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?

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???

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

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?!!!

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?

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.

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

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.

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

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

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

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).

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.

References 1. Dalmau J, Lancaster E, Martinez-Hernandez E et al. Clinical experience and

laboratory investigations in patients with anti-NMDAR encephalitis. Lancet Neurol

2011; 10:63-74.

2. Dalmau J, Gleichman AJ, Hughes EG et al. Anti-NMDA-receptor encephalitis: case

series and analysis of the effects of antibodies. Lancet Neurol 2008; 7(12):1091-

1098.

3. Pruss H, Dalmau J, Harms L et al. Retrospective analysis of NMDA receptor

antibodies in encephalitis of unknown origin. Neurology 2010;75:1735–1739.

4. Tuzun E, Dalmau J. Limbic Encephalitis and Variants: Classification, Diagnosis, and

Treatment. The Neurologist 2007; 13:261-271.

5. Dalmau J, Rosenfeld MR. Paraneoplastic syndromes of the CNS. Lancet Neurol

2008; 7: 327–40.

6. Kim SH, Kim HY, Im YT, Nam SO, Kim YM. A case of paraneoplastic limbic

encephalitis due to ovarian mature teratoma. Korean Journal Pediatr 2010; 53:603-

606.