Autoimmune encephalitis (AIE) is a group of neurological diseases caused by autoantibodies directed against brain neurons.
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Classification based on antibody type
They may be divided into several types, for example, one type is paraneoplastic disorders caused by antibodies that are directed against intracellular antigens found in association with underlying tumors. Paraneoplastic disorders have poor prognoses due largely to the malignancy itself and to neuronal death by the immunologic reaction, which is T-cell mediated rather than antibody-caused.
The second type consists of neurologic disturbances are caused by cell surface antigen-antibody reactions. This is when autoantibodies are produced against molecules on the surface of the neuron, such as ion channels or receptors.
While these are also often found to be associated with underlying cancers, they generally have a relatively good outcome and neuronal death is rare. The clinical manifestations are due to reversible effects on synaptic nerve transmission and removal of these antibodies causes symptom remission.
A third group includes encephalitis due to antibodies against synaptic proteins inside the neuron, while a fourth group contains those autoimmune encephalitides without identified antigens.
Classification based on clinically predominant features
Most of the conditions in the second group have common features of limbic inflammation. These include:
- Short-term memory impairment
- Behavioral aberrations
- Psychiatric manifestations
Those which do not have such symptoms include:
- Dopamine-receptor D2
Specific syndromes due to antibodies to cell surface antigens
Anti-NMDAR has become the leading AIE since it was first described in 2007, and is most common in women (80%) and 95% of patients are below the age of 45 years. In patients below the age of 12 or older than 45 years, however, there is an almost equal proportion of males and females.
A prodrome is present in half the patients, consisting of fever, headache, nausea and vomiting, which are followed by psychiatric and behavioral abnormalities a few days later in 95% of patients. Memory impairment, seizures and abnormal movements are quite frequent occurring in 60-90% of patients and may even initiate the clinical phase.
This phase consists of dyskinesias of the face and tongue, choreoathetoid movements, dystonia and generalized rigidity. Up to 70% of patients eventually develop difficulties with breathing, or abnormalities of the vital parameters, with loss of consciousness and status epilepticus being very common. Central hypoventilation and hemiparesis are more frequent in adults and children, respectively.
MRI imaging is nonspecific or normal, but CSF (cerebrospinal fluid) shows lymphocytic pleocytosis in almost all cases, with oligoclonal bands in many. The first is more frequent in the early stages while the latter occurs later in the disease course.
An electroencephalogram shows generalized slowing, usually diffuse or sometimes focal, and in a third of patients the pathognomonic finding called the ‘extreme delta brush’ pattern is seen, on which the diffuse generalized slowing is superimposed by beta-waves. A brain PET using fluorodeoxyglucose shows increased activity in the frontal and temporal regions, which increases with the severity of the condition.
LGI1 antibody-associated encephalitis
Limbic encephalitis is most commonly associated with these leucine-rich, glioma-inactivated 1 (LGI1) antibodies, and this affects men above 60 years, who outnumber women by a ratio of 3:1. The most common presentation is with myoclonus or tonic seizures, especially faciobrachial dystonic seizures, which denote the onset of encephalitis, a tenth have autonomic symptoms and low sodium levels occur in about 60%.
CSF shows no abnormalities on routine examination, but antibody testing is positive. The EEG is generally abnormal and shows seizure activity as well as slowing, either diffuse or focal delta waves. MRI findings show findings of limbic encephalitis, such as T2-FLAIR abnormalities in the medial half of the temporal lobe.
CASPR2 antibody-associated encephalitis
Anti-Caspr2 (contactin-associated protein-like 2) antibodies usually lead to slow-onset diffuse encephalitis and autonomic imbalance in many cases, as well as hyperexcitability of the peripheral nerves (in which case it is called Morvan’s syndrome). Neuropathic pain is seen in about 60% of cases and relapse is common following tapering of immunotherapy. Patients are typically about 60 years old.
AMPA antibody-associated encephalitis
Anti-AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptor encephalitis afflicts mostly middle aged women (90%), and manifests as limbic or psychiatric features. Though immunotherapy brings about remission, relapse is common in 60%.
Memory loss is common and complicates treatment, and often becomes irreversible after a few relapses have occurred, being accompanied by cognitive impairment. Underlying cancers of breast, lung and thymus are common.
Anti-GABA-B (γ-Aminobutyric acid B) receptor encephalitis is also a typical limbic encephalitis with seizures and memory loss, as well as behavioral aberrations, but status epilepticus or seizure activity is predominant due to the involvement of the inhibitory GABA receptors.
Occurring in older men and women, with an average age of 60 years, these patients often have other antibodies such as N-type voltage-gated calcium channels or glutamic acid decarboxylase antibodies. Lung cancer (small cell) is present in 50%, making this the most common immune encephalitis in this class of patients.
Anti-GABA-A (γ-Aminobutyric acid A) receptor encephalitis occurs in younger age groups, and presents as acute encephalitis with status epilepticus or epilepsy partialis continua when high levels of the antibody are present.
Anti-mGluR1 (metabotropic glutamate receptor 1) is rare, associated with paraneoplastic cerebellar involvement, and Hodgkin’s lymphoma is common.
Anti-mGluR5 (metabotropic glutamate receptor 5) have been reported in a few patients with Ophelia syndrome, which refers to mGluR5- antibody-associated limbic encephalitis with Hodgkin’s lymphoma. Confusion and disorientation to time is common but psychosis is rare.
Glutamic acid decarboxylase is a crucial enzyme in the synthesis of the major inhibitory neurotransmitter, GABA. GAD antibodies have been found in SPS, juvenile diabetes, limbic encephalitis and temporal lobe epilepsy. Young women are most often affected, and show high levels of antibodies. It may often co-occur with GABA(b)-receptor antibodies.
The role of GAD antibodies is not yet established, however, as they occur even in the normal population. Older patients with limbic encephalitis associated with GAD antibodies, or who also have GABA(b)-receptor antibodies, are at increased risk for small cell carcinoma of the lung or thymoma.
Anti-DNER (delta/notch-like epidermal growth factor-related receptor) is directed against a Purkinje neuron transmembrane protein and presents with cerebellar degeneration, which is often irreversible. Over 90% of these patients have Hodgkin lymphoma.
Anti-GlyR (Glycine receptor) antibodies occur in stiff-person syndrome (SPS), which may occur along a spectrum characterized by progressive encephalomyelitis with rigidity and myoclonus (PERM) at one end, and hyperekplexia at the other (pathologic startle response, or painful spasms brought on by touch, sound or emotional stimuli).
SPS is not specific for glycine-receptor antibodies, as GAD or amphiphysin antibodies are found in other clinical situations.
Anti-DPPX (dipeptidyl-peptidase-like protein-6) antibodies Dipeptidyl-peptidase-like protein-6 antibodies are directed against a part of a type of potassium channel and have diarrhea as a primary symptom along with limbic encephalitis. Hyperexcitability is also prominent, in addition to memory loss.
These are associated with basal ganglia inflammation in children and with Sydenham’s chorea.
Syndromes caused by antibodies to intracellular synaptic proteins
Anti-GAD65 (glutamic acid decarboxylase 65kd) antibodies are found in many situations and even in normal people, but high antibody levels are common in patients with neurologic symptoms. They can also be found in people with cancer syndromes and then are often associated with GABA(a) or GABA(b) autoantibodies.
Syndromes due to intracellular antigens
- Anti-Hu antibodies have the distinction of being the first onconeural antibody to be described. They present with neuropathy of sensory neurons, with or without cerebellar signs and encephalitis. Small cell cancer of the lung is very common.
- Anti-Ri (ANNA-2) antibodies present with encephalitis and/or cerebellar degeneration, and is usually linked to breast or lung cancer.
- Anti-Yo (PCA-1) antibodies occur in women suffering from ovarian or breast tumors, in 90% or more of cases, and they present with cerebellar degeneration.
- PCA-2 antibodies are seldom seen but may occur with encephalitis or cerebellar degeneration.
- Anti-CRMP-5 antibodies can present with cerebellar, cognitive, or choreiform symptoms, or cranial neuropathies.
- Anti-Ma2 antibodies occur in limbic encephalitis often in association with germ cell tumors in young males. Cerebellar and neuropathic presentations are also common.
- Susac’s syndrome, which is an autoimmune vasculopathy that causes clotting within the capillaries of the brain, as well as the retina and inner ear. Characteristic findings include occlusion of the branch retinal artery occlusions on fluorescein angiography, and snowball-like lesions or holes in the central corpus callosum on T2-weighted FLAIR imaging on MRI.
- Bickerstaff’s brainstem encephalitis includes subacute lapse of consciousness, ataxia and bilateral paralysis of eye movement, following an infection. Sometimes generalized limb weakness occurs. IgG anti-Q1b antibodies are specific for this disorder (along with Miller-Fisher syndrome) but is negative in almost a third of patients.
Clues to the existence of specific syndromes include:
- The relatively rapid development of memory impairment is a hallmark of limbic encephalitis, and is accompanied by confusion, mood changes, and seizures
- Existence of diarrhea in anti-dipeptidy-peptidase-like protein-6 antibodies
- Existence of ovarian teratoma in anti-NMDAR encephalitis
- Dystonic seizures of the face and arms in anti-LGI1 encephalitis
- Absence of initial inflammatory changes in LGI1 encephalitis
- Psychosis in anti-NMDAR/ AMPAR/GABA(b)R encephalitis
- Hyperekplexia in GlyR
- Status epilepticus in NMDAR, GABA(b) and GABA(a) antibodies
- New-onset type 1 diabetes mellitus in GAD65
- Muscle spasms or fasciculations, and neuromyotonia, in CASPR2
- SPS or exaggerated startle response in GAD65, GlyR
- Dystonia or chorea in NMDAR, D2R
- Cranial neuropathy in Hu, Ma2, Bickerstaff
- Cerebellitis in GAD65, Hu, VGCC
- Myoclonus/startle/delirium and diarrhea in dipeptidyl-peptidase-like protein-6 antibody