases)
presents with encephalomyelitis, subacute sensory neuronopathy, or cerebellar degeneration
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anti-Ma (Ta) antibodies 21
better prognosis than anti-Hu
associated with small cell lung cancer (anti-Ma1), testicular tumors (anti-Ma2)
presents with limbic encephalitis, rhombencephalitis, or cerebellar degeneration
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anti-CV2 (CRMP-5) antibodies 21
associated with small cell lung cancer and malignant thymoma
involvement of the striatum prominent
presents with encephalomyelitis, cerebellar degeneration, or choreiform movement disorders
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anti-GAD65 (glutamic acid decarboxylase 65) antibodies 21
rarely associated with tumors
presents with stiff person syndrome, limbic encephalitis, or cerebellar ataxia
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anti-amphiphysin antibodies 21
associated with small cell lung cancer, breast cancer
presents with stiff person syndrome or limbic encephalitis
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anti-Ri (ANNA-2) antibodies 21
associated with small cell lung cancer, breast cancer
presents with opsoclonus-myoclonus syndrome, encephalomyelitis, or cerebellar ataxia
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anti-Yo (PCA1) antibodies 21
associated with ovarian cancer, breast cancer
presents with cerebellar degeneration
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anti-Tr (DNER) antibodies 21
associated with Hodgkin lymphoma
presents with cerebellar degeneration
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anti-Zic4 antibodies 14
associated with small cell lung cancer
presents with cerebellar degeneration
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anti-KLHL11 (Kelch-like protein 11) antibodies 13,21
associated with testicular tumors, ovarian cancer
presents with rhombencephalitis
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anti-SOX1 (Sry-like high mobility group box 1) antibodies 21
associated with small cell lung cancer
presents with cerebellar degeneration
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anti-ANNA-3 antibodies 21
associated with small cell lung cancer
presents with limbic encephalitis, encephalomyelitis, or cerebellar degeneration
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aneti-PCA-2 (MAP1B) antibodies 24
associated with small cell lung cancer
presents with cerebellar ataxia, limbic encephalitis, or neuropathy
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anti-Homer-3 antibodies 23
very rare and unclear if there are any associations with underlying tumor or malignancy
presents with cerebellar ataxia
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anti-GFAP (glial fibrillary acid protein) antibodies (autoimmune GFAP astrocytopathy) 15
usually not associated with tumors, but ovarian teratoma is most common
broad clinical phenotype including meningoencephalitis or meningoencephalomyelitis
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anti-neurochondrin antibodies 25,26
very rare and unclear if there are any associations with underlying tumor or malignancy
presents with cerebellar ataxia, rhombencephalitis, chorea, neuropathy, or myelitis
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anti-ITPR-1 (inositol trisphosphate receptor 1) antibodies 25,27
very rare and unclear if there are any associations with underlying tumor or malignancy
presents with cerebellar ataxia or neuropathy
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anti-ARHGAP26 (RhoGTPase-activating protein 26) antibodies 25,28
very rare and unclear if there are any associations with underlying tumor or malignancy
presents with cerebellar ataxia or psychosis
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anti-AP3B2 (adaptor protein-3 beta-2) antibodies 25,30
very rare and unclear if there are any associations with underlying tumor or malignancy
presents with cerebellar ataxia or neuropathy
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group II - antibodies to cell surface antigens
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anti-NMDAR (N-methyl-D-aspartic acid receptor) antibodies 21
common
may be associated with underlying tumors (e.g. ovarian teratoma) in older patients, but younger patients may not have any underlying tumor
presents with psychiatric symptoms initially, followed by limbic encephalitis, movement disorders, and dysautonomia
mild or often absent imaging changes are common
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anti-VGKC (voltage-gated potassium channel) antibodies 21
common
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two types:
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anti-LGI1
usually not associated with underlying tumor or malignancy
presents with limbic encephalitis with often specific seizure types (e.g. faciobrachial dystonic seizures, autonomic seizures), hyponatremia
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anti-CASPR2
may be associated with thymoma
presents with limbic encephalitis, Isaacs syndrome, Morvan syndrome
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anti-GABA (gamma-aminobutyric acid) antibodies 21
similar to VGKC but less common
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two subtypes:
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usually not associated with underlying tumor or malignancy
presents with refractory epilepsy
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GABAB
may be associated with small cell lung cancer
presents with limbic encephalitis or opsoclonus-myoclonus syndrome
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anti-AMPAR (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor) antibodies 21
may be associated with small cell lung cancer, breast cancer, thymoma
presents with limbic encephalitis
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anti-D2R (dopamine-2 receptor) antibodies 21
usually not associated with underlying tumor or malignancy
presents with parkinsonsim (basal ganglia encephalitis)
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anti-GlyR (glycine receptor) antibodies 21
usually not associated with underlying tumor or malignancy
presents with stiff person syndrome, or progressive encephalomyelitis with rigidity and myoclonus (PERM)
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anti-mGluR1(metabotropic glutamate receptor 1) antibodies 21
may be associated with Hodgkin lymphoma
presents with cerebellar ataxia
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anti-mGluR5 (metabotropic glutamate receptor 5) antibodies 21
may be associated with Hodgkin lymphoma
presents with limbic encephalitis (known as Ophelia syndrome in this setting)
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anti-GluR3 (glutamate receptor 3) antibodies 22
associated with Rasmussen encephalitis
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anti-DPPX (dipeptidyl-peptidase–like protein 6) antibodies 16,21
usually not associated with underlying tumor or malignancy
presents with encephalopathy with hyperekplexia, myoclonus, tremor; often has a prodrome of gastrointestinal upset and weight loss
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anti-IgLON5 (immunoglobulin LSAMP, OBCAM, neurotrimin 5) antibodies 17,21
usually not associated with underlying tumor or malignancy
presents with a broad phenotype including sleep disorder, bulbar dysfunction, and cognitive impairment
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anti-VGCC (voltage-gated calcium channel) antibodies 21
may be associated with small cell lung cancer
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presents with cerebellar ataxia
antibodies also implicated in Lambert-Eaton myasthenic syndrome
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anti-AK5 (adenylate kinase 5) antibodies 18
very rare and unclear if there are any associations with underlying tumor or malignancy
presents with limbic encephalitis
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anti-SEZ6L2 (seizure-related 6 homolog like 2) antibodies 19
very rare and unclear if there are any associations with underlying tumor or malignancy
presents with cerebellar ataxia
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anti-neurexin-3-alpha antibodies 20
very rare and unclear if there are any associations with underlying tumor or malignancy
presents with a clinical phenotype that may mimic anti-NMDAR encephalitis
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anti-septin-5 antibodies 25,29
very rare and unclear if there are any associations with underlying tumor or malignancy
presents with cerebellar ataxia
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anti-septin-7 antibodies 31
very rare and unclear if there are any associations with underlying tumor or malignancy
presents with encephalopathy
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Radiographic features
MRI
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 hemorrhage are not common and suggest alternative diagnoses ref. The presence of hemorrhage on SWI, for example, favors 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.
Nuclear medicine
PET-CT may show increased FDG uptake 4.
Treatment and prognosis
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.
Differential diagnosis
General imaging differential considerations include:
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acute, often dramatic time course
fever
psychiatric symptoms uncommon
basal ganglia spared
may have hemorrhage
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acute, often dramatic time course
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tumor
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low-grade astrocytoma
if localized to the temporal lobe, appearances can be very similar
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diffuse T2 hyperintensity involving multiple contiguous lobes
no predilection for the limbic system
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Hashimoto encephalopathy (steroid-responsive encephalopathy associated with autoimmune thyroiditis)
sometimes considered to be a form of autoimmune encephalitis