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Guan et al. D-cycloserin for anti-NMDAR encephalitis

partial NMDA-agonist, may be a reasonable option. are a specific and reversible decrease of NMDAR
We then applied the medicine to a patient with anti- surface density due to immunoglobulin G-mediated
NMDAR encephalitis refractory to immunotherapy. internalization. The internalization is caused by
The patient’s parents signed informed consent for crosslinking of the receptors by the autoantibodies. As
[2]
publication of this report. we know, antibody-mediated receptor internalization had
been demonstrated for myasthenia gravis. Symptomatic
[3]
CASE REPORT treatment with pyridostigmine in myasthenia gravis
is relatively specific considering its mechanism. It is
A previously healthy 13-year-old female presented reasonable for neurologist to find and apply a NMDA-
with headache and nausea without fever. One week agonist to treatment of anti-NMDAR encephalitis.
later, she progressively developed agitation, cognitive
deterioration, generalized seizures, coma and D-cycloserine, known as anti-tuberculotic medicine,
hypoventilation with required mechanical ventilation. has been widely introduced to neuropsychiatric
Brain magnetic resonance imaging was normal. studies, since its central activation mechanism as a
Cerebrospinal fluid (CSF) analysis demonstrated partial NMDA-agonist has been found. [4,5] Increasing
pleiocytosis (180 white cells/µL) with a normal protein evidence suggests that D-cycloserine may be
and glucose concentration. Anti-NMDAR antibodies effective in various psychiatric diseases, including
was identified in CSF and serum confirming anti- schizophrenia, anxiety disorders, addiction, major
NMDAR encephalitis. The patient was initially depression and autism as well as in neurological
treated with intravenous immumoglobulin (IVIg) and diseases, including dementia, Alzheimer’s disease
methylprednisolone with no improvement. Four weeks and spinocerebellar degeneration. [5,6] D-cycloserine
after the onset, ovary teratoma was identified on acts at the glycine-binding site of the NMDA receptor,
ultrasound and laparoscopic resection was performed which is located at its NR1 subunit. As a partial agonist,
with pathological diagnosis of teratoma. After the D-cycloserine acts like an agonist at low doses but
operation another 2 cycles of IVIg, cyclophosphamide has antagonistic features with high doses. The doses
(IV 500 mg/m monthly) and mycophenolate of D-cycloserine used for modulation of neuroplasticity
2
mofetil（1,000 mg/d）was added because of are lower than for antituberculotic indication. The
insufficient clinical response. Five months after initial typical application in antituberculosis therapy is 250
presentation, no remarkable clinical improvement was to 500 mg twice daily. In the neuropsychiatric studies,
observed. The patients were still unconscious with D-cycloserine was administrated at a dose of 50 mg/d
recurrent seizure, chorea, tackycardia and episodes to 250 mg/d. [5,6] The pharmacological properties of
of hypoventilation requiring mechanical ventilation. D-cycloserine indicate its potential as central nervous
D-cycloserine was then administered 125 mg/d system modulator. The maximum concentration in blood
for 1 week followed 250 mg/d. Two weeks after the is reached 2 h after oral application. About 54-79% of
first administration of D-cycloserine, her symptoms oral intake reaches the CSF. [7,8]
improved gradually. Seizure and choreic movements
were reduced and hypoventilation disappeared, There are some interesting observations in
leading to discharge from the intensive care unit. Two which NMDA antagonist including ketamine may
weeks later, a further improvement was observed. improve symptoms of anti-NMDAR encephalitis.
[9]
She was able to understand simple orders. Seizure However, the administration of NMDA antagonist
and chorea had disappeared. D-cycloserine was to anti-NMDAR encephalitis is not consistent with
reduced to 125 mg/d and then stopped. The patient is the mechanism of NMDAR hypofunction in the
functionally normal now with modified Rankin Score 0 disorder and in our practice there were not obvious
at her last follow-up 1 year from disease onset. improvement after administration of ketamine
or memantine to our patients with anti-NMDAR
DISCUSSION encephalitis. Recently, Heresco-levy et al. reported
[10]
the clinical and electrophysiological effects of D-serine
We report a case of severe anti-NMDAR encephalitis in a schizophrenia patient positive for anti-NMDAR
refractory to immunotherapy and response to antibodies. D-serine was administrated in 6 weeks to
D-cycloserine. This is the first reported case in which their patient in which dose were increased gradually
this NMDA-agonist was applied to this disease. Our from 1.5 to 4 g/day.
observation indicates that D-cycloserine may be a
therapeutic option for anti-NMDAR encephalitis. This preliminary study is limited by the fact that
spontaneous remission of symptoms even after
The cellular mechanisms of anti-NMDAR encephalitis severe and long disease duration is still expected in
190 Neuroimmunology and Neuroinflammation ¦ Volume 3 ¦ August 31, 2016