A 26-year-old female presented with rapidly progressive memory deficits, psychiatric symptoms, and language disintegration. Standard tests were unremarkable but EEG showed encephalopathy. Serum tested positive for anti-NMDA receptor antibodies on two occasions. Imaging found bilateral ovarian tumors, and pathology confirmed teratomas. First-line treatment with tumor resection, IVIG, and steroids led to rapid improvement. Anti-NMDA receptor encephalitis should be considered in similar presentations, especially in young females, as prompt diagnosis and treatment including tumor removal can lead to good outcomes.

1. Quick Quiz
• A young female, previously healthy, with no significant past medical
history presents to your facility with rapidly progressive short-term
memory deficits, psychiatric symptoms, and language
disintegration…what should you think of next?

2. Quick Quiz
• A young female, previously healthy, with no significant past medical
history presents to your facility with rapidly progressive short-term
memory deficits, psychiatric symptoms, and language
disintegration…what should you think of next?
• Tox panel, it could be drugs
• Blood and urine cultures, it could be infectious
• CT and/or MRI, it could be stroke/cerebral edema
• Lumbar puncture, it could be bacterial/viral meningitis
• Psych consult, it could be a psychotic break
• Something else???

3. Anti-N-methyl-D-aspartate (NMDA) Receptor
Encephalitis:
Presentation and Treatment
Elva Angelique Van Devender, Ph.D., Pharm.D.
PGY1 Pharmacy Practice Resident
Providence Health and Services

4. Patient Case
• HPI: 26 yo female, previously healthy, presenting to the ER with
confused speech, hallucinations, and increasing bouts of bizarre
behavior at home. Admitted to psych ward with explosive mania.
Alternating periods of agitation and catatonia with orolingual facial
dyskinesias. Eventually mania gave way to a progressive,
unresponsive catatonic state.
• PMH: none
• FH/SH: no h/o mental illness/no drug or alcohol use
• Meds: none
• Labs: WNL
Normal to full-on psychosis within ten days?!!!
Unresponsive, rigid, drooling, unable to perform
ADLs within two weeks of admission?!!!

5. Patient Case
• Vital signs: normal rate and rhythm, bouts of borderline tachycardia
(100-140 bpm); labile htn 109-187/70-104
• Tests:
– Normal CT head and serial MRI scans
– Normal LP
– Normal CSF
– Negative Tox panel
– Negative urinalysis and blood cultures
– Normal chest x-ray
– Normal white count
– Abnormal EEG: dx encephalopathy…cause?

6. Anti-NMDA Receptor Encephalitis
• Anti-NMDAR encephalitis is an autoimmune disorder caused by
antibodies which attack synaptic NMDA receptors (NMDAR),
resulting in NMDAR depletion through a mechanism of crosslinking
and internalization.
– The result: a multistage illness that progresses from psychosis,
memory deficits, seizures, and language disintegration into a
state of unresponsiveness with catatonic features often
associated with abnormal movements and autonomic instability.
• Incidence: unknown; more common in children and young adults
• Relapse: 15-20%
The NMDA receptor, a glutamate receptor, is the
predominant molecular device for controlling
synaptic plasticity and memory function.

7. Signs and Symptoms
• Prominent psychiatric manifestations
– anxiety/agitation
– bizarre behavior
– hallucinations
– delusions
– disorganized thinking
• Memory deficits
• Seizures
• Decreased level of consciousness with catatonic features
• Frequent dyskinesias (orofacial, dystonias, rigidity)
• Autonomic instability (BP fluctuations, tachycardia)
• Language dysfunction

8. Causes
• Tumor (usually ovarian teratoma)
– Tumors dependent on age, sex, and ethnicity
• more frequent in women older than 18 years
• more predominant in black women than white women
• Idiopathic (up to 35% of cases)
– No tumors found
Distribution of patients by
age and presence/absence
of tumors. Data are for 400
patients with anti-NMDAR
encephalitis.

9. Patient Case
• Serum was positive for anti-NMDA receptor IgG antibodies x 2
• Scans consistent with bilateral ovarian teratomas.
– US pelvis:
• 5.8 x 4 x 5.1 cm mass on left
• 3.6 x 2.8 x 2.9 cm mass on right
– CT pelvis:
• 3.5 x 5.8 cm mass on left consistent with dermal tumor
• 2.5 x 3.3 cm nonspecific mass on right
• Surgery pathology
– Left ovary: mature teratoma (benign)
– Right ovary : immature teratoma (Stage 1)
Teratoma in an ovary, SEM
M850/0592 SciencePhoto.com

10. Treatment
• Plasma exchange
• Tumor resection
• Immunotherapy
– First line therapy: (corticosteroids, intravenous immunoglobulin)
• IVIG 0.4 g/kg daily for five days
• Methylprednisolone 1 g daily for five days
– Second-line immunotherapy (cyclophosphamide or rituximab, or
both)
• Rituximab 375 mg/m2 every week for four weeks
• Cyclophosphamide 750 mg/m2 given with first dose of
rituximab
• Immunosuppressive therapy
– Mycophenolate or azithioprine for one year

11. Recovery
• About 75% of patients with
NMDAR antibodies recover or
have mild sequelae; all other
patients remain severely disabled
or die.
• Recovery occurs in inverse order
of symptom development and is
associated with a decline of
antibody titers in both the serum
and the CSF.
• Patients are usually hospitalized
for 3-4 months followed by several
months of behavioral and physical
rehabilitation.
Improvements associated with
declining anti-NMDA titers in both the
CSF and serum in a patient with anti-
NMDAR encephalitis

12. Patient Status Update
• Our patient recovered quickly post teratoma removal.
– Prior to surgery patient catatonic, nonresponsive, eyes open
– Improvement followed within days of surgery
• Within 2 days: able to visually track people in room
• Within 1 week: able to make eye contact, blink, and nod in response
to questions
• Within 2 weeks: able to speak, laugh, ambulate with assistance
• Within 16 days: able to perform all of her own ADLs, swallow, and
eat without a tube
• Within 3 weeks: able to leave the hospital (40 days post admission)
• Oncologists opted to not go back in and remove her ovaries.
• No apparent brain dysfunction or long-term sequelae noted. Some
difficulties reported by the patient with finding words and short-term memory
loss.
• Only lab abnormality post surgery was slight transaminase elevation
(AST/ALT 40-90s/130-200s).

13. Summary
• Anti-NMDA receptor encephalitis should be suspected in any individual
(usually a child or young adult) who develops a rapid change of behavior or
psychosis, abnormal postures or movements, seizures, and variable signs of
autonomic instability.
• NMDA receptor antibody studies should be done in both the serum and CSF.
• All patients should be examined for the presence of an underlying tumor,
mainly an ovarian teratoma or a testicular germ-cell tumor.
• Treatment of IVIG (0.4 g/kg/day for 5 days) and methylprednisolone (1 g/day
for 5 days) is considered first line therapy in combination with tumor
resection.
• If patient does not respond to first-line therapy, second-line therapy
consisting of rituximab (375 mg/m2/week for 4 weeks) combined with
cyclophosphamide (750 mg/m2 x1), followed by monthly cycles of
cyclophosphamide.
• Continued immunosuppression may be necessary in some patients.

14. References
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