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Paraneoplastic limbic encephalitis
Paraneoplastic limbic encephalitis
Paraneoplastic limbic encephalitis results from an inflammation or encephalitis that mostly affects the limbic system. This part of the brain is involved in memory, emotion and behavior. Including reactions of fear and anger, and emotions associated with sexual behavior. The limbic system is closely related to the hypothalamus, which regulates the autonomic nervous system (involved in the control of blood pressure, heart rate, salivation, papillary constriction, among others), endocrine function (hormones), body temperature, food and water intake, and sleeping and wakefulness.
Inflammation of the limbic system may cause a variety of symptoms. Such as:
- mood changes (depression, irritability and anxiety),
- problems sleeping, and
- short-term memory problems
The symptoms associated with memory problems are always severe and should not be confused with mild problems sometimes caused by lack of attention, or with chronic memory problems that some patients (with other diseases) develop over months or years. In addition, many patients with limbic encephalitis develop seizures or spells (for example, sudden sensation of bad smell or taste, staring or lip smacking, cloudiness of consciousness) or sometimes, total loss of consciousness resulting in a grand mal seizure.
The combination of clinical symptoms, analysis of spinal fluid, and brain MRI and EEG findings usually suggest the diagnosis of limbic encephalitis in 80% of patients (Figure 1). None of these tests however, indicates that the limbic encephalitis is paraneoplastic. The paraneoplastic cause is confirmed when a paraneoplastic antibody is identified, or in the case that no antibody is identified, when other causes are excluded (for example viral encephalitis) and the presence of a cancer is demonstrated.
There are several forms of paraneoplastic limbic encephalitis. Some are associated with specific paraneoplastic antibodies and some without antibodies. While patients with different forms of limbic encephalitis may have similar symptoms and look the same when examined, the type of tumor and neurological outcome varies with the type of antibody found. It is important to know that there are several forms of limbic encephalitis that are not paraneoplastic. The neurological symptoms of these patients can be similar or identical to those with paraneoplastic limbic encephalitis.
A summary of the antibodies and tumors more frequently found in paraneoplastic limbic encephalitis is shown in Table.
Table: Paraneoplastic antibodies that may associate with limbic encephalitis
Limbic encephalitis, hypothalamic,* and brainstem encephalitis
Testis, lung, other
Limbic encephalitis, striatal encephalitis (chorea), cerebellar ataxia, peripheral neuropathy, uveitis
Psychiatric symptoms, abnormal movements, autonomic dysfunction
Teratomas (usually in the ovary)
*Hypothalamic pituitary hormonal deficits; decreased CSF hypocretin (associated with excessive sleepiness or narcolepsy)
There are several antibodies than can be identified in patients either with non-paraneoplastic or paraneoplastic limbic encephalitis:
Antibodies to VGKC (Figure 2): these antibodies are frequently found in patients with non-paraneoplastic limbic encephalitis, but do not completely predict that the patient does not have a cancer. In fact, about 15% of patients have a cancer, and therefore the limbic encephalitis is paraneoplastic. When this occurs the tumors are usually a thymoma or less frequently a small-cell lung cancer.
Antibodies to proteins of the cell surface of neurons of the limbic system (also called neuropil antibodies): These antibodies have been recently described and are still poorly characterized. However, analysis for these antibodies is important because they are frequent, and because their detection predicts a good chance of recovery after immunotherapy (similarly as occur in patients with VGKC antibodies). Some of these patients have thymoma, others do not have any type of tumor (Figure 3).
Patients with limbic encephalitis often improve with immunotherapy. In general, the non-paraneoplastic limbic encephalitis are more responsive to immunotherapy than the paraneoplastic limbic encephalitis. In the paraneoplastic limbic encephalitis, the tumor should always be treated.
Regardless of whether the limbic encephalitis is paraneoplastic or not, an important concept is that the detection of antibodies to proteins of the cell surface of neurons (such as VGKC, NMDAR, and neuropil antibodies) usually indicates that the disorder will respond to immunotherapy (corticosteroids and IVIg or plasma exchange). Some patients with NMDAR antibodies may need more aggressive immunotherapy.
The detection of antibodies to intracellular proteins (such as Hu, CV2/CRMP5, Ma2, amphiphysin) indicates that the immunotherapy should be directed against the T-cell response, requiring additional drugs to those used to remove the antibodies. Patients with encephalitis associated with anti-Ma2 antibodies have a better chance of improvement than patients with the other antibodies to intracellular proteins.