We report the clinical and immunological features of a new type of LE that associates with antibodies against GluR1/2 subunits of the AMPAR. The AMPAR are ionotropic glutamate receptors that are highly conserved among mammals, and mediate most of the fast excitatory neurotransmission in the brain.9
The majority of AMPAR are tetramers composed of GluR1, 2, 3 or 4 subunits that combine in a brain region-dependent manner.10
The regions with highest levels of GluR1/2 and GluR2/3 receptors are the synaptic CA3-CA1 areas of the hippocampus, followed by the subiculum, cerebellum, caudate-putamen, and cerebral cortex.11
This distribution is similar to the immunostaining of our patients' antibodies. Although GluR2 and GluR3 share sequence homology, our patients antibodies did not react with GluR3, a subunit that has been identified as an autoantigen in some patients with Rasmussen's encephalitis.12
In most respects the clinical presentation and MRI findings of anti-GluR1/2 associated encephalitis are typical of LE, and therefore this diagnosis was considered early in 9 patients. The other patient was suspected of having a rapidly progressive dementia but the MRI and antibody findings lead to the recognition of LE. Seven patients had tumors of the thymus, breast or lung, and an underlying neoplasm was excluded in the other 3 patients after extensive tumor screening. Although this follow-up may be too short to definitively exclude a neoplasm, the assessment of individual patients suggests that this disorder may occur as an autoimmune, non-paraneoplastic syndrome. For example, the patient with the shortest follow-up (8 months) is a 38 year-old woman that has fully recovered and has no risk factors for cancer. The only patient with risk factors for cancer (smoking) has been followed for 50 months without evidence for a neoplasm.
A frequent feature of anti-GluR1/2 associated LE is the tendency to relapse. A total of 14 episodes of LE (5 initial episodes and 9 relapses) occurred in 5 patients, ranging from 1 to 3 relapses in each patient. The presence of GluR1/2 antibodies in serum or CSF was demonstrated in 14/14 episodes studied. Except for two patients whose tumor was initially diagnosed at first relapse of LE, all other neurological relapses occurred in patients without tumor or without tumor recurrence. A compelling example is a patient who after successful treatment of a carcinoma of the thymus at first presentation of LE, subsequently developed 3 relapses over 101 months without evidence of tumor recurrence (total follow-up of 10 years). Taken together, the presence of a GluR1/2-expressing tumor and the susceptibility for autoimmune disorders (identified in 5 patients) either alone or combined may play a role in triggering this autoimmune disorder.
A propensity to relapse was also noted in a study of 100 patients with encephalitis and antibodies to NMDA receptor, a member of another category of ionotropic glutamate receptors.6
Although AMPAR and NMDAR are functionally related and play critical roles in synaptic plasticity,13
each autoimmunity associates with a different clinical phenotype. For example, none of the patients of the current study had an ovarian teratoma or developed dyskinesias, autonomic instability, and hypoventilation, which are common features of anti-NMDA receptor encephalitis.6,14
Neuronal plasticity can be studied through a series of models termed long-term potentiation (LTP) or depression (LTD).13
In these models synaptic strength increases or decreases in association with changes in trafficking of AMPAR.11
The results in our patients are analogous to those seen in some LTD paradigms.9
Our study shows that patients' antibodies specifically bind to AMPAR clusters causing a decrease in the number of the receptors at synapses, and to a lesser degree the total number of receptor clusters along dendrites. Since the major effect was on the synaptic location of the receptors, this finding suggests a mechanism whereby the antibodies disrupt receptor trafficking/turn over, relocating them from synaptic to extrasynaptic sites/intracellular pool. The reversibility of these effects provides an explanation for the improvement of patients' symptoms with plasma exchange, IVIg, or corticosteroids.
Nine patients dramatically improved after the first episode of LE. All nine patients received immunotherapy and when appropriate oncological therapy. However, the long-term outcome depended on the appropriate management of the relapses. In some patients treatment was challenging because in each episode they became agitated, belligerent, and unmanageable at home, yet refusing hospital admission and medication. In two patients, the recovery from each relapse was incomplete resulting in cumulative residual memory or behavioral deficits. After the third relapse both patients stabilized with prolonged use of azathioprine; one was left with moderate short-term memory deficits; the other required institutionalization in a skill nursing facility where she has been living for 3 years. Another patient, an 87-year old woman, died at the second relapse shortly after a prolonged episode of status epilepticus.
The neurological outcome was not influenced by the presence of a tumor (as long as this was well controlled), but was adversely influenced by the presence of overlapping immune responses. For example, after recovering from anti-GluR1/2 associated LE one patient suffered from prolonged residual symptoms of anti-GAD-associated stiff-person syndrome; the GluR1/2 antibodies had disappeared after treatment but the GAD antibodies remained elevated (data not shown). Another patient, with GluR1/2 and CRMP5 antibodies, had rapid neurological deterioration that resulted in death; the autopsy confirmed prominent cytotoxic T-cell infiltrates in the limbic system. A possible explanation for these outcomes is that the accompanying immune responses, particularly if associated with cytotoxic T-cell mechanisms, are more difficult to treat, or that the neuronal dysfunction is less reversible than that caused by the anti-GluR1/2 immune response, which appears to be directly mediated by antibodies.15,16
Anti-GluR1/2 associated LE represents a new category of immune-mediated encephalitis that may occur with or without systemic tumors, and shows a propensity to relapse. The disorder is treatable and can now be diagnosed serologically. Potential cases are patients who are currently categorized as “antibody negative LE” or “steroid-responsive LE”. Future studies should determine the extent of tumor association and overlapping autoimmunities, the role of chronic immune suppression in preventing relapses, and the molecular mechanisms whereby antibodies alter the synaptic localization of AMPAR.