Even Crazy People Have Real Tumors (Anti-NMDA receptor encephalitis)

March 31, 2010 in Medicine by RangelMD

Kiera Echols was psychotic. She was having hallucinations. Initially she had fever, chills, and a headache and was diagnosed as having meningitis (an infection and inflammation of the membrane that surrounds the brain and spinal cord). But then she started seeing children who were not there and complaining that she was in labor but was not pregnant. So her doctors wanted to admit her to a psychiatric unit.

What? People who don’t have a history of  a psychiatric disorder usually don’t suddenly become psychotic for purely psychiatric reasons. I.e. there needs to be a concerted effort to rule out a medical cause before resorting to long term antispychotic medical treatment. Turns out that the real cause was a Rube Goldbergesc series of causes that started with a small tumor in her ovary.

The tumor was a teratoma, a freakish, but not uncommon, conglomeration of basic cells growing out of control. Some teratomas, if they’re big enough, even contain eyeballs or tiny feet. Echols’ body recognized the tumor as an invader, and developed antibodies against it, just like it would develop antibodies against a cold virus or a form of pollen she might be allergic to. Those antibodies attacked certain neurochemicals in the brain, triggering the encephalitis [anti-NMDA receptor encephalitis] and the hallucinations.

Anti-NMDA receptor encephalitis is a paraneoplastic syndrome (a condition associated with cancer but not directly caused by tumors, metastatsis, wasting, or infections from the cancer). Kiera had a classic case. It often starts with a sudden flu-like illness with fever and headache and in a few days progresses to include psychotic symptoms as well as insomnia and decreased level of consciousness including possible catatonia, and complex-partial seizures. Because this is a limbic encephalitis and involves the deeper brain structures of the hippocampus, amygdala, cingulate gyrus, insula, and orbital-frontal cortex, it can cause movement disorders (dyskinesia), short term memory loss, and autonomic nervous system dysfunction that can result in fever, high and low blood pressure and variations in heart rate.

It is believed that tumor cells induce an immune reaction via the production of an antibody that reacts against the NR1/NR2 heteromers of a protein called the NMDA receptor. This protein in found in the postsynaptic membranes of neurons and its  function is to bind to the neurotransmitter glutamate (an amino acid) to facilitate learning and memory.  The binding of the  NMDA receptor antibody to this protein causes it to malfunction. The antibody also induces an immune response causing inflammation (encephalitis) which leads to further neurologic dysfunction.

The diagnosis is made by analysis of the blood for antibodies to the NR1/NR2 heteromers of the NMDAR protein in serum or cerebral spinal fluid (CSF). Additionally, analysis of the CSF via spinal tap is either normal or shows an increased number of lymphocytes (pleocytosis) and/or the presence of oligoclonal bands on electrophoresis of CSF. EEG shows frequent, slow, disorganized background activity with infrequent epileptic activity and an MRI of the brain may show nonspecific enhansement of cortical areas or subcortical areas in the limbic system. In short, CSF analysis, EEG, and brain imaging are usually helpful only in ruleing out other causes.

Anti-NMDA receptor antibodies are closely associated with teratomas of the ovaries. Luckily for this patient, these tumors are usually benign and are detected in 50% or more of patients older than 18 and can be in either one or both ovaries. Treatment includes medications such as systemic steroids to reduce the inflammation and immune response and measures to remove the offending antibodies such as IV imunoglobulin infusions or plasma exchange. Lastly, the teratoma(s) is resected. The prognosis is good and corrilates with resolving symptoms and decreaseing levels of anti-NMDA receptor antibodies in the blood. However, up to 20% of patients can relapse and this is usually caused by a recurrent teratoma or an occult teratoma that cannot be located. This syndrome can also occur from lung and thymic cancer so these patients should be evaluated for these conditions.

The suspicion of anti-NMDA receptor encephalitis is usually made when an acutely psychotic patient develops other neurologic symptoms such as dyskineasia and/or autonomic nervous system dysfunction that is not at all typical for a psychiatric disorder and can’t be explained as the side effects of medication or other causes. The recent febrile illness and preliminary diagnosis of meningitis helped this patient’s doctors focus on a non-psychiatric cause for the patient’s acute psychosis rather then just turfing her off to the psych ward.

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