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Case report

A 18-year-old G0 P0 without a significant medical past history presents for a short-term memory loss, anxiety, confusion, hallucinations started for about 1 week ago. She was first addressed to the psychiatry compartment. At the moment of psychiatric examination she complained about a severe frontal headache. The patient’s symptoms progressed rapidly to delirium followed by a generalized tonic-clonic seizure. She was tachycardic at 120 bpm and hypertensive. She was minimally responsive, and had diffuse hyperreflexia. Routine laboratory tests were unremarkable. An electroencephalogram revealed findings consistent with seizure activity. She was tested for infectious diseases: HIV, HSV,  cytomegalovirus, parvovirus and hepatitis, as well as autoimmune diseases - all were negative. The brain IRM revealed bilateral medial temporal lobe hyperintensity (Figure 1).
 

A lumbar punction was performed and showed inflammatory features, specifically a white blood cell count of 27 thousand/µL (95% lymphocytes) and pleyocitosis. The patient’s symptoms progressed rapidly - her seizures became intractable and resulted in bradycardia, apnea and hypotension. She was sedated and orotraheal intubated. Serum and CSF tests for NMDAR antibodies were positive. An abdominopelvin ultrasound scan was performed and revealed a 7/6.5/6 cm right ovarian complex tumor with cystic and solid component. Serum tumor markers were within normal limits CEA= 1.5 ng/ml, CA 125= 20 U/ml, CA 19-9 = 25 U/ml, AFT =3 ng/ml. An emergency exploratory laparoscopy was performed, revealing a 7-6 cm complex appearing right ovarian tumor. The left tube and ovary and the uterus appeared normal. A right salpingo-oophorectomy was performed (Figure 2).
 

The patient received broad-spectrum antibiotics and anti-epileptics, and was intubated and sedated for the next 24 hours. Histology showed: ovarian parenchyma and cystic structures with complex microscopic walls appearance including tridermic elements: brain tissue, muscle, adipose tissue, epithelial elements with an abundance of keratin, epidermal glands, respiratory epithelium, without immature or atypical cellular elements advocating for an ovarian dermoid cyst (Figure 3).
 

Post-operatively, the patient experienced rapid reversal of her neurologic impairment. She received six plasmapheresis treatments, with significant improvement in her mental status and physical limitations. The patient was discharged on post-operative day 15, hemodynamic stabile, without stiffness, motor deficits or coordination disorders, without sensitivity problems, but with short term memory impaired and visual-spatial integration impairment. Her psychometric tests showed mild cognitive impairment MoCA= 22/30 pts., MMSE=30/30 pts.

Discussion

Disturbances of memory, behavior, cognition, and seizures can result from immune-mediated encephalitis. One cause of autoimmune encephalitis is the paraneoplastic manifestation of a neoplasm⁽¹⁾. Until now, most paraneoplastic encephalitis have been associated with antibodies to intracellular onconeuronal proteins and cytotoxic T cells presumably against the same proteins⁽²⁾. These disorders usually associate with malignant tumors and are poorly responsive to immunotherapies or cancer treatment⁽³⁾.

Despite the severity of the symptoms, paraneoplastic anti-NMDAR encephalitis has a better prognosis than most other paraneoplastic encephalitides^(3,4). Resection of the tumor appeared important to obtain final recovery or sustain the improvement that in some cases started soon after immunotherapy (corticosteroids, IVIg, or plasma exchange)⁽⁴⁾.

In the California Encephalitis Project⁽⁵⁾, 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⁽⁶⁾.

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.

At presentation, this autoimmune encephalitis can be confounded with a psychiatric disorder and patients can often be submitted to psychiatric centers. Most patients appear confused, restless, agitated, with frequent paranoid or delusional thoughts sometimes alternating with quiet staring and dystonic or catatonic postures. In addition, most patients develop seizures and a subsequent decrease of level of consciousness, requiring antiepileptic medication, sedation, frequent mechanical ventilation, nutritional support, and management of episodes of autonomic instability and dyskinesias⁽⁷⁾.

A constant abnormality is the presence of CSF pleocytosis or increased protein concentration that suggests an inflammatory or immune-mediated neurological process. Otherwise, extensive evaluations to identify the cause of the encephalitis are normal or unrevealing, and the associated tumors (usually appearing as “benign” ovarian cysts) are frequently considered unrelated to the disorder⁽⁷⁾.

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)^(8,9).

Although there is little evidence to support this clinical point, most neurologists passionately believe that once the diagnosis of ovarian teratoma-induced encephalitis is made, the teratoma should be urgently removed to help reduce the risk of permanent neurologic injury⁽⁹⁾.

In patients with anti-NMDAR encephalitis and ovarian teratoma, surgical resection of the tumor and subsequent immunotherapy are the treatment modalities with the most significant effect on outcome⁽¹⁰⁾. Therefore, it would seem that early surgery in these patients would be of utmost importance in preventing worsening of neurologic status.

In patients with anti-MDAR encephalitis the presence of a tumor (usually ovarian teratoma) is dependent on age, sex and ethnicity, being more frequent above 18 years of age⁽¹¹⁾. The frequency of ovarian teratomas was 56% in women >18 years old, but only 31% in women <18 years old⁽¹²⁾.

Some patients with encephalitis have a teratoma but no detectable anti-NMDAR antibodies. In these patients, teratoma removal may be associated with improvement in the encephalitis; however, the cause of the condition may be another type of anti-neuronal antibody that has yet to be identified⁽¹³⁾.  Women with encephalitis and an ovarian teratoma, and no evidence of infectious or toxicologic causes for the encephalitis, should be considered for teratoma removal⁽¹³⁾.

In conclusion, anti-NMDAR encephalitis is a potential­ly lethal but treatable condition sometimes associated with ovarian teratomas - both mature and immature. The exact incidence of anti-NMDAR encephalitis is still unknown but it seems to be the most frequent paraneoplastic encephalitis⁽¹¹⁾.

Conclusion

Paraneoplastic encephalomyelitis (PEM) is a multifocal inflammatory disorder of the central nervous system (CNS) associated with remote neoplasia. Neurologic dysfunction probably results from an autoimmune reaction directed against onconeural antigens in the human nervous system.

Anti-NMDA receptor encephalitis is a paraneoplastic syndrome characterized by neuropsychiatric symptoms, involuntary movements, autonomic instability, and seizures.

It is more common in young females and associated with a mature ovarian teratoma⁽¹⁴⁾.

Female patients presenting with new onset of psychiatric and neurologic symptoms should be thoroughly evaluated to rule out underlying neoplasm. In the event of a diagnosis of an adnexal mass, surgical resection should be performed as soon as possible in an effort to improve neurologic outcomes⁽¹⁵⁾.

Pathologists encountering ovarian teratomas with reactive lymphoid elements should consider the possibility of anti-NMDAR encephalitis, particularly because the neurological symptoms may develop after tumor resection⁽¹⁶⁾.