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CASE. Suspected teratoma-induced encephalitis
You are on call for your practice group, resting comfortably at home, reviewing tomorrow’s office schedule and wondering if your peaceful evening will be interrupted by a call from the hospital. At 9 pm, a neurologist calls and pleads for you to come to the hospital to evaluate a 25-year-old patient with encephalitis who is intubated in the intensive care unit (ICU). You immediately wonder, “Why call me about a case of encephalitis?”
The neurologist reports the following details. Over the 2 weeks preceding hospitalization, the patient developed progressive agitation, irritability, and hallucinations. She then had a seizure. She was brought to the hospital and was observed to be hypoventilating. She was sedated, intubated, and placed on mechanical ventilation.
Imaging studies were consistent with encephalitis. A screen for toxic substances and tests for viral and bacterial infection were negative. A spinal tap showed white blood cells (WBCs) in the cerebrospinal fluid (CSF).
Earlier in the afternoon serum and CSF sent to a reference laboratory returned positive for anti–N-methyl-D-aspartate (anti-NMDA)–receptor antibodies. Emergency pelvic ultrasonography was obtained, showing a 4-cm complex ovarian mass consistent with a teratoma. Based on these findings, the neurologist diagnosed teratoma-induced encephalitis.
The neurologist insists that you immediately operate on the patient to remove the teratoma.
What would you do in this hypothetical case?
OVARIAN TERATOMA AND ENCEPHALITIS—A CAUSAL LINK
Between 2005 and 2009, Dr. Josep Dalmau and colleagues in the Department of Neurology at the University of Pennsylvania published a series of papers documenting a link between encephalitis and ovarian teratomas.1-5 The pathophysiologic connection is thought to be the presence of tissue in the ovarian teratoma that stimulates the immune system to produce anti-NMDA-receptor (anti-NMDAR) antibodies. The anti-NMDAR antibodies, and/or the related B cells, then enter the central nervous system. It is hypothesized that the antibodies deplete cell-surface NMDA receptors on NMDA-receptor–rich neurons in the limbic system. This causes neuronal dysfunction, and over time, may cause permanent loss of neurons.
The antibody-induced abnormality in neuronal function produces a constellation of neuropsychiatric changes, including disturbances of memory, behavior, and cognition, and can trigger the onset of seizures. Hypoventilation may occur, and patients severely affected by the syndrome require sedation, intubation, and mechanical ventilation.
An observational link. Observations that support the mechanistic connection between teratoma-induced production of anti-NMDAR antibodies and encephalitis are as follows:
- In cases of encephalitis associated with an ovarian teratoma, histology often shows an intense WBC infiltrate in areas of the teratoma with neural tissue.6
- Tissue in the teratoma expresses the NMDA receptor.7
- In the syndrome of ovarian teratoma and encephalitis, elevated titers of anti-NMDAR antibodies are often present in serum and CSF.
- The areas of the brain affected by the encephalitis, including limbic and forebrain structures, express the NMDA receptor.
- Interventions that reduce levels of the anti-NMDAR antibody titer, including removal of the teratoma or immunotherapy, are often associated with a marked improvement in the clinical syndrome.
Awareness among ObGyns is valuable
The vast majority of ovarian teratomas never trigger the synthesis of anti-NMDAR antibodies or the development of a disabling encephalitis.8 However, the recognition that teratomas can cause encephalitis suggests that, if a teratoma is expectantly managed, the patient and her family should be alerted to report the new onset of symptoms, such as behavioral change, that may warrant neurologic evaluation.
In the California Encephalitis Project,9 of the 761 cases of encephalitis evaluated, the most common identifiable cause of the condition in women aged 30 years and younger was anti-NMDAR encephalitis. Enterovirus was a close second as a cause of encephalitis. Well-known causes of the condition, such as Herpes simplex 1, Varicella zoster, and West Nile virus were far less common.
HOW IS A DIAGNOSIS REACHED?
In many cases of encephalitis due to an ovarian teratoma, diagnosis is made by history, as well as physical examination consistent with:
- limbic encephalitis
- imaging studies that show encephalitis
- negative test results for viral, bacterial, and toxicologic causes of encephalitis
- evidence of WBCs in the CSF
- the presence of anti–NMDAR antibodies and an ovarian teratoma.
Neuropsychologic changes observed with this disease include agitation, mood lability, speech dysfunction, hallucinations, paranoia, hypersexuality, and seizures. Movement disorders are common in patients with this disease and include orofacial dyskinesias, unilateral dystonia, opisthotonus, chorea, rigidity, and catatonia. In many cases, a prodrome of fever and headache precede the development of the full syndrome. Both mature and immature teratomas can cause the syndrome.
Related Article: Skilled US imaging of the adnexae: Ovarian Neoplasms Ilan Timor-Tritsch, MD, and Steven R. Goldstein, MD (November 2010)
OPTIMAL TREATMENT
Encephalitis due to ovarian teratoma is treated by urgent removal of the teratoma. This is in combination with immune-modulating therapy, which may include intravenous immunoglobulin (IVIG), high-dose glucocorticoids, plasmapheresis, or rituximab (a monoclonal antibody targeted to the CD20 antigen on B lymphocytes).10,11