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Autoimmune Encephalitis with Antibodies to Cell Surface Antigens
Autoimmune encephalitis with antibodies to neuronal cell surface/synaptic antigens (further referred to as autoimmune encephalitis) are a group of neuropsychiatric disorders ( Table 82.1 ) in which the antibodies produce neuronal dysfunction by direct interaction with their target antigen ( ). These disorders can occur with and without a cancer association and while they affect individuals of all ages, some syndromes preferentially affect young adults and children ( ; ). The antibody effects are reversible and although the process of recovery can be prolonged, patients with autoimmune encephalitis often have full or substantial recovery after immunotherapy. Autoimmune encephalitis syndromes are therefore different from the classical paraneoplastic encephalitis that are always cancer associated and in which the associated antibodies target intracellular neuronal proteins but do not directly mediate the neuronal dysfunction. Rather in the classical paraneoplastic encephalitis, T-cell mechanisms appear to play a predominant role and the neuronal effects are often irreversible ( ).
TABLE 82.1
Autoimmune Encephalitis with Antibodies to Cell Surface Antigens
| Antigen Target | Syndrome | Other Associations | Responses to Immunotherapies |
|---|---|---|---|
| NMDA receptor | Psychiatric symptoms, seizures, memory deficits, decreased level of consciousness, dyskinesias, seizures, and autonomic disturbances | Predominantly affects young adults, teenagers, and children with an age-related association with ovarian teratoma | Almost 80% of cases have full or substantial recoveries. Improvement occurs slowly and can continue for over 18 months |
| GABA B receptor | Limbic encephalitis with prominent seizures | Median age 62 years. About 50% of the patients have an associated cancer (SCLC or other neuroendocrine tumor). Frequent coexisting autoimmunities | Patients can have full or partial recovery, but this is dependent on tumor control |
| AMPA receptor | Limbic encephalitis with prominent psychiatric symptoms | Predominantly affects middle-aged women; about 70% with an associated cancer (breast, thymus, lung) | About 70% improve with therapy, but neurological relapses without tumor recurrence are frequent and lead to cumulative disability |
| LGI1 | Limbic encephalitis. About 60% develop hyponatremia, and less often REM behavior disorder. About 30%–40% patients faciobrachial dystonic seizures that precede the limbic encephalitis. | Median age 60 years (men > women). Less than 10% have an underlying tumor (usually thymoma) | Almost 80% have recovery but are often left with residual memory or cognitive deficits |
| CASPR2 | Morvan syndrome, limbic encephalitis, neuropathic pain, peripheral nerve hyperexcitability | Frequent coexisting autoimmunities | About 70% have full or substantial recovery |
| GABA A receptor | Rapidly progressive, severe encephalopathy with refractory seizures | Extensive MRI FLAIR/T2 cortical-subcortical abnormalities. Frequent coexisting autoimmunities (TPO, GAD antibodies) | Half of patients have good response to immunotherapy, but patients may die from medical complications during status |
| DPPX | Agitation, paranoia, hallucinations, tremor, myoclonus, and/or seizures. Less often cerebellar signs, hyperekplexia, or PERM-like syndrome. Symptoms are usually preceded by severe diarrhea | Protracted course with relapses when immunotherapy is reduced | Partial but meaningful improvement |
| mGluR5 | Encephalitis, no specific syndrome | Hodgkin lymphoma or no tumor | Full recovery |
| mGluR1 | Cerebellar ataxia | No tumor or rarely lymphoma | May respond to immunotherapy |
| Dopamine receptor 2 | Infrequent cases of basal ganglia encephalitis, Sydenham chorea | No tumor association | Improvement or full recovery with early immunotherapy |
| Neurexin 3α | Encephalopathy with seizures | No tumor association | May partially respond to immunotherapy |
| IgLON5 | Encephalopathy with REM and non-REM parasomnias, obstructive sleep apnea, stridor preceded by or concurrent with gait dysfunction, chorea, and cognitive decline | Usually chronic and slowly progressive, less often rapidly progressive | Largely unresponsive to immunotherapy. Patients usually have sudden death during wakefulness |
AMPA, Alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor; CASPR2, contactin-associated protein-like 2; DPPX, dipeptidyl-peptidase-like protein 6; FLAIR , fluid attenuated inversion recovery; GABA A , Gamma-aminobutyric acid-A; GABA B , Gamma-aminobutyric acid-B; GAD , glutamic acid decarboxylase; IGLON5 , immunoglobulin-like cell adhesion molecule 5; LGI1, leucine-rich glioma-inactivated protein-1; mGluR5, metabotropic glutamate receptor 5; mGluR1, metabotropic glutamate receptor 1; MRI , magnetic resonance imaging; NMDA, N -methyl- d -aspartate; PERM, progressive encephalomyelitis with rigidity and myoclonus; REM, rapid eye movement. SCLC , small-cell lung cancer; TPO , thyroid peroxidase.
Patients with autoimmune encephalitis develop complex neuropsychiatric symptoms including memory loss, changes in behavior or cognition, psychosis, seizures, and movement disorders. At presentation one or a few of these symptoms may predominate and can mislead the diagnosis until additional symptoms develop over days or weeks. Patients may initially be diagnosed with idiopathic encephalitis, likely viral but with negative viral studies. Autoimmune encephalitis should be included in the differential diagnosis of any patient, especially if young, with a rapidly progressive encephalopathy of unclear origin. For some disorders such as anti- N -methyl- d -aspartate receptor (NMDAR) encephalitis, patients may initially be given a primary psychiatric diagnosis, and the accompanying signs and symptoms such as abnormal movements or fever erroneously ascribed to the use of antipsychotic medication ( ; ). Some patients with autoimmune encephalitis, especially those with NMDAR antibodies, experience a viral-like prodrome including lethargy, headache, upper respiratory symptoms, nausea, diarrhea, among others ( ). In some but not all cases supporting findings such as inflammatory signs in cerebrospinal fluid (CSF) or the presence of oligoclonal bands can be useful. Abnormalities on magnetic resonance imaging (MRI) fluid-attenuated inversion recovery (FLAIR) sequences are more commonly seen in some syndromes than others, as discussed below. Any immunological type of autoimmune encephalitis can have a relapsing course and therefore the diagnosis of these disorders should be considered in a patient with a past history of encephalitis or relapsing encephalopathy.
The diagnosis of autoimmune encephalitis is confirmed by the presence of specific neuronal cell surface/synaptic antibodies in serum and CSF. While some laboratories state that evaluation of serum is sufficient, this is incorrect and CSF should always be included in the initial evaluation. A study of patients with anti-NMDAR encephalitis demonstrated that depending on how the testing was performed, up to 13% of CSF positive cases had no antibodies detectable in serum, and thus the diagnosis would have been missed (Gresa-Arribas et al., 2016). Institution of treatment should not be delayed until the results of antibody testing are available as this can negatively affect the outcome. Guidelines for the diagnosis of autoimmune encephalitis based on standard neurological assessment and routinely available laboratory testing are available ( ). Based on the level of evidence, therapy should be initiated promptly and then adjusted when antibody results become available.
The immunological trigger of autoimmune encephalitis is varied and, in many cases, is yet to be established. In some patients, the presence of a systemic tumor that expresses the target neuronal/synaptic proteins appears to be important. About 25% of patients with herpes simplex viral encephalitis develop autoimmune encephalitis after recovery from the viral infection ( ). Specific human leukocyte antigen (HLA) associations have been reported for anti-LGI1 encephalitis, anti-CASPR2 encephalitis, and anti-IgLON5 disease ( ; ). There are some patients in whom autoimmune encephalitis overlaps with demyelinating disorders ( ); whether there is a relationship between the two syndromes is not yet clear.
Specific Syndromes
Anti-NMDAR Encephalitis
Anti-NMDAR encephalitis is the most frequent antibody-associated encephalitis and the second most common cause of immune-mediated encephalitis after acute disseminated encephalomyelitis (ADEM) ( ). It is most common in young women and children who represent about 80% of patients but can also affect men and older individuals. The syndrome is highly characteristic and usually occurs as a multistage process. Patients develop acute psychiatric symptoms, seizures, memory deficits, decreased level of consciousness, and dyskinesias (orofacial, limb, and trunk) ( ; ). Autonomic instability is common, and, in some patients, it results in central hypoventilation, often requiring weeks of mechanical ventilation. Many adults are initially evaluated by psychiatry services. Patients or their families should be questioned about a viral-like prodrome that can elevate the suspicion for an autoimmune process. Children are often brought to medical attention due to mood and behavioral change at times with new-onset seizures, movement disorders, insomnia, or reduction of speech. Partial syndromes with predominant psychiatric symptoms or abnormal movements, and less severe phenotypes can occur, although almost all patients eventually develop several elements of the syndrome ( ; ). Atypical symptoms, such as cerebellar ataxia or hemiparesis, can occur and are more common in children than in adults. Approximately 40% of female patients over 18 years have uni- or bilateral ovarian teratomas compared to less than 9% of girls under 14 years of age. Younger children and men only rarely have tumors. Isolated cases with other tumor types—including teratoma of the mediastinum, small-cell lung cancer (SCLC), Hodgkin lymphoma, neuroblastoma, breast cancer, and germ-cell tumor of the testis—have been reported ( ).
In almost 80% of patients the CSF shows lymphocytic pleocytosis and, less commonly, increased proteins and/or oligoclonal bands. About 35% of the patients have increased signal on MRI FLAIR/T2 sequences and less often, faint or transient contrast enhancement of the cerebral cortex, overlaying meninges, basal ganglia, or brainstem. The electroencephalogram (EEG) is abnormal in 95% of cases and usually shows focal or generalized slow or disorganized activity without epileptic discharges that may overlap with electrographic seizures ( ). About 10%–30% of patients have a unique EEG pattern called extreme delta brush due to its similarity to the delta brush pattern seen in neonatal EEG ( ). This pattern may be associated with prolonged illness and the finding of extreme delta brush in a patient with an undiagnosed encephalopathy should raise consideration for anti-NMDAR encephalitis.
Diagnosis of the disorder is confirmed by demonstration of NMDAR antibodies in CSF and serum ( Fig. 82.1 ). As noted above, testing of CSF should be done for all initial evaluations ( ). The antibodies are immunoglobulin G (IgG) subtype and target the GluN1 (previously called NR1) subunit of the NMDAR. These antibodies are highly specific for anti-NMDAR encephalitis and are different from other less nonspecific and unrelated immunoglobulin M (IgM) and immunoglobulin A (IgA) anti-NMDA antibodies, or IgG antibodies that target other NMDAR subunits such as the GluN2 ( ). The pathogenicity of the antibodies has been shown in vitro and in vivo animal models. These studies show that the antibody binding to the NMDAR results in a reversible internalization of NMDARs that associates with a reduction of NMDAR-mediated currents ( ; )
Anti-GABA B Receptor Encephalitis
Anti-gamma-aminobutyric acid B receptor (GABA B R) encephalitis similarly affects men and women and more than half have an associated tumor, almost always a SCLC ( ). When the disorder is cancer-related, the onset of the encephalitis usually precedes the cancer diagnosis. The median age of patients in one study was 62 years, with older patients more likely to have cancer. The presenting features are almost always those of typical limbic encephalitis with memory loss, confusion, and prominent seizures ( ; ). Rare cases presenting with ataxia or opsoclonus-myoclonus have been reported, but in these cases the syndrome progresses to include limbic encephalitis ( ). Most seizures appear to have a temporal-lobe onset with secondary generalization, while some patients have status epilepticus or subclinical seizures demonstrated on EEG.
The brain MRI is abnormal is almost two-thirds of the patients, showing unilateral or bilateral medial temporal lobe FLAIR/T2 signal, which is consistent with limbic encephalitis. As in other autoimmune encephalitis, the CSF can show lymphocytic pleocytosis.
In addition to the presence of GABA B R antibodies, these patients may have other autoantibodies (e.g., TPO, ANA, GAD65) reflecting a tendency to autoimmunity or the presence of an underlying cancer (e.g., Sox1, amphiphysin, and/or Ri antibodies). In contrast to NMDAR antibodies, patient GABA B R antibodies act as selective GABA B R antagonists without causing receptor internalization ( ).
Patients who receive immunotherapy together with tumor control often have full or substantial recoveries, including cases where treatment is delayed by several months. A previously healthy 3-year-old child developed GABA B R and GABA A R antibodies with opsoclonus, limb and trunk ataxia, and seizures; he died as a result of sepsis while receiving intensive care support ( ; ).
Anti-AMPA Receptor Encephalitis
Anti-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) encephalitis predominantly affects middle-aged women (median age 62 years). Just over half the patients present with subacute (<8 weeks) symptoms of limbic encephalitis including confusion, disorientation, and memory loss ( ; ). Other patients present with limbic dysfunction in association with multifocal or diffuse encephalopathy. Unusual presentations (psychosis, motor dysfunction) have also been reported ( ; ). Seizures have been reported in under half of cases. About 60% of the patients have an underlying tumor, most often in the lung, breast, or thymus. The antibodies target the GluA1/2 subunits of the AMPAR. The binding of patient antibodies to the AMPAR results in receptor internalization; compensatory changes include insertion of GluA1 homomers in the synapses, increasing synaptic excitability ( ).
The brain MRI usually shows abnormal FLAIR signal involving the medial temporal lobes, rarely with transient signal changes in other areas. The CSF often reveals lymphocytic pleocytosis. In one reported series, half of the patients had a history of, or concurrent findings of, systemic autoimmunity such as insulin-dependent diabetes with glutamic acid decarboxylase (GAD) antibodies, hypothyroidism, or Raynaud syndrome ( ). As in GABA B R encephalitis, the presence of additional paraneoplastic immune responses related to cytotoxic T-cell mechanisms is associated with worse outcome ( ).
The majority of patients respond to immunotherapy; however, approximately half have relapses. Those with relapses usually respond to treatment, but these responses are often partial, resulting in cumulative memory or behavioral deficits. It is unclear if chronic immunosuppression has a role in preventing or reducing the risk of relapses.
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