Autoimmune encephalitis, also known as autoimmune limbic encephalitis, is an antibody-mediated brain inflammatory process, typically involving the limbic system, although all parts of the brain 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 outcomes
On this page:
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 encephalitis is 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.
In approximately 60% of cases, antineuronal antibodies are present such as the anti-Hu antibody in small cell lung cancer, the anti-Ta antibody in testicular cancers, anti-NMDA NR1 in ovarian teratomas or anti-NMDA NR2 in SLE patients.
Clinical presentation
The clinical presentation of autoimmune encephalitis is incredibly varied, with potential manifestations including 2,8:
mental status change
-
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
seizures
memory disturbance
focal neurological deficits (e.g. cerebellar dysfunction, signs localizing to the brainstem)
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 carcinoma of the lung (classic cause): anti-Hu antibodies
testicular germ cell tumor: anti-Ta 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:
voltage-gated potassium channel (VGKC) antibody encephalitis
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. 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.
-
group I - antibodies to intracellular antigens
-
anti-Hu antibodies
most common
small cell carcinoma of the lung in 75% of cases
anti-Hu syndrome consists of paraneoplastic encephalomyelitis, paraneoplastic sub-acute sensory neuropathy, and paraneoplastic cerebellar degeneration
-
anti-Ma/Ta antibodies
better prognosis than anti-Hu
diencephalic and brainstem involvement more common
ophthalmoplegia is common
-
anti-CV2 antibodies
involvement of the striatum prominent
choreiform movement disorders common
-
anti-GAD (glutamic acid decarboxylase) antibodies
usually not associated with tumors
usually classical limbic involvement with prominent seizures and stiff person syndrome
-
anti-amphiphysin antibodies
myelopathy, myoclonus and stiff person syndrome
-
anti-Ri antibodies
brainstem involvement
-
anti-Yo antibodies
typically presents with paraneoplastic cerebellar degeneration
-
-
group II - antibodies to surface antigens
-
common
usually in children and young women with no underlying tumor
older patients may have underlying tumors (e.g. ovarian teratoma)
typically present with psychiatric symptoms
mild or often absent imaging changes
-
anti-VGKC (voltage-gated potassium channel) antibodies
common
two types of antibodies: anti-LGI1, anti-CASPR2
classic features of "limbic encephalitis" with prominent seizures
extra-limbic involvement very uncommon
-
anti-GABA (gamma-aminobutyric acid) antibodies
similar to VGKC but less common
-
two subtypes:
-
frequent extralimbic involvement
-
GABAB
not infrequent underlying cancer (pulmonary neuroendocrine tumors)
-
-
anti-AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) antibodies
predominantly psychiatric symptoms
imaging changes limited to the hippocampi
-
anti-D2 dopamine antibodies
basal ganglia encephalitis
-
anti-GlyR1 (glyoxylate reductase) antibodies
stiff leg syndrome or stiff person syndrome, or progressive encephalomyelitis with rigidity and myoclonus
-
anti-mGluR1(metabotropic glutamate receptor) antibodies
lymphoma with cerebellar ataxia
-
anti-mGluR5 antibodies
associated with Ophelia syndrome
-
anti-GluR3 (glutamate receptor) antibodies
associated with Rasmussen encephalitis
-
Radiographic features
MRI
Many cases have no imaging findings, especially early in the course of the disease. Having said that, 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. Although far less common, essentially any part of the central nervous system can be involved 9.
Patchy areas of enhancement can be seen.
True diffusion restriction (i.e. low ADC values) and hemorrhage are not common and suggest alternative diagnoses.
The presence of hemorrhage on susceptibility-weighted images is in favor of other diagnoses such herpes simplex encephalitis which has otherwise very similar imaging appearance to limbic encephalitis.
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:
-
acute, often dramatic time course
fever
psychiatric symptoms uncommon
basal ganglia spared
-
acute, often dramatic time course
-
tumor
-
low-grade astrocytoma
if localized to the temporal lobe, appearances can be very similar
-
diffuse T2 hyperintensity involving multiple contiguous lobes
no predilection for the limbic system
-
Unable to process the form. Check for errors and try again.