Emerging Concepts: Treatment-Responsive Autoimmune Limbic Encephalitis

February 7, 2008

This editorial was developed for AAN.com, which is publishing expert opinions on a variety of hot topics in neurology.

Josep Dalmau, MD, PhD
University of Pennsylvania
Author Disclosure Statement

Classical versus Emerging Concepts

Limbic encephalitis was initially reported as a paraneoplastic manifestation of cancer. For many years it was thought that the disorder was extremely rare, invariably associated with cancer, and unresponsive to treatment. In the mid 1980s and 90s, the discovery of antineuronal antibodies (Hu, CV2/CRMP5, Ma2, amphiphysin, among others) reinforced some of these concepts by facilitating the identification of a subgroup of encephalitis in which the accompanying T-cell mechanisms are difficult to treat.

However, with the development of clinical criteria that includes testing for antineuronal antibodies, brain MRI, and CT or FDG-PET to uncover associated tumors, it is becoming clear that many patients with similar syndromes do not fit the above concepts.¹ The study of these patients is changing the previously accepted views on limbic encephalitis with implications beyond the limbic syndromes, paraneoplastic or not.²

New Category of Limbic Encephalitis—Importance of Cell Surface Antigens

The detection of voltage-gated potassium channel (VGKC) antibodies in some patients with limbic encephalitis was an initial step toward the identification of a new category of this condition. Antibodies in this syndrome are directed against a cell surface antigen (VGKC), whereas in previously characterized syndromes the antigens were intracellular. In 80 percent of patients with VGKC antibodies the disorder is not paraneoplastic and responses to immunotherapy are frequent. Similar antibodies may also occur in patients with a syndrome consisting of more diffuse encephalitis associated with hallucinations, sleep and autonomic dysfunction, and peripheral nerve hyperexcitability (Morvan’s syndrome).

Yet, many patients with limbic or a more diffuse encephalitis do not have any of the antibodies indicated above. In these cases, the CSF findings and response to empiric immunotherapies (e.g, IVIg, plasma exchange) suggest an immune pathogenesis.

• This hypothesis was confirmed using techniques that allow detection of antibodies to cell surface antigens other than VGKC.³,⁴ Preliminary studies suggest that the target antigens are multiple, and that some antibodies associate with highly characteristic syndromes.

Identification of Antibodies to Cell Surface Antigens

The strategy to identify antibodies to cell surface antigens relies on:

• The use of fixatives, such as paraformaldehyde, that reveal a pattern of immunolabeling affecting the neuropil of the hippocampus rather than the cell bodies, and
• Immunocytochemistry on cultures of live, non-permeabilized neurons, confirming that the antibodies bind to the neuronal cell surface (Figure).

Once a specific syndrome and pattern or immunolabeling are identified, further studies are undertaken to characterize the antigen(s). The most interesting example of a recently detected antigen of this nature are the NMDA receptors.⁵

Figure: Immunohistochemical demonstration of antibodies against a cell surface antigen (NMDA receptor). A: Hippocampus of rat showing in green the reactivity of a patient’s CSF with antibodies against NMDA receptors; note the extensive reactivity with the neuropil. Compare this reactivity with that of an antibody against an intraneuronal antigen (anti-Hu: red cells). B: Culture of live, non-permeabilized, hippocampal neurons immunolabeled with CSF containing antibodies against NMDA receptors; note the intense antibody-binding to the surface of neuronal processes (the nucleus of the neuron is shown in blue).

Antibodies to NMDA Receptors

This disorder was initially identified in young women with mature or immature ovarian teratoma who developed prominent psychiatric symptoms or memory deficits, usually preceded by prodromal fever, headache or a viral-like illness. After the initial psychiatric presentation, most patients develop seizures, decrease in the level of consciousness, orofacial or limbic dyskinesias, autonomic instability and hypoventilation. Prolonged intensive care support is frequently required.⁶ Removal of the teratoma and immunotherapy (e.g., corticosteroids, IVIg, plasma exchange, rituximab, cyclophosphamide) is often associated with improvement or total recovery. Most recently studies indicate:

• The disorder can occur without teratoma (current estimate ~35%)
• It can affect boys and adult men in addition to women, and
• Slow recovery and relapses are frequent if a tumor is not identified.

The antibodies associated with this syndrome are directed to cell surface epitopes present in assembled NR1 and NR2 subunits (NR1/NR2 heteromers) of the NMDA receptor. Thus, the technique to detect these antibodies is immunocytochemistry on cells transfected with NR1 and NR2 subunits. These antibodies should not be confused with other antibodies against NR2 subunits of the NMDA receptors that in general have poor syndrome specificity. The latter antibodies are usually identified by immunoblot techniques.

Why Is It Important To Study These Disorders?

In addition to the encephalitis associated with antibodies to NMDA receptors, there are additional encephalitides that occur in association with antibodies to other cell surface antigens and clinical syndromes. For most, the cell surface antigens are pending characterization. The importance of studying these disorders rests on the following facts:

• They affect patients of all ages, including children.
• The associated tumors can be atypical, such as teratoma or thymoma among others, which are infrequently involved in classical paraneoplastic syndromes.
• The tumors can be benign or malignant.
• The associated neurological syndromes are more responsive to immunotherapy than the paraneoplastic syndromes related with antibodies to intracellular antigens.
• Similar disorders and immune responses can occur in patients without cancer. In this respect the scenario is similar to antibody-mediated syndromes of the neuromuscular synapse, such as the Lambert-Eaton myasthenic syndrome or myasthenia gravis.
• The neurological symptoms may relapse if the disorder is not recognized. In all, the study of encephalitides associated with antibodies to cell surface antigens provides a link between immunologic processes and neuronal events involved in memory, cognition, seizures, and neuronal degeneration.

References

1. Tuzun E, Dalmau J. Limbic encephalitis and variants: classification, diagnosis and treatment. Neurologist 2007;13:261-271.
2. Graus F, Delattre JY, Antoine JC, et al. Recommended diagnostic criteria for paraneoplastic neurological syndromes. J Neurol Neurosurg Psychiatry 2004;75:1135-1140.
3. Ances BM, Vitaliani R, Taylor RA, et al. Treatment-responsive limbic encephalitis identified by neuropil antibodies: MRI and PET correlates. Brain 2005;128:1764-1777.
4. Bataller L, Kleopa KA, Wu GF, Rossi JE, Rosenfeld MR, Dalmau J. Autoimmune limbic encephalitis in 39 patients: immunophenotypes and outcomes. J Neurol Neurosurg Psychiatry 2007;78:381-385.
5. Dalmau J, Tuzun E, Wu HY, et al. Paraneoplastic anti-N-methyl-D-aspartate receptor encephalitis associated with ovarian teratoma. Ann Neurol 2007;61:25-36.
6. Iizuka T, Sakai F, Ide T, et al. Anti-NMDA receptor encephalitis in Japan. Long-term outcome without tumor removal. Neurology, in press. Epub 2007, Sept 26. DOI 10.1212/01.wnl.0000278388.90370.c3

Author Disclosure

Disclosure: Dr. Dalmau has received personal compensation as a speaker for Athena Diagnostics.